WO2016017699A1 - Dérivé d'acide azole carboxylique - Google Patents

Dérivé d'acide azole carboxylique Download PDF

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WO2016017699A1
WO2016017699A1 PCT/JP2015/071516 JP2015071516W WO2016017699A1 WO 2016017699 A1 WO2016017699 A1 WO 2016017699A1 JP 2015071516 W JP2015071516 W JP 2015071516W WO 2016017699 A1 WO2016017699 A1 WO 2016017699A1
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methyl
carboxylic acid
thiazole
phenyl
isobutoxy
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Japanese (ja)
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旭 河名
親志 金澤
正行 寺
良昌 高橋
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Teijin Pharma Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/10—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 two hetero rings linked by a carbon chain containing aromatic 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel compound having xanthine oxidase inhibitory activity, a method for producing the same, and a xanthine oxidase inhibitor containing the compound as an active ingredient.
  • the present invention includes gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, renal diseases such as diabetic nephropathy,
  • the present invention relates to an azolecarboxylic acid derivative useful as a therapeutic or prophylactic agent for diseases involving xanthine oxidase, such as respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease or autoimmune disease.
  • Xanthine oxidase is an enzyme that catalyzes the conversion of hypoxanthine to xanthine and further to uric acid in nucleic acid metabolism.
  • xanthine oxidase inhibitors reduce uric acid synthesis by inhibiting uric acid synthesis. That is, it is effective for treating hyperuricemia and various diseases resulting therefrom.
  • pathological conditions that occur as a result of persistent hyperuricemia and deposition of urate crystals include gout arthritis called gout and gout nodules. Hyperuricemia is regarded as an important factor in lifestyle-related diseases and metabolic syndrome related to obesity, hypertension, dyslipidemia, and diabetes.
  • nephropathy, urolithiasis, cardiovascular disease It is being clarified that it is a risk factor for cancer (Japan Gout / Nucleic Acid Metabolism Society Guidelines Revision Committee, edited by “Guideline for Treatment of Hyperuricemia / Gout, Second Edition”, Medical Review, 2010).
  • xanthine oxidase inhibitors are expected to be useful for the treatment of diseases involving reactive oxygen species, for example, for the treatment of cardiovascular diseases through the effect of improving vascular function, due to the activity of inhibiting the generation of reactive oxygen species. (Circulation. 2006; 114: 2508-2516).
  • allopurinol and febuxostat are used as therapeutic agents for hyperuricemia, but allopurinol has reported side effects such as Stevens-Johnson syndrome, toxic epidermal necrosis, liver damage, and renal dysfunction (Nippon Rinsho, 2003; 61, Suppul. 1: 197-201).
  • Examples of compounds having xanthine oxidase inhibitory activity include 2-phenylthiazole derivatives (Patent Documents 1 to 3), phenylpyrazole derivatives (Patent Documents 4 to 6), and triarylcarboxylic acid derivatives (Patent Documents 7 to 10).
  • 2-phenylthiazole derivatives Patent Documents 1 to 3
  • phenylpyrazole derivatives Patent Documents 4 to 6
  • triarylcarboxylic acid derivatives Patent Documents 7 to 10
  • carboxylic acid derivatives which are central bicyclic heterocycles such as 6-indolethiazole derivatives (Patent Documents 11 and 12) and 6-indolepyrazole derivatives (Patent Document 12) have been reported.
  • Patent Document 13 and Patent Document 14 report a dithiazolecarboxylic acid derivative having a benzene ring at the center.
  • Patent Document 15 and Patent Document 16 report biphenylthiazolecarboxylic acid derivatives.
  • the problem to be solved by the present invention is to provide a novel compound having xanthine oxidase inhibitory activity. Furthermore, the subject of this invention is providing the compound which has the outstanding uric acid reduction effect
  • action. Another subject of the present invention is gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, diabetic nephropathy, etc. It is intended to provide a compound useful as a therapeutic or prophylactic agent for diseases involving xanthine oxidase, such as renal diseases, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases or autoimmune diseases.
  • diseases involving xanthine oxidase such as renal diseases, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases or autoimmune diseases.
  • the present invention was completed by finding that it has a typical xanthine oxidase inhibitory activity.
  • this azole carboxylic acid derivative is used for gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, diabetic nephropathy, etc.
  • the present invention has been completed by finding that it can be a good therapeutic or preventive drug for respiratory diseases such as kidney disease, chronic obstructive pulmonary disease, inflammatory bowel disease or autoimmune disease. That is, the present invention provides [1] a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof:
  • R 0 represents the following R 01 or R 02 .
  • R 1 represents one or a plurality of alkyl groups having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group optionally substituted with a halogen atom, OR, or NRR ′ which may form a ring.
  • R and R ′ are each independently a hydrogen atom, one or more alkoxy groups having 1 to 8 carbon atoms, a halogen atom or a hydroxyl group optionally substituted with a hydroxyl group.
  • R 2 represents a hydrogen atom, an amino group, or an alkyl group having 1 to 8 carbon atoms which may be substituted with one or more halogen atoms.
  • X 1 represents CR 3 or a nitrogen atom, wherein R 3 represents a hydrogen atom or a halogen atom.
  • Ring A is an alkyl group having 1 to 6 carbon atoms which may be substituted with one or more alkoxy groups having 1 to 3 carbon atoms or a halogen atom, and the number of carbons which may be substituted with one or more halogen atoms. It represents a 5- or 6-membered monocyclic heteroarene which may be substituted with 1 to 6 alkoxy groups and 1 to 4 groups selected from the group consisting of halogen atoms. ]; [2] The heteroarene in ring A is
  • R is an aryl group optionally substituted by one or more alkyl groups having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom or a cyano group. Or a pharmaceutically acceptable salt thereof; [13] R 1 is 1 or more carbon atoms 1-3 alkyl group, an aryl group which may be substituted with an alkoxy group or halogen atom having 1-3 carbon atoms, of [1] to [9] Any of the compounds or pharmaceutically acceptable salts thereof; [14] Any compound selected from compound numbers (1) to (175) or a pharmaceutically acceptable salt thereof. .
  • a pharmaceutical composition comprising the compound according to any one of [1] to [14] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier;
  • a xanthine oxidase inhibitor comprising the compound according to any one of [1] to [14] or a pharmaceutically acceptable salt thereof as an active ingredient;
  • Gout hyperuricemia, tumor lysis syndrome, urinary calculus, hypertension comprising the compound according to any one of [1] to [14] or a pharmaceutically acceptable salt thereof as an active ingredient
  • R 4 represents the following R 41 or R 42 .
  • R 5 represents a protecting group for a carboxyl group.
  • the definitions of R 1 , R 2 , X 1 and ring A are the same as in formula (I). ] It is.
  • the present invention provides a novel compound having high xanthine oxidase inhibitory activity and a method for producing the same. Furthermore, the compounds of the present invention are particularly useful for gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, kidneys such as diabetic nephropathy, etc. It is useful as a therapeutic or prophylactic agent for diseases involving xanthine oxidase such as diseases, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases or autoimmune diseases.
  • Xanthine oxidase is generally used in the broad sense of an enzyme that catalyzes an oxidation reaction from hypoxanthine to xanthine and further to uric acid, and in the narrow sense of an oxidase-type xanthine oxidoreductase that is one of the enzymes that catalyze the reaction.
  • xanthine oxidase is a general term for enzymes that catalyze an oxidation reaction from hypoxanthine to xanthine and further to uric acid, unless otherwise specified.
  • xanthine oxidoreductase responsible for this reaction, an oxidase type and a dehydrogenase type, both of which are included in the xanthine oxidase of the present invention.
  • xanthine oxidase inhibitory activity xanthine oxidase inhibitor
  • xanthine oxidase inhibitor has the same meaning as defined above unless otherwise specified.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the “alkyl group” means a monovalent saturated linear, cyclic or branched aliphatic hydrocarbon group.
  • Examples of the “alkyl group having 1 to 8 carbon atoms” include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, isopropyl group, isobutyl group, and s-butyl.
  • t-butyl group isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3, 3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group 2-ethylbutyl group, t-pentyl group, isohexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, B propyl methyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, and cyclo
  • alkyl group having 1 to 6 carbon atoms examples include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, isopropyl group, isobutyl group, s-butyl group, t-butyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3- Dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group, 2 -Ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, methyl group,
  • the “alkylene group” means a divalent group derived by further removing one hydrogen atom at an arbitrary position from the “alkyl group”.
  • Examples of the “C 1-6 alkylene group” include methylene group, ethylene group, n-propylene group, isopropylene group, n-butylene group, isobutylene group, n-pentylene group, n-hexylene group, cyclopropylene group , Cyclobutylene group, cyclohexylene group and the like.
  • the “alkoxy group” means a monovalent saturated linear, cyclic or branched aliphatic hydrocarbon oxy group.
  • Examples of the “alkoxy group having 1 to 8 carbon atoms” include methoxy group, ethoxy group, n-propoxy group, n-butoxy group, n-pentyloxy group, n-hexaoxy group, isopropoxy group, isobutoxy group, s- Butoxy group, t-butoxy group, isopentyloxy group, 2-methylbutoxy group, neopentyloxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, cyclopropylmethoxy group, A cyclobutyl methoxy group, a cyclopentyl methoxy group, a cyclohexyl methoxy group, etc. are mentioned. Examples of the “C 1-3 al
  • the “aryl group” means a monocyclic or bicyclic monovalent aromatic hydrocarbon group having 6 to 10 carbon atoms.
  • the aryl group include a phenyl group, a naphthyl group, an indenyl group, a tetrahydronaphthyl group, an indanyl group, and an azulenyl group.
  • heteroene means a monocyclic or bicyclic aromatic heterocycle having 1 to 5 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom.
  • the “5- or 6-membered monocyclic heteroarene” means a 5- or 6-membered monocyclic one of the above “heteroarenes”.
  • heteroaryl group refers to a monocyclic or monovalent bicyclic aromatic heterocyclic group having 1 to 5 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom.
  • Heteroaryl groups include pyridyl, pyrazyl, pyrimidyl, furyl, thienyl, pyrrolyl, isoxazolyl, isothiazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoimidazolyl, benzoxazolyl, pyranyl Group, imidazolyl group, oxazolyl group, thiazolyl group, triazinyl group, triazolyl group, benzoxazolyl group, benzoisoxazolyl group and the like.
  • the “optionally substituted alkyl group having 1 to 8 carbon atoms” represents an alkyl group having 1 to 8 carbon atoms which may have one or more substituents at substitutable positions. . When a plurality of substituents are present, each substituent may be the same or different.
  • the “optionally substituted alkyl group having 1 to 6 carbon atoms”, the “optionally substituted alkyl group having 1 to 3 carbon atoms” and the like have the same meaning.
  • optionally substituted alkoxy group having 1 to 8 carbon atoms represents an alkoxy group having 1 to 8 carbon atoms which may have one or more substituents at substitutable positions. . When a plurality of substituents are present, each substituent may be the same or different.
  • the “optionally substituted alkoxy group having 1 to 6 carbon atoms”, the “optionally substituted alkoxy group having 1 to 3 carbon atoms” and the like have the same meaning.
  • the alkyl group and alkoxy may be combined to form an oxygen-containing saturated ring.
  • Such rings include oxirane, oxetane, tetrahydrofuran, tetrahydropyran and the like.
  • the “optionally substituted aryl group” means an aryl group which may have one or more substituents at substitutable positions. When a plurality of substituents are present, each substituent may be the same or different.
  • the “optionally substituted heteroarene” and the “optionally substituted heteroaryl group” refer to a heteroarene, heteroaryl optionally having one or more substituents at substitutable positions. Each represents an aryl group. When a plurality of substituents are present, each substituent may be the same or different.
  • carboxyl-protecting group means, for example, PROTECTIVE GROUPS in ORGANIC SYNTHESIS, THIRD EDITION, John Wiley & Sons, Inc.
  • “protective group for phenolic hydroxyl group” means, for example, PROTECTED GROUPS in ORGANIC SYNTHESIS, THIRD EDITION, John Wiley & Sons, Inc.
  • R 0 represents the following R 01 or R 02 .
  • R 1 forms one or more alkyl groups having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or an aryl group optionally substituted with a halogen atom, OR, and a ring.
  • NRR ′ that may be present, or SR.
  • R and R ′ are independently a hydrogen atom, one or a plurality of alkoxy groups having 1 to 8 carbon atoms, a halogen atom or an alkyl group having 1 to 8 carbon atoms which may be substituted with a hydroxyl group, 1 or A plurality of alkyl groups having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group optionally substituted with a halogen atom or a cyano group, or one or more alkyl groups having 1 to 6 carbon atoms, carbon It represents a heteroaryl group which may be substituted with an alkoxy group of 1 to 6 or a halogen atom.
  • R 1 is preferably OR.
  • R preferably represents one or more alkoxy groups having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms which may be substituted with a halogen atom or a hydroxyl group, or 1 Alternatively, the aryl group may be substituted with a plurality of alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, halogen atoms, or cyano groups.
  • it is an alkyl group having 1 to 8 carbon atoms which may be substituted with one or more alkoxy groups having 1 to 8 carbon atoms or a halogen atom.
  • Particularly preferred are isopropyl group, isobutyl group and neopentyl group.
  • R 1 is one or a plurality of alkyl groups having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group optionally substituted with a halogen atom or a cyano group, preferably one or more carbon atoms
  • R 2 represents a hydrogen atom, an amino group, or an alkyl group having 1 to 8 carbon atoms which may be substituted with one or more halogen atoms.
  • they are a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and specific examples include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group. More preferably, they are a hydrogen atom and a methyl group. Particularly preferred is a methyl group.
  • R 0 is R 01 or R 02
  • preferred R 1 and R 2 are as described above.
  • preferred R 2 can also include an amino group and an alkyl group having 1 to 3 carbon atoms which may be substituted with one or more halogen atoms.
  • R 0 is R 02
  • more preferable R 2 is a hydrogen atom and an amino group.
  • X 1 represents CR 3 or a nitrogen atom
  • R 3 represents a hydrogen atom or a halogen atom, and can be represented by the following structural formula, for example.
  • Ring A is bonded to a benzene or pyridine ring containing X 1 by a carbon atom on ring A.
  • Ring A is an alkyl group having 1 to 6 carbon atoms which may be substituted with one or more alkoxy groups having 1 to 3 carbon atoms or a halogen atom, and the number of carbons which may be substituted with one or more halogen atoms. It represents a 5- or 6-membered monocyclic heteroarene which may be substituted with 1 to 6 alkoxy groups and 1 to 4 groups selected from the group consisting of halogen atoms. Examples of the 5- or 6-membered monocyclic heteroarene in ring A include the following structures.
  • Ring A is preferably 5 or 6 optionally substituted with 1 or 2 alkyl groups having 1 to 3 carbon atoms which may be substituted with 1 or 2 alkoxy groups having 1 to 3 carbon atoms.
  • Specific examples of preferable ring A are as follows, for example.
  • the compound of the present invention is a compound that exhibits excellent xanthine oxidase inhibitory activity. Further, the compound of the present invention has an excellent uric acid lowering action. Specific examples of preferred compounds include the following compounds.
  • more preferable compounds are compounds 2, 3, 6, 9, 10, 12, 14, 15, 16, 18, 19, 20, 22, 23, 24, 25, 26, 27, 32, 33, 34. , 35, 36, 37, 38, 39, 41, 42, 43, 45, 46, 47, 48, 49, 51, 52, 53, 54, 55, 56, 58, 59, 62, 63, 65, 66 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92 93, 94, 95, 96, 97, 99, 103, 105, 106, 108, 109, 110, 111, 112, 113, 114, 122, 123, 124, 125, 126, 127, 128, 129, 130 139, 140, 14 147, 149, 150, 151, 152, 153, 154, 155,
  • R 1 , R 2 , ring A, and X 1 are the above Is the same as defined in formula (I).
  • R 5 represents a protecting group for a carboxyl group.
  • the definition of the protective group of a carboxyl group is as above-mentioned, Preferably they are a methyl group, an ethyl group, and a benzyl group.
  • Formula (I) of the present invention can be synthesized, for example, according to any of the synthetic methods described below.
  • R 1 , R 2 , X 1 and ring A are as defined in formula (I).
  • R 5 is as defined in formula (II).
  • the reagent or solvent as a condition described in the chemical formula is merely an example as described in the text.
  • Each substituent may be protected with an appropriate protecting group as necessary, and may be deprotected at an appropriate stage.
  • the protecting group of each substituent generally used in this field and a publicly known method can be adopted. . It is described in.
  • Z 1 represents a leaving group.
  • the leaving group represented by Z 1 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a method of synthesizing compound (A-2) by reacting a phenolic hydroxyl group in compound (A-1) with an alkylating reagent having a leaving group in the presence of a base.
  • Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc.
  • Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used.
  • This reaction is carried out by reacting compound (A-1) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., and then an equal amount or an excess amount of an alkylating reagent. And the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited.
  • ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N—
  • THF tetrahydrofuran
  • 1,4-dioxane 1,2-dimethoxyethane
  • 1,2-diethoxyethane N, N—
  • examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • the bromo group in the compound (A-2) is lithiated with a strong base, then reacted with a boric acid ester, and then the boronic acid ester is hydrolyzed with an acid to a boronic acid, whereby the compound (A -3).
  • compound (A-2) and boric acid ester are used in an equal amount or one in excess, and an equal amount or a small excess of strong base is added at ⁇ 78 to 0 ° C. in a solvent inert to the reaction, Usually, the reaction is carried out by adding an acid such as hydrochloric acid after reacting for 0.5 to 12 hours. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • n-butyllithium, t-butyllithium, s-butyllithium or the like is used.
  • boric acid esters include trimethoxyboric acid, triethoxyboric acid, and triisopropoxyboric acid.
  • the solvent is not particularly limited, but ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, or a mixture thereof A solvent etc. are mentioned.
  • Z 2 represents a leaving group.
  • the leaving group represented by Z 2 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a method of synthesizing compound (A-4) by coupling reaction of boronic acid compound (A-3) and a heterocyclic compound having a leaving group.
  • the compound (A-3) and the heterocyclic compound are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a base and a palladium catalyst, from room temperature to heating under reflux, usually 0.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • the base examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases And a solution obtained by diluting with water or the like.
  • the palladium catalyst tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.
  • This reaction is a conversion reaction from a cyano group to a thioamide group, and is performed by reacting an aromatic cyano group derivative represented by the above formula (A-4) with a sulfur source under acidic conditions.
  • compound (A-4) and sulfur source are used in the same amount or in excess, and in an inert solvent for reaction, in the presence of an acid, at room temperature to heating under reflux, usually 0.5 hours to 2 This is done by reacting for a day.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Hydrogen sulfide, thioacetamide or thioacetic acid is used as the sulfur source.
  • the acidic substance organic acids such as hydrochloric acid, sulfuric acid and acetic acid, or aqueous solutions of these acids are used.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • An acid such as acetic acid can also be used as a solvent.
  • Z 3 represents a leaving group.
  • the leaving group represented by Z 3 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • compounds (A-5) and (A-6) are used in an equal amount or in excess, and in an inert solvent for the reaction, usually at room temperature to heating under reflux, usually 0.5 hours to 2 days. This is done by reacting. Further, an equal amount or an excess amount of a base can be added. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as
  • Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, triethylamine, N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
  • inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate
  • metal alkoxides such as sodium ethoxide and sodium methoxide
  • triethylamine N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
  • This reaction is a method for synthesizing the compound (A-8) of the present invention by deprotecting the protecting group R 5 of the compound (A-7) with an acid or a base.
  • compound (A-7) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • R 1 of the compound of the formula (I) is OR, NRR ′ which may form a ring, or SR will be shown.
  • the bromo group in compound (A-9) is lithiated with a strong base and then reacted with boric acid ester, followed by hydrolysis of boronic acid ester to boronic acid with acid. -10).
  • an equal amount of compound (A-9) and boric acid ester or an excess of one are used, and an equal amount or a small excess of strong base is added at ⁇ 78 ° C. to 0 ° C. in a solvent inert to the reaction.
  • the reaction is usually carried out by adding an acid such as hydrochloric acid after reacting for 0.5 to 12 hours. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • n-butyllithium, t-butyllithium, s-butyllithium or the like is used.
  • boric acid esters include trimethoxyboric acid, triethoxyboric acid, and triisopropoxyboric acid.
  • the solvent is not particularly limited, but ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, or a mixture thereof A solvent etc. are mentioned.
  • Z 2 represents a leaving group.
  • the leaving group represented by Z 2 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a method for synthesizing compound (A-11) by coupling reaction of boronic acid compound (A-10) with a heterocyclic compound having a leaving group.
  • the compound (A-10) and the heterocyclic compound are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a base and a palladium catalyst, from room temperature to heating under reflux, usually 0.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Bases include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, metal alkoxides such as sodium BR> G toxide, sodium methoxide, or Examples include solutions obtained by diluting these bases with water or the like.
  • the palladium catalyst tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.
  • This reaction is a method for synthesizing compound (A-12) by lithiating, sodiumating or potassiumating alcohols, amines or thiols with a base and then reacting with compound (A-11).
  • Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc.
  • Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used.
  • DIPEA N-ethyl-N
  • DIPEA N-diisopropylamine
  • DBU 1,8-diazabicyclo [5.4.0] -7-undecene
  • This reaction is carried out at ⁇ 20 ° C. to 120 ° C. in an solvent inert to the reaction, after reacting compound (A-11) with an equal amount or a small excess of base, and then an equal amount or an excess amount of alcohols.
  • Amines or thiols are added, and the reaction is usually carried out for 0.5 to 12 hours.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • diethoxyethane N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • DMF N-di
  • This reaction is a conversion reaction from a cyano group to a thioamide group, and is performed by reacting an aromatic cyano group derivative represented by the above formula (A-12) with a sulfur source under acidic conditions.
  • the compound (A-12) and sulfur source are used in an equal amount or one of them in excess, and in an inert solvent for the reaction, in the presence of an acid, from room temperature to heating under reflux, usually from 0.5 hour to 2 This is done by reacting for a day.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Hydrogen sulfide, thioacetamide or thioacetic acid is used as the sulfur source.
  • the acidic substance organic acids such as hydrochloric acid, sulfuric acid and acetic acid, or aqueous solutions of these acids are used.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • An acid such as acetic acid can also be used as a solvent.
  • Z 3 represents a leaving group.
  • the leaving group represented by Z 3 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • compounds (A-13) and (A-6) are used in an equal amount or in excess, and in an inert solvent for the reaction, at room temperature to heating under reflux, usually 0.5 hours to 2 days This is done by reacting. Further, an equal amount or an excess amount of a base can be added. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as
  • Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, triethylamine, N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
  • inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate
  • metal alkoxides such as sodium ethoxide and sodium methoxide
  • triethylamine N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
  • This reaction is a method for synthesizing the compound (A-15) of the present invention by deprotecting the protecting group R 5 of the compound (A-14) with an acid or a base.
  • compound (A-14) is usually reacted for 0.5 hours to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • the compound of formula (A-8) can also be synthesized according to a synthesis method as described below.
  • This reaction is a conversion reaction from a cyano group to a thioamide group, and is performed by reacting an aromatic cyano group derivative represented by the above formula (A-2) with a sulfur source under acidic conditions.
  • compound (A-2) and sulfur source are used in an equal amount or in excess, and in an inert solvent for reaction, in the presence of an acid, at room temperature to heating under reflux, usually 0.5 hours to 2 This is done by reacting for a day.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Hydrogen sulfide, thioacetamide or thioacetic acid is used as the sulfur source.
  • the acidic substance organic acids such as hydrochloric acid, sulfuric acid and acetic acid, or aqueous solutions of these acids are used.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • An acid such as acetic acid can also be used as a solvent.
  • Z 3 represents a leaving group.
  • the leaving group represented by Z 3 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • compounds (B-1) and (A-6) are used in equal amounts or in excess, and the reaction is inert to the reaction at room temperature to heating under reflux, usually for 0.5 hour to 2 days. This is done by reacting. Further, an equal amount or an excess amount of a base can be added. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as
  • Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, triethylamine, N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
  • inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate
  • metal alkoxides such as sodium ethoxide and sodium methoxide
  • triethylamine N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
  • the bromo group in the compound (B-2) is lithiated with a strong base, then reacted with a boric acid ester, and then the boronic acid ester is hydrolyzed with an acid to a boronic acid, whereby the compound (B -3).
  • the compound (B-2) and boric acid ester are used in an equal amount or in an excess amount, and an equal amount or a small excess of a strong base is added at ⁇ 78 to 0 ° C. in a solvent inert to the reaction,
  • the reaction is carried out by adding an acid such as hydrochloric acid after reacting for 0.5 to 12 hours. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • n-butyllithium, t-butyllithium, s-butyllithium or the like is used.
  • boric acid esters include trimethoxyboric acid, triethoxyboric acid, and triisopropoxyboric acid.
  • the solvent is not particularly limited, but ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, or a mixture thereof A solvent etc. are mentioned.
  • Z 2 represents a leaving group.
  • the leaving group represented by Z 2 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a method of synthesizing compound (A-10) by coupling reaction of boronic acid compound (B-3) and a heterocyclic compound having a leaving group.
  • the compound (B-3) and the heterocyclic compound are used in an equal amount or one of them in excess, and in a solvent inert to the reaction, in the presence of a base and a palladium catalyst, from room temperature to heating under reflux, usually 0.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • the base examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases And a solution obtained by diluting with water or the like.
  • the palladium catalyst tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.
  • This reaction is a conversion reaction from a cyano group to a thioamide group, and is performed by reacting an aromatic cyano group derivative represented by the above formula (C-1) with a sulfur source under acidic conditions.
  • an equal amount of compound (C-1) and a sulfur source, or one of them in excess is used in an inert solvent for the reaction, in the presence of an acid, at room temperature to heating under reflux, usually for 0.5 hour to 2 hours. This is done by reacting for a day.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Hydrogen sulfide, thioacetamide or thioacetic acid is used as the sulfur source.
  • the acidic substance organic acids such as hydrochloric acid, sulfuric acid and acetic acid, or aqueous solutions of these acids are used.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • An acid such as acetic acid can also be used as a solvent.
  • Z 3 represents a leaving group.
  • the leaving group represented by Z 3 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • compounds (C-2) and (A-6) are used in an equal amount or in excess, and the reaction is inert to the reaction at room temperature to heating under reflux, usually for 0.5 hour to 2 days. This is done by reacting. Further, an equal amount or an excess amount of a base can be added. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as
  • Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, triethylamine, N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
  • inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate
  • metal alkoxides such as sodium ethoxide and sodium methoxide
  • triethylamine N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
  • This reaction is a method in which the compound (C-3) is reacted with hexamethylenetetramine (HMT) in the presence of an acid catalyst to formylate.
  • HMT hexamethylenetetramine
  • the compound (C-3) and hexamethylenetetramine (HMT) are used in an equal amount or in excess, and usually in an inert solvent in the reaction in the presence of an acid catalyst at room temperature to heating under reflux, usually 0 By reacting for 5 hours to 2 days.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the acid catalyst include formic acid, acetic acid, trifluoroacetic acid, polyphosphoric acid, and the like.
  • An acid catalyst can also be used as a solvent.
  • Z 1 represents a leaving group.
  • the leaving group represented by Z 1 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a method of synthesizing compound (C-5) by reacting a phenolic hydroxyl group in compound (C-4) with an alkylating reagent having a leaving group in the presence of a base.
  • Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc.
  • Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used.
  • This reaction is carried out by reacting compound (C-4) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., followed by an equal amount or an excess amount of an alkylating reagent. And the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited.
  • ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N—
  • THF tetrahydrofuran
  • 1,4-dioxane 1,2-dimethoxyethane
  • 1,2-diethoxyethane N, N—
  • examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • This reaction is a method in which a compound (C-5) is reacted with p-toluenesulfonylacetonitrile (C-6) to synthesize a 1,3-oxazole ring.
  • compound (C-5) and p-toluenesulfonylacetonitrile (C-6) are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a base, at room temperature to under reflux.
  • the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • Examples of the base used include carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5. 4.0] -7-undecene (DBU) and other organic amines are used.
  • carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate
  • triethylamine pyridine
  • 4-aminopyridine N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5. 4.0] -7-undecene (DBU) and other organic amines are used.
  • Solvents used in these reactions include toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2 -Dimethoxyethane, 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • solvents used in these reactions include toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2 -Dimethoxyethane,
  • the compound of formula (C-7) can also be synthesized according to the synthesis method as described below.
  • R 6 represents a protecting group for a phenolic hydroxyl group.
  • This reaction is a method of synthesizing compound (C-9) by deprotecting protecting group R 6 of compound (C-8) with an acid or a base.
  • compound (C-8) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • This reaction is a method of synthesizing compound (C-7) by reacting compound (C-9) with alcohols by Mitsunobu reaction or the like.
  • This reaction is a method of synthesizing compound (C-7) by reacting alcohols with triphenylphosphine and carbodiimide and then reacting with compound (C-9).
  • Examples of the carbodiimide used include diethyl carbodiimide and diisopropyl carbodiimide.
  • an equivalent amount or an excess amount of alcohol, triphenylphosphine and carbodiimide is usually added to 0.5 to 12 in a solvent inert to the reaction at ⁇ 20 ° C. to 120 ° C. This is done by reacting for hours.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • diethoxyethane N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • DMF N-di
  • This reaction is a method for synthesizing the compound (C-10) of the present invention by deprotecting the protecting group R 5 of the compound (C-7) with an acid or a base.
  • compound (C-7) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal or excess amount of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • This reaction is a conversion reaction from a formyl group to a cyano group, and is performed by reacting an aromatic aldehyde derivative represented by the above formula (C-5) with hydroxylamine.
  • hydroxylamine other salts such as hydrochloride thereof may be used. In that case, it is preferable to add an appropriate basic substance.
  • the reaction can be accelerated by adding 1.0 to 3.0 equivalents of acetic anhydride, acetyl chloride, trichloroacetyl chloride and the like.
  • the amount of hydroxylamine or a salt thereof used in these reactions is usually 1 equivalent or more, preferably 1.0 to 2.0 equivalents.
  • a basic substance When a basic substance is used, 1.0 to 3.0 equivalents are used with respect to the hydroxylamine salt.
  • basic substances to be used carboxylates such as sodium formate, potassium formate and sodium acetate, carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, organic amine salts such as triethylamine, pyridine and 4-aminopyridine are used. It is done.
  • the reaction is carried out in an inert solvent in the presence of a base at room temperature to heating under reflux, usually for 0.5 hour to 3 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • Solvents used in these reactions include acetic acid, formic acid, toluene, benzene, pyridine, ethyl acetate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane. 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), methanol, ethanol, 2-propanol and the like.
  • This reaction is a reaction in which a tetrazole ring is cyclized from a cyano group, and is performed by reacting an aromatic cyano group derivative represented by the above formula (D-1) with an azide compound in the presence of an acid.
  • compound (D-1) and an azide compound are used in an equal amount or in excess, and in an inert solvent for the reaction, in the presence of an acid, from room temperature to heating under reflux, usually from 0.5 hour to This is done by reacting for 2 days.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the azide compound include sodium azide and trimethylsilyl azide.
  • Examples of the acid to be used include organic acids such as formic acid and acetic acid, inorganic acids such as hydrochloric acid and sulfuric acid, and inorganic salts such as ammonium chloride and ammonium acetate.
  • Solvents used in these reactions include toluene, benzene, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1 , 2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • organic acids such as formic acid and acetic acid
  • inorganic acids such as hydrochloric acid and sulfuric acid
  • inorganic salts such as ammonium chloride and ammonium acetate.
  • This reaction is a method for synthesizing the compound (D-3) of the present invention by deprotecting the protecting group R 5 of the compound (D-2) with an acid or a base.
  • compound (D-2) is usually reacted for 0.5 hours to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • Examples of the leaving group represented by Z 4 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is performed by reacting nitrogen at the 1-position and 2-position on the tetrazole ring in compound (D-2) with an alkylating reagent having a leaving group in the presence of a base. This is a method for synthesizing D-5). This reaction is carried out at 0 ° C. to 140 ° C.
  • reaction in the presence of a base in the presence of a base using an equal amount of compound (D-2) and an alkylating reagent in a solvent inert to the reaction, or in a small excess. This is done by reacting for 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc.
  • Organic amine salts such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Is used.
  • the solvent is not particularly limited.
  • ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N—
  • THF tetrahydrofuran
  • 1,4-dioxane 1,2-dimethoxyethane
  • 1,2-diethoxyethane N, N—
  • examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • the protecting groups R 5 of the compounds (D-4) and (D-5) are deprotected with an acid or a base to synthesize the compounds (D-6) and (D-7) of the present invention.
  • compounds (D-4) and (D-5) are used in an equivalent amount or in excess of an acid or a base in a solvent inert to the reaction, and the reaction is usually carried out at room temperature to heating under reflux for 0.5 hours. Performed by reacting for ⁇ 5 days.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • This reaction is a method of synthesizing compound (E-1) by reacting compound (D-1) with hydroxylamine.
  • compound (D-1) and hydroxylamine are used in an equal amount or in excess, and in the presence of a base, in a solvent inert to the reaction, at room temperature to heating under reflux, usually 0.5 hours to 2 days This is done by reacting.
  • organic bases such as triethylamine, pyridine, 4-aminopyridine are used as the base.
  • the base used can also be used as a solvent.
  • This reaction is a method of synthesizing compound (E-3) by reacting compound (E-1) with acid chloride (E-2).
  • the compound (E-1) and acid chloride (E-2) are used in an equal amount or in excess, and in the presence of a base, in a solvent inert to the reaction, usually at room temperature to heating under reflux, usually 0.
  • the reaction is performed for 5 hours to 2 days.
  • organic bases such as triethylamine, pyridine, 4-aminopyridine are used as the base.
  • the base used can also be used as a solvent.
  • This reaction is a method for synthesizing the compound (E-4) of the present invention by deprotecting the protecting group R 5 of the compound (E-3) with an acid or a base.
  • compound (E-3) is usually reacted for 0.5 hours to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • R 8 represents an alkyl group having 1 to 3 carbon atoms
  • This reaction is a method of synthesizing the oxadiazole ring compound (E-6) by reacting the compound (E-1) with the orthoformate ester (E-5).
  • an equal amount of compound (E-1) and orthoformate ester (E-5), or an excess of either, are used in an inert solvent for the reaction in the presence of an acid at room temperature to heating under reflux.
  • the reaction is performed for 0.5 hours to 2 days.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • Examples of the orthoformate ester (E-5) include trimethyl orthoformate and triethyl orthoformate.
  • Examples of the acid used include organic acids such as formic acid, acetic acid, hydrochloric acid, sulfuric acid and trifluoroacetic acid.
  • Solvents used in these reactions include toluene, benzene, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1 , 2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • An acid such as trifluoroacetic acid may be used as a solvent. .
  • This reaction is a method for synthesizing the compound (E-7) of the present invention by deprotecting the protecting group R 5 of the compound (E-6) with an acid or a base.
  • compound (E-6) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • This reaction is a method of synthesizing compound (F-1) by reacting compound (C-5) with hydroxylamine.
  • compound (C-5) and hydroxylamine are used in an equal amount or in excess, and in the presence of a base, in a solvent inert to the reaction, at room temperature to heating under reflux, usually 0.5 hours to 2 days. This is done by reacting.
  • organic bases such as triethylamine, pyridine, 4-aminopyridine are used as the base.
  • the base used can also be used as a solvent.
  • This reaction is a method of synthesizing compound (F-2) by reacting compound (F-1) with a chlorinating reagent.
  • compound (F-1) and a chlorinating reagent are used in an equal amount or in excess, and in the presence of a base, in a solvent inert to the reaction, at room temperature to heating under reflux, usually 0.5 hours to 2 This is done by reacting for days.
  • N-chlorosuccinimide or the like can be used as the chlorinating reagent.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethylsulfoxide (DMSO), or these A mixed solvent etc. are mentioned.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethan
  • This reaction is a method of synthesizing compound (F-4) by reacting compound (F-2) with acetylene compound (F-3).
  • the compound (F-2) and the acetylene compound (F-3) are used in an equal amount or in excess, and in the presence of a base, in a solvent inert to the reaction, usually at room temperature to under reflux with heating.
  • the reaction is performed for 5 hours to 2 days.
  • Examples of the base used include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, triethylamine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) and the like.
  • inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate
  • metal alkoxides such as sodium ethoxide and sodium methoxide
  • DIPEA N-ethyl-N, N-diisopropylamine
  • DIPEA 1,8-diazabicyclo [5.4.0] -7-undecene
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • diethoxyethane N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • DMF N-di
  • This reaction is a method for synthesizing the compound (F-5) of the present invention by deprotecting the protecting group R 5 of the compound (F-4) with an acid or a base.
  • compound (F-4) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • Z 1 and Z 5 each represent a leaving group, and R 9 represents a protecting group for a carboxyl group.
  • the leaving group represented by Z 1 and Z 5 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a method of synthesizing compound (G-2) by reacting a phenolic hydroxyl group in compound (G-1) with an alkylating reagent having a leaving group in the presence of a base.
  • Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc.
  • Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used.
  • This reaction is carried out by reacting compound (G-1) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., and then an equal amount or an excess amount of an alkylating reagent. And the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited.
  • ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N—
  • THF tetrahydrofuran
  • 1,4-dioxane 1,2-dimethoxyethane
  • 1,2-diethoxyethane N, N—
  • examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • Z 5 represents a leaving group
  • R 9 represents a protecting group for a carboxyl group.
  • This reaction is a method of synthesizing compound (G-3) by deprotecting protecting group R 9 of compound (G-2) with an acid or a base.
  • compound (G-2) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • This reaction is a method of synthesizing compound (G-4) which is acid chloride from compound (G-3).
  • compound (G-3) is usually reacted for 0.5 hour to 2 days at room temperature to heating under reflux using an equal or excessive amount of a chlorinating reagent in a solvent inert to the reaction. Is done.
  • the chlorinating reagent used include thionyl chloride, oxalyl chloride, and phosphoryl chloride.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, N, N-dimethylformamide ( DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, N, N-dimethylformamide ( DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • This reaction is a method of synthesizing the compound (G-6) which is an oxadiazole ring from the compound (G-4) which is an acid chloride and the compound (G-5).
  • compound (G-4) is used in an equivalent amount or in excess of compound (G-5) in the presence of a base in a solvent inert to the reaction, and the reaction is usually carried out at room temperature to heating under reflux. The reaction is performed for a time to 2 days.
  • Examples of the base used include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, triethylamine, N-ethyl-N, Examples include organic amines such as N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU). An organic amine can also be used as a solvent.
  • inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate
  • metal alkoxides such as sodium ethoxide and sodium methoxide
  • triethylamine triethylamine
  • N-ethyl-N examples include organic amines such as N-diisopropylamine (DIPEA) and 1,8-diaza
  • This reaction is a method of synthesizing compound (G-8) by coupling compounds (G-6) and (G-7).
  • Examples of the leaving group represented by Z 5 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like.
  • compounds (G-6) and (G-7) are used in equal amounts or in excess, and in a solvent inert to the reaction, in the presence of a base and a transition metal catalyst, optionally a ligand, a carboxyl It is carried out by adding an acid and a copper (I or II) salt and reacting at room temperature to heating under reflux, usually for 0.5 hour to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Bases include lithium hydride, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, tripotassium phosphate, sodium acetate, acetic acid Metal salts of alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts, sodium salts, potassium salts, magnesium salts), metal salts of alkyl anions having 1 to 6 carbon atoms (lithium salts, sodium salts, potassium salts, magnesium salts) ), Tetra (alkyl having 1 to 4 carbon atoms) ammonium (fluoride, chloride, bromide), diisopropylethylamine, tributylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclooctane, or Examples include imidazole.
  • alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts,
  • transition metal catalyst examples include copper, palladium, cobalt, iron, rhodium, ruthenium, and iridium.
  • ligand examples include tri (t-butyl) phosphine, tri (cyclohexyl) phosphine, t-butyldicyclohexylphosphine, di (t-butyl) cyclohexylphosphine, and di (t-butyl) methylphosphine.
  • Copper (I or II) salts include copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) acetate, copper (II) fluoride, copper (II) chloride , Copper bromide (II), copper (II) iodide, copper (II) acetate and hydrates thereof, and mixtures thereof.
  • the carboxylic acid include formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid, pentanoic acid, isopentanoic acid, pivalic acid, and trifluoroacetic acid.
  • This reaction is a method for synthesizing the compound (G-9) of the present invention by deprotecting the protecting group R 5 of the compound (G-8) with an acid or a base.
  • compound (G-8) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • Z 1 and Z 6 represent a leaving group.
  • the leaving group represented by Z 1 and Z 6 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a method of synthesizing compound (H-2) by reacting a phenolic hydroxyl group in compound (H-1) with an alkylating reagent having a leaving group in the presence of a base.
  • Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc.
  • Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used.
  • This reaction is carried out by reacting compound (H-1) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., followed by an equal amount or an excess amount of an alkylating reagent. And the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited.
  • ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N—
  • THF tetrahydrofuran
  • 1,4-dioxane 1,2-dimethoxyethane
  • 1,2-diethoxyethane N, N—
  • examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • This reaction is a method of synthesizing compound (H-4) by coupling compounds (H-2) and (H-3).
  • Examples of the leaving group represented by Z 6 include an iodine atom, a bromine atom, and a chlorine atom.
  • compounds (H-2) and (H-3) are used in an equal amount or in excess, and the reaction is carried out in a solvent inert to the reaction in the presence of a base, a copper catalyst and a ligand at room temperature to heating.
  • the reaction is usually carried out under reflux for usually 0.5 hours to 3 days.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), Or these mixed solvents etc. are mentioned.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 Ethers such as diethoxyethane, halogenated hydrocarbons such as dich
  • Bases include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, metal alkoxides such as sodium ethoxide, sodium methoxide, triethylamine, N-ethyl -N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) and the like.
  • the copper catalyst include copper chloride, copper bromide, copper iodide, and copper oxide.
  • the ligand include proline, trans-N, N′-dimethylcyclohexane-1,2-diamine, N, N-dimethylaminoacetic acid, 1,10-phenanthroline and the like.
  • This reaction is a method of synthesizing compound (H-5) by brominating the ortho position of the alkoxy group of compound (H-4).
  • compound (H-4) and a bromine source are used in an equal amount or in excess, and in an inert solvent for the reaction, in the presence of an acid, from room temperature to heating under reflux, usually from 0.5 hours to This is done by reacting for 2 days.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the bromine source include bromine.
  • the acid used include organic acids such as formic acid, acetic acid, hydrochloric acid, sulfuric acid and trifluoroacetic acid.
  • the solvent used in these reactions include dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, or a mixed solvent thereof, and an acid such as acetic acid may be used as the solvent.
  • This reaction is a method of synthesizing compound (H-7) which is a borate ester by coupling compound (H-5) and pinacol diborane (H-6).
  • compounds (H-5) and (H-6) are used in equal amounts or in excess, and usually in a solvent inert to the reaction in the presence of a base and a palladium catalyst at room temperature to heating under reflux.
  • the reaction is performed for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • the base examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, and tripotassium phosphate, or solutions obtained by diluting these bases with water.
  • inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, and tripotassium phosphate, or solutions obtained by diluting these bases with water.
  • the palladium catalyst tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1'-bis (diphenylphosphino) ferrocene and the like are preferable.
  • Z 2 represents a leaving group.
  • the leaving group represented by Z 2 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a method of synthesizing compound (H-8) by coupling reaction of borate ester compound (H-7) and a heterocyclic compound having a leaving group.
  • the compound (H-7) and the heterocyclic compound are used in an equal amount or in excess, and in an inert solvent for reaction, in the presence of a base and a palladium catalyst, the reaction temperature is usually from 0 to 0 at reflux.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • the base examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases And a solution obtained by diluting with water or the like.
  • the palladium catalyst tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.
  • This reaction is a method for synthesizing the compound (H-9) of the present invention by deprotecting the protecting group R 5 of the compound (H-8) with an acid or a base.
  • compound (H-8) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • Z 1 and Z 7 represent a leaving group.
  • the leaving group represented by Z 1 and Z 7 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a method of synthesizing compound (I-2) by reacting a phenolic hydroxyl group in compound (I-1) with an alkylating reagent having a leaving group in the presence of a base.
  • Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc.
  • Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used.
  • This reaction is carried out by reacting compound (I-1) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., and then an equal amount or an excess amount of an alkylating reagent. And the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited.
  • ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N—
  • THF tetrahydrofuran
  • 1,4-dioxane 1,2-dimethoxyethane
  • 1,2-diethoxyethane N, N—
  • examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • This reaction is a method of synthesizing compound (I-3) which is a 1,3-oxazole ring by reacting compound (I-2) with p-toluenesulfonylacetonitrile (C-6).
  • compound (I-2) and p-toluenesulfonylacetonitrile (C-6) are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a base, at room temperature to under reflux.
  • the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • Examples of the base used include carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5. 4.0] -7-undecene (DBU) and other organic amines are used.
  • carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate
  • triethylamine pyridine
  • 4-aminopyridine N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5. 4.0] -7-undecene (DBU) and other organic amines are used.
  • Solvents used in these reactions include toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2 -Dimethoxyethane, 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • solvents used in these reactions include toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2 -Dimethoxyethane,
  • This reaction is a method of synthesizing compound (I-4) by coupling compounds (I-3) and (H-3).
  • Examples of the leaving group represented by Z 7 include an iodine atom, a bromine atom, and a chlorine atom.
  • compounds (I-3) and (H-3) are used in an equal amount or in excess, and the reaction is carried out in a solvent inert to the reaction in the presence of a base, a copper catalyst and a ligand at room temperature to heating.
  • the reaction is usually carried out under reflux for usually 0.5 hours to 3 days.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), Or these mixed solvents etc. are mentioned.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 Ethers such as diethoxyethane, halogenated hydrocarbons such as dich
  • Bases include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, metal alkoxides such as sodium ethoxide, sodium methoxide, triethylamine, N-ethyl -N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) and the like.
  • the copper catalyst include copper chloride, copper bromide, copper iodide, and copper oxide.
  • the ligand include proline, trans-N, N′-dimethylcyclohexane-1,2-diamine, N, N-dimethylaminoacetic acid, 1,10-phenanthroline and the like.
  • This reaction is a method for synthesizing the compound (I-5) of the present invention by deprotecting the protecting group R 5 of the compound (I-4) with an acid or a base.
  • compound (I-4) is usually reacted for 0.5 hours to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • Z 8 and Z 9 represent a leaving group.
  • the leaving group represented by Z 8 and Z 9 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a method of synthesizing compound (J-2) by lithiating or sodiumating the 4-position of pyridine in compound (J-1) with a base and then formylating with a formylating agent.
  • the base include lithium diisopropylamine (LDA) prepared from diisopropylamine and n-butyllithium.
  • LDA lithium diisopropylamine
  • Examples of the formylating agent include N, N-dimethylformamide (DMF) and N-formylmorpholine.
  • DMF N, N-dimethylformamide
  • N-formylmorpholine N, N-dimethylformamide (DMF) and N-formylmorpholine.
  • This reaction is carried out at ⁇ 78 ° C. to 0 ° C. in a solvent inert to the reaction by subjecting compound (J-1) to an equal amount or a small excess of the base, followed by an equal amount or an excess amount of formylation.
  • the reaction is usually performed by adding an agent and reacting for 0.5 to 5 hours. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, or a mixture thereof A solvent etc. are mentioned.
  • Z 8 and Z 9 represent a leaving group
  • Z 10 represents —B (OH) 2 or —B (OR 10 ) OR 11 , where R 10 and R 11 independently represent 1 carbon atom.
  • An alkyl group of ⁇ 6, or R 10 and R 11 together represent an alkylene group of 1 to 6 carbon atoms.
  • compound (J-4) is synthesized by coupling J-3).
  • Examples of the leaving group represented by Z 8 and Z 9 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • compounds (J-2) and (J-3) are used in equal amounts or in excess, and usually in a solvent inert to the reaction in the presence of a base and a palladium catalyst at room temperature to heating under reflux.
  • the reaction is performed for 0.5 hours to 2 days.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • the base examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases And a solution obtained by diluting with water or the like.
  • the palladium catalyst tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.
  • Z 8 represents a leaving group.
  • the leaving group represented by Z 8 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a conversion reaction from a formyl group to a cyano group, and is performed by reacting an aromatic aldehyde derivative represented by the above formula (J-4) with hydroxylamine.
  • hydroxylamine other salts such as hydrochloride thereof may be used. In that case, it is preferable to add an appropriate basic substance.
  • the reaction can be accelerated by adding 1.0 to 3.0 equivalents of acetic anhydride, acetyl chloride, trichloroacetyl chloride and the like.
  • the amount of hydroxylamine or a salt thereof used in these reactions is usually 1 equivalent or more, preferably 1.0 to 2.0 equivalents.
  • 1.0 to 3.0 equivalents are used with respect to the hydroxylamine salt.
  • basic substances to be used carboxylates such as sodium formate, potassium formate and sodium acetate, carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, organic amines such as triethylamine, pyridine and 4-aminopyridine are used. .
  • the reaction is carried out in an inert solvent in the presence of a base at room temperature to heating under reflux, usually for 0.5 hour to 3 days.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • Solvents used in these reactions include acetic acid, formic acid, toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1, Examples include 2-dimethoxyethane, 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), methanol, ethanol, 2-propanol and the like.
  • This reaction is a method of synthesizing compound (J-6) by coupling compound (J-5) and (G-7).
  • Examples of the leaving group represented by Z 8 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • compounds (J-5) and (G-7) are used in equal amounts or in excess, and in a solvent inert to the reaction, in the presence of a base and a transition metal catalyst, optionally a ligand, a carboxyl It is carried out by adding an acid and a copper (I or II) salt and reacting at room temperature to heating under reflux, usually for 0.5 hour to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Bases include lithium hydride, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, tripotassium phosphate, sodium acetate, acetic acid Metal salts of alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts, sodium salts, potassium salts, magnesium salts), metal salts of alkyl anions having 1 to 6 carbon atoms (lithium salts, sodium salts, potassium salts, magnesium salts) ), Tetra (alkyl having 1 to 4 carbon atoms) ammonium (fluoride, chloride, bromide), diisopropylethylamine, tributylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclooctane, or Examples include imidazole.
  • alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts,
  • transition metal catalyst examples include copper, palladium, cobalt, iron, rhodium, ruthenium, and iridium.
  • ligand examples include tri (t-butyl) phosphine, tri (cyclohexyl) phosphine, t-butyldicyclohexylphosphine, di (t-butyl) cyclohexylphosphine, and di (t-butyl) methylphosphine.
  • Copper (I or II) salts include copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) acetate, copper (II) fluoride, copper (II) chloride , Copper bromide (II), copper (II) iodide, copper (II) acetate and hydrates thereof, and mixtures thereof.
  • the carboxylic acid include formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid, pentanoic acid, isopentanoic acid, pivalic acid, and trifluoroacetic acid.
  • This reaction is a reaction in which a tetrazole ring is cyclized from a cyano group, and is performed by reacting an aromatic cyano group derivative represented by the above formula (J-6) with an azide compound in the presence of an acid.
  • compound (J-6) and an azide compound are used in an equal amount or in excess, and in an inert solvent for the reaction, in the presence of an acid, from room temperature to heating under reflux, usually from 0.5 hour to This is done by reacting for 2 days.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the azide compound include sodium azide and trimethylsilyl azide.
  • Examples of the acid to be used include organic acids such as formic acid and acetic acid, inorganic acids such as hydrochloric acid and sulfuric acid, and inorganic salts such as ammonium chloride and ammonium acetate.
  • Solvents used in these reactions include toluene, benzene, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1 , 2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • organic acids such as formic acid and acetic acid
  • inorganic acids such as hydrochloric acid and sulfuric acid
  • inorganic salts such as ammonium chloride and ammonium acetate.
  • This reaction is a method for synthesizing the compound (J-8) of the present invention by deprotecting the protecting group R 5 of the compound (J-7) with an acid or a base.
  • compound (J-7) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • This reaction is a method of synthesizing compound (K-1) by coupling compound (J-4) and (G-7).
  • Examples of the leaving group represented by Z 8 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • compounds (J-4) and (G-7) are used in equal amounts or in excess, and in a solvent inert to the reaction, in the presence of a base and a transition metal catalyst, optionally a ligand, a carboxyl It is carried out by adding an acid and a copper (I or II) salt and reacting at room temperature to heating under reflux, usually for 0.5 hour to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Bases include lithium hydride, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, tripotassium phosphate, sodium acetate, acetic acid Metal salts of alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts, sodium salts, potassium salts, magnesium salts), metal salts of alkyl anions having 1 to 6 carbon atoms (lithium salts, sodium salts, potassium salts, magnesium salts) ), Tetra (alkyl having 1 to 4 carbon atoms) ammonium (fluoride, chloride, bromide), diisopropylethylamine, tributylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclooctane, or Examples include imidazole.
  • alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts,
  • transition metal catalyst examples include copper, palladium, cobalt, iron, rhodium, ruthenium, and iridium.
  • ligand examples include tri (t-butyl) phosphine, tri (cyclohexyl) phosphine, t-butyldicyclohexylphosphine, di (t-butyl) cyclohexylphosphine, and di (t-butyl) methylphosphine.
  • Copper (I or II) salts include copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) acetate, copper (II) fluoride, copper (II) chloride , Copper bromide (II), copper (II) iodide, copper (II) acetate and hydrates thereof, and mixtures thereof.
  • the carboxylic acid include formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid, pentanoic acid, isopentanoic acid, pivalic acid, and trifluoroacetic acid.
  • This reaction is a method of synthesizing a 1,3-oxazole ring by reacting compound (K-1) with p-toluenesulfonylacetonitrile (C-6).
  • compound (K-1) and p-toluenesulfonylacetonitrile (C-6) are used in an equal amount or in excess, and in a solvent inert to the reaction in the presence of a base, from room temperature to heating under reflux.
  • the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • Examples of the base used include carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5. 4.0] -7-undecene (DBU) and other organic amines are used.
  • carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate
  • triethylamine pyridine
  • 4-aminopyridine N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5. 4.0] -7-undecene (DBU) and other organic amines are used.
  • Solvents used in these reactions include toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2 -Dimethoxyethane, 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • solvents used in these reactions include toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2 -Dimethoxyethane,
  • This reaction is a method for synthesizing the compound (K-3) of the present invention by deprotecting the protecting group R 5 of the compound (K-2) with an acid or a base.
  • compound (K-2) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • R 1 is an alkyl group having 1 or 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or an aryl group optionally substituted with a halogen atom. It is common.
  • R 6 represents a protecting group for a phenolic hydroxyl group
  • Z 11 represents a leaving group.
  • the leaving group represented by Z 11 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a method of synthesizing compound (L-2) by reacting a phenolic hydroxyl group in compound (L-1) with an alkylating reagent having a leaving group in the presence of a base.
  • Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc.
  • Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used.
  • This reaction is carried out by reacting the compound (L-1) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., followed by an equal amount or an excess amount of an alkylating reagent. And the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited.
  • ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N—
  • THF tetrahydrofuran
  • 1,4-dioxane 1,2-dimethoxyethane
  • 1,2-diethoxyethane N, N—
  • examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • R 6 represents a protecting group for a phenolic hydroxyl group.
  • This reaction is a method of synthesizing compound (L-3) by lithiating the 4-position of pyridine in compound (L-2) with a strong base and then brominating.
  • an equal amount or a small excess of strong base was added to compound (L-2) in a solvent inert to the reaction at ⁇ 78 ° C. to 0 ° C., and the reaction was usually performed for 0.5 to 12 hours. Later, by adding a bromine source.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the strong base to be used, n-butyllithium, t-butyllithium, s-butyllithium or the like is used.
  • bromination reagent examples include carbon tetrabromide.
  • the solvent is not particularly limited, and examples thereof include ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane.
  • R 6 represents a protecting group for a phenolic hydroxyl group.
  • This reaction is a method for synthesizing compound (L-4) by deprotecting protecting group R 6 of compound (L-3) with an acid or a base.
  • compound (L-3) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • Z 1 represents a leaving group.
  • the leaving group represented by Z 1 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a method of synthesizing compound (L-5) by reacting a phenolic hydroxyl group in compound (L-4) with an alkylating reagent having a leaving group in the presence of a base.
  • Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc.
  • Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used.
  • This reaction is carried out by reacting the compound (L-4) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., and then an equal amount or an excess amount of an alkylating reagent. And the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited.
  • ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N—
  • THF tetrahydrofuran
  • 1,4-dioxane 1,2-dimethoxyethane
  • 1,2-diethoxyethane N, N—
  • examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • This reaction is a method of synthesizing compound (L-6) by oxidizing the methyl group at the 2-position of pyridine in compound (L-5) with an oxidizing agent.
  • an oxidizing agent to be used, a manganese salt such as potassium permanganate is used.
  • an equal amount or a small excess of an oxidizing agent is added to compound (L-5) in a solvent inert to the reaction at 0 ° C. to 120 ° C., and the reaction is usually performed for 0.5 hour to 2 days. Is done by.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited.
  • ethers such as 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N-dimethylformamide (DMF), water or These mixed solvents are exemplified.
  • This reaction is a method of synthesizing the amide compound (L-7) by reacting the carboxyl group of the compound (L-6) with ammonia.
  • This reaction is performed according to literature methods (for example, peptide synthesis basics and experiment, Nobuo Izumiya et al., Maruzen, 1983, Comprehensive Organic Synthesis, Vol. 6, Pergamon Press, 1991, etc.)
  • the conventional amide formation reaction may be carried out by a method according to the above or a combination thereof with a conventional method, that is, by using a condensing agent well known to those skilled in the art, or an ester available to those skilled in the art.
  • amide-forming reagents include thionyl chloride, oxalyl chloride, N, N-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridinium iodide, N, N′-carbonyldiimidazole, diphenylphosphoryl chloride, diphenyl.
  • thionyl chloride, oxalyl chloride, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3 -Tetramethyluronium, hexafluorophosphate, etc. are preferred.
  • a base and a condensation aid may be used together with the amide forming reagent. Examples of the condensation aid used include N-hydroxybenzotriazole hydrate and N-hydroxysuccinimide.
  • compound (L-6) and ammonia are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a condensing agent and a base, usually at room temperature to heating under reflux, usually 0.5 It is carried out by reacting for a time to 3 days.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), Examples thereof include pyridine or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 Ethers such as diethoxyethane, halogenated hydrocarbons
  • Examples of the base used include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N, N-dimethylaniline, and 1,8-diazabicyclo [5.
  • tertiary aliphatic amines such as undec-7-ene, 1,5-azabicyclo [4.3.0] non-5-ene; pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline or Examples include aromatic amines such as isoquinoline, among which tertiary aliphatic amines are preferable, and triethylamine or N, N-diisopropylethylamine is particularly preferable.
  • This reaction is a method of synthesizing compound (L-8) by dehydrating the amide group of compound (L-7) with an acid.
  • This reaction is carried out by reacting compound (L-7) with an acid in an equivalent amount or in excess in a solvent inert to the reaction, usually at room temperature to heating under reflux, usually for 0.5 hour to 5 days. Done.
  • the solvent is not particularly limited, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform.
  • the acid include thionyl chloride, oxalyl chloride, phosphoryl chloride, and phenylphosphonyl dichloride.
  • Z 2 represents —B (OH) 2 or —B (OR 10 ) OR 11 , wherein R 10 and R 11 are independently an alkyl group having 1 to 6 carbon atoms, or R 10 and R 11 together represents an alkylene group having 1 to 6 carbon atoms.
  • Examples of the leaving group represented by Z 2 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a method of synthesizing compound (L-9) by coupling reaction of compound (L-8) and a heterocyclic compound having boric acid or boric acid ester.
  • the compound (L-8) and the heterocyclic compound are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a base and a palladium catalyst, from room temperature to heating under reflux, usually 0. It is carried out by reacting for 5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • the base examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases And a solution obtained by diluting with water or the like.
  • the palladium catalyst tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.
  • This reaction is a conversion reaction from a cyano group to a thioamide group, and is performed by reacting an aromatic cyano group derivative represented by the above formula (L-9) with a sulfur source under acidic conditions.
  • compound (L-9) and a sulfur source are used in an equal amount or in excess, and in an inert solvent for the reaction, in the presence of an acid, at room temperature to heating under reflux, usually 0.5 hours to 2 This is done by reacting for a day.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Hydrogen sulfide, thioacetamide or thioacetic acid is used as the sulfur source.
  • the acidic substance organic acids such as hydrochloric acid, sulfuric acid and acetic acid, or aqueous solutions of these acids are used.
  • the solvent is not particularly limited.
  • aromatic hydrocarbons such as benzene, toluene and xylene, alcohols such as methanol and ethanol, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1, Examples thereof include ethers such as 2-dimethoxyethane and 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • An acid such as acetic acid can also be used as a solvent.
  • Z 3 represents a leaving group.
  • the leaving group represented by Z 3 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • compounds (L-10) and (A-6) are used in an equal amount or in excess, and the reaction is inert to the reaction at room temperature to heating under reflux, usually for 0.5 hour to 2 days. This is done by reacting. Further, an equal amount or an excess amount of a base can be added. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as
  • Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, triethylamine, N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
  • inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate
  • metal alkoxides such as sodium ethoxide and sodium methoxide
  • triethylamine N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
  • This reaction is a method for synthesizing the compound (L-12) of the present invention by deprotecting the protecting group R 5 of the compound (L-11) with an acid or a base.
  • compound (L-11) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • Z 1 and Z 12 each represent a leaving group.
  • the leaving group represented by Z 1 and Z 12 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a method of synthesizing compound (M-2) by reacting a phenolic hydroxyl group in compound (M-1) with an alkylating reagent having a leaving group in the presence of a base.
  • Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc.
  • Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used.
  • This reaction is carried out by reacting compound (M-1) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., followed by an equal amount or an excess amount of an alkylating reagent. And the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited.
  • ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N—
  • THF tetrahydrofuran
  • 1,4-dioxane 1,2-dimethoxyethane
  • 1,2-diethoxyethane N, N—
  • examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • Z 12 represents a leaving group.
  • Examples of the leaving group represented by Z 12 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a method of synthesizing compound (M-3) by lithiating the 4-position of pyridine in compound (M-2) with a strong base and then formylating. In this reaction, an equal amount or a small excess of strong base was added to compound (M-2) at ⁇ 78 ° C. to 0 ° C. in a solvent inert to the reaction, and the reaction was usually carried out for 0.5 to 12 hours.
  • a formylating agent is added.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • an inert gas atmosphere such as nitrogen.
  • the strong base to be used n-butyllithium, t-butyllithium, s-butyllithium or the like is used.
  • the formylation reagent include methyl formate, hexamethylenetetramine, N, N-dimethylformamide and the like.
  • the solvent is not particularly limited, and examples thereof include ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane.
  • Z 12 represents a leaving group.
  • the leaving group represented by Z 12 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • This reaction is a method of synthesizing a 1,3-oxazole ring by reacting compound (M-3) with p-toluenesulfonylacetonitrile (C-6).
  • compound (M-3) and p-toluenesulfonylacetonitrile (C-6) are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a base, at room temperature to heating under reflux.
  • the reaction is usually carried out for 0.5 hours to 2 days.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the base used include carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.
  • DBU dimethyl sulfoxide
  • Solvents used in these reactions include toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2 -Dimethoxyethane, 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.
  • solvents used in these reactions include toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,
  • This reaction is a method of synthesizing compound (M-5) by coupling compound (M-4) and (H-3).
  • Examples of the leaving group represented by Z 12 include an iodine atom, a bromine atom, and a chlorine atom.
  • compounds (M-4) and (H-3) are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a base, a copper catalyst and a ligand, from room temperature to heating
  • the reaction is usually carried out under reflux for usually 0.5 hours to 3 days.
  • This reaction is preferably carried out in an inert gas atmosphere such as nitrogen.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), Or these mixed solvents etc. are mentioned.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 Ethers such as diethoxyethane, halogenated hydrocarbons such as dich
  • Bases include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, metal alkoxides such as sodium ethoxide, sodium methoxide, triethylamine, N-ethyl -N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) and the like.
  • the copper catalyst include copper chloride, copper bromide, copper iodide, and copper oxide.
  • the ligand include proline, trans-N, N′-dimethylcyclohexane-1,2-diamine, N, N-dimethylaminoacetic acid, 1,10-phenanthroline and the like.
  • This reaction is a method for synthesizing the compound (M-6) of the present invention by deprotecting the protecting group R 5 of the compound (M-5) with an acid or a base.
  • compound (M-5) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done.
  • the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent.
  • Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
  • the pharmaceutically acceptable salt of the compound represented by the formula (I) is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • a salt include hydrogen chloride, Salts with inorganic acids such as hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, carbonic acid; maleic acid, fumaric acid, citric acid, malic acid, tartaric acid, lactic acid, succinic acid, benzoic acid, oxalic acid, methanesulfonic acid, benzene Salts with organic acids such as sulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, formic acid; salts with amino acids such as glycine, lysine, arginine, histidine, ornithine, glutamic acid, aspartic acid; sodium, potassium, lithium Salts with alkali metals such as calcium; Salts with alkaline earth metals such as calcium and magnesium; Salt
  • present invention (I) and salts thereof include various hydrates and solvates.
  • the compounds of the present invention also include stereoisomers, racemates, and all possible optically active forms of the compounds represented by formula (I).
  • the compound represented by the formula (I) of the present invention and a pharmaceutically acceptable salt thereof have particularly excellent xanthine oxidase inhibitory activity. Due to its excellent xanthine oxidase inhibitory activity, the compounds represented by the formula (I) of the present invention and pharmaceutically acceptable salts thereof are useful as xanthine oxidase inhibitors.
  • the compound represented by the formula (I) of the present invention and a pharmaceutically acceptable salt thereof are clinically applicable as a xanthine oxidase inhibitor, gout, hyperuricemia, oncolysis syndrome, urolithiasis , Hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, kidney diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease or autoimmune disease It can be used as a therapeutic or prophylactic agent for diseases involving xanthine oxidase.
  • prevention means prevention of morbidity or onset in an individual who has not yet been affected or developed
  • treatment refers to disease or It means healing, suppressing or ameliorating symptoms.
  • the compound represented by the formula (I) and a pharmaceutically acceptable salt thereof can be made into a pharmaceutical composition together with a pharmaceutically acceptable carrier and / or diluent.
  • This pharmaceutical composition can be formed into various dosage forms and administered orally or parenterally.
  • Parenteral administration includes, for example, intravenous, subcutaneous, intramuscular, transdermal, or rectal administration.
  • Formulations containing one or more of the compounds represented by the formula (I) of the present invention or salts thereof as active ingredients are prepared using carriers, excipients and other additives that are usually used for formulation.
  • the carrier or excipient for the preparation may be either solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, etc.
  • Administration may be in any form of oral administration such as tablets, pills, capsules, granules, powders, liquids, or parenteral administration such as injections such as intravenous injection and intramuscular injection, suppositories, and transdermal. Good.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof varies depending on the type of disease, administration route, patient symptom, age, sex, body weight, etc. It can be administered in the range of 0.01 to 1000 mg per dose or divided into several doses. However, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient, or a dose exceeding the above range may be required.
  • Mass that is, actual measurement in which proton (H + ) was added to the molecular mass (M) of the compound, which was observed by the apparatus and analysis conditions described below. value), the calculated value of "M + + H” (pred. Mass), actually measured "M + + H” value calculated from the composition formula of (formula) are also shown.
  • the resulting crude product is purified by a conventional method to obtain 67.0 mg of 4-isobutoxy-3- (pyridin-2-yl) benzonitrile. It was. ESI / MS m / e: 253.1 (M + + H, C 16 H 17 N 2 O) (4) 67.0 mg of 4-isobutoxy-3- (pyridin-2-yl) benzonitrile was suspended in 0.3 mL of acetic acid and 0.5 mL of thioacetic acid, and heated at 50 ° C. for 14 hours under a nitrogen atmosphere. Thereafter, concentration under reduced pressure was performed to obtain a crude product of 4-isobutoxy-3- (pyridin-2-yl) benzene-1-carbothioamide.
  • Example 2-6 In the same manner as in Example 1, Compound Nos. 2 to 6 were synthesized.
  • Example 8-17 In the same manner as in Example 7, compound numbers 8 to 17 were synthesized.
  • reaction mixture was concentrated and purified by a conventional method, and 37.2 mg of 4-methyl-2- [4-isobutoxy-3-isothiazol-4-yl-phenyl] -1,3-thiazole-5-carboxylic acid was obtained. Obtained.
  • Example 55-66 In the same manner as in Example 18, compound numbers 55 to 66 were synthesized.
  • Example 68 Compound No. 68 was synthesized in the same manner as Example 67.
  • Ethyl 2- (4-hydroxy-3-oxazol-5-yl-phenyl) -4-methyl-1,3-thiazole-5-carboxylate (33.0 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure to give ethyl 2- [4- (cyclobutylmethoxy) -3-oxazol-5-yl) phenyl] -4-methyl-1,3-thiazole- A crude product of 5-carboxylate was obtained.
  • Example 70-83 Compound Nos. 70 to 83 were synthesized in the same manner as Example 69.
  • Example 85 Compound No. 85 was synthesized in the same manner as Example 84.
  • Example 88-105 Compound Nos. 88 to 105 were synthesized in the same manner as in Examples 86 and 87.
  • Example 108-141 In the same manner as in Example 107, Compound No. 108 - was synthesized 141.
  • Example 146 Compound No. 146 was synthesized in the same manner as Example 145.
  • Examples 150-162 In the same manner as in Example 149, Compound No. 150 - was synthesized 162.
  • Example 164 to 166 In the same manner as in Example 163, compound numbers 164 to 166 were synthesized.
  • Example 168 Compound No. 168 was synthesized in the same manner as Example 167.
  • Example 169 Synthesis of 2- (4-oxazol-5-yl-5-phenyl-2-pyridyl) -1,3-thiazole-5-carboxylic acid (Compound No. 169 ) (Synthesis Method K) (1) To 312 mg of 2-chloro-5-phenylpyridine-4-carbaldehyde obtained in Example 167, 306 mg of potassium bicarbonate, 12.9 mg of palladium (II) chloride, and 59.8 mg of copper (I) bromide were added. In addition, it was suspended in 4.0 mL of toluene.
  • Example 170 Compound No. 170 was synthesized in the same manner as Example 169.
  • the reaction mixture was acidified with 2M hydrochloric acid, 2M aqueous sodium hydroxide solution and methylene chloride were added and separated, and the aqueous layer was acidified again with 2M hydrochloric acid to give 4-bromo-5-isobutoxypyridine- 1.3 g of 2-carboxylic acid was obtained.
  • (6) Suspend 1.3 g of 4-bromo-5-isobutoxypyridine-2-carboxylic acid in 10 mL of N, N-dimethylformamide, add 722 mg of oxalyl chloride, and stir at room temperature for 2 hours in a nitrogen atmosphere. After that, 20 mL of methylene chloride was added, and aqueous ammonia was added dropwise at 0 ° C.
  • the mixture was made turbid, 45 mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was heated at 100 ° C. for 12 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated under reduced pressure, and purified by a conventional method to obtain 85 mg of 5-isobutoxy-4- (pyrimidin-5-yl) pyridine-2-carbonitrile.
  • Example 173 and 174 In the same manner as in Example 172, compound numbers 173 and 174 were synthesized.
  • Example 175 Synthesis of 1- (5-isobutoxy-4-oxazol-5-yl-2-pyridyl) -1H-pyrazole-4-carboxylic acid (Compound No. 175 ) (Synthesis Method M)
  • 2-Bromo-5-isobutoxypyridine-4-carbaldehyde was obtained from 2-bromo-5-hydroxypyridine in the same manner as in Example 171.
  • Example 176 About the compound synthesize
  • Preparation of test compound A test compound was dissolved in DMSO (manufactured by Sigma) so as to have a concentration of 20 mM, and then adjusted to a target concentration at the time of use.
  • Measurement method The xanthine oxidase inhibitory activity of the compounds of the present invention was evaluated by partially modifying the method described in the literature (Method Enzymatic Analysis, 1,521-522, 1974). This evaluation is based on the evaluation of oxidase type xanthine oxidase inhibitory activity.
  • a xanthine (manufactured by Sigma) solution prepared to 10 mM in a 20 mM sodium hydroxide solution in advance was prepared to 30 ⁇ M using a 100 mM phosphate buffer, and 75 ⁇ L / well was added to a 96-well plate.
  • Each test compound diluted with DMSO to a final concentration of 100 times was added at 1.5 ⁇ L / well, and after mixing, the absorbance at 290 nm was measured with a microplate reader SPECTRA max Plus 384 (manufactured by Molecular Devices).
  • oxidase-type xanthine oxidase (derived from buttermilk, Calbiochem) was prepared to 30.6 mU / mL using 100 mM phosphate buffer, and 73.5 ⁇ L / well was added. Immediately after mixing, the change in absorbance at 290 nm was measured for 5 minutes. The inhibition rate of the test compound was calculated by setting the enzyme activity when DMSO was added instead of the test compound solution as 100%, and a 50% inhibitory concentration against the oxidase type xanthine oxidase was calculated by fitting to a dose response curve. The results are shown in the following table. However, the symbols (+, ++, ++) in the table represent the inhibitory activity values as follows. 10.0 nM ⁇ IC 50 : + 5.0 nM ⁇ IC 50 ⁇ 10.0 nM: ++ 1.0 nM ⁇ IC 50 ⁇ 5.0 nM: +++
  • Example 177 Blood uric acid lowering effect (normal rat) The compounds Nos. 6 , 67 and 86 were confirmed to have a blood uric acid lowering effect. Test compounds suspended in 0.5% methylcellulose solution were forcibly administered to male Sprague-Dawley rats (Charles River Japan Co., Ltd.) 8-9 weeks old using an oral sonde. Two hours after administration, blood was collected from the tail vein, and plasma was separated. The blood uric acid level was measured using a uric acid measurement kit (L type Wako UA • F: Wako Pure Chemical Industries) with an absorptiometer by the uricase method, and the uric acid reduction rate was determined by the following equation.
  • a uric acid measurement kit L type Wako UA • F: Wako Pure Chemical Industries
  • Uric acid reduction rate (%) (Uric acid level of control animals ⁇ Uric acid level of animals receiving test compound) ⁇ 100 / Uric acid level of control animals
  • Compound Nos. 6 , 67 and 86 were administered at a dose of 10 mg / kg at 2 hours after administration.
  • the uric acid reduction rate was 50% or more. As described above, the strong uric acid lowering action of the compound of the present invention was shown.
  • the compound represented by the above formula (I) of the present invention and a pharmaceutically acceptable salt thereof have xanthine oxidase inhibitory activity and are clinically applicable as xanthine oxidase inhibitors.
  • Respiratory organs such as uricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, renal diseases such as diabetic nephropathy, chronic obstructive pulmonary disease It can be used as a therapeutic or prophylactic agent for diseases involving xanthine oxidase such as diseases, inflammatory bowel diseases or autoimmune diseases.

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Abstract

L'invention concerne un composé indiqué par la formule (I), un sel pharmaceutiquement acceptable de celui-ci, ou un médicament ou une composition pharmaceutique contenant ceux-ci en tant que principe actif de celui-ci, ledit composé ayant une excellente activité inhibitrice de la xanthine oxydase et étant efficace en tant qu'agent de traitement ou agent prophylactique de maladies associées à la xanthine oxydase, telles que la goutte, l'hyperuricémie, le syndrome de lyse tumorale, les calculs urinaires, l'hypertension, la dyslipidémie, le diabète, les maladies cardiovasculaires telles que l'artériosclérose et l'insuffisance cardiaque, les maladies rénales telles que la néphropathie diabétique etc, les maladies respiratoires telles que la broncho-pneumopathie chronique obstructive, etc. et les maladies auto-immunes telles que la maladie inflammatoire chronique de l'intestin, etc.
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WO2017142091A1 (fr) 2016-02-19 2017-08-24 国立大学法人鳥取大学 Médicament thérapeutique ou prophylactique pour la démence
CN113024534A (zh) * 2019-12-24 2021-06-25 武汉光谷亚太医药研究院有限公司 2-吡啶基噻唑衍生物及其应用

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US20130190366A1 (en) * 2010-02-19 2013-07-25 Cadila Healthcare Limited Substantially pure salts of febuxostat and processes for preparation thereof
JP5378988B2 (ja) * 2007-04-11 2013-12-25 キッセイ薬品工業株式会社 ５員環へテロ環誘導体及びその医薬用途

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JP5378988B2 (ja) * 2007-04-11 2013-12-25 キッセイ薬品工業株式会社 ５員環へテロ環誘導体及びその医薬用途
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Publication number Priority date Publication date Assignee Title
WO2017142091A1 (fr) 2016-02-19 2017-08-24 国立大学法人鳥取大学 Médicament thérapeutique ou prophylactique pour la démence
CN109069490A (zh) * 2016-02-19 2018-12-21 国立大学法人鸟取大学 痴呆症治疗药或预防药
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CN113024534A (zh) * 2019-12-24 2021-06-25 武汉光谷亚太医药研究院有限公司 2-吡啶基噻唑衍生物及其应用
CN113024534B (zh) * 2019-12-24 2023-03-21 武汉光谷亚太医药研究院有限公司 2-吡啶基噻唑衍生物及其应用

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