Classifications

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  • 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
  • A61K31/4164—1,3-Diazoles
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  • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
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  • 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
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  • 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
  • A61K31/415—1,2-Diazoles
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  • 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
  • A61K31/428—Thiazoles condensed with carbocyclic rings
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—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
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
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  • 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
  • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • 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
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
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  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/12—Radicals substituted by oxygen atoms

Definitions

• the present invention relates to a novel heteroaryl compound having an antidiabetic action or a salt thereof. More specifically, the present invention relates to a novel heteroaryl compound having an antidiabetic action that improves insulin resistance and controls blood glucose more safely. More specifically, a novel protein having a peroxisome proliferator-activated receptor (PPAR) activating action, a PPAR activating action, a PPAR ⁇ / activating action, or a PPAR ⁇ / ⁇ activation-modulating action. It relates to a teloaryl compound.
• PPAR peroxisome proliferator-activated receptor
• Sulfonylprea which has been known for a long time, is widely used to reduce insulin secretion, but there is a danger of hypoglycemia as a serious side effect and obesity is likely to occur.
• Rosiglitazone which is used in Europe and the United States, is also reported to have side effects such as upper respiratory tract infection, anemia, edema, and weight gain.
• Thiazolidinedione-based drugs have no concern about liver damage, circulatory side effects, etc. Has not yet been released. It is thought that thiazolidinedione drugs exert an antidiabetic effect by activating PPART /. ? Eight!
• fibrate drugs used as therapeutic agents for hyperlipidemia such as clofibrate and fenofibrate
• PPAR ⁇ activators may have a favorable effect not only on hyperlipidemia but also on diabetes. It is getting.
• Object of the present invention is to Sho resolution has P PAR alpha activating activity, P PAR gamma activation operation for, P PAR alpha / gamma activation activity or P PAR alpha / gamma activation. Regulatory action, insulin
• An object of the present invention is to provide a drug for preventing or treating diabetes which has improved resistance and excellent safety.
• the present inventors have conducted intensive studies and found that a novel heteroaryl compound activates PPAR ", PPARy, or PPARa / ⁇ , or modulates PPAR ⁇ activity to improve insulin resistance.
• the present invention has improved hyperglycemia and excellent safety and is useful for the prevention and treatment of diabetes, and completed the present invention.
• salt and the like That is, the present invention
• ring Z is an optionally substituted pyrrole ring, an optionally substituted pyrazole ring, an optionally substituted imidazole ring, an optionally substituted triazole ring, an optionally substituted indole ring, Represents an optionally substituted indazole ring, or an optionally substituted benzoimidazole ring,
• W 2 represents a single bond, One SO-, - S0 2 -, - CONR 2 -, one S0 2 NR 2 -, it may be substituted, a further two hydrogen atoms are replaced by an oxygen atom a carbonyl methylene C 2 -C 4 alkenylene, which may be formed, C 2 -C 4 alkylene, which may be substituted, and which may form a carbonyl by replacing two hydrogen atoms of methylene with an oxygen atom, or May represent a C 2 —C 4 alkynylene, in which two hydrogen atoms of methylene may be replaced by oxygen atoms to form a carbonyl;
• Ar 2 represents an optionally substituted aryl or an optionally substituted heteroaryl
• W 1 is an optionally substituted C "C 5 alkylene, optionally substituted C 2 - C 5 Al Keniren, optionally substituted C 2 - C 5 alkynylene, One Y- W 3 - (wherein, Y represents an oxygen atom, a sulfur atom or NR 2,, W 3 is one may be substituted C 4 Al Killen, optionally substituted C 2 - C 4 alkenylene or optionally substituted C 2, — C represents alkynylene :), Formula (2)
• Ar 1 represents an optionally substituted arylene or an optionally substituted heteroarylene
• X 1 is one SO ? —, One CONR 3 SO.
• W 4 represents an optionally substituted C, _C 4 alkylene
• R 1 is a carboxyl, an alkoxycarbonyl, an optionally substituted carbamoyl, an optionally substituted cyclic aminocarbonyl, an optionally substituted alkylsulfonyl aldumbamoyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted hetero arylsulfonyl carbamoylthiopheno Honoré to good, Tetorazorinore, 2, 4-Okisazori Jinjion one 5- I le, or have a substituent selected from Shiano may be further substitution CI- C 4 alkyl, halogen An atom, alkoxy optionally substituted by halogen, or one or more substituents selected from amino acid side chains, C, —C 4 alkyl, C 2 —C 4 Alkenyl, or the force that represents C 2 —C 4 alkynole,
• R 3 is carboxyl, alkoxycarbol, carbamoyl which may be substituted, cyclic aminocarbonyl which may be substituted, alkylsulfonylcarbamoyl which may be substituted, aryl which may be substituted
• Y 3 represents a single bond, an oxygen atom, or an optionally substituted nitrogen atom.
• the substituent R 7 represents a hydroxyl, alkyl, alkoxy, Al Kiruamino, m 3
• n 3 is an integer of 1 to 4
• R 21 is carboxyl, alkoxycarbonyl, substituted Optionally substituted cyclic aminocarbonyl, optionally substituted alkylsulfonylcarbamoyl, optionally substituted arylsulfonylcarbamoyl, optionally substituted heteroarylsulfonylcarbamoyl, tetrazolyl, 2, 4-O hexa oxazolidinedione one 5- I le or an Shiano, R 21 may be substituted CI- C alkyl or an Okiso, m 4, n 4 is an integer of 1 to 4, And
• R 2 , R 3 , R 4 , and R 5 are the same or different and each represent a hydrogen atom, an alkyl, or an optionally substituted arylenequinole;
• R 6 represents an alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted aralkyl.
• R 8 may be one or more, independently a hydrogen atom, a halogen atom, or an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted aryl, And the bond may be in any direction.
• R 8 may be one or more, independently a hydrogen atom, a halogen atom, or an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted aryl, And the bond may be in any direction.
• W 2 is one CONR 2 _, which may be substituted, and wherein two hydrogen atoms of methylene may be substituted with an oxygen atom to form carbonyl, C, one C 4 alkylene, or substituted C 2 —C 4 alkenylene, which may further form a carbonyl by replacing two hydrogen atoms of methylene with an oxygen atom,
• X 1 is _S0 2 —, — NR 3 SO 2 —, one NR 3 CO—, one SO. NR 3 CO—, one
• W 2 may be substituted, or two or more hydrogen atoms of methylene may be substituted with an oxygen atom to form carbonyl, C, 1 C 4 alkylene, or may be substituted.
• heteroaryl compound according to any one of the above (1) to (6), wherein W 2 is one CO—, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
• W 1 is optionally substituted C, mono-C 5 alkylene, optionally substituted C 2 —C 5 alkenylene, or — ⁇ —w 3 — (wherein Y is an oxygen atom And W 3 is an optionally substituted C, 1 C 4 alkylene.)
• Ar 1 is phenylene which may be substituted, and as a substitution mode, X 1 is a meta-position or a para-position with respect to the bonding position of W 1 .
• Ar 1 is optionally substituted phenylene, W 1 is trans C 3 —C 4 alkenylene, ⁇ is substituted at the meta position with respect to the bonding position of W 1 , and — NR 3 S 0 2 -, or a NR 3 CO- in the above (1) - hetero Ariru compound to the any one of (13), a prodrug thereof or their pharmaceutically acceptable salts.
• R 1 is a C 4 alkyl that requires carboxyl, and the alkyl is one or more selected from C, —C 4 alkyl or a side chain of an amino acid which may be further substituted.
• R 1 has a carboxyl, and the ⁇ -position of the carboxyl is substituted with two quaternary carbons (identical or different, optionally substituted C, 1 C 4 alkyl, or it is the two substituents may form a connexion ring such together with quaternary carbon bonded), Teroari Lumpur into the claimed any above which is an C 4 alkyl (1) i (14) A compound, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
• W 2 is a single bond, - SO-, - S0 2 -, one CONR 2 -, _SO 2 NR 2 -, may be substituted, is further substituted with two hydrogen atoms are oxygen atoms of the methylene groups carbonylation C 2 -C 4 alkenylene which may form a carbonyl, which may be substituted by one C 4 alkylene, which may be substituted, or wherein two hydrogen atoms of a methylene group may be replaced by an oxygen atom. Or two substituted hydrogen atoms of a methylene group may be an oxygen atom.
• Ar 2 represents an optionally substituted aryl, or an optionally substituted heteroaryl
• W 1 is substituted one may C 5 alkylene, optionally substituted C 2 - C 5 Al Keniren, optionally substituted C 2 - C 5 alkynylene or a Y- W 3, - (wherein, Y represents an oxygen atom, a sulfur atom, or NR 2 , and W 3 represents an optionally substituted Ci—C 4 alkylene, an optionally substituted C 2 —C 4 alkenylene, or an optionally substituted C 2 — represents C 4 alkynylene.
• Ar 1 represents an optionally substituted arylene or an optionally substituted heteroarylene
• R 1 is carboxyl, alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted cyclic aminocarbonyl, optionally substituted alkylsulfonyl aldumbamoyl, optionally substituted arylsulfonylcarbamoyl, tetrazolyl, or cyano C 4 alkyl, C 2 -C 4 alkenyl, or C 2 _C 4 , which has a substituent selected from the group consisting of C 4 alkyl, a halogen atom, and an amino acid which may be substituted with a side chain. Represents alkynyl,
• R 3 , R 4 , and R 5 are the same or different and each represents a hydrogen atom, an alkyl, or an optionally substituted aralkyl.
• Ring Z is the formula (8)
• R 8 may be one or more, and independently represents a hydrogen atom, a halogen atom, or an optionally substituted alkyl.
• W 1 is one which may be substituted C 5 alkylene, optionally substituted C 2 - C 5 alkenylene, optionally substituted C 2 - C 5 Aruki two alkylene or _Y- W 3, -
• Y represents an oxygen atom, a sulfur atom, or NR
• W 3 is an optionally substituted Ci—C alkylene, an optionally substituted C 2 _C 4 alkenylene, or an optionally substituted C 2 — represents C 4 alkynylene.
• W 2 ' is a single bond, One -CONR-, 2 hydrogen atoms oxygen atom substituted by formed a good Ci one C 4 alkylene optionally the Karuponiru yo be substituted ,, further methylene groups, substituted And C 2 —C 4 alkenylene which may form a carbonyl by replacing two hydrogen atoms of a methylene group with an oxygen atom.
• Ar 1 represents an optionally substituted aryl, or an optionally substituted heteroaryl,
• Ar 2 represents an optionally substituted aryl or an optionally substituted heteroaryl
• X 1 represents one NRS0 2 —, — NRCO—, — S0 2 NR—, — CONR—, —0 CONR—, one NRCONR—, or one NR CO— O—,
• R 1 ′ has a group selected from carboxyl, alkoxycarbonyl, optionally substituted rubamoyl, optionally substituted cyclic aminocarbonyl, and tetrazolyl, and further includes C, —C 4 alkyl, a halogen atom, and an amino acid. may be substituted with side chains of, Ci one C 4 alkyl, C 2 - C 4 7 alkenyl, or C 2 - C 4 alkynyl, R 8 may be a one or more, independently R represents a hydrogen atom, a halogen atom, or an optionally substituted alkyl, and R is the same or different and represents a hydrogen atom or an alkyl. Or a prodrug thereof or a pharmaceutically acceptable salt thereof.
• Two hydrogen atoms of W 2 1 methylene may be replaced by oxygen atoms to form a carbonyl, optionally substituted —C 4 alkylene, or optionally substituted C 2 —C 4
• W 1 force optionally substituted C t —C 5 alkylene, optionally substituted C 2 _C 5 alkenylene, or —Y—W 3 — (wherein Y is an oxygen atom; 3 is an optionally substituted C, —C 4 alkylene.)
• a r 1 ⁇ ⁇ is phenylene which may be substituted, and is in the meta or para position with respect to the bonding position of X 1 or W 1 in the substitution mode.
• W 1 force trans C 3 --C 4 alkenylene, which is substituted at the meta position relative to the X 1 force W 1 bond position. and one NRS0 2 -, or a single NRCO-, R is the same
• PPAR agonist, PPARyagonis comprising the heteroaryl compound, prodrug or pharmaceutically acceptable salt thereof according to any one of (1) to (28) above as an active ingredient Or PPARa / ⁇ agonist.
• a prophylactic or therapeutic agent for diabetes comprising the heteroaryl compound according to any one of (1) to (28) above, a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
• a therapeutic agent for lowering blood lipids comprising, as an active ingredient, the heteroaryl compound according to any one of the above (1) to (28), a prodrug thereof or a pharmaceutically acceptable salt thereof.
• An insulin desensitizing agent comprising, as an active ingredient, the heteroaryl compound according to any one of the above (1) to (28), a prodrug thereof, or a pharmaceutically acceptable salt thereof.
• a medicament comprising, as an active ingredient, the heteroaryl compound according to any one of the above (1) to (28), a prodrug thereof, or a pharmaceutically acceptable salt thereof.
• a PPARy partial agonist, an antagonis comprising, as an active ingredient, the heteroaryl compound according to any one of the above (1) to (28), a prodrug thereof or a pharmaceutically acceptable salt thereof. Or PPARaZy activation regulator (modulator).
• heteroaryl compound represented by the formula (1) according to the present invention in the formula is specifically described below.
• Examples of the pyrrole ring in ring Z include pyrrole-1,2-diyl, pyrrole-1,3-diyl, pyrrole-1,3,4-diyl and the like, and examples of the pyrazole ring include pyrazole-1,5-diyl, pyrazole 1 1, 4-Jiru, Pyrazole 1, Examples of the imidazole ring include, for example, imidazole-1,2-diyl, imidazole-1,5-diyl, imidazole-11,4-diinole, and imidazole-4,5-diyl.
• Is for example, 1,2,4-triazole-1,5-diyl, 1,2,4-triazole-1,3-diyl, 1,3,4-triazole-1,2-diyl, etc.
• examples include indole-1,2-diyl, indole-1,3-diyl, indonele-1,6-diinole, and the like.
• examples of the indazole ring include, for example, indazole-1,3_diyl and the like, and examples of the benzoimidazole ring. And benzimidazole-1,2, -diyl and the like.
• one C 4 alkylene hydrogen atom can form a carbonyl substituted with an oxygen atom of the methylene group, for example, linear or branched . ⁇ one.
• the C 4 7 Luque two alkylene include straight-chain or branched-chain Having C 2 _C 4 alkenylene, specifically cis or trans vinylene, cis or trans 1-propenylene, cis or trans 12-propenylene, cis or trans 1-butenylene, cis or trans 1- 2-butenylene, cis or trans 3- 3-butenylene, cis or trans 1-oxo 1- 2-propenylene, cis or trans 1- 3-oxo 1- 1-propenylene, cis or trans 1- 1-oxo 1 2-butenylene, cis or trans-1-oxo-1 1-butenylene, cis or trans 2-methyl-1-oxoxo2-prodini Down, cis or trans one 3-methylcarbamoyl ⁇ - 1- Okiso one 2- Purobe two alkylene and
• Two hydrogen atoms of methylene, which may be substituted, in W 2 may be oxygen atoms
• Examples of the C 2 —C 4 alkynylene which may be substituted with to form a carbonyl include straight-chain or branched-chain C 2 _C 4 alkynylene, specifically, ethinylene, 1-propynylene, 3-methyl- 1-propynylene, 2-propynylene, 1-oxo-12-propynylene and the like.
• the Ariru of Ariru may be substituted in the A r 2, for example phenyl, 1-naphthyl, 2-naphthyl and the like. Preferably phenyl is used.
• heteroaryl may be substituted in the A r 2, if example embodiment, nitrogen atom, oxygen atom, monocyclic or bicyclic containing 1 to 3 heteroatoms arbitrarily selected from the group consisting of sulfur atoms Heteroaryl.
• monocyclic 5-membered heteroaryl such as thiophene, furan, pyrrole, imidazo ⁇ , pyrazo ⁇ ⁇ thiazole, oxazole, isothiazole, and isooxazole, pyridine, pyrimidine, pyrazine, pyridazine
• Monocyclic 6-membered heteroaryl such as triazine, indole, isoindole, indolizine, indazole, purine, 4-diquinolysine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, benzthiazonore
• Examples include bicyclic heteroaryls such as benzoxazole, benzofuran, and benzothiophene, and more preferred are thiophene, furan, pyrrole, pyridine, pyrimidine, indole, benzthiazole, benzoxazolo
• single C 5 may be alkylene substituted at W 1 C -
• the C 5 alkylene for example, straight-chain or a C 5 alkylene branched may be mentioned, specifically, methylene emissions, ethylene, trimethylene, tetramethylene Pentamethylene, propane-1,2-diyl, butane-11,3-diyl and the like, more preferably ethylene, trimethylene and tetramethylene.
• Optionally substituted in W 1 C 2 - C 5 alkenylene C 2 - is a C 5 alkenylene, for example straight or branched C 2 - C 5 alkenylene and the like, in particular cis or Trans-vinylene, cis or trans-l-propenylene, cis or trans-l-propenylene, cis or trans-l-butenylene, cis or trans-l-butenylene, cis or trans-l-butenylene, cis or trans-l- Butenylene, cis or Is trans-3-methyl-12-propenylene, cis or trans-12-methyl-12-propenylene, cis or trans-11-methyl-12-propenylene, and more preferably, trans 11-propenylene and trans-11-butenylene.
• Optionally substituted in W 1 C 2 - C 5 alkynylene C 2 - is a C 5 alkynylene include straight chain or C 2 branched - include C 5 alkynylene, specifically Echiniren, Examples thereof include 1-propynylene, 3-methyl-11-propynylene, and 2-propynylene, and more preferably, 1-propynylene.
• Formula 2 in W 1, in Formula 3, (2) 2 (3) mm 2 , n 1 , n 2 are integers from 0 to 3, and 1 1 2 is an integer from 1 to 3.
• li l ⁇ 3, ! ! ⁇ ::! When! ! 1 :. , 1, or 2, ⁇ ⁇ ⁇ n 1 ::! 2 or 3,
• Examples of the optionally substituted C—, C 4 alkylene of ⁇ — ⁇ 4 alkylene in W 3 include, for example, linear or branched Ci—C alkylene, and specifically, methylene, ethylene, trimethylene, Examples thereof include tetramethylene, propane-1,2-diinole, and butane-11,3-diyl, and more preferably, ethylene, trimethylene, and tetramethylene.
• Optionally substituted in the W 3 C 2 - C 4 alkenylene C 2 - is a C 4 7 Luque two alkylene include straight-chain or branched C 2 - C 4 7 Luque two alkylene and the like, Specifically, cis or trans 1-vinylene, cis or trans 1-propenylene, cis or Or trans-11-butenylene, cis or trans-1-butenylene, cis or trans-3-methyl-12-propenylene, cis or trans-12-methyl-12-propenylene, and the like. Preferably, trans-11-propenylene and trans-11-butenylene are mentioned.
• Is a C 4 alkynylene for example C 2 straight or branched - - C 2 C 4 to alkynylene - optionally substituted C 2 in W 3 C 4 alkynylene and the like, in particular 1 _ And propynylene and 2-pentinylene.
• the Ariren good ⁇ Li one Ren be substituted in A r 1, for example, C 6 -.
• arylene groups specifically, 1,3-phenylene, 1,4-phenylene, naphthalene-1,3-diyl, naphthalene-1,4-diyl and the like. Preferred are 1,3-phenylene and 1,4-phenylene.
• the heteroarylene group of the optionally substituted heteroarylene in Ar 1 may be, for example, a monocyclic ring containing 1 to 3 heteroatoms arbitrarily selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. And bicyclic heteroarylene groups. Specifically, monocyclic 6-membered heteroarylenes such as pyridine-diyl, pyrimidine-diyl, pyrazine-diyl, pyridazine-diyl, and triazine-diyl, etc.
• Monocyclic 5-membered heteroarylenes such as mono-norethinole, thiazono-resinole, oxazono-resyl, isothiazole-yl, and isooxazole-zyl, etc.
• indazole-dzil pudding-dzil, 4-H-quinolidine-dzil, quinoline-dzil, isoquinoline-dzyl, phthalazine-dzyl, naphthyridine-dzyl, quinoxaringin-dznole, quinazoline-dzinn-le-z, benzthiazol And bicyclic heteroaryls such as benzyl, benzoxazole, benzofuran and benzothiophene, and more preferably pyridine, pyridine, pyrimidine and thiophene, and pyrrole.
• the names include Ile-le-Ginore, Fran-le-Ginole, and Indore-le-Gille.
• the optionally substituted 1 C 4 alkylene in W 4 includes, for example, a linear or branched C i-C alkylene, specifically, methylene, ethylene, trime Tylene, tetramethylene, propane-1,2-diyl, butane-11,3-diyl, and the like, more preferably, methylene, ethylene, and trimethylene.
• alkoxycarbonyl in R 1 and R 1 ′ examples include, for example, straight-chain or branched-chain C i—C 4 alkoxy, specifically, methoxy, ethoxy, propoxy, 2 _propoxy, 2-methyl-1-propoxy, Carboel having butoxy, 2-methyl-1-propoxy and the like are mentioned, and more preferably, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and 2-propoxycarbonyl are mentioned.
• the optionally substituted carbamoyl in RR 1 ′ includes, for example, linear or branched C i—C ealkylaminocarbonyl or linear or branched C 2 —C 12 dialkylaminocarboel No.
• Examples of the linear or branched C 1 -C 6 alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, 2-propylaminocarbonyl, and butyraminocarbonyl. And preferably straight-chain or branched —C 4 alkylaminocarboel.
• the C 2 _ C i 2 Jiarukirua amino carbonyl straight or branched chain include the same or different forces Luba moil substituted with alkyl, particularly dimethyl ⁇ amino carbonyl, Jefferies chill ⁇ amino carbonitrile Nyl, dipropylaminocarbonyl, diisopropylaminocarbonyl, dibutylaminocarbonyl, ethylmethylaminocarbonyl, methylpropylaminocarbonyl, butynolemethylaminocarbonyl, ethynolebutylaminocarbonyl, dicyclo mouth Hexylaminocarbonyl and the like, preferably straight-chain or branched C 2 —. 8- dialkylaminocarboel.
• Examples of the optionally substituted cyclic aminocarbonyl in R ⁇ R 1 ′ include a 5- to 7-membered cyclic amino that may contain an oxygen atom, a sulfur atom, or a nitrogen atom as a ring-constituting atom.
• the cyclic amino may be further substituted with an alkyl, a hydroxyl group or the like, and specific examples include pyrrolidino, piperidino, piperazinyl, 4-methylbiperazinyl, morpholino, thiomorpholino, and 4-hydroxypiperidino. More preferably, pyrrolidino, morpholino, 4-hydroxypiperidino and 4-methylpiperazur are exemplified.
• alkylsulfonylcarbamoyl at R 1 As good alkylsulfonyl, such as C straight or branched chain - of a C 6 Arukirusu Ruhoniru, specifically, methanesulfonyl, ethanesulfonyl, 1 one pro Roh Nsuruhoniru, 2-propanesulfonyl, butanesulfonyl, Torifuruorometa And methanesulfonyl, ethanesulfonol and 2-propanesulfonyl.
• alkylsulfonyl such as C straight or branched chain - of a C 6 Arukirusu Ruhoniru, specifically, methanesulfonyl, ethanesulfonyl, 1 one pro Roh Nsuruhoniru, 2-propanesulfonyl, butanesulfonyl, Torifuruoromet
• Examples of the optionally substituted arylsulfonyl of arylsulfonylcarbamoyl for R 1 include benzenesulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl, and more preferably benzenesulfonyl. Are listed.
• the substituted or unsubstituted heteroarylsulfonylcarbamoyl in R 1 may be optionally substituted heteroarylsulfonyl, for example, arbitrarily selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom.
• monocyclic or bicyclic heteroarylenes containing three heteroatoms include imidazole, pyrazole, thiophene, pyridine and the like.
• the Ci one C 4 alkyl in R ⁇ R 1 ' for example, straight-chain or branched - C 4 alkyl and the like, specifically methyl, Echiru, 1 _ propyl, 2-propyl Honoré, 1-butyl , 2-butyl and the like, and more preferably, methyl, ethyl and 1-propyl.
• R 1, C 2 in the R 1 '- The C 4 alkenyl, for example, straight-chain or branched C 2 - C 4 7 Rukeeru are mentioned, specifically, the cis or trans one Bulle, cis or trans one 1-Propenyl, cis or trans 1-butenyl, cis or trans 1-butyr, cis or trans 1-butul, cis or trans 3-butyr, cis or trans 1-3-methyl 1-2 Propenyl, cis or trans-12-methyl-12-probenyl, cis or trans-11-methy ⁇ -2-propenyl and the like.
• the C 4 alkynyl for example, straight-chain or branched C 2 - C 4 alkynyl and the like, specifically Echiniru, 1-flop Robiniru, 3-Methyl-1-propyl, 2-propynyl and the like.
• one or more, optionally substituted C! -I C 4 Alkyl, halogen atom, halogen optionally substituted alkoxy or C Amino may be substituted with a side chain acid ", one C 4
• the alkyl may be substituted linear or branched C i-C 4 alkyl. specific examples thereof include methyl, Echiru, 1-propyl, 2-propyl, 1-butyl, 2-butyl and the like, and more preferably, include methyl, Echiru, 1-propyl Can be
• alkyls When there are a plurality of such alkyls, they may be the same or different, and may combine with each other to form a ring.
• the substitution position of the alkyl is more preferably at the carbon at the ⁇ -position of the carboxylic acid.
• Upsilon 3 represents a nitrogen atom may have a substituent on the nitrogen, as the substituent in this case, methyl, Echiru, 1-propyl, 2-propyl, Ru benzyl and the like.
• alkylamino as the substituent R 7 examples include methylamino, ethylamino, 2-propylamino, ⁇ , ⁇ ⁇ ⁇ ⁇ dimethylamino, ⁇ , ⁇ ⁇ ethylamino, and more preferably ⁇ , ⁇ dimethylamino, methylamino and the like.
• RR 1 ′ halogen atom of “one or more optionally substituted CC 4 alkyl, a halogen atom, an alkoxy optionally substituted with a halogen, or an optionally substituted side chain of an amino acid”
• a fluorine atom And a chlorine atom As a concrete example, a fluorine atom And a chlorine atom.
• R 1 ⁇
• Specific examples of the alkoxy that may be substituted with halogen include methoxy, ethoxy, 1-propoxy, 2-propoxy, and trinoleolomethoxy.
• the side chain of the amino acid in RR 1 ′ “which may be further substituted with a C, —C 4 alkyl, halogen atom, or amino acid side chain” includes a side chain of an amino acid that may be substituted, Specific examples include isopropyl, isobutyl, hydroxymethyl, 3-indolemethyl, benzyl, 4-hydroxybenzyl and the like. Also, when the R 1 — X 1 part is represented by, for example, equation (6),
• Ci—C alkylene in X 3 examples include methylene, ethylene, 11-propylene, 2-propylene and the like. More preferably, X 3 represents a single bond, methylene or ethylene, and more preferably a single bond.
• substitution position of R 2 ° —X 3 is more preferably on the carbon adjacent to one N (—X 2 —) — or on the carbon adjacent to two.
• the optionally substituted Ci—C alkyl for R 21 includes, for example, methyl, ethyl, 1-propyl, 2-propyl and the like.
• the alkyl may be one or more, and when there are a plurality of the alkyls, they may be the same or different. When there are a plurality of such alkyls, they may be bonded to each other to form a ring. Furthermore, two said alkyls may be substituted on the same carbon, and when two said alkyls are substituted on the same carbon, they may combine with each other to form a spiro ring.
• alkyls When a plurality of the alkyls are present and alkyls substituted on carbons independent of each other form a ring, or when two alkyls are substituted on the same carbon and are bonded to each other to form a spiro ring, Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, and more preferably cyclopropyl, cyclobutyl and cyclopentyl.
• the alkyl of alkyl J in R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 includes, for example, a linear or branched Ci—C 7 alkyl, and specifically, Methyl, ethyl, 1-propynole, 2-propyl, cyclopropinole, cyclopropylmethinole, 2-methyl-11-propyl, 2-methyl-12-propyl, 1-butynole, 2-butyl, 3-methylinole 2-butyl , 2-Methylenol 2-butyl, cycloptynole, pentyl, hexyl, cyclohexyl, cyclohexylmethyl, etc., and more preferably, methyl, ethyl, 2-propyl, cyclopropyl, cyclopropylmethyl and the like.
• Examples of the aralkyl of “optionally substituted aralkyl” in R 2 , R 3 , R 4 and R 5 include benzyl, phenethyl, phenylpropyl and the like.
• Examples of the aryl which may be substituted in R 6 and R 8 include phenyl, 1-naphthyl and 2-naphthyl, and more preferably phenyl.
• heteroaryl of the “optionally substituted heteroaryl” for R 6 and R 8 examples include the heteroaryls exemplified as the “heteroaryl” of the “optionally substituted heteroaryl” for the above Ar 2 .
• aralkyl of “optionally substituted aralkyl” in R 6 is represented, for example, by formula (10).
• W 5 represents an optionally substituted C Cs alkylene, an optionally substituted C 2 —C 5 alkenylene, and Ar 3 represents an optionally substituted aryl or an optionally substituted heteroaryl. Represent.
• C, —C alkylene of “optionally substituted C“ C 5 alkylene ”” in W 5 examples thereof include 1 C 5 alkylene exemplified as the “optionally substituted C, —C 5 alkylene” in W 1 , and more preferred is methylene.
• the “optionally substituted heteroaryl” and the “optionally substituted heteroaryl” in Ar 3 include the “optionally substituted heteroaryl” and the “optionally substituted heteroaryl” in the aforementioned Ar 2 . And hetaryl.
• halogen atom for R 8 include a fluorine atom, a chlorine atom, and a bromine atom.
• alkoxy of “optionally substituted alkoxy” for R 8 examples include methoxy, ethoxy, 1-propoxy, 2-propoxy and the like.
• C 4 alkylene which may be us Keru substituted R 21 C one C 4 alkyl, optionally substituted at R 8 alkyl, R 6, which may be substituted in R 8 Ariru or substituted by Teroa reel also to good, W good C! -Cs alkylene optionally substituted at the 5, C 2 one optionally substituted C 5 7 Luque two, Down,
• a r 3 may be substituted in Ariru or substituted also to good Teroariru optionally substituted substituent, R 2, R 3, R 4, R 5, you Keru substituted Ararukiru to R 6, As the “substituent” of the substituent, and
• Halogen atom hydroxyl group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, alkanoyloxy, cyano, alkanoyl, optionally substituted alkoxy, optionally substituted aryloxy, alkoxy Carboxy group, carboxy group, alkylsubstituted rubamoyl, cyclic aminocarbonyl, optionally alkyl-substituted sulfamoyl, cyclic aminosulfonyl, alkylsulfonyl, arylsulfonyl, alkylsulfonyloxy, alkylthio group, etc.
• a halogen atom, a hydroxyl group, an alkyl or an alkoxy which may be substituted More preferably, a halogen atom, an optionally substituted alkoxy, and an optionally substituted alkyl are mentioned, and there may be one or more. Preferably it is 1 to 2. When there are a plurality of substituents, they may be the same or different.
• halogen atom of the “substituent” examples include a fluorine atom, a chlorine atom, and a bromine atom.
• alkyl which may be substituted for the “substituent” include, for example, methyl, ethyl, propynole, butyl, pentyl, 2-propyl, 2-methyl-1-propyl, 2-butyl, t-butyl, and 3-methylinoyl.
• alkenyl which may be substituted for the “substituent” include, for example, butyl, 2-propininole, 1-propeninole, 2-buteninole, 1-buteninole, and 2-methinol- 1-propenyl. And more preferably, 2-propenyl, 2-butyr, 2-methyl-1-propenyl.
• aryl which may be substituted for the “substituent” include, for example, phenyl, p-chloropheninole, m-chlorofeninole, o-chlorofeninole, p-funolelofeninole, m —Funoreolofeninole, o—Funoleolofeninole, p—Methoxyphenine, m—Methoxyphenine, 0—Methoxyphenine, p—Methinofenenole, m—Metinolefen, o— Methinolepheninole, p-pheninole, m-triphenylolenomethinolefeninole, o-trifluoromethylphenyl, and the like, more preferably phenyl, p-chloro-open feninole, p-me Toxifenole, p-methinolephen
• alkanoyloxy of the “substituent” examples include linear or branched C i _C 6 alkanoyloxy, more preferably formyloxy, acetyloxy, propanoyloxy, butanoyloxy, Isobutanoyloxy, pentanoyloxy and hexanoyloxy.
• Arukanoiru of the "substituent" for example C one C 6 7 Rukanoiru a straight or branched chain, and more preferably include include Kisanoiru formyl, Asechiru, Puropanoiru, blanking Tanoiru, Isobutanoinore, Pentanoiru to, .
• Examples of the optionally substituted alkoxy of the above “substituent” include, for example, methoxy, ethoxy, propoxy, 2-propoxy, 2-methyl-propoxy, butoxy, pentoxy, hexyloxy, cyclopentynoleoxy, cyclohexyloxy Hexylmethyloxy, 1-methoxy-12-ethyloxy, 1-morpholino-12-ethyloxy, 1-thiomorpholino-12-ethyloxy, 1-piberidino-2-ethyloxy, trifluoromethyloxy, etc. And more preferably methoxy, ethoxy, 2-propoxy, cyclopentyloxy, 1-morpholino-12-ethyloxy, trifluoromethyloxy.
• an adjacent alkyl When there is alkoxy, it may form a ring having a substituent with an adjacent group.
• alkoxy When there is alkoxy, it may form a ring having a substituent with an adjacent group.
• alkoxy When there is alkoxy, it may form a ring having a substituent with an adjacent group.
• alkoxy methylenedioxy, ethylenedioxy, 2-methyl-1-methylenedioxy, 2-methyl-1-ethylenedioxy, 1-oxy1-2-ethylene, Examples thereof include 1-oxy_2-propylene and the like, and more preferable examples include methylenedioxy and ethylenedioxy.
• aryloxy which may be substituted for the “substituent” include, for example, phenoxy, p-phenololephenoxy, m-phenololephenoxy, o-phenololephenoxy, P-methylphenoxy, m-methylphenoxy, Examples include aryloxy such as m-methoxyphenoxy, 1-naphthyloxy, and 2-naphthyloxy, and heteroaryloxy such as pyridyloxy, and more preferably phenoxy.
• alkoxycarbonyl of the “substituent” examples include straight-chain or branched-chain C i-C 6 alkoxycarboels, more preferably methoxycarbonyl, ethoxycanoleboninole, propoxycanolebonyl, 2 —Propoxycarbonyl, 2-methylinopropoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexinoleoxycanolevoel.
• Examples of the optionally substituted alkyl rubamoyl of the “substituent” include, for example, a linear or branched C 6 -C 6 alkylaminocarbonyl or a linear or branched C 2 -C 12 dialkylamino. Carboel. Straight or branched C! More preferably, the C 6 alkylaminocarbonyl includes methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, 2-propylaminocarbonyl, and butylaminocarbonyl.
• the C 2 _ C 1 2 dialkylaminocarbonyl straight chain or branched chain for example, the same or different alkyl substituted force Rubamoiru the like, and more preferably, dimethyl ⁇ amino carbonyl, di E chill ⁇ iminocarbonyl And dipropylaminocarbonyl, diisopropylaminocanoleboninole, dibutylaminocarbonyl, ethylmethylaminocarbonyl and the like.
• cyclic aminocarbonyl of the “substituent” examples include a 5- to 7-membered cyclic aminoamino which may contain an oxygen atom, a sulfur atom, or a nitrogen atom as a ring-constituting atom. Is further substituted with alkyl, hydroxyl, etc. May be done. Specific examples include pyrrolidinocarbonyl, piperidinocarbonyl, piperazinylcarbonyl, 4-methylpiperazinylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, 4-hydroxypiperidinocarbonyl, and more preferably Examples include morpholinocarbonyl and 4-hydroxypiperidinocarbonyl.
• Examples of the optionally substituted sulfamoyl of the above “substituent” include linear or branched C i -C 6 alkylaminosulfonyl or linear or branched C z —C i 2 dialkylaminosulfonyl Is mentioned. More preferred are methylaminosnolephonyl, ethylaminosnolephonyl, propinoleaminosnolephoninole, 2-propylaminosulfonyl, and butylaminosulfonyl. Linear or branched C 2 —.
• Examples of the 12 dialkylaminosulfonyl include, for example, sulfamoyl substituted with the same or different alkyls, more preferably dimethylaminosulfonyl, getylaminosulfonyl, dipropylaminosulfonyl, diisopropanol pinoleaminosulfonyl, dibutyl Aminosulfonyl, ethylmethylaminosulfonyl and the like.
• cyclic aminosulfonyl of the “substituent” examples include a 5- to 7-membered cyclic aminosulfonyl which may contain an oxygen atom, a sulfur atom, or a nitrogen atom as a ring-constituting atom. May be further substituted with an alkyl, a hydroxyl group or the like.
• pyrrolidinosulfonyl piberidinosulfonyl, pipera dininorelesnorefonyl, 4-methylpiperazinylsulfonyl, morpholinosulfoninole, thiomorpholinosulfonyl, 4-hydroxypiberidinosulfonyl and the like. More preferably, morpholinosulfonyl and 4-hydroxypiperidinosulfenole are exemplified.
• alkylsulfonyl of the “substituent” examples include methylsulfonyl, ethylsulfonyl, 1-propylsulfonyl, 2-propylsulfonyl, 1-butylsulfonyl, 2-butylsulfonyl, and the like. More preferably, methylsulfonyl is , 2-propylsulfonyl.
• arylsulfonyl of the “substituent” examples include, for example, benzenesulfonyl, p-tolenoleens-norefoninole, p-chloro-open-benzenesnorre-honinole, p-funoleno-open-benzenes And benzenesulfonyl, p-trifluoromethylbenzenesulfonyl, m-chlorobenzenesulfonyl, o-chlorobenzenesulfonyl and the like, more preferably benzenesulfonyl, p-chloro Benzeneszolephonyl, p-methoxybenzenesulfonyl, and p-trifluoromethylbenzenesulfonyl.
• alkylsulfonyloxy of the “substituent” examples include methylsulfonyloxy, ethylsulfonyloxy, 1-propylsulfonyloxy, 2-propynolesulfonyloxy, 1-butylsulfonyloxy, and 2-butylsulfonyloxy And more preferably, methylsulfonyloxy and 2-propylsulfonyloxy.
• alkylthio group of the “substituent” examples include methylthio, ethylthio, propylthio, butylthio, pentylthio, 2-propylthio, 2-methyl-1-propylthio, 2-butylthio, t-butinorethio, 3-methyl-2-butylthio, and 2-— Examples thereof include methyl-2-butylthio and hexylthio, and more preferably, methylthio, ethylthio, and 2-propylthio.
• Prodrugs refer to those that are chemically or biochemically hydrolyzed in vivo to regenerate the compounds of the present invention.
• the heteroaryl compound of the present invention has a carboxyl
• a compound in which the carboxyl has been converted to a suitable ester can be mentioned.
• this ester examples include methyl ester, ethyl ester, 1-propynoleestenole, 2-propyl ester, pivaloyloxymethinole ester, acetyloxymethyl ester, cyclohexylacetyloxymethyl ester, Examples thereof include 1-methylcyclohexylcarbonyloxymethyl ester, ethyloxy boninoleoxy-1-ethynole ester, and cyclohexyloxy canoleponinoleoxy-1-ethyl ester.
• heteroaryl compound of the present invention or a pharmaceutically acceptable salt thereof when the heteroaryl compound of the present invention or a pharmaceutically acceptable salt thereof has an acidic group, examples thereof include alkali metal salts such as sodium salt and potassium salt, calcium salt, and magnesium salt. And organic base salts such as triethylamine, triethanolamine, trihydroxymethylaminomethane, and amino acids. Heteroarylation of the invention When the compound or a pharmaceutically acceptable salt thereof has an acidic group, when the heteroaryl compound of the present invention or a pharmaceutically acceptable salt thereof has a basic group, for example, hydrochloride, odor, etc.
• Inorganic acid salts such as hydride, sulfate, phosphate and nitrate, and acetate, propionate, succinate, lactate, malate, tartrate, citrate and maleate
• organic salts such as fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate and ascorbate.
• the present invention also includes a prodrug of the heteroaryl compound of the formula (1).
• the present invention also includes solvates such as hydrates of the heteroaryl compounds or prodrugs of the formula (1) or pharmaceutically acceptable salts thereof, and ethanol solvates thereof.
• the heteroaryl compound can be produced, for example, by the production methods (A) and (B) described in detail below or a method analogous thereto.
• the compounds used as the starting compounds may each be used as a salt.
• Such salts include pharmaceutically acceptable salts.
• the heteroaryl portion of the heteroaryl compound of the present invention can be prepared by a method known per se, for example, a method described in The Chemistry of Heterocyclic Compounds (for example, pyrrole derivative: vol. 48 parti, part 2; pyrazonole derivative: Vo 1.22 6 parti; Triazole derivative: vol. 6 parti; Indole derivative: vo 1.25 part II, part III, part 4; Indazole derivative: vo 1.22; Benzoimidazole derivative: vol.
• R 1G represents a group excluding carboxyl and alkoxycarbonyl among the groups selected from R 1
• R 11 represents the R It represents an R 1 moiety does not have a first selected the group.
• R Q are methyl, Echiru
• X 1 is a SO.N of the X 1
• R 3 -C (— NR 4 R 5 ) N—, one CONR 3 SO 2 —, one NR 3 S ⁇ 2 —,-NR 3 CO—, one S ⁇ 2 NR 3 CO—, one S0 2 NR 3 —, one CONR 3 —, one OCO NR 3 —, one NR 3 CONR 4 —, one NR 3 CO—O—, or one O—CO—O—, and Y 11 ⁇ 12 forms X 1 Represents a substituent required as a raw material for performing For example, X 1 is one CONR 3 SO 2 - may represent, Y 11 represents one COC l, the _C0 2 H or the like, Y 12 is HNR 3 SO 2 - represents a.
• Y 11 represents one CONHR 3 and Y 12 represents C 1 S0 2 —.
• Y 11 represents an NHR 3
• Y 1 2 is C 1 SO 2 - - X 1 Gar NR 3 SO 2 represents a.
• X 1 represents —NR 3 CO—
• Y 11 represents —NHR 3
• Y 12 represents C 1 CO—.
• X 1 represents one S0 2 NR 3 CO—
• Y 11 is one S 0 2 represents NHR 3 and the like
• Y 12 represents C 1 CO—.
• Y 11 represents one S0 2 C 1 and Y 12 represents HNR 3 CO—.
• Y 11 When X 1 represents _SO 2 NR 3 —, Y 11 represents one S 0 2 C 1 and Y 12 represents HNR 3 —.
• Y 11 When X 1 represents —CONR 3 —, Y 11 represents one COC 1 and Y 12 represents HNR 3 —.
• Y 11 represents one OCOC 1 and Y 12 represents HNR 3 —.
• X 1 represents one NR 3 CON R 4 —
• X 1 represents —NR 3 CO—O—
• Y 11 represents —NHR 3 and Y 12 represents C 1 CO—O—.
• Y 11 represents one NR 3 COC 1 and Y 12 represents HO—.
• X 1 represents one O—CO—O—
• Y 11 represents one OH and Y 12 represents C 1 CO—O—.
• Y 11 represents one OCOC 1 and Y 12 represents HO—.
• Compound (101) and compound (102) can be obtained from compound (100) and compound (104), compound (100) and compound (105) by methods known per se, for example, New Experimental Chemistry Course Vol. 14 (Maruzen, 1 977), Experimental Chemistry 19-26 (Maruzen, 1992), Precision Organic Synthesis (Nankodo, 1983), Basic and Experimental Peptide Synthesis (Maruzen, 1985), etc. It can be manufactured by the method described or a method similar thereto.
• ether solvents such as ether, THF, and dioxane
• hydrocarbon solvents such as toluene, benzene, and hexane
• dichloromethane chloroform
• dichloroethane dichloroethane
• tetrachloride examples include halogenated hydrocarbon solvents such as carbon, and aprotic solvents such as dimethyl sulfoxide, dimethylformamide, and acetonitrile.
• halogenated hydrocarbon solvents such as carbon
• aprotic solvents such as dimethyl sulfoxide, dimethylformamide, and acetonitrile.
• the reaction temperature is selected from the range of about 178 ° C to about the boiling point of the solvent, and preferably the range of about 0 ° C to about the boiling point of the solvent.
• a base In this reaction, a base, a dehydrating condensing agent, and a reaction aid can be added according to each reaction.
• the base include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; metal carbonates such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate; sodium hydride; and hydrogenation power.
• Metal hydrides such as rim, alkyl metals such as n-butyllithium and s-butyllithium, triethylamine, ethyldiisopropylamine, pyridine, 1,8-diazabicyclo [5.4.0] Organic bases and the like.
• dehydrating condensing agent examples include dicyclohexylcarpoimide, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, N, N-bis (2-oxo-3-oxazolidinyl) phosphoric acid chloride And the like.
• reaction assistant examples include phase transfer catalysts such as N-hydroxybenztriazole, N, N-dimethyl-14-aminopyridine, tetra-n-butylammonium bromide, and the like.
• Compound (103) can be obtained by subjecting compound (101) to a conventional technique for protection and deprotection.
• This reaction includes, for example, a hydrolysis reaction performed in the presence of an acid or a base according to a conventional method.
• Compound (102) is obtained from compound (103) by a method known per se, for example, New Experimental Chemistry Lecture, Vol. 14 (Maruzen, published in 1977), Experimental Chemistry Lecture 19-26 (Maruzen, published in 1992) ), Precision Organic Synthesis (Nankodo, 1983), Basics and Experiments of Peptide Synthesis (Maruzen, 1985), Compendium of Organic Synthetic Methods, Vol. 1-9 (Jo hn Wi 1 ey & S ons), Comp rehensive Organic Synthesis, Vol. 1-9 (1991 Pergamon Press), Comp rehensive Organic Transcriptions (1989, VCH Pu blishers), Surveofof Organic Syn theses, Vol. 1-2 (1970, 1977, John Wiley & Sons), J.
• This reaction is one COC l or with one C0 2 H or the like, amines, reaction with Surufon'ami earth, reaction of single-CONHR and sulfonyl halides, conversion reaction from a C0 2 H into single CN, one conversion reaction from C0 2 H into Tetorazoru 5 I le, 2 represents the construction method of the 4-O hexa oxazolidinedione one 5- I le part.
• L 1 represents the same or Differently, it represents a halogen atom such as a chlorine atom, a bromine atom, an iodine atom, and a leaving group such as trifrenoleolomethanesulfonyloxy, methanesulfoninoleoxy, and p-toluenesulfoninoleoxy.
• Compound (107) can be obtained by a method known per se, for example, New Experimental Chemistry Course, Vol. 14 (Maruzen, published in 1997), Experimental Chemistry Course, Vol. 19-26 (Maruzen, published in 1999), Precision Organic Chemistry Synthesis (Nankodo, 1983), Te trahedron L et t., 36, 41 33 (1995), T etrahedron L et t., 38, 1805 (1997), Synth. Commun., 26, 1441 (1 996), J. Med. Chem., 28, 1517 (1985), and the like can be produced by a method according to the method.
• compound (107) is produced from compound (106) and compound (108) or from compound (109) and compound (110).
• Compound (107) can be obtained by reacting compound (106) with compound (108) in an inert solvent in the presence of a base.
• Examples of the base include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; metal carbonates such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate; sodium hydride; and hydrogenation.
• Metal hydrides such as potassium lime, organic bases such as triethylamine, ethyldiisopropylamine, pyridine, 1,8-diazabicyclo [5.4.0] indene-17-ene and the like.
• the inert solvent examples include ether solvents such as ether, THF, and dioxane; hydrocarbon solvents such as toluene, benzene, and hexane; and halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and tetrahydrocarbon. Solvents, aprotic solvents such as dimethylformamide, acetonitrile, and acetone, and alcohol solvents such as methanol and ethanol, and the like. These solvents may be used by mixing two or more kinds in an appropriate ratio.
• ether solvents such as ether, THF, and dioxane
• hydrocarbon solvents such as toluene, benzene, and hexane
• halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and tetrahydrocarbon.
• Solvents, aprotic solvents such as dimethylformamide, ace
• the reaction temperature is selected from the range of about 0 ° C. to around the boiling point of the solvent.
• reaction aid can be added as necessary.
• reaction assistant examples include phase transfer catalysts such as tetra-n-butylammonium bromide, hexadecyltributylphosphonium bromide, and methyltricaprylammonium chloride. Synthhesis, 5.65 (1974), Synthhesis, 447 (1975)
• Compound (107) can be obtained by reacting compound (109) with compound (110) in an inert solvent in the presence of a transition metal catalyst and a base.
• inert solvent examples include tetrahydrofuran, dioxane, and dimethoxetane.
• examples thereof include ether solvents, hydrocarbon solvents such as toluene and n-hexane, and aprotic solvents such as dimethylformamide and 1-methyl-1-pyrrolidinone.
• Examples of the base include metal carbonates such as carbon dioxide lime, sodium hydrogen carbonate, silver carbonate, and the like, and alkylamines such as triethylamine and ethylethylisopropylamine.
• transition metal catalyst examples include zero-valent palladium catalysts such as tetrakis (triphenylphosphine) palladium and palladium dibenzylidene complex, and divalent palladium catalysts such as palladium acetate and dichlorobis (triphenylphosphine) palladium. .
• reaction aid can be added as necessary.
• reaction assistant examples include monodentate ligands such as triphenylphosphine and tris (o-tolyl) phosphine, and bidentate ligands such as diphenylphosphinopropane, diphenylphosphinobutane, and diphenylphosphinophenol. A child or the like may be added.
• the reaction temperature under the transition metal catalyst is selected from the range of about 0 ° C. to about the boiling point of the solvent, and preferably the range of about 60 ° C. to about the boiling point of the solvent.
• Compound (101) can be prepared by a method known per se, for example, New Experimental Chemistry Lecture Vol. 15 (Maruzen, published in 1977), Synthesis, 375 (2000) Synthesis, 300 (2001), J. Pract. Ch. J., pp. 69, 2955 (1996), Te trahedron, 52, 5773 (1996), Pol. J. Ch em. , 70, 1 121 (1996), Synth. Commun., 28, 2983 (1998), Biog. Med. Chem. Lett., 9, 3181 (1 999) , Indian J. Chem. Sect B: Org. Chem. Incl. Med. Chem., 36, 1069 (1997), Chem.
• oxidizing agent examples include organic peroxides such as metabenzo-perbenzoic acid, perbenzoic acid, peracetic acid, and magnesium monoperphthalate, organic peroxides such as t-butyl peroxide, hydrogen peroxide, and perboric acid. Acid sodium, oxone, TPAP (tetrapropylammonium pearl tenate) and the like.
• Compound (103) can be obtained by subjecting compound (101) to a conventional technique for protection and deprotection.
• the reaction conditions can be produced by the method described in the production method (A), the production method (111), the method for producing the compound (103) from the compound (101), or a method analogous thereto.
• Compound (109) is a method known per se, for example, New Experimental Chemistry Course Vol. 14 (Maruzen, published in 1977), Experimental Chemistry Course 19-26 (Maruzen, published in 1992), Precision Organic Synthesis (Nankodo, 1983) ) Or a method similar thereto.
• the present reaction the compound (1 1 1) to give S an, dme yer reaction, a method to obtain a compound (109), or a transition metal catalyst presence, carbon-carbon bond of the compound (123) and Ar 1 I 2 Represents the formation reaction.
• Compound (109) is described in, for example, T etrahedron L et t., 36, 4133 (1995), Te trahedron L et t., 38, 1805 (197), J. Am. Chem. Soc. , 1 18, 7215 (1996), J. Am. Chem. SoC., 1 18, 721 7 (1996), J. Org. Chem., 64, 6019 (1999), J. Org. Chem., 65, 8027 (2 000), or a method analogous thereto.
• Ar 1 I 2 can be reacted with compound (123) in an inert solvent in the presence of a transition metal catalyst and a base.
• inert solvent examples include non-proton solvents such as acetonitrile and dimethylformamide, and ether solvents such as tetrahydrofuran, dioxane, and dimethoxetane. And hydrocarbon solvents such as toluene, n- hexane and the like.
• Examples of the base include alkylamines such as triethylamine, ethyldiisopropylamine, and dihexylhexylmethylamine; metal carbonates such as potassium carbonate, silver carbonate, sodium hydrogencarbonate, and cesium carbonate; and potassium t-butoxide. And metal alkoxides such as butoxycinnatridium.
• transition metal catalyst examples include tetrakis (triphenylphosphine) palladium, ano, and the like. Radium dibenzylidene complexes, zero-valent palladium catalysts such as bis (tri-t-butylphosphine) palladium, divalent palladium catalysts such as palladium acetate and dichlorobis (triphenylphosphine) palladium, platinum catalysts and nickel catalysts .
• reaction aid can be added as necessary.
• reaction aid examples include monodentate ligands such as triphenylphosphine, tris (o-tolyl) phosphine, trit-butylphosphine, diphenylphosphinopropane, diphenylphosphinobutane, diphenylphosphinobutane, and diphenylphosphinobutane.
• monodentate ligands such as triphenylphosphine, tris (o-tolyl) phosphine, trit-butylphosphine, diphenylphosphinopropane, diphenylphosphinobutane, diphenylphosphinobutane, and diphenylphosphinobutane.
• a bidentate ligand such as a liposome may be added.
• the reaction temperature is selected from the range of about 0 ° C. to around the boiling point of the solvent, preferably about 60 to about the boiling point of the solvent.
• the amount of A i ⁇ I s based on the compound (123) is selected from the range of 0.1 to 10 moles, and preferably the range of 1 to 5 moles.
• Compound (1 12) can be prepared by a method known per se, for example, The Chemical Society of Japan, Vol. 9, pp. 1204-1208 (1991), Te trahedron L et t., 39, 5701 (1 998), T etrahedron L et t. , 41, 6563 (2000), Heterocycles, 31, 1287 (1990) and the like, or a method analogous thereto.
• compound (112) can be obtained by reacting compound (111) with carbon disulfide in an inert solvent in the presence of a base, and then reacting with methyl iodide.
• the inert solvent examples include ether solvents such as ether, THF, and dioxane; aromatic hydrocarbon solvents such as toluene, benzene, and chlorobenzene; dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride. And aprotic solvents such as dimethylformamide, acetonitrile, and acetone, and methanol. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
• ether solvents such as ether, THF, and dioxane
• aromatic hydrocarbon solvents such as toluene, benzene, and chlorobenzene
• dichloromethane chloroform, 1,2-dichloroethane, and carbon tetrachloride
• aprotic solvents such as dimethylformamide, acetonitrile, and acetone, and methanol.
• the base examples include metal hydroxides such as sodium hydroxide, aluminum hydroxide such as hydroxide hydroxide, metal carbonate such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydride, hydrogenation Metal hydrides such as potassium sulfide, and organic bases such as triethylamine, ethyldiisopropylamine, pyridine, 1,8-diazabicyclo [5.4.0] indene 7-ene, and the like.
• metal hydroxides such as sodium hydroxide
• aluminum hydroxide such as hydroxide hydroxide
• metal carbonate such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydride
• hydrogenation Metal hydrides such as potassium sulfide
• organic bases such as triethylamine, ethyldiisopropylamine, pyridine, 1,8-diazabicyclo [5.4.0] indene 7-ene, and the like.
• the reaction temperature is selected from the range of about 120 ° C to around the boiling point of the solvent, and preferably the range of about 110 ° C to about 30 ° C.
• Compound (113) can be obtained by reacting with compound (119) in an inert solvent.
• the inert solvent include ether solvents such as ether, THF, and dioxane; aromatic hydrocarbon solvents such as toluene, benzene, and benzene; dichloromethane, chloroform; 1,2-dichloroethane; and carbon tetrachloride.
• aprotic solvents such as dimethylformamide, acetonitrile, acetone and the like. These solvents may be used by mixing two or more kinds at an appropriate ratio.
• the reaction temperature is selected from the range of about 120 ° C. to about the boiling point of the solvent, and preferably the range of about 0 ° C. to about the boiling point of the solvent.
• halogenated hydrocarbon solvent examples include dichloromethane, chloroform, 1,2-dichloroethane, tetrachloromethane, and the like.
• halogenating agent examples include chlorine, sulfuryl chloride, bromine, and iodine.
• the reaction temperature with the halogenating agent is selected from the range of about 160 ° C to about 80 ° C, and preferably the range of about 110 ° C to 25 ° C.
• the inert solvent examples include ether solvents such as ether, THF, and dioxane, aromatic hydrocarbon solvents such as toluene, benzene, and benzene, dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride. And other non-proton solvents such as dimethylformamide, acetonitrile and acetone, and alcohol solvents such as methanol and ethanol. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
• the reaction temperature is selected from the range of about 120 ° C to near the boiling point of the solvent, and preferably the range of about 0 ° C to about 80 ° C.
• reaction aid can be added as necessary.
• reaction aid examples include silver salts such as silver nitrate and silver carbonate, and organic bases such as triethylamine, ethyldiisopropylamine, pyridine, 1,8-diazabicyclo [5.4.0] indene-7-ene, and the like. Is mentioned.
• Compound (115) can be converted to compounds (116) and (114) by the method described in Production method (A), Production method (1-1), or a method analogous thereto.
• the order in which the compound (112) is reacted with the compound (117) and the compound (117) and the compound (118), respectively, is not specified. Can be changed. Further, the production method when X 1 is a guanidine skeleton is not limited to the production method described above, but is changed to a method known per se, for example, a method described in WOO 1_05774 or a method analogous thereto. It may be manufactured.
• Y 13 represents an oxygen atom, a sulfur atom, _CO 2 —, _NR 3 —, and Pg is a protecting group.
• the compound (122) is a method known per se, for example, New Experimental Chemistry Course, Vol. 14 (Maruzen, published in 1977), Experimental Chemistry Course 19-26 (Maruzen, published in 1992), Precision Organic Synthesis (Nankodo, issued in 1983), etc., or a method analogous thereto.
• Compound (124) can be obtained by reacting compound (122) with compound (123) in an inert solvent in the presence of a transition metal catalyst and a base.
• the reaction conditions can be prepared by the method of preparation described in Process (A) Process (1 -2) Compound (123) and the compound from Ar I 2 (109) or a method analogous thereto.
• the compound (124) may be subjected to a catalytic hydrogenation reaction as necessary, and the “optionally substituted C ⁇ Cs alkylene” can be produced by the catalytic hydrogenation reaction.
• the reaction can be carried out by a method known per se, for example, the method described in Shin-Jikken Kagaku Koza Vol. 15 (Maruzen, published in 1977) or a method analogous thereto. It can be carried out in an active solvent in the presence of a metal catalyst.
• the inert solvent examples include protic solvents such as acetic acid, methanol, and ethanol; aprotic solvents such as ethyl acetate, acetonitrile, and dimethyl sulfoxide; and ether solvents such as tetrahydrofuran, dioxane, and dimethoxetane.
• protic solvents such as acetic acid, methanol, and ethanol
• aprotic solvents such as ethyl acetate, acetonitrile, and dimethyl sulfoxide
• ether solvents such as tetrahydrofuran, dioxane, and dimethoxetane.
• the hydrogen pressure in a hydrogen atmosphere is selected from the range of 1 to 150 atm, preferably 1 to 10 atm.
• reaction aid can be added as necessary.
• reaction aid for example, an acid such as sulfuric acid, hydrochloric acid, perchloric acid, phosphoric acid, oxalic acid, and trifluorophenol, and a base such as phenylethylamine and triethylamine may be added.
• an acid such as sulfuric acid, hydrochloric acid, perchloric acid, phosphoric acid, oxalic acid, and trifluorophenol
• a base such as phenylethylamine and triethylamine
• the reaction temperature is selected from the range of about 0 ° C to about 150 ° C, preferably the range of about 20 ° C to about 100 ° C.
• Compound (125) can be obtained by subjecting compound (124) to a conventional technique for protection and deprotection.
• Compound (126) and compound (128) can be produced by a method known per se, for example, the production method (A) It can be produced by the same method as described in the production method (1-14), the production method (A), the production method (1-2), or a method analogous thereto.
• Compound (127) is obtained from compound (137) by a method known per se, for example, New Experimental Chemistry Lecture, Vol. 14 (Maruzen, published in 1977), Experimental Chemistry Lecture 1926 (Maruzen, published in 1992) ), Precision organic synthesis (Nankodo, issued in 1983) or the like, or a method similar thereto, and a usual technique for protection and deprotection. Manufacturing method (1-6)
• Compound (155) and compound (129) can be obtained by methods known per se, for example, New Experimental Chemistry Course, Vol. 14 (Maruzen, published in 1977), Experimental Chemistry Course Vol. 1926 (Maruzen, published in 1992), Precision
• the compound can be produced by a method described in Organic Synthesis (Nankodo, published in 1983) or a method analogous thereto, and the introduction of a protecting group can be carried out using ordinary techniques for protection and deprotection.
• the conversion of the compound (155) into the compound (124) is carried out by a method known per se, for example, the production method described in the production method (A) (1-2) s (1-5) or a method analogous thereto. It can be manufactured by combining.
• Compound (134) can be produced according to a method known per se, for example: Med. Chem. 40 1619 (1997), New J. Chem. 18, 643 (1994), J. Org. Chem., 58 974 (1 993), Chem. Lett. 323 (1999), Heterocycles, 34, 303 (1992), Synth. Commun., 25 761 (1 995), J. Org. Ch em. 6 5, 4039 (2000), He terocycles, 33, 813 (1992), J. Heterocycl. Chem., 29, 1357 (1992), J. Heterocycl. Chem., 28, 1189 (1991) J. Chem. Pharm.
• Compound (135) and compound (136) can be obtained by methods known per se, for example, New Experimental Chemistry Course, Vol. 14 (Maruzen, published in 1977), Experimental Chemistry Course Vol. 19-26 (Maruzen, published in 1992), It can be produced by a method described in Precision Organic Synthesis (Nankodo, issued in 1983) or a method analogous thereto.
• Compound (123) and compound (137) can be obtained by methods known per se, for example, New Experimental Chemistry Course, Vol. 14 (Maruzen, published in 1977), Experimental Chemistry Course 19-26 (Maruzen, issued in 1992), Precision Organic Synthesis (Nankodo, published in 1983), etc., or a method similar thereto.
• compound (123) is produced from compound (134) and compound (136), or compound (137) is produced from compound (134) and compound (135).
• Compound (123) can be obtained by reacting compound (134) with compound (136) in an inert solvent in the presence of a base.
• metal carbonates such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydride, sodium hydroxide
• Metal alkoxides such as toxide and potassium t-butoxide
• metal hydrides such as potassium hydride, triethylamine, ethyldiisopropylamine, pyridine, 1,8-diazabicyclo [5.4.0]
• organic metals such as n-butyllithium and s-butyllithium.
• the inert solvent examples include ether solvents such as ether, THF, and dioxane; hydrocarbon solvents such as toluene, benzene, and hexane; halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride; Examples include aprotic solvents such as dimethylformamide, acetonitrile, and acetone, and alcohol solvents such as methanol and ethanol. These solvents may be used by mixing two or more kinds in an appropriate ratio.
• ether solvents such as ether, THF, and dioxane
• hydrocarbon solvents such as toluene, benzene, and hexane
• halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride
• Examples include aprotic solvents such as dimethylformamide, acetonitrile, and ace
• reaction aid can be added as necessary.
• reaction assistant include a phase transfer catalyst such as tetra-n-butylammonium bromide.
• the reaction temperature is selected from the range of about 0 ° C to near the boiling point of the solvent, and preferably ranges from about 0 ° C to the vicinity of the boiling point of the solvent.
• Compound (137) can be obtained by reacting compound (134) with compound (135) in an inert solvent in the presence of a base.
• Compound from the above compound (134) and compound (136) It can be manufactured by a method similar to or similar to the manufacture of the product (123).
• compound (134) can be synthesized as follows.
• ring Z represents pyrrole or indole
• W 6 represents alkylene, alkenylene, or alkynylene defined by W 2 (provided that carbon 1 L 2 is an alkoxy group such as methoxy, ethoxy, etc., an alkylamino group such as N-methyl-N-methoxy group, N, N-dimethylamino group, and a halogen group such as chloro group.
• the compound (164) is obtained by reacting the ring Z with a Grignard reagent in an inert solvent and then reacting with the compound (161).
• the inert solvent examples include ether solvents such as tetrahydrofuran, ether and dioxane, and aromatic hydrocarbon solvents such as toluene and benzene. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
• Grignard reagent examples include alkylmagnesium halides such as ethylmagnesium bromide.
• the reaction temperature is selected from the range of about 120 ° C. to about the boiling point of the solvent, and preferably the range of about 0 ° C. to about 60 ° C.
• Compound (163) can be obtained by subjecting compound (160), whose ring Z is protected, to a Friedel-Crafts reaction with compound (161) after a Lewis acid treatment in an inert solvent.
• Compound (160) is a compound in which a protecting group is applied to the nitrogen atom at position 1 of ring Z, and examples of the protecting group include phenylsulfonyl, toluylsulfonyl and the like.
• a protecting group include phenylsulfonyl, toluylsulfonyl and the like.
• a base such as NaH
• the reaction can be carried out by reacting such as luchloride.
• the Friedel-Crafts reaction can be performed, for example, according to J. Org. Chem., 48, 3214-3219 (1983) and the like. Specifically, A1C1 3, BF 3 'OEt 2, ZnCl 2, SnCl Lewis acids presence of such 4, dichloromethane, in an inert solvent dichloroethane, usually, 10. The reaction can be carried out at a temperature within the range of the boiling point of the solvent.
• the reaction position can be controlled by the type of Lewis acid.
• the A1C1 3 it is possible to reaction at the 3-position (Org. Chem., 48, 3214-3219 (1983)), the use of the BF 3 'OEt 2, can be reacted at the 2-position .
• Compound (163) can also be obtained by treating compound (160) with a base in an inert solvent and then reacting with compound (162).
• the inert solvent examples include ether solvents such as ether, tetrahydrofuran and dioxane, hydrocarbon solvents such as benzene and toluene, halogen solvents such as chloroform and dichloromethane, and these solvents. Or two or more kinds may be mixed at an appropriate ratio.
• ether solvents such as ether, tetrahydrofuran and dioxane
• hydrocarbon solvents such as benzene and toluene
• halogen solvents such as chloroform and dichloromethane
• Examples of the base include lithium diisopropylamide, lithium-1,2,6,6-tetramethylpiperidine and the like.
• the reaction temperature is selected from about 178 ° C to around the boiling point of the solvent, and preferably in the range of about 178 ° C to about 0 ° C during the base treatment. During the reaction, a range of about 120 ° C to about 60 ° C can be mentioned.
• the compound (163) can be obtained by deprotecting the compound (163).
• the reaction can be carried out in a mixed solvent of methanol, ethanol or the like and water in the presence of a base such as sodium hydroxide or potassium hydroxide at a temperature in the range of 10 ° C to the boiling point of the solvent.
• W 2 represents —SO 2 —
• it can be produced by the method described in Heterocycles, 1998, 48 (1), 155-159, or a method similar thereto.
• compound (134) and compound (124) can be synthesized as follows.
• Compound (163) can be synthesized by subjecting compound (160), whose ring Z is protected, to a base treatment in an inert solvent and then reacting with compound (162).
• Compound (160) is a compound wherein the nitrogen atom at position 1 of ring Z is protected, and examples of the protective group include dimethylsulfamoyl.
• One of the nitrogen atoms on ring Z can be protected with dimethylsulfamoyl by, for example, reacting dimethylsulfamoyl chloride or the like in an inert solvent such as toluene in the presence of a base such as triethylamine. it can.
• the inert solvent examples include ether solvents such as ether, THF, and dioxane; hydrocarbon solvents such as toluene, benzene, and hexane; and halogen solvents such as chloroform and dichloromethane. These solvents may be used by mixing two or more kinds in an appropriate ratio.
• Examples of the base include alkylamines such as triethylamine and ethyldiisopropyl, n-butyllithium, N, N-diisopropyllithiumamide and the like.
• the reaction temperature is selected from the range of about ⁇ 78 ° C. to about the boiling point of the solvent during the treatment with the base, preferably the range of about ⁇ 78 ° C. to about 0 ° C., and the reaction temperature with the compound (162).
• the reaction may be carried out at a temperature of from about 120 ° C. to about the boiling point of the solvent, preferably from about 0 ° C. to about 50 ° C.
• Compound (164) can be obtained by deprotecting compound (163).
• Compound (167) can be synthesized by treating compound (160) with a base in an inert solvent in the same manner as described above, and reacting with aryl aldehyde.
• Compound (167) can also be synthesized by reacting compound (165) with aryl aryl salt, aryl magnesium bromide or the like in an inert solvent.
• the inert solvent include ether solvents such as ether, THF, and dioxane; hydrocarbon solvents such as toluene, benzene, and hexane; and halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, and tetrachlorocarbon. Hydrogen solvents and the like can be mentioned.
• the reaction temperature is selected from the range of about 120 ° C to about the boiling point of the solvent, and preferably the range of about 0 ° C to about 80 ° C.
• Compound (168) can be obtained by reacting compound (167) with an oxidizing agent in an inert solvent.
• the inert solvent examples include halogen solvents such as chloroform and dichloromethane.
• the oxidizing agent examples include chromic acids such as manganese dioxide and pyridinum chromate, and oxidation with dimethyl sulfoxide in combination with oxalyl chloride and the like.
• the reaction temperature is selected from the range of about -78 ° C to near the boiling point of the solvent, and preferably the range of about 120 ° C to about 60 ° C.
• Compound (169) can be obtained by deprotecting compound (168).
• W 2 represents —SO 2 _
• Production method (2) which can be produced by the method described in 1543-1545 or a method analogous thereto.
• the compound of the formula (1) can be produced by forming a bond between Ar W 1 .
• Compound (101) and compound (102) can be obtained from compound (123) and compound (139) and compound (123) and compound (138) by a method known per se, for example, Synth. 111, 513, ⁇ 981, J. Am. Chem. Soc., 111, 314 (1 987), J. Org. Chem., 37, 2320 (1972), Experimental Chemistry Lecture 25, Maruzen (published in 1992), Pa 11 adium Reagents and Catalysts Innovations in Organic Synthesis (Jiro T suji, 1995), etc. It can be manufactured by a method or a method analogous thereto.
• Compound (101) and compound (102) can be obtained by reacting compound (123) with compound (139) and compound (123) with compound (138) in the presence of a transition metal catalyst and a base in an inert solvent. .
• the reaction conditions can be prepared by the method of preparation described in Process (A) Process (1 2) Compound (123) and the compound from Ar I 2 (109) or a method analogous thereto.
• the compound (101) and the compound (102) may be subjected to a catalytic hydrogenation reaction, if necessary, and the “optionally substituted C, _C 5 alkylene” can be produced by the catalytic hydrogenation reaction.
• the reaction conditions and the like can be produced by a method similar to or similar to the conditions for the catalytic hydrogenation reaction of compound (124) described in Production method (A), Production method (14).
• the conversion of compound (101) to compound (103) and compound (102) can be produced by the method described in Production method (A), Production method (1-1), or a method analogous thereto.
• the conversion of compound (127) into compound (146) and compound (145) can be performed, for example, by the production method (A), the production method (1-7), the production method (A), the production method (1-4), and the production method (A ) Manufacturing method It can be manufactured by a method similar to the method described in (1-1) or a combination thereof.
• Compound (138) and compound (139) can be obtained from compound (140) and compound (104) and compound (140) and compound (105), respectively, by methods known per se, for example, New Experimental Chemistry Course Vol. 14 (Maruzen, 1 977), Laboratory Chemistry 19-26 (Maruzen, 1992), Precise Organic Synthesis (Nankodo, 1983), Peptide Synthesis Basics and Experiments (Maruzen, 1985), etc. It can be manufactured by the method described or a method analogous thereto. The reaction conditions and the like can be produced by the same method as or a method analogous to the method for synthesizing compound (101) and compound (102) described in Production method (A), Production method (11-1).
• the conversion of compound (138) to compound (141) and compound (139) can be produced by the method described in Production method (A), Production method (1-1), or a method analogous thereto.
• Compound (148) can be produced by a method known per se, for example, the production method (A), the method described in production method (1-2), or a method analogous thereto.
• the compound (139) can be produced from the compound (150) by a method known per se, for example, the production method (A) The same method as the production method described in the production method (1-3) or a method analogous thereto it can.
• the compound (170) can be produced, for example, by forming a bond at each of the binding sites shown in the above figures a and bc.
• the production method in the case of producing by forming a bond at each of the binding sites b and c can be produced by the method described in the production method (A) described above or a method analogous thereto.
• the compound (171) is defined as shown below, and the production method is described in detail. W 2 -Ar 2
• Manufacturing method (B-1) It can be produced according to the reaction conditions described or a method analogous thereto.
• Y 2 represents —NR 3 CO— or CONR 3 —
• it can be produced using the corresponding raw materials and by the reaction conditions described in Production method (A) Production method (11-1) or a method analogous thereto. it can.
• the method described in Chem. Pharm. Bu i 1., 50, 1 349 (2002), or the like It can be manufactured by a method. For example, it can be manufactured by the following method.
• Compound (176) and compound (177) can be produced by the method described in Production method (A), Production method (2-2), or a method analogous thereto.
• Y 2 is - NR 6 -, - N ( CO-OR 6) one, -N (CO- NR 3 - R 6) -, - N (CO-R 6) -, -N (S0 2 - R 6)
• it can be manufactured by the following method. 1 ⁇ W-Ar 1 _Q OHC— W 4 '-Ar 1 _Q R ° 0 2 C— R 11 -L P g one N— W— Ar 1 — Q
• Y 3 is, - CO- O-, one CO- NR 3 -, - S0 2 -, - CO- and represents (represent a bond left is bonded to the nitrogen),
• the production of compound (181) from compound (178) and compound (180), and the production of compound (186) from compound (178) and compound (185) include, for example, reductive amination reaction.
• Can be manufactured by The conditions for the reductive amination reaction are described in, for example, J. Org. Chem., 61, 3849 (1996), J. Org. Chem., 62, 1240 (1997), Experimental Chemistry Course 20 It can be manufactured by the method described in Maki (Maruzen, issued in 1992), or a method similar thereto.
• the inert solvent used in the reaction examples include ether solvents such as ether, THF, and dioxane; hydrocarbon solvents such as toluene, benzene, and hexane; dichloromethane, chloroform, dichloroethane, and tetrachlorocarbon. And aprotic solvents such as dimethylformamide, acetonitrile and acetone, and alcoholic solvents such as methanol and ethanol. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
• the reaction temperature is selected from the range of about 0 ° C to around the boiling point of the solvent.
• a reaction assistant can be added to this reaction as needed, and examples thereof include acids such as acetic acid, p-toluenesnolephonic acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, and sulfuric acid. .
• Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, and the like.
• Compound (181) can also be produced by reacting compound (179) with compound (180).
• the production conditions are the same as or similar to the method for producing compound (123) from compound (134) and compound (136) described in Production method (A) Production method (1-7). be able to.
• the production method (A) The production method (1-1), the production method (A) (1-7) It can be manufactured by combining the methods described or methods analogous thereto.
• compound (192) is used in place of compound (180), compound (193) is used in place of compound (185), and compound (194) is used in place of compound (108).
• the compound (183) and the compound (191) can be produced in a shorter process.
• the heteroaryl compound or the prodrug of the present invention may have asymmetry or may have a substituent having an asymmetric carbon.
• the body exists.
• the compounds of the present invention include mixtures of these isomers and isolated ones. An example of a method for obtaining such an optical isomer purely includes optical resolution.
• the compound of the present invention or an intermediate thereof is dissolved in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, or 2-propanol; an ether solvent such as gethyle ether; an ester solvent such as ethyl acetate; Aromatic carbonization such as toluene Hydrogen-based solvents, acetonitrile, etc.
• an inert solvent for example, an alcohol solvent such as methanol, ethanol, or 2-propanol; an ether solvent such as gethyle ether; an ester solvent such as ethyl acetate; Aromatic carbonization such as toluene Hydrogen-based solvents, acetonitrile, etc.
• optically active acids for example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, lactic acid, tartaric acid, o-diisopropylidene tartaric acid, Salts can also be formed with dicarboxylic acids such as malic acid, and sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid.
• heteroaryl compound or prodrug of the present invention or an intermediate thereof has an acidic substituent such as carboxyl, an optically active amine (for example, an organic amine such as ⁇ -phenethylamine, cun, quinidine, cinchonidine, cinchonine, strychnine, etc.). ) And salts.
• an optically active amine for example, an organic amine such as ⁇ -phenethylamine, cun, quinidine, cinchonidine, cinchonine, strychnine, etc.
• the temperature at which the salt is formed is in the range of 10 ° C. to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature to near the boiling point of the solvent. Before the precipitated salt is collected by filtration, the salt can be cooled, if necessary, to improve the yield.
• the amount of the optically active acid or amine used is in the range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent, relative to the substrate.
• the crystals are placed in an inert solvent (for example, alcohol solvents such as methanol, ethanol, and 2-propanol; ether solvents such as ethyl ether; ester solvents such as ethyl acetate; aromatic hydrocarbon solvents such as toluene; Recrystallization with acetonitrile and the like and a mixed solvent thereof can also obtain a high-purity optically active salt.
• an inert solvent for example, alcohol solvents such as methanol, ethanol, and 2-propanol; ether solvents such as ethyl ether; ester solvents such as ethyl acetate; aromatic hydrocarbon solvents such as toluene; Recrystallization with acetonitrile and the like and a mixed solvent thereof can also obtain a high-purity optically active salt.
• the obtained salt can be treated with an acid or base by a usual method to obtain a free form.
• the heteroaryl compound of the present invention or a salt thereof can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form. Parenterally, it can be administered in the form of topical administration, injection, transdermal, nasal, and the like.
• topical administration examples include capsules, tablets, pills, powders, cachets, suppositories, and liquid preparations.
• injection include a sterile solution or suspension.
• the topical administration agent include creams, ointments, lotions, transdermal agents (ordinary patches, matrixes) and the like.
• compositions are formulated in a conventional manner, together with pharmaceutically acceptable excipients and additives.
• Pharmaceutically acceptable excipients and additives include carriers, binders, flavors, buffers, thickeners, coloring agents, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, etc.
• Can be Pharmaceutically acceptable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, ratatose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcenorelose, low melting wax. And cocoa butter.
• Capsules can be formulated by incorporating a compound of the present invention together with a pharmaceutically acceptable carrier.
• the compounds of the present invention can be mixed with pharmaceutically acceptable excipients or placed in a capsule without excipients. Cassiers can be produced in a similar manner.
• Solutions for injection include solutions, suspensions, and emulsions.
• aqueous solution, water-propylene glycol solution and the like can be mentioned.
• the solution can also be prepared in the form of a solution of polyethylene glycol or / and propylene dalicol, which may include water.
• a liquid preparation suitable for oral administration can be produced by adding the compound of the present invention to water and adding a coloring agent, a flavor, a stabilizing agent, a sweetening agent, a solubilizing agent, a thickening agent and the like as needed.
• a liquid preparation suitable for oral administration can be produced by adding the compound of the present invention to water together with a dispersant to make it viscous.
• the thickener include pharmaceutically acceptable natural or synthetic gums, resins, methylsenolerose, sodium carboxymethylcellulose, and known suspending agents.
• topical preparation examples include the above-mentioned liquid preparations, creams, aerosols, sprays, powders, lotions, ointments and the like.
• the above-mentioned preparation for topical administration can be prepared by mixing the compound of the present invention with a pharmaceutically acceptable diluent and carrier usually used.
• Ointments and creams are obtained, for example, by formulating an aqueous or oily base with a thickener and / or a gelling agent.
• the base for example, water, liquid paraffin, vegetable oil (peanut oil, castor oil, etc.) and the like can be mentioned.
• the thickener include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycol, lanolin, hydrogenated lanolin, honey and the like.
• Lotions may be added to an aqueous or oily base with one or more pharmaceutically acceptable stabilizers, suspending agents, emulsifiers, diffusing agents, thickeners, coloring agents, fragrances, etc. .
• the powder is formulated with a pharmaceutically acceptable powder base.
• a pharmaceutically acceptable powder base Luk, lactose, starch and the like.
• Drops may be formulated with an aqueous or non-aqueous base and one or more pharmaceutically acceptable diffusing agents, suspending agents, solubilizing agents, and the like.
• the topical preparation may contain, if necessary, a preservative such as methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, or benzalkonidum octolide, or a bacterial growth inhibitor.
• a preservative such as methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, or benzalkonidum octolide, or a bacterial growth inhibitor.
• the heteroaryl compound of the present invention or a salt thereof can be administered to a diabetic patient, particularly a type 2 diabetic or non-insulin-dependent diabetic patient. Further, or the heteroaryl compound or a salt thereof of the present invention can control the blood glucose level of a diabetic patient.
• the dosage and frequency of administration at this time vary depending on the symptoms, age, body weight, dosage form, etc., but in the case of oral administration, it is usually in the range of about 1 to about 50 mg / day for adults. It can be administered, preferably in the range of about 5 to about 10 mg, in single or divided doses.
• the dose When administered as an injection, the dose can be in the range of about 0.1 to about 30 Omg, preferably in the range of about 1 to about 10 Omg, which can be administered once or divided into several doses.
• Specific examples of the compound having the formula (1) obtained by the invention include, for example, the compounds shown in Tables 1 to 9 shown below.
• Solution A 0.05% aqueous trifluoroacetic acid
• Solution B acetonitrile containing 0.035% trifluoroacetic acid
• the filtrate was concentrated under normal pressure to about 50 Om1, and hexane (500 mL) was added. Further, the mixture was concentrated to about 500 ml, cooled to 10 ° C, and the crystals were collected by filtration. This was washed with hexane and toluene in that order and dried to obtain the title compound (315 g, 71%).
• THF solution of this acid chloride was added dropwise to a mixture of D-valine methyl ester hydrochloride (150 mg, 0.895 mmol) and triethylamine (0.20 g, 1.98 mmol) in THF (3 ml). The mixture was stirred at 25 ° C for 4 hours. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
• (2 ml) and methanol (2 ml) 1N lithium hydroxide aqueous solution (2 ml) was added, and the mixture was stirred at 10 to 25 ° C for 40 minutes.
• the methanol and THF in the reaction solution were distilled off, and the residue was diluted with water and washed with getyl ether.
• the aqueous layer was acidified by adding diluted hydrochloric acid, and extracted with ethyl acetate.
• the organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound.
• Example 12 The compound of 2-2 (105 mg, 0.212 mmol) was dissolved in 10 ml of ethanol, 10 ml of a 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at 50 ° C for 2 hours. The reaction solution was cooled to 0 ° C., made acidic by adding 4N aqueous hydrochloric acid, and the resulting white crystals were collected by filtration. The obtained crystals were washed with 1N aqueous hydrochloric acid and dried under reduced pressure to give the title compound (97.3 mg, 96%).
• N_Methyl-1-N [(3- ⁇ (IE) -3— [2 -— (4-Methylbenzoyl) 1-1H—pyrrole-11-yl] prop-1--1-eninolephenyl ⁇ sulfonyl) glycine
• the organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate.
• the residue obtained by evaporating the solvent under reduced pressure was dissolved in 50 ml of chloroform, and manganese dioxide (5.00 g, 5.75 mmol) was added, followed by stirring at 60 ° C for 3 hours.
• the reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (64.0 mg, 46%).
• Example 20-1 The compound of Example 20-1 (1.00 g, 5.71 mmol) was dissolved in 30 ml of THF and stirred at -78 ° C. To this solution was added n-butyllithium (1.57 M hexane solution, 3.9 ml, 6.3 mmol), and the mixture was stirred at -78 ° C for 30 minutes. Next, a solution of 4- (isobutyl) benzaldehyde (1.39 g, 8.57 mmol) in THF (5 ml) was added, the temperature was raised to room temperature, and the mixture was stirred overnight.
• the reaction solution was filtered through celite, and the solvent of the filtrate was distilled off under reduced pressure.
• the obtained residue was dissolved in 20 ml of THF, 50 ml of 4N diluted hydrochloric acid was added, and the mixture was refluxed for 4 hours. While stirring under ice-cooling, a 4 N aqueous sodium hydroxide solution was added dropwise to neutralize the mixture, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain the title compound (397 mg, 31%).
• Example 20-2 The compound of Example 20-2 (397 mg, 1.74 mmol) was dissolved in 5 ml of THF, and potassium t-butoxide (215 mg, 1.91 mmol) was added. After stirring at 10 to 25 ° C for 30 minutes, aryl bromide (279 mg, 2.61 mmol) was added, and the mixture was stirred at 40 ° C for 4 hours. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and azeotroped with hexane to obtain the title compound (458 mg, 98%).
• Example 21 In the same manner as in Example 15, the compound of Example 21 was synthesized.
• Example 44-1 Using the compound of Example 44-1 and the compound of Reference Example 13-13, the title compound was synthesized by palladium coupling in the same manner as in Reference Example 5, followed by hydrolysis.
• Example 44 Using the compound of Example 12 and L-parin methyl ester hydrochloride, the title compound was obtained by synthesis in the same manner as in Example 1.
• the title compound was synthesized in the same manner as in Example 1 using 4-odobenzoic acid and L-valine methyl ester hydrochloride.
• Example 49 The title compound was synthesized in the same manner as in Example 46-2 using the compound of Example 11 and the compound of Reference Example 1-3.
• reaction solution was diluted with water and extracted with ethyl acetate / toluene (1/1).
• the organic layer was washed with aqueous sodium sulfite, water (twice) and saturated saline (twice), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
• Example 52-3 To a solution of the compound of Example 52-3 (373 mg, 1.28 mmol) and the compound of Reference Example 13 (282 rag, 1.28 mmol) in DMF (10 ml), was added sodium hydrogen carbonate (0.22 g, 2.62 mmol), Benzyltriethylammonium bromide (0.35 g, 1.29 mmol) and palladium acetate (30 mg, 0.13 mmol) were added, and the mixture was stirred at 65 ° C for 5 hours and at 75 ° C for 9 hours. Anti Aqueous sodium thiosulfate was added to the reaction solution, and extracted with ethyl acetate.
• Example 54-4 After hydrolyzing the compound of Example 54-4 in the same manner as in Reference Example 5-2, the title compound was synthesized in the same manner as in Example 3.
• This methyl ester was dissolved in methanol (1 ml) and THF (1 ml), and IN lithium hydroxide solution (1 ml) was added.
• the reaction mixture was heated at 10 to 25 ° C for 65 hours at 70 ° C. And stirred for 8 hours.
• the reaction solution was diluted with water and washed with getyl ether.
• the aqueous layer was made acidic with 5% potassium hydrogen sulfate and extracted with ethyl acetate.
• the organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (9 mg, yield 65%).
• Example 6 After hydrolyzing the compound of 2-1 in the same manner as in Reference Example 5-2, the title compound was synthesized in the same manner as in Example 3.
• a solution of the compound of Example 64-1 (2.79 g, 12.9 mmol) in toluene (15 ml) was added to a mixture of a 20% aqueous solution of titanium trichloride (52 g, 67 mmol) and methanol (50 ml) under heating and reflux. The mixture was added dropwise over time, and the reaction solution was stirred for 30 minutes while heating under reflux. The reaction solution was cooled to room temperature, and sodium hydrogen carbonate (powder, 31 g) was added little by little. The reaction solution was diluted with water and ethyl acetate, and insolubles were removed by filtration.
• Example 67 In the same manner as in Example 66, the compounds of Examples 67 to 69 were synthesized.
• Example 66 In the same manner as in Example 66, the compounds of Examples 67 to 69 were synthesized.
• the title compound was obtained in the same manner as in Example 1 using 2-funoleo mouth_5-odobenzoic acid and methyl 2-aminoisobutyrate hydrochloride as raw materials.
• the reaction solution was diluted with water and washed with getyl ether.
• the aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate.
• the organic layer was washed with water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a carboxylic acid form (6.0 g).
• the carboxylic acid form (6.0 g) was dissolved in methanol (100 ml).
• Examples 82 to 85 were synthesized from the corresponding olefin form.
• the above methyl ester mixture (47 mg) was dissolved in THF (1 ml), and to this THF solution were added methanol (1 ml) and an aqueous lithium hydroxide solution (1 ml), and the mixture was stirred at 10 to 25 ° C for 3 hours. did.
• the reaction solution was diluted with water and washed with getyl ether.
• the aqueous layer was made weakly acidic (pH about 4) by adding 5% aqueous potassium hydrogen sulfate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (16 mg, 11% over two steps).
• N-Butyllithium (1.59 M in hexane, 8.2 ml, 13.0 mmol) was added to a solution of 2,2,6,6-tetramethylpiperidine (1.8 g, 12.8 mmol) in THF (20 ml) at -78 ° C. The mixture was dropped, and the temperature was raised to room temperature over 30 minutes. The reaction solution was cooled again to ⁇ 78 ° C., and a solution of 1-benzenesulfonolone 1H-pyrrole (2.5 g, 12.1 mmol) in THF (20 ml) was added.
• the reaction solution was stirred as it was for 10 minutes, and the compound of Example 87-1 (2.53 g, 12.3 mmol ) In THF (20 ml) was added dropwise.
• the reaction solution was returned to room temperature over 30 minutes and stirred at 10 to 25 ° C for 2 hours.
• a 5% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
• the organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off.
• Example 87-2 The compound of Example 87-2 (1.96 g, 5.58 mmol) was hydrolyzed in the same manner as in Reference Example 1-2 to obtain the title compound (0.97 g, 82%).

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