WO2018149284A1 - Inhibiteur de kinase, son procédé de préparation et son utilisation - Google Patents

Inhibiteur de kinase, son procédé de préparation et son utilisation Download PDF

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WO2018149284A1
WO2018149284A1 PCT/CN2018/074263 CN2018074263W WO2018149284A1 WO 2018149284 A1 WO2018149284 A1 WO 2018149284A1 CN 2018074263 W CN2018074263 W CN 2018074263W WO 2018149284 A1 WO2018149284 A1 WO 2018149284A1
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compound
formula
group
alkyl
halogen
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PCT/CN2018/074263
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English (en)
Chinese (zh)
Inventor
刘钢
于华
唐建川
杜静
王坤建
刘金明
蔡家强
曾宏
宋宏梅
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN201880001642.XA priority Critical patent/CN109071498B/zh
Publication of WO2018149284A1 publication Critical patent/WO2018149284A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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

Definitions

  • the present invention relates to an inhibitor of apoptosis signal-regulating kinase 1 (ASK1), a pharmaceutical composition comprising the same, a process for the preparation thereof and an intermediate thereof, and the use thereof for preventing or treating ASK1-mediated diseases.
  • ASK1 apoptosis signal-regulating kinase 1
  • the mitogen-activated protein kinase (MAPK) signaling cascade combines different extracellular and intracellular cohorts with appropriate cellular stress responses including cell growth, differentiation, inflammation, and cell dying. Death (Kumar, S., Boehm, J. and Lee., JC (2003) Nat. Rev. Drug Dis. 2: 717-726; Pimienta, G. and Pascual, J. (2007) Cell Cycle, 6: 2826 -2632).
  • MAPK exists in the form of MAP3K, MAP2K, and MAPK, which are sequentially activated.
  • MAPK3 responds directly to environmental signals and phosphorylates MAP2K, which in turn phosphorylates specific MAPKs.
  • MAPK then mediates an appropriate cellular response by phosphorylating a cellular matrix comprising a transcription factor that regulates gene expression.
  • Apoptosis signal-regulated kinase 1 is a member of the mitogen-activated protein kinase kinase kinase (“MAP3K”) family that activates c-Jun N-terminal protein kinase (“JNK”) and p38 MAP kinase (Ichijo, H., Nishida, E., Irie, K., Dijke, PT, Saitoh, M., Moriguchi, T., Matsumoto, K., Miyazono, K. and Gotoh, Y. (1997) Science, 275, 90-94).
  • MAP3K mitogen-activated protein kinase kinase kinase kinase
  • JNK c-Jun N-terminal protein kinase
  • JNK c-Jun N-terminal protein kinase
  • Activation of ASK1 can be achieved by a variety of stimuli including oxidative stress, reactive oxygen species (ROS), LPS, TNF- ⁇ , FasL, ER stress, and increased intracellular calcium concentration (Hattori, K., Naguro, I., Runchel, C. and Ichijo, H. (2009) Cell Comm. Signal. 7: 1-10; Takeda, K., Noguchi, T., Naguro, I. and Ichijo, H. (2007) Annu. Rev. Pharmacol. Toxicol. 48: 1-8.27).
  • ROS reactive oxygen species
  • ASK1 is activated via autophosphorylation at Thr838 and, in turn, phosphorylates MAP2K (eg, MKK3/6 and MKK4/7), which subsequently phosphorylates and activates p38 and JNK MAPK, respectively.
  • MAP2K eg, MKK3/6 and MKK4/7
  • ASK1 activation and signaling are reported to include conditions and diseases caused by chronic fatty and fibrotic degeneration (eg, nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH)), neurodegenerative diseases, cardiovascular Disease, diabetes (including diabetic nephropathy and other complications of diabetes), inflammatory diseases, autoimmune diseases, respiratory diseases (including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and acute lung injury) And play an important role in a variety of diseases of metabolic disorders.
  • chronic fatty and fibrotic degeneration eg, nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH)
  • NASH nonalcoholic steatohepatitis
  • neurodegenerative diseases eg, cardiovascular disease, diabetes (including diabetic nephropathy and other complications of diabetes), inflammatory diseases, autoimmune diseases, respiratory diseases (including chronic obstructive pulmonary disease (COPD), idi
  • ASK1 is involved in organ damage following ischemia and reperfusion in the heart, brain, and kidney (Watanabe et al., (2005) BBRC 333, 562-567; Zhang et al., (2003) Life Sci 74-37-43; Terada Et al. (2007) BBRC 364: 1043-49).
  • ASK1 inhibitors can remedy or improve the lives of patients with such diseases.
  • the present invention provides a compound for use as an ASK1 inhibitor having good inhibitory activity against ASK1, good physicochemical properties (e.g., solubility, physical and/or chemical stability), good pharmacokinetic properties (e.g., good organisms) Excellent properties such as availability, suitable blood concentration, half-life and duration of action), good safety (lower toxicity and/or fewer side effects, wider therapeutic window).
  • good physicochemical properties e.g., solubility, physical and/or chemical stability
  • good pharmacokinetic properties e.g., good organisms
  • Excellent properties such as availability, suitable blood concentration, half-life and duration of action
  • good safety lower toxicity and/or fewer side effects, wider therapeutic window.
  • One aspect of the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein Said compound has the structure of formula (I):
  • R 2 is selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, and -OC 1-6 alkyl, wherein the alkyl group is optionally substituted with one or more halogens;
  • Q is selected from C, C(R 4 ) and N;
  • W 1 , W 2 , W 3 , W 4 , W 5 , W 6 and W 7 are each independently selected from C(R 4 ) and N;
  • both W 5 and W 6 are C(R 4 )
  • the two R 4 together with the carbon atom to which they are attached, are optionally taken together to form a 5 member, optionally substituted by C 1-6 alkyl, hydroxy or halogen.
  • X, Y and Z are each independently selected from a direct bond, C(R 4 ), C(R 4 )(R 5 ), N, N(R 4 ) and O;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl; or when R 6 and R 7 are bonded to the same nitrogen atom, R 6 and R 7 are attached thereto The nitrogen atom optionally together form a 3-10 membered heterocyclic group;
  • n 0, 1, or 2.
  • compositions comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof, N- An oxide, an isotopically labeled compound, a metabolite or prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semisolid formulation, a liquid formulation or a gaseous formulation.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or Use of a medicament or a pharmaceutical composition of the invention in the manufacture of a medicament for use as an ASK1 inhibitor.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or A pharmaceutical or a pharmaceutical composition of the invention for use as an ASK1 inhibitor.
  • Another aspect of the invention provides a method of preventing or treating an ASK1-mediated disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer thereof , polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.
  • Another aspect of the invention provides a process for the preparation of the compounds of the invention and intermediates used in the process.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • an alkyl group has from 1 to 12, such as from 1 to 6 carbon atoms.
  • C1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl) Base, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), optionally substituted by one or more (such as 1 to 3) suitable substituents Substituted by halogen (in this case the group is referred to as "haloalkyl”) (eg CH 2 F, CHF 2 , CF 3 , CCl 3 , C 2 F 5 , C 2 Cl
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl or tert-butyl).
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having from 2 to 6 carbon atoms (“C 2-6 alkenyl”).
  • the alkenyl group is, for example, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 2-butenyl group, a 3-butenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, and 2 Hexyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compounds of the invention may exist in pure E (enthafen) form, pure Z (zusammen) form, or any mixture thereof.
  • alkynyl refers to a monovalent hydrocarbon radical containing one or more triple bonds, which preferably has 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).
  • cyclooctyl cyclodecyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl Or bicyclo [5.2.0] anthracenyl, decahydronaphthyl, etc.), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents.
  • the cycloalkyl has 3 to 15 carbons Atom.
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl). Or cyclohexyl), which is optionally substituted by one or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl.
  • heterocyclyl refers to a saturated or partially unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8 or 9 carbons in the ring.
  • the 3-10 membered heterocyclic group is a group having 3 to 10 carbon atoms and a hetero atom in the ring, such as, but not limited to, an oxiranyl group, an aziridine group, an azetidinyl group ( Azetidinyl), oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyridyl Oryl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
  • an oxiranyl group an aziridine group
  • an azetidinyl group Azetidinyl
  • oxetanyl tetrahydrofuranyl
  • dioxolinyl pyrrolidinyl
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system.
  • C6-14 aryl means an aromatic group containing from 6 to 14 carbon atoms, such as phenyl or naphthyl.
  • the aryl group is optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • aralkyl as used herein preferably denotes an aryl-substituted alkyl group, wherein the aryl group and the alkyl group are as defined herein.
  • the aryl group can have from 6 to 14 carbon atoms and the alkyl group can have from 1 to 6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • heteroaryl refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, In particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and it contains at least one hetero atom which may be the same or different (the hetero atom is, for example, oxygen, nitrogen or sulfur), and additionally In each case it may be benzofused.
  • the heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thia A oxazolyl group or the like, and a benzo derivative thereof; or a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group or the like, and a benzo derivative thereof.
  • halo or halogen group, as used herein, is defined to include F, Cl, Br or I.
  • substituted means that one or more (eg, one, two, three, or four) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the The atomic valence of the specified atom in the present case and the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent may be unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together independently The optional substituents selected are substituted. If the nitrogen of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected. Substitute substitution.
  • each substituent is selected independently of the other.
  • each substituent may be the same or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.
  • the substituents of the substituents may be derived from any suitable position of the substituent, unless otherwise indicated.
  • the invention also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass prevailing in nature. Or atomic substitution of mass.
  • suitable contain a compound of the present invention isotopes include (but are not limited to) isotopes of hydrogen (e.g., deuterium (2 H), tritium (3 H)); isotopes of carbon (e.g.
  • Chlorine isotope eg 36 Cl
  • fluorine isotopes eg 18 F
  • iodine isotopes eg 123 I and 125 I
  • nitrogen isotopes eg 13 N and 15 N
  • oxygen isotopes eg 15 O
  • phosphorus isotope eg 32 P
  • sulfur isotope eg 35 S
  • Certain isotopically-labeled compounds of the invention e.g., those incorporating radioisotopes
  • are useful in drug and/or substrate tissue distribution studies e.g., assays).
  • the radioisotope ruthenium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron emitting isotopes eg, 11 C, 18 F, 15 O, and 13 N
  • PET positron emission tomography
  • Isotopically labeled compounds of the invention can be prepared by replacing the previously employed non-labeled reagents with suitable isotopically labeled reagents by methods analogous to those described in the accompanying routes and/or examples and preparations.
  • the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be substituted with an isotope, for example, D 2 O, acetone-d 6 or DMSO-d 6 .
  • stereoisomer denotes an isomer formed by at least one asymmetric center.
  • a compound having one or more (eg, one, two, three or four) asymmetric centers it can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Diastereomers.
  • Specific individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.
  • Solid lines can be used in this article Solid wedge Virtual wedge
  • the carbon-carbon bonds of the compounds of the invention are depicted.
  • the use of solid lines to delineate linkages bonded to an asymmetric carbon atom is intended to include all possible stereoisomers at the carbon atom (eg, specific enantiomers, racemic mixtures, etc.).
  • the use of a solid or virtual wedge to characterize a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown.
  • solid and virtual wedges are used to define relative stereochemistry rather than absolute stereochemistry.
  • the compounds of the invention are intended to be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist.
  • the compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).
  • the invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which are administered to a patient in need thereof
  • the compound of the invention, or a metabolite or residue thereof, can be provided directly or indirectly after the drug.
  • a “compound of the invention” it is also intended to encompass the various derivative forms described above for the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include aspartate, glucoheptonate, gluconate, orotate, palmitate, and other similar salts.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, magnesium salts, and other similar salts.
  • esters means an ester derived from a compound of the formulae herein, which includes a physiologically hydrolyzable ester (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the invention). Compound).
  • the compounds of the invention may also be esters per se.
  • the compound of the present invention may exist in the form of a solvate (preferably a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • the amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
  • N-oxides are capable of forming N-oxides because nitrogen requires the use of a lone pair of electrons to oxidize to oxides; those skilled in the art will recognize that N-oxides can be formed.
  • Nitrogen-containing heterocycle Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • the synthesis of N-oxides for the preparation of heterocyclic and tertiary amines is well known to those skilled in the art and includes the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl groups.
  • MCPBA m-chloroperoxybenzoic acid
  • Hydrogen peroxide such as t-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane oxidize heterocyclic and tertiary amines.
  • metabolites of the compounds of the invention i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.
  • the invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to or into the body It can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • Prodrugs of the invention may, for example, be known by those skilled in the art as “pro-moiety” (e.g., “Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" It is prepared in place of the appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention containing a protecting group.
  • a protecting group In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. This can be achieved by conventional protecting groups, such as those described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is incorporated herein by reference.
  • the protecting group can be removed at a suitable subsequent stage using methods known in the art.
  • the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein the compound has the structure of formula (I):
  • R 2 is selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, and -OC 1-6 alkyl, wherein the alkyl group is optionally substituted with one or more halogens;
  • Q is selected from C, C(R 4 ) and N;
  • W 1 , W 2 , W 3 , W 4 , W 5 , W 6 and W 7 are each independently selected from C(R 4 ) and N;
  • both W 5 and W 6 are C(R 4 )
  • the two R 4 together with the carbon atom to which they are attached, are optionally taken together to form a 5 member, optionally substituted by C 1-6 alkyl, hydroxy or halogen.
  • X, Y and Z are each independently selected from a direct bond, C(R 4 ), C(R 4 )(R 5 ), N, N(R 4 ) and O;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl; or when R 6 and R 7 are bonded to the same nitrogen atom, R 6 and R 7 are attached thereto The nitrogen atom optionally together form a 3-10 membered heterocyclic group;
  • n 0, 1, or 2.
  • X, Y or Z when X, Y or Z is C(R 4 ) or N, it is bonded to a double bond; when X, Y or Z is C(R 4 )(R 5 ), N(R When 4 ) or O, it is not connected to the double bond.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or a prodrug wherein the compound has the structure of formula (II):
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or pre- Medicament wherein the compound has the structure of formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) or formula (IX):
  • the compound of formula (IV) is a compound of formula (IV)-1 or a compound of formula (IV)-2:
  • the compound of formula (V) is a compound of formula (V)-1 or a compound of formula (V)-2:
  • the compound of formula (VIII) is a compound of formula (VIII)-1 or a compound of formula (VIII)-2:
  • the compound of formula (IX) is a compound of formula (IX)-1 or a compound of formula (IX)-2:
  • the present invention provides a compound of any of the above formulas or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof a metabolite or prodrug
  • R 1 is selected from the group consisting of isopropyl, cyclopropyl,
  • the present invention provides a compound of any of the above formulas or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof a metabolite or prodrug wherein R 3 is selected from the group consisting of:
  • the above groups are optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -OH, methyl, ethyl, n-propyl, isopropyl, n-Butyl, sec-butyl, tert-butyl, cyclopropyl and -CF 3 .
  • R 3 is selected from
  • R 3 is selected from
  • the present invention provides a compound of any of the above formulas or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof a metabolite or prodrug wherein R 4 is selected from the group consisting of H, F, Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, Cyclopropyl,
  • R 4 is selected from the group consisting of F, Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and cyclopropyl.
  • the present invention provides a compound of any of the above formulas or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof a metabolite or prodrug, wherein W 1 , W 2 , W 3 , W 4 , W 5 , W 6 and W 7 are each independently selected from the group consisting of CH, CF, C-CH 3 , N,
  • W 1 , W 2 , W 3 , W 4 , W 5 , W 6 and W 7 are each independently selected from the group consisting of CF, C-CH 3 and N.
  • the present invention provides a compound of any of the above formulas or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof a metabolite or prodrug, wherein W 1 , W 2 are selected from N; W 3 , W 4 , W 5 and W 7 are selected from CH; and W 6 is selected from CH,
  • the present invention encompasses compounds obtained by any combination of the various embodiments.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or pre- Medicament wherein the compound is selected from the group consisting of
  • the invention provides a compound of formula (IN-8):
  • Hal 1 is a halogen such as F, Cl, Br or I;
  • the compound of the formula (IN-8) is preferably:
  • the invention provides a method of preparing a compound of formula (IN-8) comprising the steps of:
  • Hal 1 , Hal 2 and Hal 3 are the same or different halogens, such as F, Cl, Br or I;
  • reaction conditions of each step are as follows:
  • IN-1 is obtained by halogenation to give IN-2, a halogenating reagent such as Cl 2 , Br 2 , I 2 or N-bromosuccinimide (NBS), preferably in an aprotic solvent (for example) In carbon tetrachloride);
  • a halogenating reagent such as Cl 2 , Br 2 , I 2 or N-bromosuccinimide (NBS)
  • NBS N-bromosuccinimide
  • the second step reacting IN-3 with DMF-DMA to obtain IN-4, and the reaction is preferably carried out under heating;
  • the third step cyclization of IN-4 with R 1 -NH 2 to obtain IN-5, the reaction is preferably carried out in the presence of an acid such as acetic acid in an aprotic solvent such as acetonitrile;
  • Step 4 IN-5 is first subjected to a diazotization reaction (preferably in the presence of an acid (preferably a mineral acid such as hydrobromic acid) with a nitrite (such as sodium nitrite), followed by a halogenation reaction (halogenation reagent) For example, Cl 2 , Br 2 or I 2 ), to obtain IN-6;
  • a diazotization reaction preferably in the presence of an acid (preferably a mineral acid such as hydrobromic acid) with a nitrite (such as sodium nitrite), followed by a halogenation reaction (halogenation reagent)
  • halogenation reaction halogenation reagent
  • Step 5 IN-6 is reacted with hydrazine to obtain IN-7, and the reaction is preferably carried out in a protic solvent such as ethanol;
  • the invention provides a method of preparing a compound of formula (IV)-1, comprising the steps of:
  • Hal 1 , Hal 2 and Hal 3 are the same or different halogens, such as F, Cl, Br or I;
  • PG is a hydroxy protecting group including, but not limited to, benzyl, triphenylmethyl, tetrahydropyranyl, formyl, acetyl, benzoyl, and silyl groups (eg, trimethylsilyl, triethyl) Silyl group, tert-butyldimethylsilyl group, etc.);
  • LG is selected from H and halogen
  • R a and R a ' are each independently selected from H and C 1-6 alkyl at each occurrence; or R a and R a' together with the group to which they are attached form a 5-10 membered ring system (eg, common Composition );
  • reaction conditions of each step are as follows:
  • First step the hydroxyl group in the compound of formula (IV)-1-a is treated with a suitable hydroxy protecting group (for example benzyl) under the corresponding conditions (for example in the presence of an organic base or an inorganic base such as potassium carbonate).
  • a suitable hydroxy protecting group for example benzyl
  • Protected in a polar solvent eg DMF to give a compound of formula (IV)-1-b;
  • Second step the cation of the formula (IV)-1-b and R 3 -LG under the catalysis of a metal or metal salt such as a copper salt catalyst such as CuO, Cu 2 O or CuI in an organic or inorganic base (for example In the presence of potassium carbonate, optionally in the presence of a metal ligand such as 8-hydroxyquinoline, a compound of formula (IV)-1-c is obtained;
  • a metal or metal salt such as a copper salt catalyst such as CuO, Cu 2 O or CuI
  • organic or inorganic base for example In the presence of potassium carbonate, optionally in the presence of a metal ligand such as 8-hydroxyquinoline, a compound of formula (IV)-1-c is obtained;
  • the third step the compound of the formula (IV)-1-c is subjected to conditions for removing the PG group (for example, when PG is a benzyl group, the conditions are hydrogenation in a hydrogen atmosphere under palladium/carbon catalysis).
  • the removal is carried out to obtain a compound of the formula (IV)-1-d;
  • Step 4 reacting a compound of formula (IV)-1-d with a formamide such as DMF (the reaction is preferably carried out in an aprotic solvent such as toluene under heating (for example at 90-150 ° C) To carry out a compound of formula (IV)-1-e;
  • a formamide such as DMF
  • Step 5 The compound of the formula (IV)-1-e is reacted in the presence of an organic base (for example, pyridine) or an inorganic base, and a halogen (for example, Br 2 or I 2 ) to give the formula (IV)-1- a compound of f;
  • an organic base for example, pyridine
  • a halogen for example, Br 2 or I 2
  • the sixth step the compound of the formula (IV)-1-f is catalyzed by a palladium catalyst (for example Pd(dppf)Cl 2 ) with a boric acid or a boric acid ester (for example, a pinacol borate), preferably in an organic base. Or reacting in the presence of an inorganic base such as potassium acetate to provide a compound of formula (IV)-1-g;
  • a palladium catalyst for example Pd(dppf)Cl 2
  • a boric acid or a boric acid ester for example, a pinacol borate
  • Step 7 Catalyzing the compound of the formula (IV)-1-g with the compound Int-3-E under the catalysis of a palladium catalyst (for example Pd(dppf)Cl 2 ), preferably in an organic or inorganic base (for example potassium carbonate) The reaction is carried out in the presence of a compound of formula (IV)-1.
  • a palladium catalyst for example Pd(dppf)Cl 2
  • an organic or inorganic base for example potassium carbonate
  • the invention provides a method of preparing a compound of formula (V)-1, comprising the steps of:
  • Hal 1 is halogen, such as F, Cl, Br or I;
  • R' is selected from the group consisting of -OH, -OC 1-6 alkyl and halogen
  • LG is selected from H and halogen
  • R a and R a ' are each independently selected from H and C 1-6 alkyl at each occurrence;
  • reaction conditions of each step are as follows:
  • the compound of formula (V)-1-a is firstly present in the presence of an acid halide reagent such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, SOCl 2 or oxalyl chloride.
  • an acid halide reagent such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, SOCl 2 or oxalyl chloride.
  • an acid halide compound for example, an acid chloride compound or an acid bromide compound
  • Int-3-D for example, an organic base (for example, pyridine) or an inorganic base
  • Second step reacting a compound of formula (V)-1-b with a formamide such as DMF (the reaction is preferably carried out in an aprotic solvent such as toluene under heating (for example at 90-150 ° C) To carry out a compound of formula (V)-1-c;
  • a formamide such as DMF
  • the third step the compound of the formula (V)-1-c is reacted in an aprotic solvent (for example, toluene) under heating (for example, at 90 to 150 ° C) to obtain a compound of the formula (V)-1-d. ;as well as
  • an aprotic solvent for example, toluene
  • the fourth step catalyzing the formula (V)-1-d and R 3 -LG in a metal or metal salt (for example, a copper salt catalyst such as CuO, Cu 2 O or CuI) in an organic or inorganic base (for example The reaction of the metal ligand (for example, 8-hydroxyquinoline) is optionally carried out in the presence of potassium carbonate) to give a compound of formula (V)-1.
  • a metal or metal salt for example, a copper salt catalyst such as CuO, Cu 2 O or CuI
  • organic or inorganic base for example
  • the reaction of the metal ligand for example, 8-hydroxyquinoline
  • potassium carbonate for example, potassium carbonate
  • the invention provides a method of preparing a compound of formula (V)-2, comprising the steps of:
  • each group is as defined above; and the reaction is carried out under hydrogenation conditions (for example hydrogenation in a hydrogen atmosphere under palladium on carbon catalysis).
  • the invention provides a method of preparing a compound of formula (VIII)-2, comprising the steps of:
  • Hal 1 and Hal 3 are the same or different halogens, such as F, Cl, Br or I;
  • LG is selected from H and halogen
  • reaction conditions of each step are as follows:
  • the first step the cation of the formula (VIII)-2-a and R 3 -LG under the catalysis of a metal or metal salt (for example a copper salt catalyst such as CuO, Cu 2 O or CuI) in an organic or inorganic base (for example In the presence of potassium carbonate, optionally in the presence of a metal ligand such as 8-hydroxyquinoline, a compound of formula (VIII)-2-b is obtained;
  • a metal or metal salt for example a copper salt catalyst such as CuO, Cu 2 O or CuI
  • organic or inorganic base for example In the presence of potassium carbonate, optionally in the presence of a metal ligand such as 8-hydroxyquinoline, a compound of formula (VIII)-2-b is obtained;
  • Second step reacting a compound of formula (VIII)-2-b with an azide salt (for example sodium azide) in the presence of a strong acid such as a strong mineral acid such as concentrated sulfuric acid to give formula (VIII)-2 a compound of -c;
  • an azide salt for example sodium azide
  • Third step catalyzing the compound of formula (VIII)-2-c with the compound Int-3-E under the catalysis of a palladium catalyst such as Pd(dppf)Cl 2 or Pd 2 (dba) 3 , preferably in an organic base or Reaction of the inorganic base (e.g., potassium carbonate or cesium carbonate), optionally in the presence of a ligand (e.g., Xantphos), provides a compound of formula (VIII)-2.
  • a palladium catalyst such as Pd(dppf)Cl 2 or Pd 2 (dba) 3
  • an organic base or Reaction of the inorganic base e.g., potassium carbonate or cesium carbonate
  • a ligand e.g., Xantphos
  • the invention provides a method of preparing a compound of formula (VII), comprising the steps of:
  • Hal 1 is halogen, such as F, Cl, Br or I;
  • R' is selected from the group consisting of -OH, -OC 1-6 alkyl and halogen
  • LG is selected from H and halogen
  • reaction conditions of each step are as follows:
  • the compound of formula (VII)-a is first formed into an acyl group in the presence of an acid halide reagent such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, SOCl 2 or oxalyl chloride.
  • an acid halide reagent such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, SOCl 2 or oxalyl chloride.
  • a halogen compound such as an acid chloride compound or an acid bromide compound
  • a second step reacting a compound of the formula (VII)-b with a nitrite such as sodium nitrite in the presence of a strong acid such as a strong mineral acid such as concentrated hydrochloric acid to give a compound of (VII)-c;
  • a strong acid such as a strong mineral acid such as concentrated hydrochloric acid
  • the third step catalyzing the formula (VII)-c and R 3 -LG in a metal or metal salt (for example, a copper salt catalyst such as CuO, Cu 2 O or CuI) in an organic or inorganic base (for example, potassium carbonate).
  • a metal or metal salt for example, a copper salt catalyst such as CuO, Cu 2 O or CuI
  • an organic or inorganic base for example, potassium carbonate.
  • the reaction of the metal ligand for example, 8-hydroxyquinoline
  • the invention provides a method of preparing a compound of formula (VI), comprising the steps of:
  • Hal 1 and Hal 2 are the same or different halogens, such as F, Cl, Br or I;
  • LG is selected from H and halogen
  • R a and R a ' are each independently selected from H and C 1-6 alkyl at each occurrence;
  • reaction conditions of each step are as follows:
  • First step the presence of a compound of formula (VI)-a with an acid halide such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, SOCl 2 or oxalyl chloride in the presence of formamide (eg DMF)
  • an acid halide such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, SOCl 2 or oxalyl chloride
  • formamide eg DMF
  • a second step reacting a compound of formula (VI)-b with Int-3-D in the presence of an organic base such as pyridine or an inorganic base to provide a compound of formula (VI)-c;
  • a metal or a metal salt for example, a copper salt catalyst such as CuO, Cu 2 O or CuI
  • organic or inorganic base for example
  • the reaction of the metal ligand for example, 8-hydroxyquinoline
  • potassium carbonate for example, potassium carbonate
  • the invention provides a method of preparing a compound of formula (IX)-1 comprising the steps of:
  • Hal 1 and Hal 3 are the same or different halogens, such as F, Cl, Br or I;
  • LG is selected from H and halogen
  • reaction conditions of each step are as follows:
  • the first step the cation of the formula (IX)-1-a and R 3 -LG under the catalysis of a metal or metal salt such as a copper salt catalyst such as CuO, Cu 2 O or CuI, in an organic or inorganic base (for example In the presence of potassium carbonate or cesium carbonate, optionally in the presence of a metal ligand such as 8-hydroxyquinoline, a compound of formula (IX)-1-b is obtained;
  • a metal or metal salt such as a copper salt catalyst such as CuO, Cu 2 O or CuI
  • Second step catalyzing the compound of formula (IX)-1-b with the compound Int-3-E under the catalysis of a palladium catalyst such as Pd(dppf)Cl 2 or Pd 2 (dba) 3 , preferably in an organic base or In the presence of an inorganic base such as potassium carbonate, cesium carbonate or sodium t-butoxide, optionally in the presence of a ligand such as Xantphos, to give a compound of formula (IX)-1-c;
  • a palladium catalyst such as Pd(dppf)Cl 2 or Pd 2 (dba) 3
  • an organic base such as potassium carbonate, cesium carbonate or sodium t-butoxide
  • a ligand such as Xantphos
  • compositions and methods of treatment are provided.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof, or a pharmaceutically acceptable salt thereof
  • the pharmaceutical composition may further comprise one or more additional therapeutic agents.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolism thereof Use of a prodrug or prodrug or a pharmaceutical composition of the invention in the manufacture of a medicament for use as an ASK1 inhibitor.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolism thereof Or a prodrug or a pharmaceutical composition of the invention for use as an ASK1 inhibitor.
  • the invention provides a method of preventing or treating an ASK1-mediated disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester thereof, Stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.
  • the compounds of the invention are used for the prevention or treatment of ASK1-mediated diseases, including conditions and diseases caused by chronic fatty and fibrotic degeneration (eg, nonalcoholic fatty liver disease (NAFLD) or non-alcoholic Fatty hepatitis (NASH), primary sclerosing cholangitis, extrahepatic cholestasis; liver fibrosis; obstructive or chronic inflammatory disorders of the liver; cirrhosis; cirrhosis caused by alcohol or viral infection Forms of hepatitis-related cholestasis and fibrotic lesions; autoimmune diseases; respiratory diseases (including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and acute lung injury); inflammatory diseases Chronic kidney disease; cardiovascular disease; diabetes (including diabetic nephropathy and other complications of diabetes); metabolic disorders; organ damage after ischemia and reperfusion of the heart, brain and kidneys, and neurodegenerative diseases.
  • chronic fatty and fibrotic degeneration
  • “Pharmaceutically acceptable carrier” in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like.
  • the composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the invention may act systemically and/or locally.
  • they may be administered in a suitable route, for example by injection (for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation) or transdermal administration; or by oral, buccal, or oral administration.
  • injection for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation
  • transdermal administration or by oral, buccal, or oral administration.
  • compositions of the invention may be administered in a suitable dosage form.
  • the dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.
  • an effective amount refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.
  • the dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.
  • an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day.
  • a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
  • the amount or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg, particularly preferably from 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, and the like.
  • treating means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or one or more symptoms of such a condition or condition, or Prevention of such a condition or condition or one or more symptoms of such condition or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein.
  • “Non-human animals” in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).
  • compositions of the invention may further comprise one or more additional therapeutic or prophylactic agents including, but not limited to, PPAR alpha/delta agonists (GFT505), type 2 and type 5 chemotaxis Factor receptor antagonist (cenicriviroc [CVC]), fatty acid-bile acid conjugate (aramchol), FXR agonist (Obecholic acid, GS-9674, LJN-452, EDP-305).
  • additional therapeutic or prophylactic agents including, but not limited to, PPAR alpha/delta agonists (GFT505), type 2 and type 5 chemotaxis Factor receptor antagonist (cenicriviroc [CVC]), fatty acid-bile acid conjugate (aramchol), FXR agonist (Obecholic acid, GS-9674, LJN-452, EDP-305).
  • the structure of the compound was confirmed by nuclear magnetic resonance spectroscopy ( 1 H NMR) or mass spectrometry (MS).
  • the chemical shift ( ⁇ ) is given in parts per million (ppm).
  • the 1 H NMR measurement was performed on a JEOL Eclipse 400 nuclear magnetic instrument.
  • the test solvent was deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or hexamethyl dimethyl sulfoxide (DMSO-d 6 ). It is tetramethylsilane (TMS).
  • the preparative high performance liquid chromatography was carried out using a Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250 x 20 mm column).
  • Thin layer chromatography was carried out using an aluminum plate (20 x 20 cm) manufactured by Merck, and thin layer preparative chromatography was carried out using a silica gel plate of GF254 (0.4 to 0.5 nm) having a specification of Yantai.
  • the reaction is detected by thin layer chromatography (TLC) or LC-MS using a developing solvent system including a dichloromethane and methanol system, a n-hexane and ethyl acetate system, and a petroleum ether and ethyl acetate system depending on the compound to be separated.
  • the developing agent system is adjusted by the difference in polarity (by adjusting the volume ratio of the solvent or adding triethylamine or the like).
  • the microwave reaction was carried out using a Biotage Initiator + (400 W, RT ⁇ 300 ° C) microwave reactor.
  • Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the stationary phase.
  • the system of the eluent includes a dichloromethane and methanol system and a n-hexane and ethyl acetate system, and the eluent system is adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.) get on).
  • the reaction temperature is room temperature (20 ° C ⁇ 30 ° C)
  • the reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company or Tiber Chemical.
  • the third step preparation of 3,6-dibromoisobenzofuran-1(3H)-one (Int-1)
  • reaction mixture was made to a weak basic with 2N NaOH solution, extracted with ethyl acetate, and the ethyl acetate layer was washed with aqueous sodium thiosulfate, dried, filtered, concentrated and purified to give compound (Int-3-e) ( 2.8 g, yield: 72%).
  • Step 5 Preparation of 2-mercapto-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine (Int-3)
  • a compound (Int-) was prepared by a method similar to that in Intermediate Preparation Example 3 except that 1,1,1-trifluoropropan-2-amine (2.0 g, 17.7 mmol) was used instead of isopropylamine in the third step. 5) (150 mg).
  • a compound (Int-) was prepared by a method similar to that in Intermediate Preparation Example 3 except that 1,1,1-trifluoropropan-2-amine (4.0 g, 35.4 mmol) was used instead of isopropylamine in the third step. 6) (450 mg).
  • Second step 7-(4-cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine
  • Second step 7-(4-cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-(1,1,1-trifluoropropan-2-yl)-4H-1, Preparation of 2,4-triazol-3-yl)pyridin-2-yl)pyridazine-1(2H)-one (3)
  • Step 6 6-(4-Cyclopropyl-1H-imidazol-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan Preparation of alk-2-yl)-4H-chromen-4-one (4-g)
  • Step 7 6-(4-Cyclopropyl-1H-imidazol-1-yl)-3-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)-4H-chromen-4-one (4)
  • Example 7 7-(4-Cyclopropyl-1H-imidazol-1-yl)-4-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-3,4-dihydrobenzo[f][1,4]oxaza Preparation of -5(2H)-one (7)
  • 6-Bromochroman-4-one (7-a) (1.0 g, 4.4 mmol) was dissolved in DMSO (10 mL).
  • Compound (Int-2) (528 mg, 4.8 mmol), CuI (125 mg, 0.66 mmol) ), 8-hydroxyquinoline (96 mg, 0.66 mmol) and K 2 CO 3 (1.22 g, 8.8 mmol).
  • the mixture was heated at 110-120 °C overnight.
  • the reactant was concentrated under reduced pressure in vacuo and purified by preparative HPLC to afford compound (7-b) (302 mg, yield: 27%).
  • the third step 7-(4-cyclopropyl-1H-imidazol-1-yl)-4-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-3,4-dihydrobenzo[f][1,4]oxaza Preparation of -5(2H)-one (7)
  • Second step Preparation of 1-(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-(methylamino)phenyl)ethan-1-one (43-c)
  • the third step 1-(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-(methylamino)phenyl)-2-(6-(4-isopropyl-4H- Preparation of 1,2,4-triazol-3-yl)pyridin-2-yl)ethan-1-one (43-d)
  • the third step 6-(4-isopropyl-1H-imidazol-1-yl)-3-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)quinazoline-4(3H)-one (9)
  • Example 12 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)-6-(1-methylpiperidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (37)
  • the fourth step 5-bromo-6-(4-cyclopropyl-2-indolyl-1H-imidazol-1-yl)-2,3-dihydro-1H-inden-1-one (37-e) preparation
  • the compound (37-d) (6.6 g, 21.4 mmol) was dissolved in acetic acid (80 mL), and potassium thiocyanate (4.2 g, 42.8 mmol) was added thereto, and the mixture was heated to 110 ° C for 8 hours, and the reaction solution was depressurized. The acetic acid was evaporated, and water (100 mL) was added, and ethyl acetate was evaporated. (6.8 g of a brown solid, used directly in the next step).
  • Step 5 Preparation of 5-bromo-6-(4-cyclopropyl-1H-imidazol-1-yl)-2,3-dihydro-1H-inden-1-one (37-f)
  • Step 6 Preparation of 6-bromo-7-(4-cyclopropyl-1H-imidazol-1-yl)-3,4-dihydroisoquinolin-1(2H)-one (37-g)
  • the compound (37-f) (4.0 g, 12.6 mmol) was dissolved in chloroform (80 mL), methanesulfonic acid (12.1 g, 126 mmol) was added, and the mixture was cooled to 0 ° C in an ice bath, then sodium azide (2.5 g) was added in portions. , 37.8 mmol), after adding, slowly returning to room temperature and stirring overnight, the reaction solution was quenched with 1N aqueous sodium The organic compound (37-g) (3.6 g, yield: 85.9%) was evaporated to dryness.
  • Step 7 4-(7-(4-Cyclopropyl-1H-imidazol-1-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3 Of 6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (37-h)
  • Step 8 7-(4-Cyclopropyl-1H-imidazol-1-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroisoquine Preparation of porphyrin-1(2H)-one hydrochloride (37-i)
  • Step 9 7-(4-Cyclopropyl-1H-imidazol-1-yl)-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3,4 -Preparation of dihydroisoquinoline-1(2H)-one (37-j)
  • Step 10 7-(4-Cyclopropyl-1H-imidazol-1-yl)-6-(1-methylpiperidin-4-yl)-3,4-dihydroisoquinoline-1 (2H Preparation of -ketone (37-k)
  • the compound (37-j) (410 mg, 1.2 mmol) was dissolved in anhydrous ethanol (20 mL), and then, then,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
  • Example 13 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)-6-(3-morpholinoprop-1-yn-1-yl)-3,4-dihydroisoquinolin-1(2H)-one (38)
  • Second step 7-(4-cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine
  • Example 14 7-(4-Cyclopropyl-1H-imidazol-1-yl)-6-(3-hydroxyprop-1-yn-1-yl)-2-(6-(4-isopropyl) Of -4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3,4-dihydroisoquinoline-1(2H)-one (39)
  • Example 15 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-(1-hydroxypropan-2-yl)-4H-1,2,4-tri Preparation of oxazol-3-yl)pyridin-2-yl)-3,4-dihydroisoquinoline-1(2H)-one (40)
  • Steps 1 to 5 2-(6-(4-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-4H-1,2,4-tri Zyrid-3-yl)pyridin-2-yl)-7-(4-cyclopropyl-1H-imidazol-1-yl)-3,4-dihydroisoquinoline-1(2H)-one (40- Preparation of f)
  • Step 6 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-(1-hydroxypropan-2-yl)-4H-1,2,4-tri Preparation of oxazol-3-yl)pyridin-2-yl)-3,4-dihydroisoquinoline-1(2H)-one (40)
  • the second step 1-(2-amino-5-(4-cyclopropyl-1H-imidazol-1-yl)phenyl)-2-(6-(4-isopropyl-4H-1,2, Preparation of 4-triazol-3-yl)pyridin-2-yl)ethan-1-one (41-c)
  • Example 18 7-(6-Cyclopropylpyridin-3-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-2- Preparation of pyridazine-1(2H)-one (42)
  • the inhibitory effect of the compound on the ASK1 enzyme was determined using the HTRF KinEZSE-STK (Cisbio) kit.
  • the ASK1 enzyme was pre-incubated with different concentrations of test compound for 30 min at room temperature, and then the substrate and adenosine triphosphate (ATP) were added to initiate the reaction. After incubation for 120 min at room temperature, TK antibody-cryptate and streptavidin-XL665 were added and assayed.
  • the vehicle control group (DMSO) was used as the negative control, and the buffer group (excluding the ASK1 enzyme) was used as the blank control.
  • the relative inhibitory activity percentage of the test compounds at different concentrations was calculated by the following formula:
  • Relative inhibitory activity percentage 1 - (different concentrations of test compound group - buffer group) / (solvent group - buffer group) * 100%
  • y is the relative inhibitory activity percentage
  • max and min are the maximum and minimum values of the fitted curve
  • x is the logarithmic concentration of the compound
  • Hillslope is the slope of the curve.
  • the pcDNA3.1-ASK1 expression vector was constructed and co-transfected into HEK293 cells with pGL4.44[luc2P/AP1RE/Hygro] vector, plated at 3 ⁇ 10 4 cells/well, and incubated with different concentrations of test compounds for 24 h, then Bright was used.
  • -Glo TM luciferase assay system Promega
  • luciferase activity in cells according to the instructions of the detection method.
  • DMSO vehicle group
  • y is the relative inhibitory activity percentage
  • max and min are the maximum and minimum values of the fitted curve
  • x is the logarithmic concentration of the compound
  • Hillslope is the slope of the curve.
  • the compounds of the examples of the present invention exhibited a good swelling inhibition rate; the compounds of the examples of the present invention have a good effect on the improvement of fatty liver, inflammation, and fibrosis.
  • the compounds of the examples of the invention have both good pharmacokinetic properties, pharmacodynamic properties and excellent safety.

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Abstract

La présente invention concerne un inhibiteur de kinase 1 de régulation du signal d'apoptose (ASK1), une composition pharmaceutique le comprenant, son procédé de préparation et un intermédiaire de celui-ci, ainsi que l'utilisation de celui-ci pour prévenir ou traiter des maladies induites par l'ASK1.
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US10150755B2 (en) 2017-04-05 2018-12-11 Seal Rock Therapeutics, Inc. ASK1 inhibitor compounds and uses thereof
CN109265443A (zh) * 2017-07-18 2019-01-25 南京圣和药业股份有限公司 作为ask抑制剂的杂环化合物及其应用
CN109456308A (zh) * 2017-09-06 2019-03-12 南京圣和药业股份有限公司 作为ask抑制剂的杂环化合物及其应用
US10246439B2 (en) 2017-05-25 2019-04-02 Enanta Pharmaceuticals, Inc. Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
US10253018B2 (en) 2017-05-25 2019-04-09 Enanta Pharmaceuticals, Inc. Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
CN109956928A (zh) * 2017-12-14 2019-07-02 四川科伦博泰生物医药股份有限公司 吡啶类化合物、其制备方法及用途
US10450301B2 (en) 2017-05-25 2019-10-22 Enanta Pharmaceuticals, Inc. Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
WO2019213244A1 (fr) 2018-05-02 2019-11-07 Enanta Pharmaceuticals, Inc. Inhibiteurs de la kinase 1 régulant le signal d'apoptose contenant des tétrazoles et leurs méthodes d'utilisation
JP2020507565A (ja) * 2017-02-28 2020-03-12 イーライ リリー アンド カンパニー イソキノリンおよびナフチドリン化合物
US10597382B2 (en) 2017-08-28 2020-03-24 Enanta Pharmaceuticals, Inc. Tetrazole containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
WO2020080742A1 (fr) 2018-10-18 2020-04-23 Cj Healthcare Corporation Nouveaux dérivés de benzooxazinone ou de benzothiazinone substitués par (isopropyl-triazolyl)pyridinyle et leur utilisation
US10683279B2 (en) 2017-05-12 2020-06-16 Enanta Pharmaceuticals, Inc. Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
US10683289B2 (en) 2018-05-02 2020-06-16 Enanta Pharmaceuticals, Inc. Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
CN111808079A (zh) * 2020-08-05 2020-10-23 中国药科大学 吲哚类ask1小分子抑制剂及其制备方法和应用
WO2021018951A1 (fr) * 2019-07-30 2021-02-04 Janssen Pharmaceutica Nv Dérivés de phtalazin-1-one utiles en tant qu'inhibiteurs de grk2
US10968199B2 (en) 2018-08-22 2021-04-06 Enanta Pharmaceuticals, Inc. Cycloalkyl-containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
US11345699B2 (en) 2018-11-19 2022-05-31 Enanta Pharmaceuticals, Inc. Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
US11434249B1 (en) 2018-01-02 2022-09-06 Seal Rock Therapeutics, Inc. ASK1 inhibitor compounds and uses thereof
US11466033B2 (en) 2019-03-25 2022-10-11 Enanta Pharmaceuticals, Inc. Substituted pyridines as apoptosis signal-regulating kinase 1 inhibitors

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US10787435B2 (en) 2017-01-22 2020-09-29 Fuijan Cosunter Pharmaceutical Co. Ltd. ASK1 inhibitor and preparation method and use thereof
CN110294742B (zh) * 2018-03-21 2023-01-31 山东轩竹医药科技有限公司 并环类ask1抑制剂及其应用
CN113234053B (zh) * 2021-05-30 2022-12-20 吉林农业大学 裂环羽扇豆烷衍生物及在制备ask1抑制剂中的应用

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JP2020507565A (ja) * 2017-02-28 2020-03-12 イーライ リリー アンド カンパニー イソキノリンおよびナフチドリン化合物
US10150755B2 (en) 2017-04-05 2018-12-11 Seal Rock Therapeutics, Inc. ASK1 inhibitor compounds and uses thereof
US10683279B2 (en) 2017-05-12 2020-06-16 Enanta Pharmaceuticals, Inc. Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
US11560368B2 (en) 2017-05-12 2023-01-24 Enanta Pharmaceuticals, Inc. Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
US10988458B2 (en) 2017-05-12 2021-04-27 Enanta Pharmaceuticals, Inc. Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
US10450301B2 (en) 2017-05-25 2019-10-22 Enanta Pharmaceuticals, Inc. Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
US10253018B2 (en) 2017-05-25 2019-04-09 Enanta Pharmaceuticals, Inc. Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
US10246439B2 (en) 2017-05-25 2019-04-02 Enanta Pharmaceuticals, Inc. Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
CN109265443B (zh) * 2017-07-18 2022-11-29 南京圣和药业股份有限公司 作为ask抑制剂的杂环化合物及其应用
CN109265443A (zh) * 2017-07-18 2019-01-25 南京圣和药业股份有限公司 作为ask抑制剂的杂环化合物及其应用
US10597382B2 (en) 2017-08-28 2020-03-24 Enanta Pharmaceuticals, Inc. Tetrazole containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
CN109456308B (zh) * 2017-09-06 2022-11-29 南京圣和药业股份有限公司 作为ask抑制剂的杂环化合物及其应用
CN109456308A (zh) * 2017-09-06 2019-03-12 南京圣和药业股份有限公司 作为ask抑制剂的杂环化合物及其应用
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US11434249B1 (en) 2018-01-02 2022-09-06 Seal Rock Therapeutics, Inc. ASK1 inhibitor compounds and uses thereof
US10683289B2 (en) 2018-05-02 2020-06-16 Enanta Pharmaceuticals, Inc. Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
US11834436B2 (en) 2018-05-02 2023-12-05 Enanta Pharmaceuticals, Inc. Tetrazole containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
WO2019213244A1 (fr) 2018-05-02 2019-11-07 Enanta Pharmaceuticals, Inc. Inhibiteurs de la kinase 1 régulant le signal d'apoptose contenant des tétrazoles et leurs méthodes d'utilisation
US11008304B2 (en) 2018-05-02 2021-05-18 Enanta Pharmaceuticals, Inc. Tetrazole containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
US10968199B2 (en) 2018-08-22 2021-04-06 Enanta Pharmaceuticals, Inc. Cycloalkyl-containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
JP2022500478A (ja) * 2018-10-18 2022-01-04 エイチケー イノ．エヌ コーポレーション 新規な（イソプロピル−トリアゾリル）ピリジニル置換されたベンゾオキサジノン又はベンゾチアジノン誘導体及びその用途
KR102288434B1 (ko) * 2018-10-18 2021-08-12 에이치케이이노엔 주식회사 신규한 (이소프로필-트리아졸릴)피리디닐 치환된 벤조옥사지논 또는 벤조티아지논 유도체 및 이의 용도
CN112839943A (zh) * 2018-10-18 2021-05-25 怡诺安有限公司 新型(异丙基-三唑基)吡啶基取代的苯并噁嗪酮或苯并噻嗪酮衍生物及其用途
KR20200044268A (ko) * 2018-10-18 2020-04-29 에이치케이이노엔 주식회사 신규한 (이소프로필-트리아졸릴)피리디닐 치환된 벤조옥사지논 또는 벤조티아지논 유도체 및 이의 용도
JP7263509B2 (ja) 2018-10-18 2023-04-24 エイチケー イノ．エヌ コーポレーション 新規な（イソプロピル－トリアゾリル）ピリジニル置換されたベンゾオキサジノン又はベンゾチアジノン誘導体及びその用途
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US11345699B2 (en) 2018-11-19 2022-05-31 Enanta Pharmaceuticals, Inc. Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
US11466033B2 (en) 2019-03-25 2022-10-11 Enanta Pharmaceuticals, Inc. Substituted pyridines as apoptosis signal-regulating kinase 1 inhibitors
WO2021018951A1 (fr) * 2019-07-30 2021-02-04 Janssen Pharmaceutica Nv Dérivés de phtalazin-1-one utiles en tant qu'inhibiteurs de grk2
CN111808079A (zh) * 2020-08-05 2020-10-23 中国药科大学 吲哚类ask1小分子抑制剂及其制备方法和应用

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