WO2018207882A1 - Composés hétérocycliques - Google Patents

Composés hétérocycliques Download PDF

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WO2018207882A1
WO2018207882A1 PCT/JP2018/018158 JP2018018158W WO2018207882A1 WO 2018207882 A1 WO2018207882 A1 WO 2018207882A1 JP 2018018158 W JP2018018158 W JP 2018018158W WO 2018207882 A1 WO2018207882 A1 WO 2018207882A1
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group
ring
acid
compound
examples
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祐己 半矢
信二 中村
三木　隆
▲琢▼ 亀井
温子 落田
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武田薬品工業株式会社
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—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 two hetero rings
    • C07D405/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • 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 provides a binding inhibitory action between bromodomain and extra-terminal domain (BET) family proteins (sometimes abbreviated as “BET family proteins” herein) and acetylated histones.
  • BET family proteins sometimes abbreviated as “BET family proteins” herein
  • Can have autoimmune disease and / or inflammatory disease eg, rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic Lupus erythematosus
  • a compound expected to be useful as a preventive or therapeutic agent for neurodegenerative diseases eg, Alzheimer's disease.
  • the BET family protein inhibitory action refers to the binding inhibitory action between BET family proteins and acetylated histones (including RelA, GATA1, Cyclin T, and TWIST, but acetylated histones are preferred).
  • BET family proteins are a family consisting of BRD2, BRD3, BRD4 and BRDT. These proteins recognize acetylated lysine residues via the bromodomain and bind to acetylated histones or other acetylated proteins. This interaction plays an important role in various gene expression including cytokine production. Cytokines are proteins secreted by cells of the immune system and transmit signals to specific cells. There are various cytokines, most are involved in immunity and inflammation, and are also involved in cell proliferation, cell differentiation, cell death, wound healing, etc. (Non-patent Document 1).
  • BET family proteins usually play a role in inflammatory / immune responses through gene expression such as IL-6 and TNF ⁇ , but their excessive interactions are infectious diseases, rheumatoid arthritis, multiple sclerosis, idiopathic lung It is involved in many immune related diseases such as fibrosis and cancer (Non-patent Document 2).
  • Tocilizumab an anti-IL-6 receptor antibody, is approved as an IL-6 signaling inhibitor, and etanercept, infliximab, adalimumab, etc., which are therapeutic agents for rheumatoid arthritis, etc., are approved as TNF ⁇ signaling inhibitors.
  • BET family protein inhibitors are cytokine-mediated diseases such as autoimmune diseases and / or inflammatory diseases (eg, rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, Inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus, etc.) and cancer.
  • inflammatory diseases eg, rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, Inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus, etc.
  • apabetalone is known to have a BET family protein inhibitory action, and is being clinically tested as a therapeutic agent for Alzheimer's disease.
  • BET family protein inhibitors can be therapeutic agents for neuro
  • the object of the present invention is to have BET family protein inhibitory action, and to have an autoimmune disease and / or inflammatory disease (eg, rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, inflammatory bowel disease, Sjogren It is intended to provide a compound expected to be useful as a preventive or therapeutic agent for a syndrome, Behcet's disease, systemic lupus erythematosus), a neurodegenerative disease (eg, Alzheimer's disease), and a medicine containing the same.
  • an autoimmune disease and / or inflammatory disease eg, rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, inflammatory bowel disease, Sjogren It is intended to provide a compound expected to be useful as a preventive or therapeutic agent for a syndrome, Behcet's disease, systemic lupus erythematos
  • Ring A represents an optionally substituted aromatic ring
  • R 1 represents a hydrogen atom, a cyano group, a C 1-6 alkoxy-carbonyl group or a carbamoyl group
  • R 2 represents a hydrogen atom, a cyano group, a carboxy group, a C 1-6 alkoxy-carbonyl group, a carbamoyl group or a 5- to 6-membered monocyclic aromatic heterocyclic group.
  • a salt thereof in this specification, sometimes abbreviated as “compound (I)”.
  • Ring A is (1) a halogen atom, (2) a cyano group, (3) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (4) 1 to 3 A C 1-6 alkoxy group optionally substituted with a halogen atom of (5) a mono- or di-C 1-6 alkylamino group, (6) a C 1-6 alkyl-carbonylamino group and (7) C Benzene ring, naphthalene ring, thiophene ring, pyrazole ring, pyridine ring, pyrimidine ring, benzothiophene ring, benzofuran ring, each of which may be further substituted with 1 to 3 substituents selected from 1-6 alkylsulfonyl groups A pyrrolopyridine ring, an indole ring, an isoquinoline ring or a quinoline ring, [1] The compound or a salt thereof according to [1].
  • a medicament comprising the compound according to [1] or a salt thereof.
  • a method for inhibiting a BET family protein in a mammal comprising administering an effective amount of the compound according to [1] or a salt thereof to the mammal.
  • the present invention may have a BET family protein inhibitory action, and may have an autoimmune disease and / or inflammatory disease (eg, rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, inflammatory bowel disease, Sjogren's syndrome,
  • an autoimmune disease and / or inflammatory disease eg, rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, inflammatory bowel disease, Sjogren's syndrome
  • inflammatory disease eg, rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, inflammatory bowel disease, Sjogren's syndrome
  • each substituent has the following definition.
  • examples of the “halogen atom” include fluorine, chlorine, bromine and iodine.
  • examples of the “C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl.
  • Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2- Difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-tri Examples include fluoropentyl, hexyl, and 6,6,6-trifluorohexyl.
  • examples of the “C 2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- Examples include methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
  • examples of the “C 2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- Examples include pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl.
  • examples of the “C 3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2. 2] Octyl, bicyclo [3.2.1] octyl, and adamantyl.
  • the "optionally halogenated C 3-10 also be cycloalkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 3- A 10 cycloalkyl group.
  • examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • examples of the “C 3-10 cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • examples of the “C 6-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.
  • examples of the “C 7-16 aralkyl group” include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.
  • examples of the “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • the "optionally halogenated C 1-6 alkoxy group” for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1-6 An alkoxy group is mentioned.
  • Examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyl.
  • Examples include oxy and hexyloxy.
  • examples of the “C 3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.
  • examples of the “C 1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
  • the "optionally halogenated C 1-6 alkylthio group optionally" for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1-6 An alkylthio group is mentioned.
  • examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio.
  • examples of the “C 1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2- Examples include dimethylpropanoyl, hexanoyl, and heptanoyl.
  • examples of the “ optionally halogenated C 1-6 alkyl-carbonyl group” include C 1 optionally having 1 to 7, preferably 1 to 5 halogen atoms.
  • a -6 alkyl-carbonyl group is mentioned. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
  • examples of the “C 1-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, Examples include pentyloxycarbonyl and hexyloxycarbonyl.
  • examples of the “C 6-14 aryl-carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl.
  • examples of the “C 7-16 aralkyl-carbonyl group” include phenylacetyl and phenylpropionyl.
  • examples of the “5- to 14-membered aromatic heterocyclic carbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl.
  • examples of the “3- to 14-membered non-aromatic heterocyclic carbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.
  • examples of the “mono- or di-C 1-6 alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl.
  • examples of the “mono- or di-C 7-16 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.
  • examples of the “C 1-6 alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.
  • the "optionally halogenated C 1-6 alkyl sulfonyl group” for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1- 6 alkylsulfonyl group is mentioned.
  • examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl.
  • examples of the “C 6-14 arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.
  • examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, and a substituted group.
  • An optionally substituted amino group an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl ( SH) group and optionally substituted silyl group.
  • examples of the “hydrocarbon group” include, for example, a C 1-6 alkyl group, a C 2-6 alkenyl group, Examples thereof include a C 2-6 alkynyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group, and a C 7-16 aralkyl group.
  • examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group which may have a substituent selected from the following substituent group A.
  • substituent group A (1) a halogen atom, (2) Nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionally halogenated C 1-6 alkoxy group, (7) C 6-14 aryloxy group (eg, phenoxy, naphthoxy), (8) C 7-16 aralkyloxy group (eg, benzyloxy), (9) 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy), (10) 3 to 14-membered non-aromatic heterocyclic oxy group (eg, morpholinyloxy, piperidinyloxy), (11) C 1-6 alkyl-carbonyloxy group (eg, acetoxy, propanoyloxy), (12) C 6-14 aryl-carbony
  • the number of the substituents in the “optionally substituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
  • examples of the “heterocyclic group” include, for example, a nitrogen atom, a sulfur atom and a ring atom other than a carbon atom.
  • an aromatic heterocyclic group (ii) a non-aromatic heterocyclic group, and (iii) a 7 to 10-membered heterocyclic bridge group each containing 1 to 4 heteroatoms selected from oxygen atoms .
  • the “aromatic heterocyclic group” (including the “5- to 14-membered aromatic heterocyclic group”) is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing 1 to 4 heteroatoms is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing 1 to 4 heteroatoms is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • Suitable examples of the “aromatic heterocyclic group” include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1 5-, 6-membered monocyclic aromatic heterocyclic groups such as 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl; Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyri
  • non-aromatic heterocyclic group examples include, for example, a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom 3 to 14-membered (preferably 4 to 10-membered) non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from Suitable examples of the “non-aromatic heterocyclic group” include aziridinyl, oxiranyl, thiylyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolidinyl, pyra
  • preferable examples of the “7 to 10-membered heterocyclic bridged ring group” include quinuclidinyl and 7-azabicyclo [2.2.1] heptanyl.
  • examples of the “nitrogen-containing heterocyclic group” include those containing at least one nitrogen atom as a ring-constituting atom among the “heterocyclic groups”.
  • examples of the “optionally substituted heterocyclic group” include a heterocyclic group which may have a substituent selected from the substituent group A described above.
  • the number of substituents in the “optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
  • acyl group is, for example, “1 selected from a halogen atom, an optionally halogenated C 1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, and a carbamoyl group.
  • the “acyl group” also includes a hydrocarbon-sulfonyl group, a heterocyclic-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclic-sulfinyl group.
  • the hydrocarbon-sulfonyl group is a sulfonyl group to which a hydrocarbon group is bonded
  • the heterocyclic-sulfonyl group is a sulfonyl group to which a heterocyclic group is bonded
  • the hydrocarbon-sulfinyl group is a hydrocarbon group.
  • a sulfinyl group to which is bonded and a heterocyclic-sulfinyl group mean a sulfinyl group to which a heterocyclic group is bonded.
  • the “acyl group” a formyl group, a carboxy group, a C 1-6 alkyl-carbonyl group, a C 2-6 alkenyl-carbonyl group (eg, crotonoyl), a C 3-10 cycloalkyl-carbonyl group ( Examples, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 cycloalkenyl-carbonyl group (eg, 2-cyclohexenecarbonyl), C 6-14 aryl-carbonyl group, C 7-16 aralkyl- Carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered
  • Diallylcarbamoyl mono- or di-C 3-10 cycloalkyl-carbamoyl group (eg, cyclopropylcarbamoyl), mono- or di-C 6-14 aryl-carbamoyl group (eg, phenylcarbamoyl), mono- or Di-C 7-16 aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1-6 alkyl-thiocarbamoyl group (eg, methylthio) Carbamoyl, N-ethyl-N-methyl Okarubamoiru), mono - or di -C 2-6 alkenyl - thiocarbamoyl group (e.g., diallyl thio carbamoyl), mono - or di cycl
  • examples of the “optionally substituted amino group” include, for example, a “C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A” C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7 -16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl Groups, mono- or di-C 1-6 alkyl-carbamoyl groups, mono- or di-C 7-16 aralkyl-carbamoyl groups, C 1-6 alkylsulfonyl groups and C 6- And an amino
  • Suitable examples of the optionally substituted amino group include an amino group, a mono- or di- (optionally halogenated C 1-6 alkyl) amino group (eg, methylamino, trifluoromethylamino, Dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 alkenylamino groups (eg, diallylamino), mono- or di-C 3-10 cycloalkylamino groups (eg, Cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 arylamino group (eg, phenylamino), mono- or di-C 7-16 aralkylamino group (eg, benzylamino, dibenzylamino), mono - or di - (optionally halogenated C 1-6 alkyl) - carbonyl amino group (e.g., a Chiru
  • examples of the “optionally substituted carbamoyl group” include, for example, a “C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A” C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7 -16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di -C 1-6 alkyl - carbamoyl group and mono- - or di -C 7-16 aralkyl - 1 or 2 substituents selected from a carbamoyl group
  • Suitable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C 1-6 alkyl-carbamoyl group, a mono- or di-C 2-6 alkenyl-carbamoyl group (eg, diallylcarbamoyl group).
  • Mono- or di-C 3-10 cycloalkyl-carbamoyl groups eg cyclopropylcarbamoyl, cyclohexylcarbamoyl
  • mono- or di-C 6-14 aryl-carbamoyl groups eg phenylcarbamoyl
  • mono- or Di-C 7-16 aralkyl-carbamoyl group mono- or di-C 1-6 alkyl-carbonyl-carbamoyl group (eg acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 aryl-carbonyl-carbamoyl Groups (eg, benzoylcarbamoyl)
  • a 5- to 14-membered aromatic heterocyclic carbamoyl group eg, pyridylcarbamoyl
  • pyridylcarbamoyl pyridylcarb
  • examples of the “optionally substituted thiocarbamoyl group” include, for example, “C 1-6 alkyl each optionally having 1 to 3 substituents selected from Substituent Group A” Group, C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7-16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di -C 1-6 alkyl - carbamoyl group and mono- - or di -C 7-16 aralkyl - one or two location selected from a carbamoyl
  • thiocarbamoyl group which may be substituted include a thiocarbamoyl group, a mono- or di-C 1-6 alkyl-thiocarbamoyl group (eg, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthio).
  • examples of the “optionally substituted sulfamoyl group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”.
  • the optionally substituted sulfamoyl group include sulfamoyl group, mono- or di-C 1-6 alkyl-sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethyl).
  • examples of the “optionally substituted hydroxy group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”.
  • Suitable examples of the optionally substituted hydroxy group include a hydroxy group, a C 1-6 alkoxy group, a C 2-6 alkenyloxy group (eg, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy).
  • C 3-10 cycloalkyloxy group eg, cyclohexyloxy
  • C 6-14 aryloxy group eg, phenoxy, naphthyloxy
  • C 7-16 aralkyloxy group eg, benzyloxy, phenethyloxy
  • C 1-6 alkyl-carbonyloxy group eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy
  • C 6-14 aryl-carbonyloxy group eg, benzoyloxy
  • C 7-16 aralkyl- A carbonyloxy group eg benzylcarbonyloxy)
  • 5 to 14-membered aromatic heterocyclic carbonyloxy group e.g., nicotinoyl oxy
  • 3 to 14-membered non-aromatic heterocyclic carbonyloxy group e.g., piperidinylcarbonyl oxy
  • examples of the “optionally substituted sulfanyl group” include a “C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A”.
  • C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group and 5 to Examples thereof include a sulfanyl group optionally having a substituent selected from a 14-membered aromatic heterocyclic group and a halogenated sulfanyl group.
  • the optionally substituted sulfanyl group include a sulfanyl (—SH) group, a C 1-6 alkylthio group, a C 2-6 alkenylthio group (eg, allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10 cycloalkylthio group (eg, cyclohexylthio), C 6-14 arylthio group (eg, phenylthio, naphthylthio), C 7-16 aralkylthio group (eg, benzylthio, phenethylthio), C 1-6 alkyl-carbonylthio group (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 aryl-carbonylthio group (eg, benzoylthio), 5-
  • examples of the “optionally substituted silyl group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”
  • a silyl group optionally having 1 to 3 substituents selected from a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group and a C 7-16 aralkyl group ” Can be mentioned.
  • Preferable examples of the optionally substituted silyl group include a tri-C 1-6 alkylsilyl group (eg, trimethylsilyl, tert-butyl (dimethyl) silyl).
  • examples of the “hydrocarbon ring” include a C 6-14 aromatic hydrocarbon ring, a C 3-10 cycloalkane, and a C 3-10 cycloalkene.
  • examples of the “C 6-14 aromatic hydrocarbon ring” include benzene and naphthalene.
  • examples of “C 3-10 cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.
  • examples of “C 3-10 cycloalkene” include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene.
  • examples of the “heterocycle” include aromatic heterocycles each containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom. Non-aromatic heterocycles may be mentioned.
  • the “aromatic heterocycle” is, for example, a 5- to 14-membered member containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom ( Preferred is a 5- to 10-membered aromatic heterocyclic ring.
  • Suitable examples of the “aromatic heterocycle” include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadi 5- to 6-membered monocyclic aromatic heterocycle such as azole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazol
  • non-aromatic heterocyclic ring is, for example, a 3 to 14 member containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom. (Preferably 4 to 10 membered) non-aromatic heterocycle.
  • non-aromatic heterocycle examples include aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline.
  • examples of the “aromatic ring” of the “optionally substituted aromatic ring” include the above “C 6-14 aromatic hydrocarbon ring” and “aromatic heterocycle”. As the above, the above-mentioned “substituent” can be mentioned.
  • Ring A represents an aromatic ring which may be further substituted.
  • the “aromatic ring” of the “optionally substituted aromatic ring” represented by ring A includes a C 6-10 aromatic hydrocarbon ring (eg, benzene ring, naphthalene ring), other than carbon atoms as ring constituent atoms 5- to 10-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom (for example, thiophene ring, pyrazole ring, pyridine ring, pyrimidine ring, benzothiophene ring, Benzofuran ring, pyrrolopyridine ring, indole ring, isoquinoline ring, quinoline ring) and the like.
  • the “aromatic ring” of the “optionally substituted aromatic ring” represented by ring A may have 1 to 3 (preferably 1 or 2) substituents at substitutable positions.
  • substituents include (1) halogen atoms (eg, fluorine atoms, chlorine atoms), (2) cyano groups, (3) optionally substituted C 1-6 alkyl groups (eg, methyl, isopropyl) , Tert-butyl), (4) an optionally substituted C 1-6 alkoxy group (eg, methoxy), (5) a mono- or di-C 1-6 alkylamino group (eg, dimethylamino), ( 6) C 1-6 alkyl-carbonylamino group (eg, acetylamino), (7) C 1-6 alkylsulfonyl group (eg, methylsulfonyl) and the like.
  • each substituent may be the same or different.
  • Ring A is preferably substituted with (1) a halogen atom (eg, fluorine atom, chlorine atom), (2) a cyano group, (3) 1 to 3 halogen atoms (eg, fluorine atom).
  • a good C 1-6 alkyl group eg, methyl, isopropyl, tert-butyl
  • a C 1-6 alkoxy group eg, optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom)) , Methoxy
  • mono- or di-C 1-6 alkylamino groups eg, dimethylamino
  • (6) C 1-6 alkyl-carbonylamino groups eg, acetylamino
  • C 1 -6 alkylsulfonyl group e.g., methylsulfonyl
  • 3 preferably 1 or 2
  • Ring A is more preferably further substituted with 1 to 3 (preferably 1 or 2) substituents selected from (1) a cyano group and (2) a C 1-6 alkyl-carbonylamino group, respectively. It may be a benzene ring or a pyridine ring. Ring A is more preferably a benzene ring which may be further substituted with 1 to 3 (preferably 1 or 2) cyano groups.
  • R 1 represents a hydrogen atom, a cyano group, a C 1-6 alkoxy-carbonyl group or a carbamoyl group.
  • R 1 is preferably a hydrogen atom.
  • R 2 represents a hydrogen atom, a cyano group, a carboxy group, a C 1-6 alkoxy-carbonyl group, a carbamoyl group or a 5- to 6-membered monocyclic aromatic heterocyclic group.
  • Examples of the “5- to 6-membered monocyclic aromatic heterocyclic group” represented by R 2 include imidazolyl and the like.
  • R 2 is preferably a hydrogen atom, a cyano group, a carboxy group, a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl), a carbamoyl group or imidazolyl.
  • R 2 is more preferably a hydrogen atom or a carbamoyl group, and even more preferably a carbamoyl group.
  • Ring A is (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) cyano group, (3) 1 to 3 halogen atoms (e.g., fluorine atom) optionally C 1 optionally substituted with -6 alkyl group (eg, methyl, isopropyl, tert-butyl), (4) C 1-6 alkoxy group (eg, methoxy) optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom) , (5) mono- or di-C 1-6 alkylamino groups (eg dimethylamino), (6) C 1-6 alkyl-carbonylamino groups (eg acetylamino) and (7) C 1-6 alkyl A benzene ring, naphthalene ring, thiophene ring, pyrazole, each of which may be further substituted with 1 to 3
  • a halogen atom e.g., fluorine
  • R 2 is a hydrogen atom, a cyano group, a carboxy group, a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl), a carbamoyl group or imidazolyl.
  • R 2 is a hydrogen atom, a cyano group, a carboxy group, a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl), a carbamoyl group or imidazolyl.
  • Ring A may be further substituted with 1 to 3 (preferably 1 or 2) substituents selected from (1) a cyano group and (2) a C 1-6 alkyl-carbonylamino group, A benzene ring or a pyridine ring; R 1 is a hydrogen atom; R 2 is a hydrogen atom or a carbamoyl group, Compound (I).
  • Ring A is a benzene ring which may be further substituted with 1 to 3 (preferably 1 or 2) cyano groups; R 1 is a hydrogen atom; R 2 is a carbamoyl group, Compound (I).
  • compound (I) include the compounds of Examples 1 to 38 and 40 to 126 described later.
  • examples of such a salt include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, and a basic or acidic amino acid.
  • examples include salt.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt.
  • the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, And salts with dicyclohexylamine and N, N-dibenzylethylenediamine.
  • salt with inorganic acid include salts with hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid and phosphoric acid.
  • salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid And salts with p-toluenesulfonic acid.
  • salts with basic amino acids include salts with arginine, lysine and ornithine.
  • salt with acidic amino acid include salts with aspartic acid and glutamic acid.
  • Pharmaceutically acceptable salts include, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or the like when the compound has a basic functional group; or acetic acid, phthalic acid And salts with organic acids such as fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or the like when the compound has a basic functional group
  • acetic acid phthalic acid
  • salts with organic acids such as fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.) An ammonium salt and the like.
  • Compound (I) may be used as a prodrug.
  • a prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. Or a compound that undergoes hydrolysis or the like by gastric acid or the like and changes to compound (I).
  • Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated or phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation or tert-butylated compounds); compounds Compounds in which the hydroxy group of (I) is acylated, alkylated, phosphorylated or borated (eg, the hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, Alanylated or dimethylaminomethylcarbonylated compounds); compounds of compound (I)
  • the prodrug of compound (I) changes to compound (I) under physiological conditions as described in Yodogawa Shoten 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163 to 198. It may be.
  • the prodrug may form a salt, and examples of the salt include those exemplified as the salt in compound (I).
  • Compound (I) may be labeled with an isotope (eg, 3 H, 13 C, 14 C, 18 F, 35 S, 125 I) or the like.
  • Compound (I) labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) used in Positron Emission Tomography (PET), and is useful in fields such as medical diagnosis. It is expected.
  • PET tracer Positron Emission Tomography
  • compound (I) may be a hydrate, a non-hydrate, a solvate or a solvate.
  • a deuterium converter obtained by converting 1 H into 2 H (D) is also encompassed in compound (I).
  • Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture.
  • the crystal can be produced according to a crystallization method known per se.
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each with different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • isomers such as enantiomers or diastereomers may exist. All such isomers and mixtures thereof are included within the scope of the present invention. In addition, isomers due to conformation or tautomerism may be produced, and such isomers or mixtures thereof are also included in the compound (I) of the present invention.
  • the raw materials and reagents used in each step in the following production method and the obtained compound may each form a salt.
  • Examples of such salts include those similar to the salts of the aforementioned compound of the present invention.
  • the compound obtained in each step is a free compound, it can be converted into a target salt by a method known per se.
  • the compound obtained in each step is a salt, it can be converted into a free form or other types of desired salts by a method known per se.
  • the compound obtained in each step remains in the reaction solution or is obtained as a crude product and can be used in the next reaction.
  • the compound obtained in each step is concentrated from the reaction mixture according to a conventional method. , Crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography and the like, and can be isolated and / or purified.
  • the reaction time may vary depending on the reagent and solvent to be used, but unless otherwise specified, is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.
  • the reaction temperature may vary depending on the reagent and solvent to be used, but is usually ⁇ 78 ° C. to 300 ° C., preferably ⁇ 78 ° C. to 150 ° C. unless otherwise specified.
  • the pressure may vary depending on the reagent and solvent used, but unless otherwise specified, is usually 1 to 20 atmospheres, preferably 1 to 3 atmospheres.
  • a Microwave synthesizer such as an initiator manufactured by Biotage may be used.
  • the reaction temperature may vary depending on the reagent and solvent to be used, but unless otherwise specified, is usually room temperature to 300 ° C., preferably 50 ° C. to 250 ° C.
  • the reaction time may vary depending on the reagent and solvent to be used, but unless otherwise specified, is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.
  • the reagent is used in an amount of 0.5 equivalent to 20 equivalents, preferably 0.8 equivalent to 5 equivalents, relative to the substrate.
  • the reagent is used in an amount of 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate.
  • the reagent also serves as a reaction solvent, the amount of solvent is used as the reagent.
  • these reactions are performed without solvent or dissolved or suspended in a suitable solvent.
  • the solvent include the solvents described in the examples or the following.
  • Alcohols methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, 2-methyl-2-butanol, etc .
  • Ethers diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc .
  • Aromatic hydrocarbons chlorobenzene, toluene, xylene, etc .
  • Saturated hydrocarbons cyclohexane, hexane, etc .
  • Amides N, N-dimethylformamide, N-methylpyrrolidone, etc .
  • Halogenated hydrocarbons dichloromethane, carbon tetrachloride, etc .
  • Nitriles acetonitrile, etc.
  • Sulfoxides dimethyl sulfoxide and the like; Aromatic organic bases: pyridine, etc .; Acid anhydrides: acetic anhydride, etc .; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc .; Inorganic acids: hydrochloric acid, sulfuric acid, etc .; Esters: ethyl acetate and the like; Ketones: acetone, methyl ethyl ketone, etc .; water. Two or more of the above solvents may be mixed and used at an appropriate ratio.
  • Inorganic bases sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, etc .
  • Organic bases triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0]- 7-undecene, imidazole, piperidine, N, N-diisopropylethylamine and the like;
  • Metal alkoxides sodium ethoxide, potassium tert-butoxide and the like;
  • Alkali metal hydrides sodium hydride, etc .;
  • Metal amides sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc .
  • Organic lithiums n
  • an acid or an acidic catalyst is used in the reaction in each step, for example, the following acids and acidic catalysts, or acids and acidic catalysts described in the examples are used.
  • Inorganic acids hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc .
  • Organic acids acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc .
  • Lewis acid boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like.
  • reaction in each step is a method known per se, for example, the 5th edition Experimental Chemistry Course, Volumes 13 to 19 (Edited by The Chemical Society of Japan); New Experimental Chemistry Course, Volumes 14 to 15 (Japan) Chemistry Association); Fine Organic Chemistry Revised 2nd Edition (LF Tietze, Th. Eicher, Nanedo); Revised Organic Name Reaction, its mechanism and points (by Hideo Togo, Kodansha); ORGANIC SYNTHES Collective Volume I-VII ( John Wiley & Sons Inc); Modern Organic Synthesis in the Laboratory A Collection of Standard Exploratory Procedures (Jie Jack Li, UFFOR by JJFORD) VERSITY publication); Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol.
  • the protection or deprotection reaction of the functional group is carried out according to a method known per se, for example, “Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M., et al., Wiley-Interscience). The method described in Thimeme's 2004 “Protecting Groups 3rd Ed.” (By PJ Kocienski) or the like, or the method described in the examples.
  • protecting groups for hydroxyl groups such as alcohol and phenolic hydroxyl groups
  • ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether and tetrahydropyranyl ether
  • carboxylate-type protecting groups such as acetate Sulfonic acid ester type protecting groups such as methanesulfonic acid ester
  • carbonate ester type protecting groups such as tert-butyl carbonate.
  • the protecting group for the carbonyl group of the aldehyde include an acetal-type protecting group such as dimethylacetal; and a cyclic acetal-type protecting group such as 1,3-dioxane.
  • Examples of the protecting group for the carbonyl group of the ketone include a ketal-type protecting group such as dimethyl ketal; a cyclic ketal-type protecting group such as 1,3-dioxane; an oxime-type protecting group such as O-methyloxime; and N, N-dimethyl And hydrazone-type protecting groups such as hydrazone.
  • Examples of the protecting group for the carboxy group include ester-type protecting groups such as methyl ester; amide-type protecting groups such as N, N-dimethylamide.
  • thiol-protecting group examples include ether-type protecting groups such as benzylthioether; ester-type protecting groups such as thioacetate ester, thiocarbonate, and thiocarbamate.
  • protecting groups for amino groups and aromatic heterocycles such as imidazole, pyrrole and indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; alkylamines such as N-triphenylmethylamine Type protecting groups, and sulfonamide type protecting groups such as methanesulfonamide.
  • the protecting group can be removed by a method known per se, for example, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (for example, trimethylsilyl iodide). And trimethylsilyl bromide) or a reduction method.
  • a method known per se for example, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (for example, trimethylsilyl iodide). And trimethylsilyl bromide) or a reduction method.
  • the reducing agent used is lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride
  • Metal hydrides such as hydrogenated triacetoxyboron tetramethylammonium; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid;
  • a catalyst such as palladium-carbon or a Lindlar catalyst.
  • the oxidizing agent used includes peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, tert-butyl hydroperoxide; tetrabutylammonium perchlorate, etc.
  • mCPBA m-chloroperbenzoic acid
  • hydrogen peroxide hydrogen peroxide
  • tert-butyl hydroperoxide hydrogen peroxide
  • tetrabutylammonium perchlorate etc.
  • Perchlorates such as sodium chlorate; Chlorites such as sodium chlorite; Periodic acids such as sodium periodate; High-valent iodine reagents such as iodosylbenzene; Manganese dioxide; Reagents having manganese such as potassium manganate; Leads such as lead tetraacetate; Reagents having chromium such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent; N-bromosuccinimide (NBS) Halogen compounds such as oxygen; ozone; sulfur trioxide / pyridine complex; tetraacid Osmium; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.
  • PCC pyridinium chlorochromate
  • PDC pyridinium dichromate
  • NBS N-bromosuccinimide
  • the radical initiator used is an azo compound such as azobisisobutyronitrile (AIBN); 4-4′-azobis-4-cyanopentanoic acid (ACPA) Water-soluble radical initiators such as triethylboron in the presence of air or oxygen, and benzoyl peroxide.
  • AIBN azobisisobutyronitrile
  • ACPA 4-4′-azobis-4-cyanopentanoic acid
  • Water-soluble radical initiators such as triethylboron in the presence of air or oxygen, and benzoyl peroxide.
  • the radical reaction reagent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium iodide.
  • Examples of Wittig reagents used include alkylidene phosphoranes.
  • the alkylidene phosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.
  • the reagents used include phosphonoacetate esters such as methyl dimethylphosphonoacetate and ethyl ethyl diethylphosphonoacetate; bases such as alkali metal hydrides and organolithiums Can be mentioned.
  • a reagent used includes a combination of a Lewis acid and an acid chloride, or a Lewis acid and an alkylating agent (eg, alkyl halides, alcohols, olefins, etc.).
  • a Lewis acid and an acid chloride or a Lewis acid and an alkylating agent (eg, alkyl halides, alcohols, olefins, etc.).
  • an organic acid or an inorganic acid can be used in place of the Lewis acid
  • an acid anhydride such as acetic anhydride can be used in place of the acid chloride.
  • a nucleophile eg, amines, imidazole, etc.
  • a base eg, organic bases, etc.
  • a nucleophilic addition reaction with a carbanion In each step, a nucleophilic addition reaction with a carbanion, a nucleophilic 1,4-addition reaction with a carbanion (Michael addition reaction), or a nucleophilic substitution reaction with a carbanion, a base used to generate a carbanion Examples thereof include organic lithiums, metal alkoxides, inorganic bases, and organic bases.
  • examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide; alkylmagnesium halides such as methylmagnesium bromide.
  • the Grignard reagent can be prepared by a method known per se, for example, by reacting alkyl halide or aryl halide with metal magnesium using ether or tetrahydrofuran as a solvent.
  • reagents include an active methylene compound (eg, malonic acid, diethyl malonate, malononitrile, etc.) sandwiched between two electron-withdrawing groups and a base (eg, organic bases, Metal alkoxides and inorganic bases) are used.
  • active methylene compound eg, malonic acid, diethyl malonate, malononitrile, etc.
  • a base eg, organic bases, Metal alkoxides and inorganic bases
  • phosphoryl chloride and an amide derivative eg, N, N-dimethylformamide, etc.
  • examples of the azidation agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, and sodium azide.
  • DPPA diphenylphosphoryl azide
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
  • examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like.
  • examples of the carbonyl compound used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone.
  • examples of amines used include primary amines such as ammonia and methylamine; secondary amines such as dimethylamine and the like.
  • azodicarboxylic acid esters eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.
  • triphenylphosphine eg, triphenylphosphine
  • the reagents used include acyl halides such as acid chloride and acid bromide; acid anhydrides, active ester compounds, and sulfate ester compounds. And activated carboxylic acids.
  • carboxylic acid activators include carbodiimide condensing agents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD); 4- (4,6-dimethoxy-1,3,5- Triazine condensing agents such as triazin-2-yl) -4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenyl Azide phosphate (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukayama reagent); thionyl chloride; haloformates such as ethyl chloroformate Lower alkyl; O- (7-azabenzotriazol-1-yl) -N, N, N ′, N
  • additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) may be further added to the reaction.
  • HOBt 1-hydroxybenzotriazole
  • HOSu N-hydroxysuccinimide
  • DMAP dimethylaminopyridine
  • the metal catalyst used is palladium acetate (II), tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethyl).
  • Palladium compounds such as phosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride; tetrakis (triphenylphosphine) nickel (0 Nickel compounds such as tris (triphenylphosphine) rhodium (III) chloride; cobalt compounds; copper compounds such as copper oxide and copper (I) iodide; platinum compounds and the like.
  • a base may be added to the reaction, and examples of such a base include inorganic bases.
  • diphosphorus pentasulfide is typically used as the thiocarbonylating agent.
  • 2,4-bis (4-methoxyphenyl) is used.
  • Reagents having 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure such as -1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson reagent) May be used.
  • halogenating agents used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. Is mentioned.
  • the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.
  • the halogenating agent used is an acid halide of hydrohalic acid and an inorganic acid.
  • bromination such as phosphorus chloride include 48% hydrobromic acid.
  • a method of obtaining an alkyl halide from alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide may be used.
  • a method of synthesizing an alkyl halide through a two-step reaction in which an alcohol is converted into a sulfonate ester and then reacted with lithium bromide, lithium chloride, or sodium iodide may be used.
  • examples of the reagent used include alkyl halides such as ethyl bromoacetate; phosphites such as triethyl phosphite and tri (isopropyl) phosphite.
  • examples of the sulfonylating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic acid anhydride, and p-toluenesulfonic acid anhydride.
  • each step when a hydrolysis reaction is performed, an acid or a base is used as a reagent.
  • acid hydrolysis reaction of tert-butyl ester is performed, formic acid or triethylsilane may be added to reductively trap tert-butyl cations produced as a by-product.
  • examples of the dehydrating agent used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N, N'-dicyclohexylcarbodiimide, alumina, and polyphosphoric acid.
  • Compound (I) can be produced, for example, from compound (2) by the following method.
  • B (OR) 2 represents boronic acid or a boronic acid ester. That is, R independently represents a hydrogen atom or a C 1-6 alkyl group, or a boron-containing heterocyclic ring (eg, dioxaborolane or dioxaborinane substituted with four methyl groups) together with adjacent oxygen and boron atoms.
  • R independently represents a hydrogen atom or a C 1-6 alkyl group, or a boron-containing heterocyclic ring (eg, dioxaborolane or dioxaborinane substituted with four methyl groups) together with adjacent oxygen and boron atoms.
  • the boronic acid ester include boronic acid pinacolate.
  • rings A, R 1 and R 2 can be used in the usual organic reactions such as halogenation reaction, acylation reaction, sulfonylation reaction, alkylation reaction, hydrolysis reaction, Use amination reaction, amidation reaction, esterification reaction, etherification reaction, oxidation reaction, reduction reaction, protection reaction, deprotection reaction, coupling reaction, addition reaction, elimination reaction, substitution reaction alone or in combination. Can be converted.
  • Compound (2) and compound (3) used as raw materials when producing compound (I) can be produced by a method known per se.
  • the functional group in the molecule can be converted to the target functional group by combining a chemical reaction known per se.
  • the chemical reaction include an oxidation reaction, a reduction reaction, an alkylation reaction, an acylation reaction, a urealation reaction, a hydrolysis reaction, an amination reaction, an esterification reaction, an aryl coupling reaction, and a deprotection reaction.
  • Compound (I) obtained by the above production method can be isolated and purified by known means, for example, solvent extraction, pH conversion of a solution, phase transfer, crystallization, recrystallization, and chromatography.
  • compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and are synthesized by a known synthesis method and separation method, respectively. Can be obtained as a single product.
  • compound (I) has an optical isomer
  • the optical isomer resolved from the compound is also encompassed in compound (I).
  • the optical isomer can be produced by a method known per se.
  • the optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.
  • a method known per se for example, fractional recrystallization method, chiral column method, diastereomer method and the like are used.
  • Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, ( ⁇ )-1-phenethylamine, cinchonine, ( ⁇ )-cinchonidine, brucine, etc.
  • Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, ( ⁇ )-1-phenethylamine, cinchonine, ( ⁇ )-cinchonidine, brucine, etc.
  • Chiral column method A method in which a racemate or a salt thereof is separated by applying to an optical isomer separation column (chiral column).
  • an optical isomer separation column chiral column
  • a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series manufactured by Daicel Corporation, and water, various buffers (eg, phosphate buffer),
  • Optical isomers are separated by developing an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) as a single or mixed solution.
  • an organic solvent eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.
  • Diastereomer method A mixture of racemates is converted into a mixture of diastereomers by chemical reaction with an optically active reagent, and this mixture is converted into a single mixture through ordinary separation means (for example, fractional recrystallization method, chromatography method, etc.).
  • the compound (I) when the compound (I) has a hydroxyl group or a primary or secondary amino group in the molecule, the compound and an optically active organic acid (for example, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid], ( ⁇ )-Menthoxyacetic acid and the like) are subjected to a condensation reaction to give ester or amide diastereomers, respectively.
  • an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
  • compound (I) When compound (I) is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely when it is obtained as a salt, it is known per se. It can be converted into a free form or other desired salt by the method or a method analogous thereto.
  • Compound (I) can be used as a preventive or therapeutic agent for various diseases described below for mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.). obtain.
  • Compound (I) is, for example, (1) Inflammatory diseases (eg, acute pancreatitis, chronic pancreatitis, asthma, bronchial asthma, adult dyspnea syndrome, chronic obstructive pulmonary disease (COPD), inflammatory bone disease, inflammatory lung disease, celiac disease, hepatitis, Systemic inflammatory response syndrome (SIRS), inflammation after surgery or trauma, pneumonia, nephritis, meningitis, cystitis, sore throat, gastric mucosal damage, spondylitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, Pulmonary sarcoidosis), (2) Autoimmune diseases (eg, psoriasis, rheumatoi
  • the compound (I) of the present invention is particularly useful for the prevention / treatment of rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus or Alzheimer's disease It may be useful as an agent.
  • the compound (I) of the present invention can be expected to have an excellent therapeutic effect on the above diseases based on an excellent BET family protein inhibitory activity and action.
  • Compound (I) has excellent solubility in water, the second liquid of the Japanese Pharmacopoeia Dissolution Test, or the second liquid of the Japanese Pharmacopoeia Disintegration Test, and has pharmacokinetics (eg, blood drug half-life, intracerebral transitivity, metabolic stability) Excellent in sex and CYP inhibition) and low in toxicity (eg, acute, chronic, genotoxic, reproductive, cardiotoxicity, drug interaction, carcinogenicity, phototoxicity, etc.) ), And excellent properties as a pharmaceutical product with few side effects, etc., so that it is orally administered to mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.) Or can be safely administered parenterally.
  • mammals eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.
  • the dose of compound (I) may vary depending on the subject of administration, administration route, and symptoms, and is not particularly limited.
  • Compound (I) when orally administered to an adult patient (adult, body weight 40 to 80 kg, eg 60 kg) of each of the above diseases, Compound (I) can be administered, for example, at 0.001 to 1000 mg / kg body weight per day, preferably 0.01 to 100 mg / kg body weight per day, more preferably 0.1 to 10 mg / kg body weight per day. obtain. This amount can be administered in 1 to 3 divided doses per day.
  • a pharmaceutical comprising compound (I) is a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia). Etc.), compound (I) can be used alone or as a pharmaceutical composition in which compound (I) and a pharmacologically acceptable carrier are mixed.
  • various organic or inorganic carriers commonly used as starting materials can be used.
  • excipients lubricants, binders and disintegrants
  • liquid preparations solvents, solubilizers, suspending agents, isotonic agents, buffering agents, And soothing agents may be used.
  • formulation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
  • excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light
  • excipients include anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate.
  • lubricant examples include magnesium stearate, calcium stearate, talc and colloidal silica.
  • Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples include propylmethylcellulose and polyvinylpyrrolidone.
  • disintegrant examples include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.
  • Suitable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Is mentioned.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone , Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate
  • polyvinyl alcohol, polyvinylpyrrolidone Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
  • Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.
  • buffer solutions of phosphate, acetate, carbonate, citrate and the like Preferable examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • a preferred example of the soothing agent is benzyl alcohol.
  • Preferable examples of the preservative include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.
  • Preferable examples of the antioxidant include sulfite and ascorbate.
  • the colorant examples include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (Eg, the aluminum salt of the water-soluble edible tar dye) and natural dyes (eg, ⁇ -carotene, chlorophyll, bengara).
  • water-soluble edible tar dyes eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.
  • water-insoluble lake dyes Eg, the aluminum salt of the water-soluble edible tar dye
  • natural dyes eg, ⁇ -carotene, chlorophyll, bengara
  • Suitable examples of sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.
  • Examples of the pharmaceutical dosage form of the present invention include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules).
  • films eg, oral disintegrating films, oral mucosal film
  • injections eg,
  • compositions can be controlled-release preparations such as immediate-release preparations or sustained-release preparations (eg, sustained-release microcapsules).
  • the content of compound (I) varies depending on the form of the preparation, but is usually 0.01 to 100% by weight, preferably 0 as the amount of compound (I) relative to the whole preparation (the whole medicament). About 1 to 50% by weight, more preferably about 0.5 to 20% by weight.
  • coating may be performed for the purpose of taste masking, enteric properties or sustainability.
  • coating base used for coating examples include sugar coating base, water-soluble film coating base, enteric film coating base and sustained-release film coating base.
  • sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan and carnauba wax can be used in combination.
  • water-soluble film coating base examples include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name) ], Synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan.
  • enteric film coating bases include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name) ] Acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)]; natural products such as shellac.
  • cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate
  • methacrylic acid copolymer L (Eudragit L (trade name) ]
  • Acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer
  • sustained-release film coating base examples include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit Acrylic polymer such as NE (trade name)].
  • cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit Acrylic polymer such as NE (trade name)].
  • the above-mentioned coating bases may be used by mixing two or more of them in an appropriate ratio.
  • a light-shielding agent such as titanium oxide or iron sesquioxide can be used.
  • compound (I) When compound (I) is applied to each of the above-mentioned diseases, it can be appropriately used in combination with a drug or therapeutic method usually used for those diseases.
  • a drug that can be used in combination with compound (I) include, for example, an acetylcholinesterase inhibitor (eg, donepezil, rivastigmine, galantamine, zanapezil), an antidementia drug (eg, Memantine), ⁇ amyloid protein production, secretion, accumulation, aggregation and / or deposition inhibitor, ⁇ secretase inhibitor (eg, 6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl ] Tetralin, 6- (4-biphenylyl) methoxy-2- (N, N-dimethylamino) methyltetralin, 6- (4-biphenylyl) methoxy-2-
  • Compound (I) can also be used in combination with a method for transplanting neural stem cells, neural progenitor cells or fetal neural tissue prepared from embryonic stem cells and neural tissue, and such agents as immunosuppressants after such transplantation.
  • concomitant drugs include the following. Diabetes treatment agent, diabetic complication treatment agent, hyperlipidemia treatment agent, antihypertensive agent, anti-obesity agent, diuretic agent, chemotherapeutic agent, immunotherapy agent, antithrombotic agent, cachexia improving agent, anti-inflammatory agent, Antacids, stomachic drugs, digestive drugs, intestinal drugs, antidiarrheals, analgesics and antispasmodics, antipyretic analgesics, central nervous stimulants, sedatives, antihistamines, anti-cytokine drugs, antitussives, expectorants, bronchodilators Anti-acetylcholine, vitamins, metabolic components, herbal medicines and herbal extracts, analgesics, anticonvulsants, etc.
  • Two or more of the above concomitant drugs can be used in combination at an appropriate ratio.
  • the amount of each other agent can be reduced within a safe range in consideration of the opposite effect of those agents. Thus, the adverse effects that would be caused by these agents can be safely prevented.
  • Compound (I) can be used in combination with non-drug therapy.
  • non-drug therapy (1) surgery; (2) pressor chemotherapy using angiotensin II or the like; (3) gene therapy; (4) hyperthermia; (5) cryotherapy; (6) (7) Radiotherapy; (8) Immunotherapy; (9) Regenerative medicine; (10) Cell therapy; (11) Artificial organs; (12) Psychotherapy or psychosocial therapy; (13) Exercise therapy or physical therapy; (14) electrical stimulation therapy (eg, deep brain stimulation therapy, etc.).
  • Compound (I) By combining Compound (I) with a concomitant drug, (1) The dose can be reduced compared to the case where Compound (I) or a concomitant drug is administered alone. (2) Depending on the patient's symptoms (mild, severe, etc.), a drug to be used in combination with Compound (I) can be selected. (3) By selecting a concomitant drug having a different mechanism of action from compound (I), the treatment period can be set longer. (4) By selecting a concomitant drug having an action mechanism different from that of Compound (I), the therapeutic effect can be sustained. (5) By using the compound (I) and a concomitant drug in combination, an excellent effect such as a synergistic effect can be obtained.
  • the combined use of Compound (I) and a concomitant drug is referred to as “the concomitant drug of the present invention”.
  • the administration time of Compound (I) and the concomitant drug is not limited, and Compound (I) or a pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof are administered to an administration subject. It can be administered simultaneously, and can be administered with a time difference.
  • the dose of the concomitant drug can be appropriately selected according to the administration subject, administration route, disease, combination, etc., in accordance with the clinically used dose.
  • the administration form of the concomitant drug of the present invention is not particularly limited as long as compound (I) and the concomitant drug are combined at the time of administration.
  • Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating compound (I) and a concomitant drug, and (2) separate preparation of compound (I) and concomitant drug.
  • the concomitant drug of the present invention can be used as a pharmaceutical composition obtained by mixing Compound (I) or (and) the above concomitant drug and a pharmacologically acceptable carrier in the same manner as the drug of the present invention. .
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of Compound (I) and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • a molecular ion peak is observed, but it may be observed as a fragment ion.
  • a free molecular ion peak or a fragment ion peak is usually observed.
  • Example 1 2- (1-Acetylpiperidin-4-yl) -3-phenyl-1-benzofuran-5-carboxamide A) tert-butyl 4- (5- (methoxycarbonyl) -1-benzofuran-2-yl) piperidine-1-carboxylate tert-butyl 4-ethynylpiperidine-1-carboxylate (11.1 g) and DMF (300 ml ), Methyl 4-hydroxy-3-iodobenzoate (17.7 g), TEA (10.7 g), copper (I) iodide (1.0 g) and dichloropalladium-triphenylphosphine complex (3.7 g) at room temperature. Added in.
  • Methyl 2- (1-acetylpiperidin-4-yl) -1-benzofuran-5-carboxylate Methyl 2- (piperidin-4-yl) -1-benzofuran-5-carboxylate hydrochloride (1: 1) To a mixture of (8.5 g) and THF (150 ml), acetic anhydride (4.4 g) and TEA (8.7 g) were added at room temperature. The mixture was stirred at 60 ° C. for 2 hours under an argon atmosphere. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
  • Example 3 N- (3- (2- (1-Acetylpiperidin-4-yl) -1benzofuran-3-yl) phenyl) acetamide 1- (4- (3-bromo-1-benzofuran-2-yl) piperidine-1 -Il) ethanone (48.3 mg), 3-acetamidophenylboronic acid (41.2 mg) in dioxane (3.0 ml) -water (0.5 ml), potassium carbonate (63.6 mg), tetrakis (triphenylphosphine) palladium (0 ) (9.2 mg) was added, degassed with argon for 5 minutes, sealed and stirred at 90 ° C. for 16 hours.
  • Example 4 2- (1-Acetylpiperidin-4-yl) -3- (2-cyanophenyl) -1-benzofuran-5-carboxamide A) 2- (1-acetylpiperidin-4-yl) -3- (2-cyanophenyl) -1-benzofuran-5-carboxylic acid methyl ester 2- (1-acetylpiperidin-4-yl) -3-bromo -1-Benzofuran-5-carboxylic acid methyl ester (400 mg), (2-cyanophenyl) boronic acid (465 mg), tetrakis (triphenylphosphine) palladium (0) (40 mg), 2M aqueous potassium carbonate solution (1.05 ml) and 1,2-dimethoxyethane (5 ml) were stirred at 80 ° C.
  • Example 5 (4- (3- (Pyridin-2-yl) -1-benzofuran-2-yl) piperidin-1-yl) ethanone 1- (4- (3-Bromo-1-benzofuran-2-yl) piperidine -1-yl) ethanone (26 mg), 2-pyridinylboronic acid tri (hydroxymethyl) ethane ester lithium salt (34.2 mg), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium ( A mixture of II) (5.66 mg), copper chloride (I) (7.92 mg), cesium carbonate (65 mg) and DMF (1 ml) was stirred at 110 ° C.
  • Example compounds are shown in the following table. MS in the table indicates actual measurement.
  • the compounds of Examples 6 to 38 and 40 to 126 in the following table were produced according to the methods shown in the above Examples or a method analogous thereto.
  • Test example 1 Construction of human BRD4 expression plasmid Human BRD4 cDNA is composed of two types of Primer 5'-ATAATAGGATCCATGTCTGCGGAGAGCGGCCCT-3 '(hBRD4-BamHI-F) (SEQ ID NO: 1) and 5'-ATAATAGCGGCCGCTTAGGTGGGAGGGGGCACTGCC. It was obtained by performing PCR using -3 ′ (hBRD4-St-NotI-R1431) (SEQ ID NO: 2). PCR was performed using PrimeStar GXL DNA Polymerase (Takara Bio) (1) 98 ° C, 1 minute, (2) 98 ° C, 10 seconds, 68 ° C, 90 seconds 35 times, (3) 72 ° C, Reacted for 1 minute.
  • PrimeStar GXL DNA Polymerase (Takara Bio) (1) 98 ° C, 1 minute, (2) 98 ° C, 10 seconds, 68 ° C, 90 seconds 35 times, (3) 72 ° C, Reacted for 1 minute.
  • BRD4 bromodomain 2 protein A plasmid containing the gene sequence of hBRD4 (342-460; BRD4BD2) with GST-His tag added at the N-terminus was transformed into ECOS Competent E. coli BL21 (DE3) (Nippon Gene). An expression strain was obtained.
  • the frozen cells were suspended in Lysis buffer (50 mM Tris-HCl, 150 mM NaCl, 5 U / mL Benzonase nuclease (Novagen), 1 mM DTT) and crushed with an ultrasonic crusher sonifier (Branson).
  • Lysis buffer 50 mM Tris-HCl, 150 mM NaCl, 5 U / mL Benzonase nuclease (Novagen), 1 mM DTT
  • the disrupted solution is centrifuged for 20 minutes (15,000 rpm, 4 ° C), the supernatant is purified by NiNTA affinity chromatography, and then equilibrated with 50 mM HEPES, 150 mM NaCl, 5% Glycerol, 1 mM DTT Buffer. Gel filtration was performed with 60 Superdex 200 pg (GE healthcare).
  • the obtained purified protein was quantified with BCA protein assay kit (PIERCE) using BSA as
  • the binding activity between BRD4 and acetylated histone H4 peptide was measured by TR-FRET method.
  • the reaction solution was 50 mM HEPES (pH 7.5), 50 mM NaCl, 0.5 mM CAPS, 1 mM DTT, 0.01% BSA. After adding the test compound to the final concentration of 10 nM BRD4 bromodomain 2 (BRD4BD2), room temperature For 30 minutes.
  • Formulation Example 1 (Manufacture of capsules) 1) 30 mg of the compound of Example 1 2) Fine powder cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg 60 mg total 1), 2), 3) and 4) are mixed and filled into gelatin capsules.
  • Formulation Example 2 Manufacture of tablets
  • the compounds of the present invention may have a BET family protein inhibitory action, and may be an autoimmune disease and / or an inflammatory disease (eg, rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, inflammatory bowel disease, Sjogren Syndrome, Behcet's disease, systemic lupus erythematosus), neurodegenerative diseases (eg, Alzheimer's disease) and the like are expected to be useful as preventive or therapeutic agents.
  • an autoimmune disease and / or an inflammatory disease eg, rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, inflammatory bowel disease, Sjogren Syndrome, Behcet's disease, systemic lupus erythematosus
  • neurodegenerative diseases eg, Alzheimer's disease

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Abstract

L'invention concerne des composés qui peuvent avoir une action inhibitrice sur les protéines de la famille BET et sont supposés être utiles en tant qu'agents pour la prévention ou le traitement, par exemple, de maladies auto-immunes et/ou de maladies inflammatoires (par exemple, la polyarthrite rhumatoïde, la sclérose en plaques, la fibrose pulmonaire idiopathique, le psoriasis, la maladie inflammatoire de l'intestin, le syndrome de Sjögren, la maladie de Behçet, le lupus érythémateux systémique), de maladies neurodégénératives (par exemple la maladie d'Alzheimer), etc. L'invention concerne également un composé représenté par la formule (I) (les symboles individuels dans la formule sont décrits dans la description), et ses sels.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03264583A (ja) * 1990-03-14 1991-11-25 Dai Ichi Seiyaku Co Ltd ピペリジン誘導体及びその製造中間体
JP2005008631A (ja) * 2003-05-29 2005-01-13 New Industry Research Organization ベンゾフラン化合物、およびそれを含有してなる医薬組成物
JP2016540831A (ja) * 2013-11-18 2016-12-28 フォーマ セラピューティクス，インコーポレイテッド Ｂｅｔブロモドメイン阻害剤としてのテトラヒドロキノリン組成物
WO2017024412A1 (fr) * 2015-08-12 2017-02-16 Neomed Institute Benzimidazoles substitués, préparation et utilisation de ceux-ci en tant qu'agents pharmaceutiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03264583A (ja) * 1990-03-14 1991-11-25 Dai Ichi Seiyaku Co Ltd ピペリジン誘導体及びその製造中間体
JP2005008631A (ja) * 2003-05-29 2005-01-13 New Industry Research Organization ベンゾフラン化合物、およびそれを含有してなる医薬組成物
JP2016540831A (ja) * 2013-11-18 2016-12-28 フォーマ セラピューティクス，インコーポレイテッド Ｂｅｔブロモドメイン阻害剤としてのテトラヒドロキノリン組成物
WO2017024412A1 (fr) * 2015-08-12 2017-02-16 Neomed Institute Benzimidazoles substitués, préparation et utilisation de ceux-ci en tant qu'agents pharmaceutiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TREJO, A. ET AL.: "Design and Synthesis of 4- Azaindoles as Inhibitors of p38 MAP Kinase", JOURNAL OF MEDICINAL CHEMISTRY, vol. 46, no. 22, 19 September 2003 (2003-09-19), pages 4702 - 4713, XP009120733, DOI: doi:10.1021/jm0301787 *

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