WO2012070114A1 - Sulfamide derivative having npy y5 receptor antagonism - Google Patents

Sulfamide derivative having npy y5 receptor antagonism Download PDF

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Publication number
WO2012070114A1
WO2012070114A1 PCT/JP2010/070876 JP2010070876W WO2012070114A1 WO 2012070114 A1 WO2012070114 A1 WO 2012070114A1 JP 2010070876 W JP2010070876 W JP 2010070876W WO 2012070114 A1 WO2012070114 A1 WO 2012070114A1
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substituted
unsubstituted
compound
pharmaceutically acceptable
aromatic heterocycle
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PCT/JP2010/070876
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French (fr)
Japanese (ja)
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隆行 奥野
直樹 神山
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塩野義製薬株式会社
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Priority to PCT/JP2010/070876 priority Critical patent/WO2012070114A1/en
Publication of WO2012070114A1 publication Critical patent/WO2012070114A1/en

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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • the present invention relates to a novel sulfamide derivative having NPY Y5 receptor antagonistic activity and useful as a pharmaceutical, particularly as an anti-obesity drug.
  • Neuropeptide Y (hereinafter referred to as NPY) is a peptide consisting of 36 amino acid residues and was isolated from pig brain in 1982. NPY is widely distributed in the central nervous system and peripheral tissues of humans and animals.
  • NPY has been found to have a feeding promoting action, an anticonvulsant action, a learning promoting action, an anxiolytic action, an antistress action, etc. in the central nervous system, and depression, It may be deeply involved in central nervous system diseases such as Alzheimer's dementia and Parkinson's disease.
  • central nervous system diseases such as Alzheimer's dementia and Parkinson's disease.
  • NPY causes contraction of smooth muscles such as blood vessels and myocardium, and is thus considered to be involved in cardiovascular disorders.
  • metabolic diseases such as obesity, diabetes, and hormonal abnormalities (see Non-Patent Document 1). Therefore, a pharmaceutical composition having an NPY receptor antagonistic action may be a prophylactic or therapeutic agent for various diseases involving the NPY receptor as described above.
  • Non-Patent Document 2 subtypes of Y1, Y2, Y3, Y4, Y5 and Y6 have been discovered so far (see Non-Patent Document 2).
  • the Y5 receptor is involved in at least the feeding function, and it has been suggested that the antagonist becomes an anti-obesity drug (see Non-Patent Documents 3 to 5).
  • Patent Document 1 describes a benzimidazole derivative and an imidazopyridine derivative having a sulfonyl group having an NPY Y5 receptor antagonistic action. Further, amine derivatives having a sulfonyl group having an NPY Y5 receptor antagonistic action are described in Patent Documents 2, 3 and the like. In addition, Patent Documents 4 and 5 describe that amide derivatives having a sulfonyl group have NPY Y5 antagonistic activity. Patent Document 14 describes that a pyrazole derivative has NPY Y5 antagonistic activity. These compounds differ in structure from the compounds of the present invention. Further, a compound having a structure different from that of the compound of the present invention but having NPY Y5 antagonistic activity is disclosed in Patent Document 6 and the like.
  • An object of the present invention is to provide a novel sulfamide derivative having an excellent NPY Y5 receptor antagonistic action.
  • the present inventors have succeeded in synthesizing a novel compound having an excellent NPY Y5 receptor antagonistic action. Moreover, it discovered that this compound showed the strong body weight suppression effect. Furthermore, the present inventors have also found that the compounds of the present invention have little inhibition on drug metabolizing enzymes, and have good metabolic stability and water solubility. The compound of the present invention has low toxicity and is sufficiently safe for use as a medicine.
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl, R 1 and R 2 together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing aromatic heterocycle or a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, or R 1 and R 5 together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, X is an aromatic hetero
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl, R 1 and R 2 together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing aromatic heterocycle or a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, or R 1 and R 5 together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, X is an aromatic heterocycle or a non-aromatic heterocycle,
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, (2) (5) The compound according to any one of the above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 1 is hydrogen or substituted or unsubstituted alkyl;
  • R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, its pharmaceutical Top acceptable salts or solvates thereof.
  • R 1 and R 2 together with the adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, The pharmaceutically acceptable salt or solvate thereof.
  • R 3 is each independently substituted or unsubstituted phenyl.
  • Treatment of a disease involving NPY Y5, comprising administering the compound according to any one of (2) to (12) above, a pharmaceutically acceptable salt thereof, or a solvate thereof, or Prevention method.
  • (16) The use of the compound according to any one of (2) to (12) above, a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving NPY Y5. use.
  • the pharmaceutical composition according to the above (13) which is a medicament for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity.
  • Obesity-related diseases include bulimia, hypertension, impaired glucose tolerance, diabetes, metabolic syndrome, lipid metabolism abnormality, arteriosclerosis, hyperuricemia, gout, fatty liver, proteinuria, endometrial cancer, breast cancer, prostate (18)
  • Prevention or treatment of obesity or obesity-related diseases comprising administering the compound according to any one of (2) to (12) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a method for treating or preventing a disease involving NPY Y5, which is used for weight management in obesity comprising administering a drug used for management.
  • the compound of the present invention exhibits NPY Y5 receptor antagonistic activity, and is associated with drugs, especially NPY Y5, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, It is very useful as a medicine for the treatment or prevention of hypertension, cerebral hyperemia, congestive heart failure or sleep disorder.
  • drugs especially NPY Y5 receptor antagonistic activity, and is associated with drugs, especially NPY Y5, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, It is very useful as a medicine for the treatment or prevention of hypertension, cerebral hyperemia, congestive heart failure or sleep disorder.
  • the compound of the present invention since the compound of the present invention exhibits an effective anti-feeding action, it is very useful for weight management, weight loss, and weight maintenance after weight loss in obesity.
  • it is very useful as a medicament for treating or preventing diseases in which obesity is a risk factor, such as diabetes,
  • Halogen includes fluorine, chlorine, bromine and iodine. In particular, fluorine and chlorine are preferable.
  • Alkyl means a linear or branched hydrocarbon group having 1 to 10 carbon atoms. Examples include alkyl having 1 to 6 carbon atoms, alkyl having 1 to 4 carbon atoms, alkyl having 1 to 3 carbon atoms, and the like.
  • Alkenyl means a straight or branched hydrocarbon group having 2 to 10 carbon atoms having one or more double bonds at an arbitrary position. Examples include alkenyl having 2 to 8 carbon atoms and alkenyl having 3 to 6 carbon atoms. Examples thereof include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl and the like.
  • Alkynyl means a linear or branched hydrocarbon group having 2 to 10 carbon atoms having one or more triple bonds at any position. Examples include alkynyl having 2 to 6 carbon atoms, alkynyl having 2 to 4 carbon atoms, and the like. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. In addition to one or more triple bonds at any position, alkynyl may further have a double bond.
  • Cycloalkyl means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms. Examples include cycloalkyl having 3 to 6 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, and the like. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned.
  • Cycloalkenyl means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 7 carbon atoms. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. Cycloalkenyl also includes bridged cyclic unsaturated aliphatic hydrocarbon groups and spiro hydrocarbon groups having an unsaturated bond in the ring.
  • Aryl means a monocyclic or polycyclic aromatic carbocyclic group.
  • phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned.
  • a condensed aromatic hydrocarbon cyclic group in which a cycloalkane (ring derived from the above “cycloalkyl”) or a cycloalkene (ring derived from the “cycloalkenyl”) is condensed is also included.
  • indanyl, indenyl, biphenylenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned.
  • “Aromatic heterocycle” means an aromatic ring having one or more heteroatoms arbitrarily selected from O, S and N in the ring. Includes monocyclic or polycyclic aromatic heterocycles. “Monocyclic aromatic heterocycle” means a 4- to 8-membered monocyclic aromatic ring having one or more heteroatoms arbitrarily selected from O, S and N in the ring.
  • Examples include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole, furan, and thiophene.
  • a 5-membered or 6-membered monocyclic aromatic heterocycle is preferable.
  • the “polycyclic aromatic heterocycle” refers to the above “monocyclic aromatic heterocycle”, an aromatic carbocycle (ring derived from the above “aryl”), an aromatic heterocycle, a cycloalkane (the above “cycloalkane”).
  • a ring derived from “alkyl” or a ring fused with a cycloalkene (ring derived from “cycloalkenyl” above).
  • the “nitrogen-containing aromatic heterocycle” means a monocyclic or polycyclic aromatic heterocycle having at least one nitrogen atom in the ring.
  • Examples of the “monocyclic nitrogen-containing aromatic heterocycle” include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, isoxazole, oxazole, oxadiazole, isothiazole, and thiazole. , Thiadiazole and the like.
  • Examples of the ⁇ polycyclic nitrogen-containing aromatic heterocycle '' include, for example, indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benziso
  • Two-ring nitrogen-containing compounds such as oxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzothiazole, benzothiadiazole, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, thiazolopyridine
  • Aromatic heterocycles 3-ring nitrogen-containing aromatic heterocycles such as carbazole, acridine, phenothiazine, phenoxazine and the like
  • Heteroaryl means a monocyclic or polycyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring.
  • the group includes a group derived from the above “monocyclic aromatic heterocycle” and a group derived from the above “polycyclic aromatic heterocycle”.
  • Examples of the ⁇ monocyclic aromatic heterocyclic group '' include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, Thienyl and the like can be mentioned.
  • polycyclic aromatic heterocyclic group examples include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl , Benzoxazolyl, benzoxiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyra Bicyclic aromatic heterocyclic groups such as dinopyridazinyl, oxazolopyridyl, thiazolopy
  • Non-aromatic heterocycle means a non-aromatic ring having one or more heteroatoms arbitrarily selected from O, S and N in the ring. Includes monocyclic or polycyclic non-aromatic heterocycles. “Monocyclic non-aromatic heterocycle” means a 4- to 8-membered monocyclic non-aromatic ring having one or more hetero atoms arbitrarily selected from O, S and N in the ring.
  • Examples include thiazole, oxazolidine, thiazolidine and the like. In particular, a 5-membered or 6-membered monocyclic non-aromatic heterocycle is preferable.
  • Polycyclic non-aromatic heterocycle refers to the above “monocyclic non-aromatic heterocycle”, aromatic carbocycle (ring derived from the above “aryl”), aromatic heterocycle, monocyclic A non-aromatic heterocycle, a cycloalkane (ring derived from the above “cycloalkyl”) or a cycloalkene (ring derived from the “cycloalkenyl”) is condensed.
  • aromatic carbocycle ring derived from the above “aryl”
  • aromatic heterocycle monocyclic
  • a cycloalkane ring derived from the above “cycloalkyl”
  • a cycloalkene ring derived from the “cycloalkenyl
  • the “nitrogen-containing non-aromatic heterocycle” means a monocyclic or polycyclic non-aromatic heterocycle having at least one nitrogen atom in the ring.
  • Monocyclic nitrogen-containing non-aromatic heterocycle '' includes, for example, azetidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, oxadiazine, dihydropyridine, thiomorpholine, tetrahydrothiazole, tetrahydro Examples include isothiazole, oxazolidine, thiazolidine and the like.
  • Examples of the “polycyclic nitrogen-containing non-aromatic heterocycle” include indoline, isoindoline, dihydrobenzothiadiazole and the like.
  • Heterocyclyl means a non-aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring.
  • a monocyclic non-aromatic heterocyclic group (a group derived from the above “monocyclic non-aromatic heterocyclic ring”) or a polycyclic non-aromatic heterocyclic group (the above “polycyclic non-aromatic heterocyclic group”); Group derived from “aromatic heterocycle”.
  • ⁇ monocyclic non-aromatic heterocyclic group '' include dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidino, piperidino, piperazinyl, piperazinoyl , Morpholinyl, morpholino, oxadiazinyl, dihydropyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, oxazolidyl, thiazolidyl and the like.
  • polycyclic non-aromatic heterocyclic group examples include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like. In the case of a polycyclic non-aromatic heterocyclic group, any ring may have a bond.
  • Alkoxy means a group in which the above “alkyl” is bonded to an oxygen atom. Specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, pentoxy, neopentoxy, hexoxy, isohexoxy, n-heptoxy, isoheptoxy, n -Octoxy, isooctoxy and the like.
  • Haloalkyl and haloalkoxy mean a group in which the “halogen” is bonded to the “alkyl” and “alkoxy”.
  • Aryloxy means a group in which the above “aryl” is bonded to an oxygen atom. Specific examples include phenoxy, naphthoxy, anthryloxy, phenanthryloxy, indanyloxy, indenyloxy, biphenylyloxy, acenaphthyloxy, tetrahydronaphthyloxy, fluorenyloxy and the like.
  • alkenyloxy means a group bonded to an oxygen atom.
  • Alkylthio “alkenylthio”, “cycloalkylthio”, “cycloalkenylthio”, “arylthio”, “heteroarylthio” and “heterocyclylthio” are the above-mentioned “alkyl”, “alkenyl”, “cycloalkyl” ”,“ Cycloalkenyl ”,“ aryl ”,“ heteroaryl ”and“ heterocyclyl ”mean a group bonded to a sulfur atom.
  • Alkoxycarbonyl means a group in which the oxygen atom of “alkoxy”, “alkenyloxy”, “cycloalkyloxy”, “cycloalkenyloxy”, “aryloxy”, “heteroaryloxy” and “heterocyclyloxy” is bonded to a carbonyl group .
  • Alkylcarbonyl “alkenylcarbonyl”, “cycloalkylcarbonyl”, “cycloalkenylcarbonyl”, “arylcarbonyl”, “heteroarylcarbonyl” and “heterocyclylcarbonyl” are the above “alkyl”, “alkenyl”.
  • Cycloalkyl “cycloalkenyl”, “aryl”, “heteroaryl” and “heterocyclyl” mean a group bonded to a carbonyl group.
  • Alkylsulfonyl “alkenylsulfonyl”, “cycloalkylsulfonyl”, “cycloalkenylsulfonyl”, “arylsulfonyl”, “heteroarylsulfonyl” and “heterocyclylsulfonyl” are the above “alkyl”, “alkenyl”.
  • Cycloalkyl “cycloalkenyl”, “aryl”, “heteroaryl” and “heterocyclyl” mean a group bonded to a sulfonyl group.
  • the bond of the divalent group may be bonded to the same or different atom.
  • the divalent group may be bonded so as to form a bicyclo ring or a spiro ring as well as a case where the bond of the divalent group is bonded to an adjacent atom. Any position may be substituted with one or more groups selected from these.
  • substituted or unsubstituted cycloalkyl eg, cyclohexyl
  • alkylene eg, —CH 2 —CH 2 —
  • substituent of “substituted or unsubstituted aryl” is a group represented by the formula: —N (R 7 )-(alkylene) -O—, the following groups are exemplified.
  • substituent is another divalent group, it may be substituted in the same manner as described above.
  • “Acyl” means (1) a linear or branched alkylcarbonyl or alkenylcarbonyl having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 4 carbon atoms, (2) cycloalkylcarbonyl having 4 to 9 carbon atoms, preferably 4 to 7 carbon atoms and (3) arylcarbonyl having 7 to 11 carbon atoms are included.
  • Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioyl, methacryloyl, crotonoyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl and benzoyl.
  • acyloxy means a group in which the above “acyl” is bonded to an oxygen atom.
  • the compounds of the present invention all have NPY Y5 receptor antagonistic action, but particularly preferred compounds include the following compounds in the formula (I).
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or A compound that is unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl.
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.
  • R 1 and R 2 are each independently hydrogen; alkyl; alkyl substituted with halogen or cyano; alkoxy;
  • R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl.
  • R 1 is hydrogen or substituted or unsubstituted alkyl; A compound wherein R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl.
  • R 1 is hydrogen; alkyl; or alkyl substituted with cyano; A compound wherein R 2 is alkyl; alkyl substituted with halogen or cyano; alkoxy; cycloalkyl; aryl.
  • a compound in which R 1 and R 2 together with the adjacent nitrogen atom form piperidine, oxo substituted oxazolidine or morpholine.
  • R 3 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.
  • R 3 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted Morpholinyl, substituted or unsubstituted morpholino, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperidino, substituted or unsubstituted benzodioxolyl, substituted or unsubstituted dihydrobenzoxaziny
  • R 3 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted Morpholinyl, substituted or unsubstituted morpholino, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperidino, substituted or unsubstituted benzodioxolyl, substituted or unsubstituted dihydrobenzoxazinyl Or substituted or unsubstituted indazolyl (each substituted group is halogen, cyano, nitro, nitroso, azide, oxo
  • R 3 is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl (the substituents are each selected from halogen, cyano, nitro, azide, oxo, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy and haloalkoxy A compound which is the above group).
  • a compound in which R 3 is substituted or unsubstituted phenyl or pyridyl (the substituent is one or more groups selected from halogen, cyano, and alkoxy).
  • R 3 is substituted or unsubstituted phenyl (the substituent is one or more groups selected from halogen, cyano, and alkoxy).
  • R 4 is halogen, cyano, nitro, nitroso, azide, oxo, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, Hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl Oxy, substituted or unsubstituted heterocyclyloxy, Mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or un
  • R 4 is halogen, cyano, oxo, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted aryloxy.
  • R 4 is halogen, cyano, oxo, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy or substituted or unsubstituted aryloxy (the substituents are halogen, cyano, nitro, Nitroso, azide, oxo, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, haloalkoxy, alkenyloxy, mercapto, alkylthio, alkenylthio, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, carbamoyl, formyl, alkylcarbonyl, alkenylcarbonyl, And one or more groups selected from sulfino, sulfo, alkylsulfonyl, alkenylsulfonyl, sulfamoyl and
  • R 4 is halogen, cyano or substituted or unsubstituted alkyl.
  • R 4 is halogen, cyano, or substituted or unsubstituted alkyl (the substituents are one or more groups selected from halogen, cyano, nitro, azide, oxo, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, and haloalkoxy, respectively) Compound).
  • R 4 is halogen, cyano, or alkyl.
  • R 5 is hydrogen or substituted or unsubstituted alkyl.
  • a compound wherein R 5 is hydrogen or alkyl having 1 to 3 carbon atoms.
  • a compound wherein R 5 is hydrogen.
  • a compound wherein m is 1 or 2.
  • a compound wherein m is 1.
  • a compound wherein n is 0-2.
  • a compound wherein n is 0 or 1.
  • R is halogen, oxo, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl.
  • p is an integer of 0-2.
  • a compound wherein X is an aromatic heterocycle or a non-aromatic heterocycle.
  • a compound in which X is indole, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, imidazole, pyrazole, pyrrole, triazole, pyridine, imidazopyridine or benzimidazole.
  • a compound wherein X is indole, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, pyrazole, pyrrole or benzimidazole.
  • a compound wherein X is pyrazole.
  • a compound in which X is a group selected from the following. (The bond from cyclohexane, (R 3 ) m, and (R 4 ) n may be bonded to any substitutable atom on the ring.)
  • a group represented by (X ′ is an aromatic heterocycle or non-aromatic heterocycle having a bond to the cyclohexane ring adjacent to the nitrogen atom in the ring.) The compound which is group shown by these.
  • the compound represented by the formula (I) is formula: (In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).) And / or the formula: (In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).) Means a compound represented by Particularly preferably, formula: (In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).) It is a compound shown by these.
  • the compound of the present invention is capable of producing each compound and includes pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable salts” include, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; salts of organic acids such as paratoluenesulfonic acid, methanesulfonic acid, oxalic acid or citric acid; ammonium, Examples include salts of organic bases such as trimethylammonium or triethylammonium; salts of alkali metals such as sodium or potassium; and salts of alkaline earth metals such as calcium or magnesium.
  • the compound of the present invention includes its solvate.
  • Preferable examples include hydrates and alcohol hydrates.
  • the compound of the present invention has an asymmetric carbon atom, it includes racemates, both enantiomers and all stereoisomers (geometric isomers, epimers, enantiomers, etc.). Moreover, when this invention compound has a double bond, when E body and Z body may exist, both are included.
  • the prodrug of the compound of the present invention is included in the scope of the compound of the present invention.
  • Prodrugs of the compounds of the present invention are functional derivatives of the compounds of the present invention and are easily converted into the compounds of the present invention in vivo. Therefore, the “compound” of the present invention is a specifically disclosed compound or a compound that is not specifically disclosed in some cases, but is administered to a patient with a disease involving NPY Y5 in vivo. Including compounds that convert to The usual procedures for selection and formulation of suitable prodrug derivatives are described, for example, in Design of Prodrugs ed (ed. H. Bundgaard, Elsevier, 1985).
  • the compound represented by formula (I) which is the compound of the present invention can be synthesized, for example, by the following method.
  • Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).
  • Compound (III-1) is reacted with a compound represented by the formula: R 1 (R 2 ) NSO 2 Hal to obtain a compound represented by formula (I).
  • the compound represented by the formula (III-2) is reacted with a compound represented by the formula: R 5 Hal to obtain a compound represented by the formula (I).
  • the above reaction can be performed using a base.
  • pyridine triethylamine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride and the like can be used.
  • the above reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
  • Use solvents such as tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixed solvents thereof. Can do.
  • the above reaction may be carried out while protecting R 3 and R 4 on X, and may be deprotected after the reaction.
  • the compound of the present invention can be synthesized as follows. (In the formula, Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).)
  • Compound (III-1) is reacted with a compound represented by the formula: R 1 (R 2 ) NSOHal to obtain compound (III-3). Further, the obtained compound (III-3) is oxidized to obtain a compound represented by the formula (I).
  • the step of using the compound represented by the formula: R 1 (R 2 ) NSOHal can be performed in the presence of a base.
  • a base pyridine, triethylamine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used.
  • the above reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
  • Use solvents such as tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixed solvents thereof.
  • the oxidation step can be performed using an oxidizing agent.
  • oxidizing agent examples include m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, pertrifluoroacetic acid, sodium periodate, sodium hypochlorite, potassium permanganate, and sodium tungstate.
  • the above reaction may be carried out while protecting R 3 and R 4 on X, and may be deprotected after the reaction.
  • the compound (X-4), which is an intermediate of the compound of the present invention can be synthesized using the synthesis method shown below.
  • Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).
  • Process A The compound (X-1) having the substituent R 5 corresponding to the target compound and the compound represented by the formula: R 1 (R 2 ) NSO 2 Hal are treated with a base in an appropriate solvent to give the compound (X-2) Get.
  • the reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
  • Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane (methylene chloride), toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixtures thereof
  • a solvent or the like can be used.
  • it is dichloromethane.
  • These solvents may be appropriately selected and used in combination with a base.
  • triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Triethylamine is preferred. It is preferable to use 1 to 5 equivalents of a base relative to compound (X-1).
  • Process B Compound (X-2) is treated with a base in a suitable solvent to give compound (X-3). The reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
  • barium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide or the like can be used. Sodium hydroxide is preferable.
  • tetrahydrofuran dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, mixed solvents thereof, etc. are used. Is possible. Tetrahydrofuran and / or ethanol are preferred. These solvents may be appropriately selected and used in combination with a base.
  • Process C Compound (X-3) is treated with a halogenating agent in a suitable solvent and reacted at 0 ° C. to 50 ° C.
  • halogenating agent examples include oxalyl chloride, thionyl chloride, thionyl bromide, phosphorus pentachloride, phosphorus oxychloride and the like. Oxalyl chloride is preferred. It is preferable to use 1 to 5 equivalents of a halogenating agent relative to compound (X-3). Further, dimethylformamide may be added as a catalyst.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, Pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Methylene chloride and / or dimethylformamide are preferable. These solvents may be appropriately selected and used in combination with a halogenating agent.
  • an active ester may be obtained instead of the acid halide using acetic anhydride, methanesulfonyl chloride, or ethyl chlorocarbonate, and used in the next step D.
  • Process D The acid halide or active ester obtained in Step C and ethyl acetate are reacted in a suitable solvent in the presence of Lewis acid and N-alkylimidazole at ⁇ 100 ° C. to 0 ° C. for several minutes to several hours. Addition yields compound (X-4).
  • titanium tetrachloride As the Lewis acid, titanium tetrachloride, tin tetrachloride, aluminum trichloride, boron trifluoride ether complex, boron trichloride, trimethylsilyl trifluoromethanesulfonate (TMSOTf), zinc dichloride, or the like can be used. Titanium tetrachloride is preferable.
  • N-alkylimidazole N-methylimidazole, N-ethylimidazole and the like can be used. N-methylimidazole is preferable.
  • N, N′-diisopropylethylamine, diethylamine, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used.
  • N, N′-diisopropylethylamine is preferred.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Preference is given to methylene chloride and / or ethyl acetate. These solvents may be appropriately selected and used in combination with a base.
  • the compound of the present invention can be synthesized from compound (X-4) using the synthesis method shown below.
  • Hal is halogen
  • R 6 is a group derivable to R 3 , R 4 or R 3 or R 4.
  • Each other symbol has the same meaning as each symbol in the compound represented by the formula (I). .
  • Process E Compound (X-4) is reacted with hydrazine (eg, hydrazine monohydrate) in a suitable solvent to give compound (X-5). The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Preferably, it is methanol.
  • a compound represented by the formula: NH 2 NHR 6 can also be used.
  • R 6 can be introduced into the hydrazine ring simultaneously with the hydroxy group.
  • Process F By a conventional method, the compound represented by the formula (I) can be obtained by attaching the substituents R 3 and R 4 corresponding to the target compound using the compound (X-5).
  • Process G The compound (X-4) and the compound represented by the formula: Hal-C ( ⁇ O) —R 6 are treated with a base in an appropriate solvent to obtain a compound (X-6). The reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
  • Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane (methylene chloride), toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixtures thereof
  • a solvent or the like can be used.
  • it is dichloromethane.
  • triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, metallic sodium and the like can be used.
  • Pyridine is preferred. It is preferable to use 1 to 5 equivalents of a base relative to compound (X-4).
  • the step can also be performed in the presence of an activator.
  • the activator magnesium chloride, magnesium bromide, magnesium iodide and the like can be used. Preferably, it is magnesium chloride. It is preferable to use 1 to 5 equivalents of an activator with respect to compound (X-4).
  • Process H Compound (X-6) is treated with a base in a suitable solvent to give compound (X-7). The reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
  • Solvents include dimethyl sulfoxide, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane (methylene chloride), toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, A mixed solvent thereof or the like can be used. Preferred is dimethyl sulfoxide. These solvents may be appropriately selected and used in combination with a base.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Preferably, it is methanol.
  • Step A the amino group of the compound (X-1) having the substituent R 5 corresponding to the target compound is protected by a conventional method, and the formula: (In the formula, B is a protecting group, and other symbols are the same as the symbols in the compound represented by formula (I).)
  • Compound (Xa-1) represented by the above can be obtained and Step B to Step I can also be carried out.
  • the protecting group include benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl and the like. Preferably, it is benzyloxycarbonyl.
  • step I deprotection is carried out by a conventional method, and the formula: (In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).) To obtain a compound (Xa-2) represented by the formula:
  • Compound (Xa-2) can be treated with a base represented by the formula: R 1 (R 2 ) —N—SO 2 -Hal in a suitable solvent with a base to obtain a compound represented by formula (I). .
  • the reaction conditions are the same as in step A.
  • compound (IV-4) which is an intermediate of the compound of the present invention, can be synthesized using the synthesis method shown below.
  • Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).
  • Solvents include tetrahydrofuran, dimethylformamide, dimethylacetamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, Acetonitrile, water, a mixed solvent thereof or the like can be used.
  • Preferred is dimethylformamide.
  • Step b Compound (IV-2) and sulfonyl halide are reacted in a suitable solvent in the presence of a base to obtain compound (IV-3).
  • the reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • sulfonyl halide p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride and the like can be used.
  • base triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Triethylamine is preferred. It is preferable to use 1 to 5 equivalents of a base relative to compound (IV-2).
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, Pentane, heptane, dioxane, acetone, acetonitrile, a mixed solvent thereof and the like can be used.
  • it is methylene chloride.
  • These solvents may be appropriately selected and used in combination with a base.
  • DABCO (1,4-Diazabicyclo [2,2,2 ] octane), HCl, H 2 SO 4, acetic acid, CF 3 COOH, toluenesulfonic acid, p- toluenesulfonic acid and the like. DABCO is preferable.
  • Process c Compound (IV-3) is treated with a base in a suitable solvent to give compound (IV-4). The reaction may be performed at ⁇ 50 ° C. to 50 ° C. for several minutes to several hours.
  • the base n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium, hydrazine, propanethiol lithium salt and the like can be used.
  • Strong bases are preferred, such as n-butyllithium.
  • the solvent methylene chloride, tetrahydrofuran, diethyl ether, toluene, benzene, xylene, cyclohexane, hexane, pentane, heptane, dioxane, acetone and the like can be used. Tetrahydrofuran and / or hexane are preferable.
  • These solvents may be appropriately selected and used in combination with a base.
  • the compound of the present invention can be synthesized as follows. (In the formula, Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).) Step d N-bromosuccinimide is added to compound (V-1) in a suitable solvent to give compound (V-2). The reaction may be performed at ⁇ 50 ° C. to room temperature for several minutes to several hours.
  • Process e Compound (V-3) is obtained by adding ethyl halogenocarbonate to compound (V-2) in a suitable solvent. The reaction may be performed at 0 ° C. to 100 ° C.
  • Solvents include tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, dichloromethane, toluene, benzene, pyridine, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, Acetone, methanol, ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used, but the present invention can also be performed without a solvent. Tetrahydrofuran and / or pyridine are preferable. The reaction may be performed in the presence of a base. As the base, pyridine, N-methylmorpholine, dimethylaniline and the like can be used.
  • Process f Compound (V-3) and compound (IV-4) are reacted in a suitable solvent in the presence of a base to obtain compound (V-4).
  • the reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • the base triethylamine, DBU, sodium carbonate, potassium carbonate, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Preferred are triethylamine, potassium carbonate and the like.
  • Solvents include tetrahydrofuran, dimethylformamide, dimethylacetamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, Propanol, acetonitrile, water, a mixed solvent thereof or the like can be used.
  • Preferred is dimethylformamide.
  • catalysts examples include Pd (PPh3) 4 (tetrakistriphenylphosphine palladium), PdCl2 (PPh3) 2 (dichlorobistriphenylphosphine palladium), Pd (DBA) (bisdibenzylideneacetone palladium), copper iodide, DABCO and the like. It is done. Preferred is dichlorobistriphenylphosphine palladium and / or copper iodide.
  • Process g Compound (V-4) is treated with a base in a suitable solvent to give compound (I-3). The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • Tetrabutylammonium fluoride Use as bases tetrabutylammonium fluoride, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, hydrazine, propanethiol lithium salt, etc. Can do. Tetrabutylammonium fluoride is preferred.
  • Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, etc.
  • a mixed solvent or the like can be used.
  • Tetrahydrofuran is preferable. These solvents may be appropriately selected and used in combination with a base.
  • lithium diisopropylamine lithium tetramethylpiperidide, n-butyllithium, sec-butyllithium, tert-butyllithium, methyllithium, methyllithium, or the like can be used.
  • Lithium diisopropylamine is preferable.
  • the solvent tetrahydrofuran, diethyl ether, toluene, benzene, xylene, cyclohexane, hexane, pentane, heptane, dioxane, a mixed solvent thereof or the like can be used. Tetrahydrofuran is preferable. These solvents may be appropriately selected and used in combination with a base.
  • Step i Compound (VI-2) is treated with a base in a suitable solvent to give compound (VI-3).
  • the reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
  • the base barium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide or the like can be used. Sodium hydroxide is preferable.
  • solvent tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, mixed solvents thereof, etc. are used. Is possible. Preferably, it is ethanol. These solvents may be appropriately selected and used in combination with a base.
  • Step j Compound (VI-4) is obtained by treating compound (VI-3) with a base in a suitable solvent and reacting with diphenylphosphoric acid azide. The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • the base diisopropylamine, triethylamine, dimethylaminopyridine and the like can be used. Triethylamine is preferable.
  • solvent tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, chloroform, dioxane, acetone, acetonitrile, butanol, a mixed solvent thereof or the like can be used. T-butanol is preferable.
  • These solvents may be appropriately selected and used in combination with a base.
  • Process k Compound (VI-4) and compound (IV-4) are reacted in an appropriate solvent in the presence of a base to obtain compound (VI-5). The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours. The reaction conditions are the same as in step f.
  • Process l Compound (VI-5) is treated with a base in a suitable solvent to give compound (I-4).
  • the reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • As the base 1,8-diazabicyclo [5,4,0] -7-undecene, tetrabutylammonium fluoride, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, metal alkoxide and the like can be used. 1,8-diazabicyclo [5,4,0] -7-undecene is preferred.
  • solvent tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used. is there. Methanol and / or water are preferred. These solvents may be appropriately selected and used in combination with a base. In the compounds (VI-1), (VI-2), (VI-3), (VI-4), and (VI-5) in steps h to l, compounds having different nitrogen atom positions and numbers are used. Thus, the compound represented by the formula (I) in which X is various aromatic heterocycles can be synthesized.
  • the compound of the present invention can be synthesized as follows.
  • Y represents R 3 , R 4 or hydrogen in formula (I).
  • Other symbols are the same as those in the compound represented by formula (I).
  • Process m A compound (VII-1) having a substituent R 1 , R 2 , or R 5 corresponding to the target compound (the synthesis method is described in WO2001 / 037826) is treated with a dehydrating agent in an appropriate solvent, and 0 ° C. to 50 ° C. The reaction mixture is reacted for several minutes to several hours to convert it into an acid halide, and further, N, O-dimethylhydroxyamine hydrochloride is added, and in a suitable solvent at 0 ° C.
  • compound (VII-2) examples include oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, acetic anhydride, methanesulfonyl chloride, ethyl chlorocarbonate and the like. Oxalyl chloride is preferred. It is preferable to use 1 to 5 equivalents of a dehydrating agent relative to compound (VII-1). Further, dimethylformamide may be added as a catalyst.
  • triethylamine As the base, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, potassium carbonate, sodium carbonate, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Triethylamine is preferred.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, Pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Methylene chloride and / or dimethylformamide are preferable. These solvents may be appropriately selected and used in combination with a base.
  • the compound represented by compound (VII-2) is treated with a methylating reagent in an appropriate solvent to obtain compound (VII-3).
  • the reaction may be performed at ⁇ 80 ° C. to 100 ° C. for several minutes to several hours.
  • methylating reagent methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, or methyllithium can be used.
  • Preferred are methylmagnesium bromide and methylmagnesium chloride. It is preferable to use 1 to 5 equivalents of a Grignard reagent relative to compound (VII-2).
  • tetrahydrofuran diethyl ether, toluene, benzene, xylene, cyclohexane, hexane, pentane, heptane, dioxane, a mixed solvent thereof or the like can be used.
  • Tetrahydrofuran and / or diethyl ether are preferred.
  • These solvents may be appropriately selected and used in combination with a methylating reagent.
  • Process o Compound (VII-3) and an aldehyde having a substituent R 3 corresponding to the target compound are treated with a base in an appropriate solvent to obtain compound (VII-4).
  • the reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • the base triethylamine, pyridine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, butyllithium, LDA, sodium methoxide and the like can be used.
  • Sodium hydroxide is preferred.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, pentane, heptane, dioxane, methanol, Ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Preferably, it is methanol. These solvents may be appropriately selected and used in combination with a base.
  • Process p Compound (VII-4) and nitromethane are treated with a base in an appropriate solvent to obtain compound (VII-5).
  • the reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • As the base tetrabutylammonium fluoride, potassium fluoride, cesium fluoride, diethylamine, triethylamine, pyridine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used.
  • Preferred is diethylamine.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, Those mixed solvents can be used. Preferably, it is methanol. These solvents may be appropriately selected and used in combination with a base.
  • Process q Compound (VII-5) is treated with a base at 0 ° C. to 100 ° C. for several minutes to several hours in a suitable solvent, further treated with methanol at 0 ° C. to 65 ° C. for several minutes to several hours, and then treated with acid.
  • compound (VII-6) is obtained.
  • the base diethylamine, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used.
  • it is potassium hydroxide.
  • As the acid concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid and the like can be used.
  • it is concentrated sulfuric acid.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, Ethanol, propanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Methanol and / or tetrahydrofuran are preferred. These solvents may be appropriately selected and used in combination with a base or an acid.
  • Process r Compound (VII-6) is reacted with ammonium acetate in a suitable solvent to give compound (I-5).
  • the reaction may be performed at room temperature to 150 ° C. for several minutes to several hours.
  • Solvents include acetic acid, methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, diisopropyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, acetic acid Ethyl, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, propanol, acetonitrile, water, a mixed solvent thereof or the like can be used.
  • it is acetic acid.
  • Solvents include acetic acid, methylene chloride, tetrahydrofuran, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, methanol, ethanol, acetonitrile, and mixtures thereof
  • a solvent or the like can be used. Acetonitrile is preferred.
  • Process t Compound (VIII-3) is obtained by reacting compound (VIII-2) with hexamethylenetetramine in a suitable solvent. The reaction may be performed at room temperature to 100 ° C.
  • Solvents include acetic acid, methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, those A mixed solvent or the like can be used. Preferably, it is chloroform.
  • Step u Compound (VIII-3) is reacted with an acid in an appropriate solvent to give compound (VIII-4).
  • the reaction may be performed at room temperature to 100 ° C. for several minutes to several hours.
  • As the acid concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid and the like can be used. Concentrated hydrochloric acid is preferred.
  • Process v Compound (VIII-5) is obtained by reacting compound (VII-1) having substituents R 1 , R 2 and R 5 corresponding to the target compound and compound (VIII-4). The reaction conditions are the same as in step m above.
  • Process w Compound (I-6) can be obtained by subjecting compound (VIII-5) to the same method as in step r above.
  • the compound of the present invention can be synthesized as follows.
  • Y represents R 3 , R 4 or hydrogen in formula (I).
  • Each other symbol has the same meaning as each symbol in the compound represented by formula (I).
  • Process x Compound (IX-1) having substituents R 3 and R 4 corresponding to the target compound is reacted with halogenomethyl in a suitable solvent to obtain a compound represented by compound (IX-2).
  • the reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Acetonitrile is preferred.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Tetrahydrofuran is preferable.
  • Step z Compound (VI-7) is obtained by treating compound (X-3) and compound (X-2) with a base in a suitable solvent. The reaction may be performed at 50 ° C. to 150 ° C. for several minutes to several hours.
  • a base diethylamine, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, hydrazine, propanethiol lithium salt and the like can be used. Triethylamine is preferable.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Preferably, it is ethanol.
  • a compound in which R 1 and R 5 together with the adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle can also be synthesized as follows. (In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).
  • the benzene ring in the formula may have a substituent, or another ring instead of the benzene ring. It may be.)
  • Compound (I-1) is reacted with H 2 NSO 2 NH 2 in the presence of a base to give compound (I-8).
  • a base pyridine or the like can be used.
  • R 5 is hydrogen or substituted or unsubstituted alkyl.
  • R 5 is hydrogen.
  • Other symbols are as defined in the compound represented by formula (I).)
  • R 5 is hydrogen or substituted or unsubstituted alkyl.
  • the other symbols have the same meanings as those in the compound represented by formula (I).
  • R 5 is hydrogen.
  • R 5 is hydrogen or substituted or unsubstituted alkyl and R 8 is substituted or unsubstituted alkyl.
  • R 5 is hydrogen and R 8 is methyl, ethyl, isopropyl or tert -Butyl, and other symbols are the same as the symbols in the compound represented by formula (I).
  • R 5 is hydrogen or substituted or unsubstituted alkyl. Preferably, R 5 is hydrogen.
  • Other symbols are as defined in the compound represented by formula (I).) A compound represented by formula (I).
  • the compounds of the present invention are effective for all diseases involving NPY Y5, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension, cerebral hyperemia, congestive heart failure or sleep disorders It is particularly useful for the prevention and / or treatment of obesity and weight management in obesity. It is also effective for the prevention and / or treatment of diseases in which obesity is a risk factor, such as diabetes, hypertension, hyperlipidemia, arteriosclerosis, and acute coronary syndrome. Furthermore, the compound of the present invention has not only an NPY Y5 receptor antagonistic action but also a usefulness as a medicine, and has any or all of the following excellent features.
  • CYP enzymes for example, CYP1A2, CYP2C9, CYP3A4, etc.
  • CYP1A2, CYP2C9, CYP3A4, etc. The inhibitory action against CYP enzymes is weak.
  • Good pharmacokinetics such as high bioavailability and moderate clearance.
  • Low toxicity such as anemia-inducing action.
  • i) Does not cause reproductive toxicity (eg, teratogenicity).
  • j) Does not cause gastrointestinal disorders for example, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).
  • the compound of the present invention has low affinity for NPY Y1 and Y2 receptors and high Y5 receptor selectivity.
  • NPY induces a sustained vasoconstrictive action in the periphery, but this action is mainly mediated by the Y1 receptor. Since the Y5 receptor is not involved in such an action at all, the possibility of inducing side effects based on peripheral vasoconstriction is low, and a pharmaceutical composition containing the compound of the present invention as an active ingredient can be preferably used as a safe medicine. It is considered possible.
  • the pharmaceutical composition containing the compound of the present invention as an active ingredient suppresses food intake and exhibits an anti-obesity effect. Therefore, side effects such as indigestion as seen in drugs that exhibit anti-obesity effects by inhibiting digestion and absorption, and central side effects such as antidepressant effects such as serotonin transporter inhibitors that exhibit anti-obesity effects Not doing so is one of the features of the pharmaceutical composition.
  • Oral administration may be prepared and administered in a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods.
  • a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods.
  • parenteral administration any commonly used dosage forms such as injections such as intramuscular administration and intravenous administration, suppositories, percutaneous absorption agents, inhalants and the like can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.
  • отное отное отное отное о ⁇ ное ком ⁇ онентs such as excipients, binders, wetting agents, disintegrants, lubricants, diluents and the like suitable for the dosage form are mixed with an effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition. can do. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.
  • excipients such as excipients, binders, wetting agents, disintegrants, lubricants, diluents and the like suitable for the dosage form are mixed with an effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition. can do. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.
  • Excipients include lactose, sucrose, glucose, starch, calcium carbonate, crystalline cellulose and the like.
  • binder include methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin, and polyvinyl pyrrolidone.
  • disintegrant include carboxymethyl cellulose, carboxymethyl cellulose sodium, starch, sodium alginate, agar powder or sodium lauryl sulfate.
  • the lubricant include talc, magnesium stearate, and macrogol.
  • cacao butter, macrogol, methyl cellulose or the like can be used as a suppository base.
  • solubilizers when preparing as liquid or emulsion or suspension injections, commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. are added as appropriate. You may do it. In the case of oral administration, flavoring agents, fragrances and the like may be added.
  • the dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
  • the pharmaceutical composition of the present invention can also be used in combination with other anti-obesity drugs (agents that can be used for weight management in obesity and obesity).
  • the administration therapy of the pharmaceutical composition of the present invention can also be used in combination with known diet therapy, drug therapy, exercise and the like.
  • the following methods are also within the scope of the present invention.
  • a pharmaceutically acceptable salt thereof or a solvate thereof a drug used for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity is administered.
  • a method for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity Drugs used for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity to patients undergoing prevention or treatment by administration of the compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof
  • a method for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity which comprises administering
  • Examples of drugs used for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity include compounds having anorectic effect (selective serotonin reuptake inhibitors such as fenfluramine and fluoxetine; mazindol, etc.), nutrients
  • a compound having an inhibitory action on digestion and absorption compounds having an inhibitory action on sugar absorption ( ⁇ -glucosidase inhibitors such as acarbose and voglibose; SGLT-2 inhibitors such as dapagliflozin, remogliflozin and KGT-1075);
  • Example 1 First Step of Synthesis of Compound Ia-1 Methylene chloride (50 ml) was added to compound 1 (10 g, 48.1 mmol), and then dimethylsulfamoyl chloride (10.4 ml, 96.0 mmol) and triethylamine (26.7 ml, 193 mmol) were added under ice-cooling. The mixture was stirred for 4 hours with cooling. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound 2.
  • Second step Compound 2 was dissolved in ethanol (15 ml) and tetrahydrofuran (30 ml), sodium hydroxide (2.89 g, 72.2 mmol) dissolved in 10 ml of water was added, and the mixture was stirred at room temperature for 5 hours. After part of the organic solvent was distilled off under reduced pressure, the reaction solution was poured into dilute hydrochloric acid, acidified, and extracted with chloroform. The organic layer was washed with water, further washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain Compound 3 quantitatively.
  • N-methylimidazole (4.09 ml, 51.3 mmol) in methylene chloride (50 ml) -ethyl acetate (6.70 mL, 68.4 mmol) was added a solution of acid chloride (42.7 mmol) in methylene chloride (50 ml) at -60 ° C.
  • titanium tetrachloride (15.6 ml, 141 mmol) was further added dropwise at the same temperature, followed by stirring for 30 minutes.
  • N, N′-diisopropylethylamine (26.9 ml, 154 mmol) was added to the reaction mixture, and the mixture was stirred at ⁇ 40 ° C.
  • Example 2 Synthesis of Compound Ia-9 and Compound IIa-3 First Step Acetonitrile (40 ml) and water (20 ml) were added to compound 1 (10 g, 48.1 mmol), and then benzyloxycarbonyl chloride (8.25 ml, 57.8 mmol) and triethylamine (26.7 ml, 193 mmol) under ice-cooling. And stirred for 4 hours with ice cooling. The reaction solution was poured into dilute hydrochloric acid, acidified, and extracted with ethyl acetate.
  • Second step Compound 8 (14.7 g, 48.1 mmol) was dissolved in ethanol (60 ml) and tetrahydrofuran (30 ml), 2N aqueous sodium hydroxide solution (120 ml, 240 mmol) was added, and the mixture was stirred at room temperature for 4 hr.
  • the reaction solution was poured into dilute hydrochloric acid, acidified, extracted with chloroform, the organic layer was washed with water, and further washed with saturated brine. At this time, some of the target product was precipitated as crystals, and they were collected by filtration.
  • the organic layer of the filtrate was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain crystals.
  • N-methylimidazole (1.04 ml, 13.0 mmol) in methylene chloride (50 ml) -ethyl acetate (1.69 mL, 17.3 mmol) is added a solution of acid chloride (10.8 mmol) in methylene chloride (50 ml) at -60 ° C.
  • titanium tetrachloride (3.94 ml, 35.7 mmol) was further added dropwise at the same temperature, followed by stirring for 30 minutes.
  • N, N′-diisopropylethylamine (6.80 ml, 38.9 mmol) was added to the reaction mixture, and the mixture was stirred at ⁇ 40 ° C.
  • Acetonitrile (20 ml) was added to 2-chloroethanol (0.374 ml, 5.58 mmol), then chlorosulfonyl isocyanate (0.484 ml, 5.58 mmol) was added under ice cooling, and the mixture was stirred at the same temperature for 30 min. Active species were obtained.
  • Acetonitrile (100 ml) was added to compound 13 (1.50 g, 5.07 mmol), then N-methylmorpholine (2.79 ml, 25.4 mmol) was added under ice cooling, and the reaction activity prepared above at the same temperature. Seeds were dripped.
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl; R 1 and R 2 may be combined with an adjacent nitrogen atom to form a substituted or unsubstituted nitrogen-containing aromatic heterocyclic ring or a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic ring.
  • Second step (R 1 and R 2 are as defined above.)
  • Compound 17 (1 eq), zinc powder (0.2 eq), zinc cyanide (0.6 eq) are dissolved in dimethylacetamide, Pd (P t Bu 3 ) 2 (0.1 eq) is added under a nitrogen stream, and the mixture is stirred at 95 ° C. for several hours. To do.
  • the reaction mixture is then poured into water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel chromatography to obtain the desired product 18.
  • These compounds 16 to 18 are also compounds of the present invention.
  • Test Example 1-1 Affinity for Mouse NPY Y5 Receptor
  • a cDNA sequence encoding the mouse NPY Y5 receptor was expressed in the expression vector pME18S (Takebe et al. Mol. Cell.Biol.8, 466-472).
  • the obtained expression vector was transfected into a host cell CHO using LipofectAMINE reagent (trademark, Invitrogen) according to the instruction manual, and NPY Y5 receptor stably expressing cells were obtained.
  • Membrane preparations prepared from CHO cells expressing mouse NPY Y5 receptor were assay buffer together with the compounds of the present invention and 30,000 cpm [ 125 I] peptide YY (final concentration 60 pM: manufactured by GE Healthcare).
  • the solution was incubated in a solution (20 mM HEPES-Hanks buffer containing 0.1% bovine serum albumin, pH 7.4) at 25 ° C. for 2 hours, and then filtered through a glass filter GF / C treated with 1% polyethyleneimine. After washing with 50 mM Tris-HCl buffer, pH 7.4, the radioactivity on the glass filter was determined with a gamma counter.
  • Non-specific binding was measured in the presence of 200 nM peptide YY, and the 50% inhibitory concentration (IC 50 value) of the test compound for specific peptide YY binding was determined [Inui, A. et al. et al. Endocrinology 131, 2090-2096 (1992)].
  • IC 50 value 50% inhibitory concentration of the test compound for specific peptide YY binding was determined [Inui, A. et al. et al. Endocrinology 131, 2090-2096 (1992)].
  • the results are shown in Table 1.
  • the compound according to the present invention inhibited the binding of peptide YY (NPY and homologous substances) to the mouse NPY Y5 receptor. That is, this compound showed affinity for the mouse NPY Y5 receptor.
  • Test Example 1-2 Affinity for Human NPY Y5 Receptor
  • a cDNA sequence encoding the human NPY Y5 receptor was expressed in the expression vector pME18S (Takebe et al. Mol. Cell. Biol. 8, 466- 472).
  • the obtained expression vector is transfected into a host cell CHO using LipofectAMINE reagent (trademark, Invitrogen) according to the instruction manual to obtain NPY Y5 receptor stably expressing cells.
  • Membrane preparation prepared from CHO cells expressing human NPY Y5 receptor was assay buffer together with the compound of the present invention and 30,000 cpm [ 125 I] peptide YY (final concentration 60 pM: manufactured by GE Healthcare). Incubate in a liquid (20 mM HEPES-Hanks buffer containing 0.1% bovine serum albumin, pH 7.4) at 25 ° C. for 2 hours, and then filter through a glass filter GF / C treated with 1% polyethyleneimine. . After washing with 50 mM Tris-HCl buffer, pH 7.4, the radioactivity on the glass filter is determined with a gamma counter.
  • Non-specific binding is measured in the presence of 200 nM peptide YY, and the 50% inhibitory concentration (IC 50 value) of the test compound for specific peptide YY binding is determined [Inui, A. et al. et al. Endocrinology 131, 2090-2096 (1992)].
  • Test Example 2 Rat and Mouse Brain Migration Evaluation Using the cassette dosing method (Drug. Metab. Dispos. (2001); 29, 957-966), rat (Crl; CD (SD), ⁇ , 8weeks) 30 minutes after intravenous administration (0.5 mg / mL / kg), for mice (Jcl; C57BL / 6J, J, 8weeks), plasma and brain 3 hours or 5 hours after oral administration (2 mg / 10 mL / kg) From the concentration, brain transferability (brain / plasma partition coefficient; Kp) was evaluated.
  • Test Example 3 Pharmacokinetic Evaluation in Rats Using the cassette dosing method, the half-life was determined from the change in plasma concentration after intravenous administration (0.5 mg / mL / kg) in rats (Crl; CD (SD), ⁇ , 8 weeks). (T1 / 2) and systemic clearance (CLtot) were evaluated.
  • Test Example 4 cAMP Production Inhibitory Action in CHO Cells After CHO cells expressing human NPY Y5 receptor were incubated at 37 ° C. for 20 minutes in the presence of 2.5 mM isobutylmethylxanthine (SIGMA), the compounds according to the present invention was added and incubated for 5 minutes, after which 50 nMNPY and 10 ⁇ M forskolin (Sigma) were added and incubated for 30 minutes. After stopping the reaction by adding 1N HCl, the amount of cAMP in the supernatant was measured using EIA kit (manufactured by Amersham LIFE SIENCE). The inhibitory action of NPY on cAMP production by forskolin stimulation was taken as 100%, and the 50% inhibitory concentration (IC 50 value) of the compound according to the present invention for this NPY action was determined.
  • SIGMA isobutylmethylxanthine
  • NPY Y5 Receptor Selectivity Test Example 1-2 and Y1-expressing cell (human neuroblastoma, SK-N-MC) membrane sample and Y2-expressing cell (human neuroblastoma, SMS-KAN) membrane sample were used.
  • the test is performed in the same manner, and the affinity of the compound of the present invention for the NPY Y1 receptor and the NPY Y2 receptor is measured. As a result, it can be confirmed that the compound according to the present invention has NPY Y5 receptor selectivity.
  • Test Example 6 Feeding Inhibitory Action Under ether anesthesia, skin was incised along the midline from the external occipital crest to the back of the nose of male C57BL / 6J mice (12-14 weeks old, 25-30 g) to expose the upper skull . A hole having a diameter of about 1 mm was formed using an electric drill at a position about 1 mm rearward from the exposed part bregma toward lamda, about 1 mm from the midline to the left side.
  • a 0.5% hydroxypropylmethylcellulose aqueous solution (manufactured by Shin-Etsu Chemical Co., Ltd.) or a test substance suspended in this aqueous solution is forcibly orally administered to mice after waking up from anesthesia, and NPY Y5 receptor-specific agonist 1 hour after administration ([CPP 1-7 , NPY 19-23 , Ala 31 , Aib 32 , Gln 34 ] -hPanalytic Polypeptide: manufactured by Tocris Co.) 0.1 nmol was injected from the head opening previously provided using a cannula.
  • mice The food intake of mice was measured 2 hours and 4 hours after the injection, and the difference in food intake between the group administered with 0.5% hydroxypropylmethylcellulose solution and the group administered with the test substance was investigated.
  • the compound of the present invention when administered at a dose of 12.5 mg / kg, the amount of food intake was significantly suppressed compared to the case where 0.5% hydroxypropylmethylcellulose was administered.
  • the food intake after 2 hours and 4 hours after injection was 0.28 ⁇ 0.05 g and 0.57 ⁇ 0.08 g, respectively. Met.
  • the amount of food consumed 2 hours and 4 hours after injection in the 0.5% hydroxypropylmethylcellulose solution administration group (Group B) was 0.62 ⁇ 0.06 g and 1.37 ⁇ 0.08 g, respectively.
  • the amount of food consumed in the 0.5% hydroxypropylmethylcellulose solution administration group (Group C) in which no NPY Y5 receptor-specific agonist was injected was 0.10 ⁇ 0.03 g, 0.13 ⁇ 0.02 g, and Group C If the value of A is subtracted from the A and B groups and converted, the feeding suppression rates for the B group at 2 hours and 4 hours after the injection in the A group are 65.1% and 64.1%, respectively.
  • Test Example 7 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) The degree to which the metabolite production was inhibited by the test compound was evaluated.
  • reaction conditions are as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan ( CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsomes 0.2 mg protein / mL; test drug concentration 1, 5, 10, 20 ⁇ mol / L (4 points).
  • reaction solution in a 96-well plate 5 kinds of each substrate, human liver microsome, and test drug are added in the above composition in 50 mM Hepes buffer solution, and NADPH as a coenzyme is added to start a metabolic reaction as an index.
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the supernatant of the centrifugation was analyzed with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite), Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.
  • Formulation Examples are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet Compound (I) 15 mg Starch 15mg Lactose 15mg Crystalline cellulose 19mg Polyvinyl alcohol 3mg 30ml distilled water Calcium stearate 3mg Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 3 Granules Compound (I) 30 g Lactose 265g Magnesium stearate 5g After mixing well, compression molding, pulverizing, sizing, and sieving to make granules of appropriate size.
  • the compound of the present invention exhibits NPY Y5 receptor antagonistic action. Therefore, the compound of the present invention is used as a medicament for the prevention or treatment of eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension, cerebral hyperemia, congestive heart failure, sleep disorders, etc. Very useful. In addition, since the compound of the present invention exhibits an effective anti-feeding action, it is very useful for weight management, weight loss, and weight maintenance after weight loss in obesity. Furthermore, it is very useful as a medicament for treating or preventing diseases in which obesity is a risk factor, such as diabetes, hypertension, hyperlipidemia, arteriosclerosis, and acute coronary syndrome.
  • obesity is a risk factor

Abstract

The present invention provides, as a novel compound having NPY Y5 receptor antagonism, a compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate of the same. In formula (I): R1 and R2 independently represent each hydrogen, substituted or unsubstituted alkyl,or the like, or R1 and R2 may form, together with the adjacent nitrogen atom, a substituted or unsubstituted nitrogen-containing aromatic heterocycle or a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle; X represents an aromatic heterocycle or a non-aromatic heterocycle; R3s independently represent each substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl; R4s independently represent each halogen, cyano, or the like; R5 represents hydrogen, substituted or unsubstituted alkyl, etc.; m is an integer of 0-2; n is an integer of 0-5: Rs independently represent each halogen, oxo, or the like; and p is an integer of 0-2.

Description

ＮＰＹ　Ｙ５受容体拮抗作用を有するスルファミド誘導体NPY sulfamide derivative with Y5 receptor antagonism
　本発明はＮＰＹ　Ｙ５受容体拮抗作用を有し、医薬、特に、抗肥満薬として有用な新規スルファミド誘導体に関する。 The present invention relates to a novel sulfamide derivative having NPY Y5 receptor antagonistic activity and useful as a pharmaceutical, particularly as an anti-obesity drug.
　ニューロペプチドＹ（以下、ＮＰＹとする）は３６個のアミノ酸残基からなるペプチドで、１９８２年に豚の脳から分離された。ＮＰＹはヒトおよび動物の中枢神経系および末梢組織に広く分布している。 Neuropeptide Y (hereinafter referred to as NPY) is a peptide consisting of 36 amino acid residues and was isolated from pig brain in 1982. NPY is widely distributed in the central nervous system and peripheral tissues of humans and animals.
　これまでの報告において、ＮＰＹは中枢神経系においては摂食促進作用、抗痙攣作用、学習促進作用、抗不安作用、抗ストレス作用等を有していることが判明しており、さらにうつ病、アルツハイマー型痴呆、パーキンソン病等の中枢神経系疾患に深く関与している可能性もある。また、末梢組織においては、ＮＰＹは血管等の平滑筋や心筋の収縮を引き起こすため、循環器系障害にも関与していると考えられる。さらには肥満症、糖尿病、ホルモン異常等の代謝性疾患にも関与していることが知られている（非特許文献１参照）。従って、ＮＰＹ受容体拮抗作用を有する医薬組成物は上記のようなＮＰＹ受容体が関与する種々の疾患に対する予防または治療薬となる可能性がある。 In previous reports, NPY has been found to have a feeding promoting action, an anticonvulsant action, a learning promoting action, an anxiolytic action, an antistress action, etc. in the central nervous system, and depression, It may be deeply involved in central nervous system diseases such as Alzheimer's dementia and Parkinson's disease. In peripheral tissues, NPY causes contraction of smooth muscles such as blood vessels and myocardium, and is thus considered to be involved in cardiovascular disorders. Furthermore, it is known to be involved in metabolic diseases such as obesity, diabetes, and hormonal abnormalities (see Non-Patent Document 1). Therefore, a pharmaceutical composition having an NPY receptor antagonistic action may be a prophylactic or therapeutic agent for various diseases involving the NPY receptor as described above.
　ＮＰＹ受容体には、現在までにＹ１、Ｙ２、Ｙ３、Ｙ４、Ｙ５およびＹ６のサブタイプが発見されている（非特許文献２参照）。Ｙ５受容体は少なくとも摂食機能に関与しており、その拮抗剤は抗肥満薬になることが示唆されている（非特許文献３～５参照）。 In the NPY receptor, subtypes of Y1, Y2, Y3, Y4, Y5 and Y6 have been discovered so far (see Non-Patent Document 2). The Y5 receptor is involved in at least the feeding function, and it has been suggested that the antagonist becomes an anti-obesity drug (see Non-Patent Documents 3 to 5).
　特許文献１には、ＮＰＹ　Ｙ５受容体拮抗作用を有するスルホニル基を有するベンゾイミダゾール誘導体およびイミダゾピリジン誘導体が記載されている。また、ＮＰＹ　Ｙ５受容体拮抗作用を有するスルホニル基を有するアミン誘導体が特許文献２、３等に記載されている。その他、特許文献４、５等にはスルホニル基を有するアミド誘導体がＮＰＹ　Ｙ５拮抗活性を有する旨記載されている。特許文献１４には、ピラゾール誘導体がＮＰＹ　Ｙ５拮抗活性を有する旨記載されている。これらの化合物は、本発明化合物とは構造が異なる。
　また、本発明化合物と構造が異なるがＮＰＹ　Ｙ５拮抗活性を有する化合物が特許文献６等に開示されている。 Patent Document 1 describes a benzimidazole derivative and an imidazopyridine derivative having a sulfonyl group having an NPY Y5 receptor antagonistic action. Further, amine derivatives having a sulfonyl group having an NPY Y5 receptor antagonistic action are described in Patent Documents 2, 3 and the like. In addition, Patent Documents 4 and 5 describe that amide derivatives having a sulfonyl group have NPY Y5 antagonistic activity. Patent Document 14 describes that a pyrazole derivative has NPY Y5 antagonistic activity. These compounds differ in structure from the compounds of the present invention.
Further, a compound having a structure different from that of the compound of the present invention but having NPY Y5 antagonistic activity is disclosed in Patent Document 6 and the like.
　本願化合物と類似構造を有する誘導体が特許７～９および１５に記載されているが、作用が全く異なるものであり、本発明を示唆するものではない。
　また、本発明化合物と類似構造を有するピラゾール誘導体が特許文献１０～１３に記載されているが、作用が全く異なるものであり、本発明を示唆するものではない。 Derivatives having a similar structure to the compound of the present application are described in Patents 7 to 9 and 15, but their actions are completely different and do not suggest the present invention.
Further, although pyrazole derivatives having a structure similar to that of the compound of the present invention are described in Patent Documents 10 to 13, they have completely different actions and do not suggest the present invention.
国際公開第２００５／０８０３４８号International Publication No. 2005/080348 国際公開第２００７／１２５９５２号International Publication No. 2007/1255952 国際公開第２００９／０５４４３４号International Publication No. 2009/054434 国際公開第０１／０３７８２６号International Publication No. 01/037826 国際公開第２００６／００１３１８号International Publication No. 2006/001318 国際公開第２００３／１０４２５５号International Publication No. 2003/104255 国際公開第２００１／００５７７０号International Publication No. 2001/005770 国際公開第２００４／０４３９６２号International Publication No. 2004/043962 国際公開第２００４／０５２８６２号International Publication No. 2004/052862 国際公開第９８／５２９４０号International Publication No. 98/52940 米国特許第６９７９６８６号明細書US Pat. No. 6,979,686 国際公開第２０００／３１０６３号International Publication No. 2000/31063 国際公開第２００４／０７２０３３号International Publication No. 2004/072033 国際公開第２００９／１３１０９６号International Publication No. 2009/131096 国際公開第２０１０／０９６４６２号International Publication No. 2010/096462
　本発明の目的は、優れたＮＰＹ　Ｙ５受容体拮抗作用を有する新規スルファミド誘導体を提供することにある。 An object of the present invention is to provide a novel sulfamide derivative having an excellent NPY Y5 receptor antagonistic action.
　本発明者らは、鋭意研究の結果、優れたＮＰＹ　Ｙ５受容体拮抗作用を有する新規化合物の合成に成功した。また、該化合物が強い体重抑制効果を示すことを見出した。さらに、本発明者らは、本発明化合物について、薬物代謝酵素に対する阻害が少なく、代謝安定性および水溶性が良いことも見出した。また、本発明化合物は毒性が低く、医薬として使用するために十分安全である。 As a result of intensive studies, the present inventors have succeeded in synthesizing a novel compound having an excellent NPY Y5 receptor antagonistic action. Moreover, it discovered that this compound showed the strong body weight suppression effect. Furthermore, the present inventors have also found that the compounds of the present invention have little inhibition on drug metabolizing enzymes, and have good metabolic stability and water solubility. The compound of the present invention has low toxicity and is sufficiently safe for use as a medicine.
　すなわち、本発明は、以下に関する。
（１）式（Ｉ）：
Figure JPOXMLDOC01-appb-C000006
（式中、
Ｒ１およびＲ２はそれぞれ独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリールまたは置換若しくは非置換のヘテロサイクリルであり、
Ｒ１およびＲ２は隣接する窒素原子と一緒になって置換若しくは非置換の含窒素芳香族ヘテロ環または置換若しくは非置換の含窒素非芳香族ヘテロ環を形成してもよく、または
Ｒ１およびＲ５は隣接する窒素原子と一緒になって置換若しくは非置換の含窒素非芳香族ヘテロ環を形成してもよく、
Ｘは芳香族ヘテロ環または非芳香族へテロ環であり、
Ｒ３はそれぞれ独立して、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリールまたは置換若しくは非置換のヘテロサイクリルであり、
Ｒ４はそれぞれ独立して、ハロゲン、シアノ、ニトロ、ニトロソ、アジド、オキソ、
置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、
ヒドロキシ、置換若しくは非置換のアルコキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロサイクリルオキシ、
メルカプト、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のシクロアルキルチオ、置換若しくは非置換のシクロアルケニルチオ、置換若しくは非置換のアリールチオ、置換若しくは非置換のヘテロアリールチオ、置換若しくは非置換のヘテロサイクリルチオ、
カルボキシ、置換若しくは非置換のアルコキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のシクロアルキルオキシカルボニル、置換若しくは非置換のシクロアルケニルオキシカルボニル、置換若しくは非置換のアリールオキシカルボニル、置換若しくは非置換のヘテロアリールオキシカルボニル、置換若しくは非置換のヘテロサイクリルオキシカルボニル、置換若しくは非置換のカルバモイル、
ホルミル、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のシクロアルキルカルボニル、置換若しくは非置換のシクロアルケニルカルボニル、置換若しくは非置換のアリールカルボニル、置換若しくは非置換のヘテロアリールカルボニル、置換若しくは非置換のヘテロサイクリルカルボニル、
スルフィノ、スルホ、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のシクロアルキルスルホニル、置換若しくは非置換のシクロアルケニルスルホニル、置換若しくは非置換のアリールスルホニル、置換若しくは非置換のヘテロアリールスルホニル、置換若しくは非置換のヘテロサイクリルスルホニル、置換若しくは非置換のスルファモイルまたは置換若しくは非置換のアミノであり、
Ｒ５は水素、置換若しくは非置換のアルキルまたは置換若しくは非置換のアリールであり、
ｍは０～２の整数であり、
ｎは０～５の整数であり、
Ｒはそれぞれ独立して、ハロゲン、オキソ、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルであり、
ｐは０～２の整数である）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＮＰＹＹ５受容体拮抗作用を有する医薬組成物。
（２）式（Ｉ）：
Figure JPOXMLDOC01-appb-C000007
（式中、
Ｒ１およびＲ２はそれぞれ独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリールまたは置換若しくは非置換のヘテロサイクリルであり、
Ｒ１およびＲ２は隣接する窒素原子と一緒になって置換若しくは非置換の含窒素芳香族ヘテロ環または置換若しくは非置換の含窒素非芳香族ヘテロ環を形成してもよく、または
Ｒ１およびＲ５は隣接する窒素原子と一緒になって置換若しくは非置換の含窒素非芳香族ヘテロ環を形成してもよく、
Ｘは芳香族へテロ環または非芳香族ヘテロ環であり、
Ｒ３はそれぞれ独立して、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリールまたは置換若しくは非置換のヘテロサイクリルであり、
Ｒ４はそれぞれ独立して、ハロゲン、シアノ、ニトロ、ニトロソ、アジド、オキソ、
置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、
ヒドロキシ、置換若しくは非置換のアルコキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロサイクリルオキシ、
メルカプト、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のシクロアルキルチオ、置換若しくは非置換のシクロアルケニルチオ、置換若しくは非置換のアリールチオ、置換若しくは非置換のヘテロアリールチオ、置換若しくは非置換のヘテロサイクリルチオ、
カルボキシ、置換若しくは非置換のアルコキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のシクロアルキルオキシカルボニル、置換若しくは非置換のシクロアルケニルオキシカルボニル、置換若しくは非置換のアリールオキシカルボニル、置換若しくは非置換のヘテロアリールオキシカルボニル、置換若しくは非置換のヘテロサイクリルオキシカルボニル、置換若しくは非置換のカルバモイル、
ホルミル、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のシクロアルキルカルボニル、置換若しくは非置換のシクロアルケニルカルボニル、置換若しくは非置換のアリールカルボニル、置換若しくは非置換のヘテロアリールカルボニル、置換若しくは非置換のヘテロサイクリルカルボニル、
スルフィノ、スルホ、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のシクロアルキルスルホニル、置換若しくは非置換のシクロアルケニルスルホニル、置換若しくは非置換のアリールスルホニル、置換若しくは非置換のヘテロアリールスルホニル、置換若しくは非置換のヘテロサイクリルスルホニル、置換若しくは非置換のスルファモイルまたは置換若しくは非置換のアミノであり、
Ｒ５は水素、置換若しくは非置換のアルキルまたは置換若しくは非置換のアリールであり、
ｍは０～２の整数であり、
ｎは０～５の整数であり、
Ｒはそれぞれ独立して、ハロゲン、オキソ、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルであり、
ｐは０～２の整数である）で示される化合物（但し、以下の化合物を除く。
Figure JPOXMLDOC01-appb-C000008
）、
その製薬上許容される塩またはそれらの溶媒和物。
（３）Ｘがインドール、ピロロピリジン、ピロロピリミジン、ピロロピラジン、イミダゾール、ピラゾール、ピロール、トリアゾール、ピリジン、イミダゾピリジンまたはベンゾイミダゾールである、（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（４）Ｘがピラゾールである、（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（５）式：
Figure JPOXMLDOC01-appb-C000009
で示される基が、
Figure JPOXMLDOC01-appb-C000010
で示される基であり、
ｎが０または１である、
（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（６）ｍが１である、（２）～（５）いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（７）Ｒ１およびＲ２がそれぞれ独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキルまたは置換若しくは非置換のアリールである、（２）～（５）いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（８）Ｒ２が置換若しくは非置換のアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキルまたは置換若しくは非置換のアリールである、（２）～（５）いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（９）Ｒ１が水素または置換若しくは非置換のアルキルであり、
Ｒ２が置換若しくは非置換のアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキルまたは置換若しくは非置換のアリールである、（２）～（５）いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１０）Ｒ１およびＲ２が隣接する窒素原子と一緒になって置換若しくは非置換の含窒素非芳香族ヘテロ環を形成している、（２）～（５）いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１１）Ｒ３がそれぞれ独立して、置換または非置換のフェニルである、
（２）～（５）いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１２）Ｒ４がそれぞれ独立して、ハロゲン、シアノまたは置換若しくは非置換のアルキルである、（２）～（５）いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１３）（２）～（１２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を有効成分とする医薬組成物。
（１４）ＮＰＹ　Ｙ５受容体拮抗作用を有する、（１３）記載の医薬組成物。
（１５）上記（２）～（１２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、ＮＰＹ　Ｙ５の関与する疾患の治療または予防方法。
（１６）ＮＰＹ　Ｙ５の関与する疾患の治療または予防剤を製造するための、上記（２）～（１２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物の使用。
（１７）ＮＰＹ　Ｙ５受容体の関与する疾患を治療または予防するための、上記（２）～（１２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１８）肥満若しくは肥満関連疾患の予防若しくは治療又は肥満における体重管理のための医薬である上記（１３）記載の医薬組成物。
（１９）肥満関連疾患が、過食症、高血圧、耐糖能異常、糖尿病、代謝症候群、脂質代謝異常、動脈硬化、高尿酸血症、痛風、脂肪肝、蛋白尿、子宮内膜癌、乳癌、前立腺癌、大腸癌、変形性関節症、腰痛症、閉塞性睡眠時無呼吸症候群、冠動脈疾患、脳梗塞、月経異常、プラダーウィリー症候群、フレーリッヒ症候群又はピックウィック症候群である（１８）記載の医薬組成物。
（２０）上記（２）～（１２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、肥満若しくは肥満関連疾患の予防若しくは治療又は肥満における体重管理のために用いられる、ＮＰＹ　Ｙ５の関与する疾患の治療または予防方法。
（２１）肥満若しくは肥満関連疾患の予防若しくは治療又は肥満における体重管理のために用いられる、上記（２）～（１２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（２２）上記（２）～（１２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物と併用して、肥満若しくは肥満関連疾患の予防若しくは治療又は肥満における体重管理のために用いられる薬剤を投与することを特徴とする、肥満若しくは肥満関連疾患の予防若しくは治療又は肥満における体重管理の方法。
（２３）上記（２）～（１２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物の投与による予防または治療を受けている患者に、肥満若しくは肥満関連疾患の予防若しくは治療又は肥満における体重管理のために用いられる薬剤を投与することを特徴とする、肥満若しくは肥満関連疾患の予防若しくは治療又は肥満における体重管理の方法。 That is, the present invention relates to the following.
(1) Formula (I):
Figure JPOXMLDOC01-appb-C000006
(Where
R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl,
R 1 and R 2 together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing aromatic heterocycle or a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, or R 1 and R 5 together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle,
X is an aromatic heterocycle or a non-aromatic heterocycle,
Each R 3 is independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl;
Each R 4 is independently halogen, cyano, nitro, nitroso, azide, oxo,
Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
Hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl Oxy, substituted or unsubstituted heterocyclyloxy,
Mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, Substituted or unsubstituted heterocyclylthio,
Carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or Unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl,
Formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted hetero Arylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl,
Sulfino, sulfo, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted A heteroarylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amino,
R 5 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
m is an integer from 0 to 2,
n is an integer from 0 to 5,
Each R is independently halogen, oxo, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
p is an integer of 0 to 2, and a pharmaceutical composition having an NPYY5 receptor antagonistic action, comprising a compound represented by the formula: pharmaceutically acceptable salts thereof or solvates thereof.
(2) Formula (I):
Figure JPOXMLDOC01-appb-C000007
(Where
R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl,
R 1 and R 2 together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing aromatic heterocycle or a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, or R 1 and R 5 together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle,
X is an aromatic heterocycle or a non-aromatic heterocycle,
Each R 3 is independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl;
Each R 4 is independently halogen, cyano, nitro, nitroso, azide, oxo,
Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
Hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl Oxy, substituted or unsubstituted heterocyclyloxy,
Mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, Substituted or unsubstituted heterocyclylthio,
Carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or Unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl,
Formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted hetero Arylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl,
Sulfino, sulfo, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted A heteroarylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amino,
R 5 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
m is an integer from 0 to 2,
n is an integer from 0 to 5,
Each R is independently halogen, oxo, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
p is an integer of 0 to 2 (excluding the following compounds).
Figure JPOXMLDOC01-appb-C000008
),
The pharmaceutically acceptable salt or solvate thereof.
(3) The compound according to (2), pharmaceutically acceptable salt thereof, or the like, wherein X is indole, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, imidazole, pyrazole, pyrrole, triazole, pyridine, imidazopyridine or benzimidazole Solvates.
(4) The compound according to (2), pharmaceutically acceptable salt or solvate thereof, wherein X is pyrazole.
(5) Formula:
Figure JPOXMLDOC01-appb-C000009
A group represented by
Figure JPOXMLDOC01-appb-C000010
A group represented by
n is 0 or 1;
(2) The compound, its pharmaceutically acceptable salt or solvate thereof as described in (2).
(6) The compound according to any one of (2) to (5), pharmaceutically acceptable salt or solvate thereof, wherein m is 1.
(7) R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, (2) (5) The compound according to any one of the above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(8) The compound according to any one of (2) to (5), wherein R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl. , A pharmaceutically acceptable salt thereof or a solvate thereof.
(9) R 1 is hydrogen or substituted or unsubstituted alkyl;
The compound according to any one of (2) to (5), wherein R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, its pharmaceutical Top acceptable salts or solvates thereof.
(10) The compound according to any one of (2) to (5), wherein R 1 and R 2 together with the adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, The pharmaceutically acceptable salt or solvate thereof.
(11) R 3 is each independently substituted or unsubstituted phenyl.
(2) to (5) The compound, pharmaceutically acceptable salt or solvate thereof according to any one of (2) to (5).
(12) The compound according to any one of (2) to (5), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein each R 4 is independently halogen, cyano, or substituted or unsubstituted alkyl. object.
(13) A pharmaceutical composition comprising as an active ingredient the compound according to any one of (2) to (12), a pharmaceutically acceptable salt thereof or a solvate thereof.
(14) The pharmaceutical composition according to (13), which has an NPY Y5 receptor antagonistic action.
(15) Treatment of a disease involving NPY Y5, comprising administering the compound according to any one of (2) to (12) above, a pharmaceutically acceptable salt thereof, or a solvate thereof, or Prevention method.
(16) The use of the compound according to any one of (2) to (12) above, a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving NPY Y5. use.
(17) The compound, its pharmaceutically acceptable salt or solvate thereof according to any one of (2) to (12) above for treating or preventing a disease involving NPY Y5 receptor.
(18) The pharmaceutical composition according to the above (13), which is a medicament for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity.
(19) Obesity-related diseases include bulimia, hypertension, impaired glucose tolerance, diabetes, metabolic syndrome, lipid metabolism abnormality, arteriosclerosis, hyperuricemia, gout, fatty liver, proteinuria, endometrial cancer, breast cancer, prostate (18) The pharmaceutical composition according to (18), which is cancer, colorectal cancer, osteoarthritis, low back pain, obstructive sleep apnea syndrome, coronary artery disease, cerebral infarction, menstrual abnormality, Praderwillie syndrome, Freirich syndrome or Pickwick syndrome .
(20) Prevention or treatment of obesity or obesity-related diseases, comprising administering the compound according to any one of (2) to (12) above, a pharmaceutically acceptable salt thereof, or a solvate thereof. Alternatively, a method for treating or preventing a disease involving NPY Y5, which is used for weight management in obesity.
(21) The compound according to any one of the above (2) to (12), a pharmaceutically acceptable salt thereof or a solvent thereof used for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity Japanese products.
(22) Prevention or treatment of obesity or obesity-related diseases or body weight in obesity in combination with the compound according to any one of (2) to (12) above, a pharmaceutically acceptable salt thereof, or a solvate thereof A method for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity, comprising administering a drug used for management.
(23) Obesity or obesity-related disease in a patient undergoing prevention or treatment by administration of the compound according to any one of (2) to (12) above, a pharmaceutically acceptable salt thereof, or a solvate thereof A method for the prevention or treatment of obesity or obesity-related diseases or the weight management in obesity, comprising administering a drug used for the prevention or treatment of obesity or weight management in obesity.
　本発明化合物はＮＰＹ　Ｙ５受容体拮抗作用を示し、医薬品、特にＮＰＹ　Ｙ５の関与する疾患、例えば、摂食障害、肥満症、神経性食欲昂進症、性的障害、生殖障害、鬱病、癲癇発作、高血圧、脳溢血、鬱血心不全または睡眠障害等の治療または予防のための医薬として非常に有用である。また、本発明化合物は有効な摂食抑制作用を示すことから、肥満症における体重管理、体重減量、体重減量後の体重維持のために非常に有用である。さらに、肥満がリスクファクターとなる疾患、例えば糖尿病、高血圧、高脂血症、動脈硬化、急性冠症候群等の治療または予防のための医薬として非常に有用である。 The compound of the present invention exhibits NPY Y5 receptor antagonistic activity, and is associated with drugs, especially NPY Y5, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, It is very useful as a medicine for the treatment or prevention of hypertension, cerebral hyperemia, congestive heart failure or sleep disorder. In addition, since the compound of the present invention exhibits an effective anti-feeding action, it is very useful for weight management, weight loss, and weight maintenance after weight loss in obesity. Furthermore, it is very useful as a medicament for treating or preventing diseases in which obesity is a risk factor, such as diabetes, hypertension, hyperlipidemia, arteriosclerosis, and acute coronary syndrome.
　以下に本明細書中で使用する各用語を説明する。なお、本明細書中、各用語は単独で使用されている場合も、または他の用語と一緒になって使用されている場合も、特に記載の無い限り、同一の意義を有する。 The terms used in this specification are explained below. In addition, in this specification, each term has the same meaning, whether used alone or in combination with other terms, unless otherwise specified.
　「ハロゲン」とは、フッ素、塩素、臭素およびヨウ素を包含する。特にフッ素および塩素が好ましい。 “Halogen” includes fluorine, chlorine, bromine and iodine. In particular, fluorine and chlorine are preferable.
　「アルキル」とは、炭素数１～１０の直鎖または分枝状の炭化水素基を意味する。炭素数１～６のアルキル、炭素数１～４のアルキル、炭素数１～３のアルキル等を包含する。例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、ヘキシル、イソヘキシル、ｎ－へプチル、イソヘプチル、ｎ－オクチル、イソオクチル、ｎ－ノニル、ｎ－デシル等が挙げられる。 “Alkyl” means a linear or branched hydrocarbon group having 1 to 10 carbon atoms. Examples include alkyl having 1 to 6 carbon atoms, alkyl having 1 to 4 carbon atoms, alkyl having 1 to 3 carbon atoms, and the like. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl , N-nonyl, n-decyl and the like.
　「アルケニル」とは、任意の位置に１以上の二重結合を有する炭素数２～１０の直鎖または分枝状の炭化水素基を意味する。炭素数２～８のアルケニル、炭素数３～６のアルケニル等を包含する。例えば、ビニル、プロペニル、イソプロペニル、ブテニル、イソブテニル、プレニル、ブタジエニル、ペンテニル、イソペンテニル、ペンタジエニル、ヘキセニル、イソヘキセニル、ヘキサジエニル、ヘプテニル、オクテニル、ノネニル、デセニル等が挙げられる。 “Alkenyl” means a straight or branched hydrocarbon group having 2 to 10 carbon atoms having one or more double bonds at an arbitrary position. Examples include alkenyl having 2 to 8 carbon atoms and alkenyl having 3 to 6 carbon atoms. Examples thereof include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl and the like.
　「アルキニル」とは、任意の位置に１以上の三重結合を有する炭素数２～１０の直鎖状または分枝状の炭化水素基を意味する。炭素数２～６のアルキニル、炭素数２～４のアルキニル等を包含する。例えば、エチニル、プロピニル、ブチニル、ペンチニル、ヘキシニル、ヘプチニル、オクチニル、ノニニル、デシニル等が挙げられる。アルキニルは任意の位置の１以上の三重結合の他、さらに二重結合を有していてもよい。 “Alkynyl” means a linear or branched hydrocarbon group having 2 to 10 carbon atoms having one or more triple bonds at any position. Examples include alkynyl having 2 to 6 carbon atoms, alkynyl having 2 to 4 carbon atoms, and the like. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. In addition to one or more triple bonds at any position, alkynyl may further have a double bond.
　「シクロアルキル」とは、炭素数３～８の環状飽和炭化水素基を意味する。炭素数３～６のシクロアルキル、炭素数５または６のシクロアルキル等を包含する。例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロへプチル、シクロオクチル等が挙げられる。 “Cycloalkyl” means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms. Examples include cycloalkyl having 3 to 6 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, and the like. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned.
　「シクロアルケニル」とは、炭素数３～７個の環状不飽和脂肪族炭化水素基を意味する。例えば、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロヘキサジエニルが挙げられる。シクロアルケニルには、環中に不飽和結合を有する橋かけ環状不飽和脂肪族炭化水素基およびスピロ炭化水素基も含まれる。 “Cycloalkenyl” means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 7 carbon atoms. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. Cycloalkenyl also includes bridged cyclic unsaturated aliphatic hydrocarbon groups and spiro hydrocarbon groups having an unsaturated bond in the ring.
　「アリール」とは、単環または多環の芳香族炭素環式基を意味する。例えば、フェニル、ナフチル、アントリル、フェナントリル等が挙げられる。また、シクロアルカン（上記「シクロアルキル」から誘導される環）またはシクロアルケン（上記「シクロアルケニル」から誘導される環）が縮合した縮合芳香族炭化水素環式基も包含する。例えば、インダニル、インデニル、ビフェニレニル、アセナフチル、テトラヒドロナフチル、フルオレニル等が挙げられる。 “Aryl” means a monocyclic or polycyclic aromatic carbocyclic group. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned. Further, a condensed aromatic hydrocarbon cyclic group in which a cycloalkane (ring derived from the above “cycloalkyl”) or a cycloalkene (ring derived from the “cycloalkenyl”) is condensed is also included. For example, indanyl, indenyl, biphenylenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned.
　「芳香族へテロ環」とは、Ｏ、ＳおよびＮから任意に選択されるヘテロ原子を環内に１以上有する芳香族環を意味する。単環または多環の芳香族へテロ環を包含する。
　「単環の芳香族ヘテロ環」とは、Ｏ、ＳおよびＮから任意に選択されるヘテロ原子を環内に１以上有する４～８員の単環芳香族環を意味する。例えば、ピロール、イミダゾール、ピラゾール、ピリジン、ピリダジン、ピリミジン、ピラジン、トリアゾール、トリアジン、テトラゾール、イソオキサゾール、オキサゾール、オキサジアゾール、イソチアゾール、チアゾール、チアジアゾール、フラン、チオフェン等が挙げられる。特に、５員または６員の単環芳香族ヘテロ環が好ましい。
　「多環の芳香族ヘテロ環」とは、上記「単環の芳香族ヘテロ環」に芳香族炭素環（上記「アリール」から誘導される環）、芳香族ヘテロ環、シクロアルカン（上記「シクロアルキル」から誘導される環）またはシクロアルケン（上記「シクロアルケニル」から誘導される環）が縮合した環を意味する。例えば、インドール、イソインドール、インダゾール、インドリジン、キノリン、イソキノリン、シンノリン、フタラジン、キナゾリン、ナフチリジン、キノキサリン、プリン、プテリジン、ベンズイミダゾール、ベンズイソオキサゾール、ベンズオキサゾール、ベンズオキサジアゾール、ベンゾイソチアゾール、ベンゾチアゾール、ベンゾチアジアゾール、ベンゾフラン、イソベンゾフラン、ベンゾチオフェン、ベンゾトリアゾール、イミダゾピリジン、トリアゾロピリジン、イミダゾチアゾール、ピラジノピリダジン、オキサゾロピリジン、チアゾロピリジン等の２環の芳香族へテロ環；カルバゾール、アクリジン、キサンテン、フェノチアジン、フェノキサチイン、フェノキサジン、ジベンゾフラン等の３環の芳香族へテロ環等が挙げられる。 “Aromatic heterocycle” means an aromatic ring having one or more heteroatoms arbitrarily selected from O, S and N in the ring. Includes monocyclic or polycyclic aromatic heterocycles.
“Monocyclic aromatic heterocycle” means a 4- to 8-membered monocyclic aromatic ring having one or more heteroatoms arbitrarily selected from O, S and N in the ring. Examples include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole, furan, and thiophene. In particular, a 5-membered or 6-membered monocyclic aromatic heterocycle is preferable.
The “polycyclic aromatic heterocycle” refers to the above “monocyclic aromatic heterocycle”, an aromatic carbocycle (ring derived from the above “aryl”), an aromatic heterocycle, a cycloalkane (the above “cycloalkane”). A ring derived from “alkyl” or a ring fused with a cycloalkene (ring derived from “cycloalkenyl” above). For example, indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzo A bicyclic aromatic heterocycle such as thiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, thiazolopyridine; carbazole, Examples include tricyclic aromatic heterocycles such as acridine, xanthene, phenothiazine, phenoxathiin, phenoxazine, and dibenzofuran. It is.
　「含窒素芳香族ヘテロ環」とは、少なくとも１以上の窒素原子を環内に有する単環または多環の芳香族へテロ環を意味する。
　「単環の含窒素芳香族へテロ環」としては、例えば、ピロール、イミダゾール、ピラゾール、ピリジン、ピリダジン、ピリミジン、ピラジン、トリアゾール、トリアジン、テトラゾール、イソオキサゾール、オキサゾール、オキサジアゾール、イソチアゾール、チアゾール、チアジアゾール等が挙げられる。
　「多環の含窒素芳香族へテロ環」としては、例えば、インドール、イソインドール、インダゾール、インドリジン、キノリン、イソキノリン、シンノリン、フタラジン、キナゾリン、ナフチリジン、キノキサリン、プリン、プテリジン、ベンズイミダゾール、ベンズイソオキサゾール、ベンズオキサゾール、ベンズオキサジアゾール、ベンゾイソチアゾール、ベンゾチアゾール、ベンゾチアジアゾール、ベンゾトリアゾール、イミダゾピリジン、トリアゾロピリジン、イミダゾチアゾール、ピラジノピリダジン、オキサゾロピリジン、チアゾロピリジン等の２環含窒素芳香族ヘテロ環；カルバゾール、アクリジン、フェノチアジン、フェノキサジン等の３環含窒素芳香族ヘテロ環等が挙げられる。 The “nitrogen-containing aromatic heterocycle” means a monocyclic or polycyclic aromatic heterocycle having at least one nitrogen atom in the ring.
Examples of the “monocyclic nitrogen-containing aromatic heterocycle” include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, isoxazole, oxazole, oxadiazole, isothiazole, and thiazole. , Thiadiazole and the like.
Examples of the `` polycyclic nitrogen-containing aromatic heterocycle '' include, for example, indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benziso Two-ring nitrogen-containing compounds such as oxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzothiazole, benzothiadiazole, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, thiazolopyridine Aromatic heterocycles: 3-ring nitrogen-containing aromatic heterocycles such as carbazole, acridine, phenothiazine, phenoxazine and the like.
　「ヘテロアリール」とは、Ｏ、ＳおよびＮから任意に選択されるヘテロ原子を環内に１以上有する単環または多環の芳香族へテロ環式基を意味する。例えば、上記「単環の芳香族ヘテロ環」から誘導される基、上記「多環の芳香族ヘテロ環」から誘導される基を含有する。
　「単環の芳香族ヘテロ環式基」としては、例えば、ピロリル、イミダゾリル、ピラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアゾリル、トリアジニル、テトラゾリル、イソオキサゾリル、オキサゾリル、オキサジアゾリル、イソチアゾリル、チアゾリル、チアジアゾリル、フリル、チエニル等が挙げられる。
　「多環の芳香族ヘテロ環式基」としては、例えば、インドリル、イソインドリル、インダゾリル、インドリジニル、キノリニル、イソキノリニル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンゾイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、オキサゾロピリジル、チアゾロピリジル等の２環の芳香族へテロ環式基；カルバゾリル、アクリジニル、キサンテニル、フェノチアジニル、フェノキサチニル、フェノキサジニル、ジベンゾフリル等の３環の芳香族へテロ環式基等が挙げられる。多環の芳香族へテロ環式基である場合、結合手をいずれの環に有していてもよい。 “Heteroaryl” means a monocyclic or polycyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring. For example, the group includes a group derived from the above “monocyclic aromatic heterocycle” and a group derived from the above “polycyclic aromatic heterocycle”.
Examples of the `` monocyclic aromatic heterocyclic group '' include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, Thienyl and the like can be mentioned.
Examples of the “polycyclic aromatic heterocyclic group” include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl , Benzoxazolyl, benzoxiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyra Bicyclic aromatic heterocyclic groups such as dinopyridazinyl, oxazolopyridyl, thiazolopyridyl; carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathi Le, phenoxazinyl, heterocyclic groups such as the aromatic tricyclic dibenzofuryl and the like. In the case of a polycyclic aromatic heterocyclic group, any ring may have a bond.
　「非芳香族へテロ環」とは、Ｏ、ＳおよびＮから任意に選択されるヘテロ原子を環内に１以上有する非芳香族環を意味する。単環または多環の非芳香族へテロ環を包含する。
　「単環の非芳香族へテロ環」とは、Ｏ、ＳおよびＮから任意に選択されるヘテロ原子を環内に１以上有する４～８員の単環非芳香族環を意味する。例えば、ジオキサン、チイラン、オキシラン、オキサチオラン、アゼチジン、チアン、ピロリジン、ピロリン、イミダゾリジン、イミダゾリン、ピラゾリジン、ピラゾリン、ピペリジン、ピペラジン、モルホリン、オキサジアジン、ジヒドロピリジン、チオモルホリン、テトラヒドロフラン、テトラヒドロピラン、テトラヒドロチアゾール、テトラヒドロイソチアゾール、オキサゾリジン、チアゾリジン等が挙げられる。特に、５員または６員の単環非芳香族ヘテロ環が好ましい。
　「多環の非芳香族へテロ環」とは、上記「単環の非芳香族ヘテロ環」に芳香族炭素環（上記「アリール」から誘導される環）、芳香族ヘテロ環、単環の非芳香族へテロ環、シクロアルカン（上記「シクロアルキル」から誘導される環）またはシクロアルケン（上記「シクロアルケニル」から誘導される環）が縮合した環を意味する。例えば、インドリン、イソインドリン、クロマン、イソクロマン等が挙げられる。 “Non-aromatic heterocycle” means a non-aromatic ring having one or more heteroatoms arbitrarily selected from O, S and N in the ring. Includes monocyclic or polycyclic non-aromatic heterocycles.
“Monocyclic non-aromatic heterocycle” means a 4- to 8-membered monocyclic non-aromatic ring having one or more hetero atoms arbitrarily selected from O, S and N in the ring. For example, dioxane, thiirane, oxirane, oxathiolane, azetidine, thiane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, oxadiazine, dihydropyridine, thiomorpholine, tetrahydrofuran, tetrahydropyran, tetrahydrothiazole, tetrahydroiso Examples include thiazole, oxazolidine, thiazolidine and the like. In particular, a 5-membered or 6-membered monocyclic non-aromatic heterocycle is preferable.
“Polycyclic non-aromatic heterocycle” refers to the above “monocyclic non-aromatic heterocycle”, aromatic carbocycle (ring derived from the above “aryl”), aromatic heterocycle, monocyclic A non-aromatic heterocycle, a cycloalkane (ring derived from the above “cycloalkyl”) or a cycloalkene (ring derived from the “cycloalkenyl”) is condensed. For example, indoline, isoindoline, chroman, isochroman and the like can be mentioned.
　「含窒素非芳香族ヘテロ環」とは、少なくとも１以上の窒素原子を環内に有する単環または多環の非芳香族へテロ環を意味する。
　「単環の含窒素非芳香族へテロ環」としては、例えば、アゼチジン、ピロリジン、ピロリン、イミダゾリジン、イミダゾリン、ピラゾリジン、ピラゾリン、ピペリジン、ピペラジン、モルホリン、オキサジアジン、ジヒドロピリジン、チオモルホリン、テトラヒドロチアゾール、テトラヒドロイソチアゾール、オキサゾリジン、チアゾリジン等が挙げられる。
　「多環の含窒素非芳香族へテロ環」としては、例えば、インドリン、イソインドリン、ジヒドロベンゾチアジアゾール等が挙げられる。 The “nitrogen-containing non-aromatic heterocycle” means a monocyclic or polycyclic non-aromatic heterocycle having at least one nitrogen atom in the ring.
`` Monocyclic nitrogen-containing non-aromatic heterocycle '' includes, for example, azetidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, oxadiazine, dihydropyridine, thiomorpholine, tetrahydrothiazole, tetrahydro Examples include isothiazole, oxazolidine, thiazolidine and the like.
Examples of the “polycyclic nitrogen-containing non-aromatic heterocycle” include indoline, isoindoline, dihydrobenzothiadiazole and the like.
　「ヘテロサイクリル」とは、Ｏ、ＳおよびＮから任意に選択されるヘテロ原子を環内に１以上有する非芳香族へテロ環式基を意味する。単環の非芳香族へテロ環式基（上記「単環の非芳香族へテロ環」から誘導される基）、または多環の非芳香族へテロ環式基（上記「多環の非芳香族へテロ環」から誘導される基）を含有する。
　「単環の非芳香族ヘテロ環式基」として、具体的には、ジオキサニル、チイラニル、オキシラニル、オキサチオラニル、アゼチジニル、チアニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、ピペリジル、ピペリジノ、ピペラジニル、ピペラジノ、モルホリニル、モルホリノ、オキサジアジニル、ジヒドロピリジル、チオモルホリニル、チオモルホリノ、テトラヒドロフリル、テトラヒドロピラニル、テトラヒドロチアゾリル、テトラヒドロイソチアゾリル、オキサゾリジル、チアゾリジル等が挙げられる。
　「多環の非芳香族ヘテロ環式基」として、具体的には、インドリニル、イソインドリニル、クロマニル、イソクロマニル等が挙げられる。多環の非芳香族へテロ環式基である場合、結合手をいずれの環に有していてもよい。 “Heterocyclyl” means a non-aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring. A monocyclic non-aromatic heterocyclic group (a group derived from the above “monocyclic non-aromatic heterocyclic ring”) or a polycyclic non-aromatic heterocyclic group (the above “polycyclic non-aromatic heterocyclic group”); Group derived from “aromatic heterocycle”.
Specific examples of `` monocyclic non-aromatic heterocyclic group '' include dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidino, piperidino, piperazinyl, piperazinoyl , Morpholinyl, morpholino, oxadiazinyl, dihydropyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, oxazolidyl, thiazolidyl and the like.
Specific examples of the “polycyclic non-aromatic heterocyclic group” include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like. In the case of a polycyclic non-aromatic heterocyclic group, any ring may have a bond.
　「アルコキシ」とは、上記「アルキル」が酸素原子に結合した基を意味する。具体的には、メトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｎ－ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、ｎ－ペントキシ、ペントキシ、ネオペントキシ、ヘキソキシ、イソヘキソキシ、ｎ－へプトキシ、イソヘプトキシ、ｎ－オクトキシ、イソオクトキシ等が挙げられる。 “Alkoxy” means a group in which the above “alkyl” is bonded to an oxygen atom. Specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, pentoxy, neopentoxy, hexoxy, isohexoxy, n-heptoxy, isoheptoxy, n -Octoxy, isooctoxy and the like.
　「ハロアルキル」および「ハロアルコキシ」とは、上記「ハロゲン」が上記「アルキル」および「アルコキシ」に結合した基を意味する。 “Haloalkyl” and “haloalkoxy” mean a group in which the “halogen” is bonded to the “alkyl” and “alkoxy”.
　「アリールオキシ」とは、上記「アリール」が酸素原子に結合した基を意味する。具体的には、フェノキシ、ナフトキシ、アントリルオキシ、フェナントリルオキシ、インダニルオキシ、インデニルオキシ、ビフェニリルオキシ、アセナフチルオキシ、テトラヒドロナフチルオキシ、フルオレニルオキシ等が挙げられる。 “Aryloxy” means a group in which the above “aryl” is bonded to an oxygen atom. Specific examples include phenoxy, naphthoxy, anthryloxy, phenanthryloxy, indanyloxy, indenyloxy, biphenylyloxy, acenaphthyloxy, tetrahydronaphthyloxy, fluorenyloxy and the like.
　「アルケニルオキシ」、「シクロアルキルオキシ」、「シクロアルケニルオキシ」、「ヘテロアリールオキシ」および「ヘテロサイクリルオキシ」とは、上記「アルケニル」、「シクロアルキル」、「シクロアルケニル」、「ヘテロアリール」および「ヘテロサイクリル」が酸素原子に結合した基を意味する。 "Alkenyloxy", "cycloalkyloxy", "cycloalkenyloxy", "heteroaryloxy" and "heterocyclyloxy" are the above "alkenyl", "cycloalkyl", "cycloalkenyl", "heteroaryl" And “heterocyclyl” means a group bonded to an oxygen atom.
　「アルキルチオ」、「アルケニルチオ」、「シクロアルキルチオ」、「シクロアルケニルチオ」、「アリールチオ」、「ヘテロアリールチオ」および「ヘテロサイクリルチオ」とは、上記「アルキル」、「アルケニル」、「シクロアルキル」、「シクロアルケニル」、「アリール」、「ヘテロアリール」および「ヘテロサイクリル」が硫黄原子に結合した基を意味する。 “Alkylthio”, “alkenylthio”, “cycloalkylthio”, “cycloalkenylthio”, “arylthio”, “heteroarylthio” and “heterocyclylthio” are the above-mentioned “alkyl”, “alkenyl”, “cycloalkyl” ”,“ Cycloalkenyl ”,“ aryl ”,“ heteroaryl ”and“ heterocyclyl ”mean a group bonded to a sulfur atom.
　「アルコキシカルボニル」、「アルケニルオキシカルボニル」、「シクロアルキルオキシカルボニル」、「シクロアルケニルオキシカルボニル」、「アリールオキシカルボニル」、「ヘテロアリールオキシカルボニル」および「ヘテロサイクリルオキシカルボニル」とは、上記「アルコキシ」、「アルケニルオキシ」、「シクロアルキルオキシ」、「シクロアルケニルオキシ」、「アリールオキシ」、「ヘテロアリールオキシ」および「ヘテロサイクリルオキシ」の酸素原子がカルボニル基に結合した基を意味する。 “Alkoxycarbonyl”, “alkenyloxycarbonyl”, “cycloalkyloxycarbonyl”, “cycloalkenyloxycarbonyl”, “aryloxycarbonyl”, “heteroaryloxycarbonyl” and “heterocyclyloxycarbonyl” Means a group in which the oxygen atom of “alkoxy”, “alkenyloxy”, “cycloalkyloxy”, “cycloalkenyloxy”, “aryloxy”, “heteroaryloxy” and “heterocyclyloxy” is bonded to a carbonyl group .
　「アルキルカルボニル」、「アルケニルカルボニル」、「シクロアルキルカルボニル」、「シクロアルケニルカルボニル」、「アリールカルボニル」、「ヘテロアリールカルボニル」および「ヘテロサイクリルカルボニル」とは、上記「アルキル」、「アルケニル」、「シクロアルキル」、「シクロアルケニル」、「アリール」、「ヘテロアリール」および「ヘテロサイクリル」がカルボニル基に結合した基を意味する。 “Alkylcarbonyl”, “alkenylcarbonyl”, “cycloalkylcarbonyl”, “cycloalkenylcarbonyl”, “arylcarbonyl”, “heteroarylcarbonyl” and “heterocyclylcarbonyl” are the above “alkyl”, “alkenyl”. , “Cycloalkyl”, “cycloalkenyl”, “aryl”, “heteroaryl” and “heterocyclyl” mean a group bonded to a carbonyl group.
　「アルキルスルホニル」、「アルケニルスルホニル」、「シクロアルキルスルホニル」、「シクロアルケニルスルホニル」、「アリールスルホニル」、「ヘテロアリールスルホニル」および「ヘテロサイクリルスルホニル」とは、上記「アルキル」、「アルケニル」、「シクロアルキル」、「シクロアルケニル」、「アリール」、「ヘテロアリール」および「ヘテロサイクリル」がスルホニル基に結合した基を意味する。 “Alkylsulfonyl”, “alkenylsulfonyl”, “cycloalkylsulfonyl”, “cycloalkenylsulfonyl”, “arylsulfonyl”, “heteroarylsulfonyl” and “heterocyclylsulfonyl” are the above “alkyl”, “alkenyl”. , “Cycloalkyl”, “cycloalkenyl”, “aryl”, “heteroaryl” and “heterocyclyl” mean a group bonded to a sulfonyl group.
　「置換若しくは非置換のアルキル」、「置換若しくは非置換のアルケニル」、「置換若しくは非置換のアルキニル」、「置換若しくは非置換のアルコキシ」、「置換若しくは非置換のアルケニルオキシ」、「置換若しくは非置換のアルキルチオ」、「置換若しくは非置換のアルケニルチオ」、「置換若しくは非置換のアルコキシカルボニル」、「置換若しくは非置換のアルケニルオキシカルボニル」、「置換若しくは非置換のアルキルカルボニル」、「置換若しくは非置換のアルケニルカルボニル」、「置換若しくは非置換のアルキルスルホニル」または「置換若しくは非置換のアルケニルスルホニル」の置換基としては、ハロゲン、シアノ、ニトロ、ニトロソ、アジド、アシル、アシルオキシ、イミノ、ヒドロキシ、アルコキシ、ハロアルコキシ、アルキニルオキシ、シクロアルキル、シクロアルキルオキシ、シクロアルケニル、シクロアルケニルオキシ、アリール、アリールオキシ、ヘテロアリール、ヘテロアリールオキシ、ヘテロサイクリル、ヘテロサイクリルオキシ、
メルカプト、アルキルチオ、アルケニルチオ、シクロアルキルチオ、シクロアルケニルチオ、アリールチオ、ヘテロアリールチオ、ヘテロサイクリルチオ、カルボキシ、アルコキシカルボニル、アルケニルオキシカルボニル、シクロアルキルオキシカルボニル、シクロアルケニルオキシカルボニル、アリールオキシカルボニル、ヘテロアリールオキシカルボニル、ヘテロサイクリルオキシカルボニル、カルバモイル、ホルミル、アルキルカルボニル、アルケニルカルボニル、シクロアルキルカルボニル、シクロアルケニルカルボニル、アリールカルボニル、ヘテロアリールカルボニル、ヘテロサイクリルカルボニル、スルフィノ、スルホ、アルキルスルホニル、アルケニルスルホニル、シクロアルキルスルホニル、シクロアルケニルスルホニル、アリールスルホニル、ヘテロアリールスルホニル、ヘテロサイクリルスルホニル、スルファモイル、アミノ、オキソ等が挙げられる。任意の位置がこれらから選択される１以上の基で置換基を有していてもよい。　 "Substituted or unsubstituted alkyl", "substituted or unsubstituted alkenyl", "substituted or unsubstituted alkynyl", "substituted or unsubstituted alkoxy", "substituted or unsubstituted alkenyloxy", "substituted or unsubstituted "Substituted alkylthio", "Substituted or unsubstituted alkenylthio", "Substituted or unsubstituted alkoxycarbonyl", "Substituted or unsubstituted alkenyloxycarbonyl", "Substituted or unsubstituted alkylcarbonyl", "Substituted or unsubstituted Substituents of “substituted alkenylcarbonyl”, “substituted or unsubstituted alkylsulfonyl” or “substituted or unsubstituted alkenylsulfonyl” include halogen, cyano, nitro, nitroso, azide, acyl, acyloxy, imino, hydroxy, alkoxy , Haloal Alkoxy, alkynyloxy, cycloalkyl, cycloalkyloxy, cycloalkenyl, cycloalkenyloxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy,
Mercapto, alkylthio, alkenylthio, cycloalkylthio, cycloalkenylthio, arylthio, heteroarylthio, heterocyclylthio, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, aryloxycarbonyl, heteroaryloxy Carbonyl, heterocyclyloxycarbonyl, carbamoyl, formyl, alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, sulfino, sulfo, alkylsulfonyl, alkenylsulfonyl, cycloalkyl Sulfonyl, cycloalkenylsulfoni , Arylsulfonyl, heteroarylsulfonyl, heterocyclyl sulfonyl, sulfamoyl, amino, oxo and the like. Any position may be substituted with one or more groups selected from these.
　「置換若しくは非置換のシクロアルキル」、「置換若しくは非置換のシクロアルケニル」、「置換若しくは非置換のアリール」、「置換若しくは非置換のヘテロアリール」、「置換若しくは非置換のヘテロサイクリル」、「置換若しくは非置換の含窒素芳香族ヘテロ環」、「置換若しくは非置換の含窒素非芳香族ヘテロ環」、「置換若しくは非置換のシクロアルキルオキシ」、「置換若しくは非置換のシクロアルケニルオキシ」、「置換若しくは非置換のアリールオキシ」、「置換若しくは非置換のヘテロアリールオキシ」、「置換若しくは非置換のヘテロサイクリルオキシ」、「置換若しくは非置換のシクロアルキルチオ」、「置換若しくは非置換のシクロアルケニルチオ」、「置換若しくは非置換のアリールチオ」、「置換若しくは非置換のヘテロアリールチオ」、「置換若しくは非置換のヘテロサイクリルチオ」、「置換若しくは非置換のシクロアルキルオキシカルボニル」、「置換若しくは非置換のシクロアルケニルオキシカルボニル」、「置換若しくは非置換のアリールオキシカルボニル」、「置換若しくは非置換のヘテロアリールオキシカルボニル」、「置換若しくは非置換のヘテロサイクリルオキシカルボニル」、「置換若しくは非置換のカルバモイル」、「置換若しくは非置換のシクロアルキルカルボニル」、「置換若しくは非置換のシクロアルケニルカルボニル」、「置換若しくは非置換のアリールカルボニル」、「置換若しくは非置換のヘテロアリールカルボニル」、「置換若しくは非置換のヘテロサイクリルカルボニル」、「置換若しくは非置換のシクロアルキルスルホニル」、「置換若しくは非置換のシクロアルケニルスルホニル」、「置換若しくは非置換のアリールスルホニル」、「置換若しくは非置換のヘテロアリールスルホニル」、「置換若しくは非置換のヘテロサイクリルスルホニル」、「置換若しくは非置換のスルファモイル」または「置換若しくは非置換のアミノ」の置換基としては、アルキル、ハロアルキル、アルケニル、アルキニル、ハロゲン、シアノ、ニトロ、ニトロソ、アジド、アシル、アシルオキシ、イミノ、ヒドロキシ、アルコキシ、ハロアルコキシ、アルキニルオキシ、シクロアルキル、シクロアルキルオキシ、シクロアルケニル、シクロアルケニルオキシ、アリール、アリールオキシ、ヘテロアリール、ヘテロアリールオキシ、ヘテロサイクリル、ヘテロサイクリルオキシ、メルカプト、アルキルチオ、アルケニルチオ、シクロアルキルチオ、シクロアルケニルチオ、アリールチオ、ヘテロアリールチオ、ヘテロサイクリルチオ、カルボキシ、アルコキシカルボニル、アルケニルオキシカルボニル、シクロアルキルオキシカルボニル、シクロアルケニルオキシカルボニル、アリールオキシカルボニル、ヘテロアリールオキシカルボニル、ヘテロサイクリルオキシカルボニル、カルバモイル、ホルミル、アルキルカルボニル、アルケニルカルボニル、シクロアルキルカルボニル、シクロアルケニルカルボニル、アリールカルボニル、ヘテロアリールカルボニル、ヘテロサイクリルカルボニル、スルフィノ、スルホ、アルキルスルホニル、アルケニルスルホニル、シクロアルキルスルホニル、シクロアルケニルスルホニル、アリールスルホニル、ヘテロアリールスルホニル、ヘテロサイクリルスルホニル、スルファモイル、アミノ、オキソ、アルキレン、アルキレンジオキシ、式：－Ｎ（Ｒ７）－（アルキレン）－Ｏ－で示される基、式：－Ｎ（Ｒ７）－（アルキレン）－Ｎ（Ｒ７）－で示される基（Ｒ７はそれぞれ独立して水素またはアルキル）等が挙げられる。二価の基で置換されている場合は、該二価の基の結合手は、同一または異なる原子と結合していてもよい。該二価の基の結合手が隣接する原子に結合置換する場合のみならず、ビシクロ環やスピロ環を形成するように結合していてもよい。任意の位置がこれらから選択される１以上の基で置換されていてもよい。 “Substituted or unsubstituted cycloalkyl”, “substituted or unsubstituted cycloalkenyl”, “substituted or unsubstituted aryl”, “substituted or unsubstituted heteroaryl”, “substituted or unsubstituted heterocyclyl”, "Substituted or unsubstituted nitrogen-containing aromatic heterocycle", "Substituted or unsubstituted nitrogen-containing non-aromatic heterocycle", "Substituted or unsubstituted cycloalkyloxy", "Substituted or unsubstituted cycloalkenyloxy" , “Substituted or unsubstituted aryloxy”, “substituted or unsubstituted heteroaryloxy”, “substituted or unsubstituted heterocyclyloxy”, “substituted or unsubstituted cycloalkylthio”, “substituted or unsubstituted Cycloalkenylthio, substituted or unsubstituted arylthio, substituted or unsubstituted Heteroarylthio ”,“ substituted or unsubstituted heterocyclylthio ”,“ substituted or unsubstituted cycloalkyloxycarbonyl ”,“ substituted or unsubstituted cycloalkenyloxycarbonyl ”,“ substituted or unsubstituted aryloxycarbonyl ” , “Substituted or unsubstituted heteroaryloxycarbonyl”, “substituted or unsubstituted heterocyclyloxycarbonyl”, “substituted or unsubstituted carbamoyl”, “substituted or unsubstituted cycloalkylcarbonyl”, “substituted or "Unsubstituted cycloalkenylcarbonyl", "substituted or unsubstituted arylcarbonyl", "substituted or unsubstituted heteroarylcarbonyl", "substituted or unsubstituted heterocyclylcarbonyl", "substituted or unsubstituted cycloaryl" Killsulfonyl "," substituted or unsubstituted cycloalkenylsulfonyl "," substituted or unsubstituted arylsulfonyl "," substituted or unsubstituted heteroarylsulfonyl "," substituted or unsubstituted heterocyclylsulfonyl "," substituted Alternatively, the substituent of “unsubstituted sulfamoyl” or “substituted or unsubstituted amino” includes alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, nitroso, azide, acyl, acyloxy, imino, hydroxy, alkoxy, halo. Alkoxy, alkynyloxy, cycloalkyl, cycloalkyloxy, cycloalkenyl, cycloalkenyloxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyl Oxy, mercapto, alkylthio, alkenylthio, cycloalkylthio, cycloalkenylthio, arylthio, heteroarylthio, heterocyclylthio, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, aryloxycarbonyl, hetero Aryloxycarbonyl, heterocyclyloxycarbonyl, carbamoyl, formyl, alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, sulfino, sulfo, alkylsulfonyl, alkenylsulfonyl, Cycloalkylsulfonyl, cycloalkenyl Ruhoniru, arylsulfonyl, heteroarylsulfonyl, heterocyclyl sulfonyl, sulfamoyl, amino, oxo, alkylene, alkylenedioxy, formula: -N (R 7) - (alkylene) -O- a group represented the formula: -N And a group represented by (R 7 )-(alkylene) -N (R 7 ) — (R 7 is independently hydrogen or alkyl). In the case of substitution with a divalent group, the bond of the divalent group may be bonded to the same or different atom. The divalent group may be bonded so as to form a bicyclo ring or a spiro ring as well as a case where the bond of the divalent group is bonded to an adjacent atom. Any position may be substituted with one or more groups selected from these.
　例えば、「置換若しくは非置換のシクロアルキル（例：シクロヘキシル）」の置換基がアルキレン（例：－ＣＨ２－ＣＨ２－）の場合、以下のように置換していてもよい。
Figure JPOXMLDOC01-appb-C000011
 For example, when the substituent of “substituted or unsubstituted cycloalkyl (eg, cyclohexyl)” is alkylene (eg, —CH 2 —CH 2 —), it may be substituted as follows.
Figure JPOXMLDOC01-appb-C000011
　例えば、「置換若しくは非置換のアリール」の置換基がアルキレンジオキシの場合、以下の基等が例示される。
Figure JPOXMLDOC01-appb-C000012
 For example, when the substituent of “substituted or unsubstituted aryl” is alkylenedioxy, the following groups are exemplified.
Figure JPOXMLDOC01-appb-C000012
　例えば、「置換若しくは非置換のアリール」の置換基が式：－Ｎ（Ｒ７）－（アルキレン）－Ｏ－で示される基の場合、以下の基等が例示される。
Figure JPOXMLDOC01-appb-C000013
　置換基が他の二価の基の場合も、上記と同様に置換されていてもよい。 For example, when the substituent of “substituted or unsubstituted aryl” is a group represented by the formula: —N (R 7 )-(alkylene) -O—, the following groups are exemplified.
Figure JPOXMLDOC01-appb-C000013
When the substituent is another divalent group, it may be substituted in the same manner as described above.
　「アシル」とは
（１）炭素数１～１０、さらに好ましくは炭素数１～６、最も好ましくは炭素数１～４の直鎖もしくは分枝状のアルキルカルボニルもしくはアルケニルカルボニル、
（２）炭素数４～９、好ましくは炭素数４～７のシクロアルキルカルボニルおよび
（３）炭素数７～１１のアリールカルボニルを包含する。具体的には、ホルミル、アセチル、プロピオニル、ブチリル、イソブチリル、バレリル、ピバロイル、ヘキサノイル、アクリロイル、プロピオロイル、メタクリロイル、クロトノイル、シクロプロピルカルボニル、シクロヘキシルカルボニル、シクロオクチルカルボニルおよびベンゾイル等を包含する。 “Acyl” means (1) a linear or branched alkylcarbonyl or alkenylcarbonyl having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 4 carbon atoms,
(2) cycloalkylcarbonyl having 4 to 9 carbon atoms, preferably 4 to 7 carbon atoms and (3) arylcarbonyl having 7 to 11 carbon atoms are included. Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioyl, methacryloyl, crotonoyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl and benzoyl.
　「アシルオキシ」とは、上記「アシル」が酸素原子に結合した基を意味する。 “Acyloxy” means a group in which the above “acyl” is bonded to an oxygen atom.
　本発明化合物は全てＮＰＹ　Ｙ５受容体拮抗作用を有しているが、特に好ましい化合物としては、式（Ｉ）における以下の化合物が挙げられる。 The compounds of the present invention all have NPY Y5 receptor antagonistic action, but particularly preferred compounds include the following compounds in the formula (I).
Ｒ１およびＲ２がそれぞれ独立して水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリールまたは置換若しくは非置換のヘテロサイクリルである化合物。

Ｒ１およびＲ２がそれぞれ独立して水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキルまたは置換若しくは非置換のアリールである化合物。

Ｒ１およびＲ２がそれぞれ独立して水素；アルキル；ハロゲンまたはシアノで置換されているアルキル；アルコキシ；シクロアルキル；である化合物。

Ｒ２が置換若しくは非置換のアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキルまたは置換若しくは非置換のアリールである化合物。

Ｒ１が水素または置換若しくは非置換のアルキルであり、
Ｒ２が置換若しくは非置換のアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキルまたは置換若しくは非置換のアリールである化合物。

Ｒ１が水素；アルキル；またはシアノで置換されているアルキル；であり、
Ｒ２がアルキル；ハロゲンまたはシアノで置換されているアルキル；アルコキシ；シクロアルキル；アリールである化合物。

Ｒ１およびＲ２が隣接する窒素原子と一緒になって置換若しくは非置換の含窒素芳香族ヘテロ環または置換若しくは非置換の含窒素非芳香族ヘテロ環を形成している化合物。

Ｒ１およびＲ２が隣接する窒素原子と一緒になって置換若しくは非置換の含窒素非芳香族ヘテロ環を形成している化合物。

Ｒ１およびＲ２が隣接する窒素原子と一緒になってピペリジン、オキソで置換されているオキサゾリジンまたはモルホリンを形成している化合物。

Ｒ１およびＲ５は隣接する窒素原子と一緒になって置換若しくは非置換の含窒素非芳香族ヘテロ環を形成している化合物。

式：
Figure JPOXMLDOC01-appb-C000014
で示される基が、
式：
Figure JPOXMLDOC01-appb-C000015
で示される基である化合物。 R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or A compound that is unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl.

A compound wherein R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.

A compound wherein R 1 and R 2 are each independently hydrogen; alkyl; alkyl substituted with halogen or cyano; alkoxy;

A compound wherein R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl.

R 1 is hydrogen or substituted or unsubstituted alkyl;
A compound wherein R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl.

R 1 is hydrogen; alkyl; or alkyl substituted with cyano;
A compound wherein R 2 is alkyl; alkyl substituted with halogen or cyano; alkoxy; cycloalkyl; aryl.

A compound in which R 1 and R 2 together with the adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing aromatic heterocyclic ring or a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic ring.

A compound in which R 1 and R 2 together with an adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle.

A compound in which R 1 and R 2 together with the adjacent nitrogen atom form piperidine, oxo substituted oxazolidine or morpholine.

A compound in which R 1 and R 5 together with an adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle.

formula:
Figure JPOXMLDOC01-appb-C000014
A group represented by
formula:
Figure JPOXMLDOC01-appb-C000015
The compound which is group shown by these.
Ｒ３が置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリールまたは置換若しくは非置換のヘテロサイクリルである化合物。

Ｒ３が置換若しくは非置換のフェニル、置換若しくは非置換のピリジル、置換若しくは非置換のピリミジニル、置換若しくは非置換のピラジニル、置換若しくは非置換のチアゾリル、置換若しくは非置換のオキサゾリル、置換若しくは非置換のモルホリニル、置換若しくは非置換のモルホリノ、置換若しくは非置換のピロリジニル、置換若しくは非置換のピペリジル、置換若しくは非置換のピペリジノ、置換若しくは非置換のベンゾジオキソリル、置換若しくは非置換のジヒドロベンゾオキサジニルまたは置換若しくは非置換のインダゾリルである化合物。

Ｒ３が置換若しくは非置換のフェニル、置換若しくは非置換のピリジル、置換若しくは非置換のピリミジニル、置換若しくは非置換のピラジニル、置換若しくは非置換のチアゾリル、置換若しくは非置換のオキサゾリル、置換若しくは非置換のモルホリニル、置換若しくは非置換のモルホリノ、置換若しくは非置換のピロリジニル、置換若しくは非置換のピペリジル、置換若しくは非置換のピペリジノ、置換若しくは非置換のベンゾジオキソリル、置換若しくは非置換のジヒドロベンゾオキサジニルまたは置換若しくは非置換のインダゾリル
（それぞれ置換基は、ハロゲン、シアノ、ニトロ、ニトロソ、アジド、オキソ、アルキル、ハロアルキル、アルケニル、アルキニル、ヒドロキシ、アルコキシ、ハロアルコキシ、アルケニルオキシ、メルカプト、アルキルチオ、アルケニルチオ、カルボキシ、アルコキシカルボニル、アルケニルオキシカルボニル、カルバモイル、ホルミル、アルキルカルボニル、アルケニルカルボニル、スルフィノ、スルホ、アルキルスルホニル、アルケニルスルホニル、スルファモイル、アミノアルキレンジオキシ、モルホリノおよび式：－Ｎ（Ｒ７）－（アルキレン）－Ｏ－で示される基から選ばれる１以上の基である）である化合物。

Ｒ３が置換若しくは非置換のフェニルまたは置換若しくは非置換のピリジル
（それぞれ置換基は、ハロゲン、シアノ、ニトロ、アジド、オキソ、アルキル、ハロアルキル、アルケニル、アルキニル、ヒドロキシ、アルコキシおよびハロアルコキシから選ばれる１以上の基である）である化合物。

Ｒ３が置換若しくは非置換のフェニルまたはピリジル
（置換基は、ハロゲン、シアノ、アルコキシから選ばれる１以上の基である）である化合物。

Ｒ３が置換若しくは非置換のフェニル
（置換基は、ハロゲン、シアノ、アルコキシから選ばれる１以上の基である）である化合物。 A compound wherein R 3 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.

R 3 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted Morpholinyl, substituted or unsubstituted morpholino, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperidino, substituted or unsubstituted benzodioxolyl, substituted or unsubstituted dihydrobenzoxazinyl Or a compound that is substituted or unsubstituted indazolyl.

R 3 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted Morpholinyl, substituted or unsubstituted morpholino, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperidino, substituted or unsubstituted benzodioxolyl, substituted or unsubstituted dihydrobenzoxazinyl Or substituted or unsubstituted indazolyl (each substituted group is halogen, cyano, nitro, nitroso, azide, oxo, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, haloalkoxy, alkenyloxy, Lucapto, alkylthio, alkenylthio, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, carbamoyl, formyl, alkylcarbonyl, alkenylcarbonyl, sulfino, sulfo, alkylsulfonyl, alkenylsulfonyl, sulfamoyl, aminoalkylenedioxy, morpholino and formula: —N ( A compound represented by R 7 )-(alkylene) -O—.

R 3 is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl (the substituents are each selected from halogen, cyano, nitro, azide, oxo, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy and haloalkoxy A compound which is the above group).

A compound in which R 3 is substituted or unsubstituted phenyl or pyridyl (the substituent is one or more groups selected from halogen, cyano, and alkoxy).

A compound in which R 3 is substituted or unsubstituted phenyl (the substituent is one or more groups selected from halogen, cyano, and alkoxy).
Ｒ４がハロゲン、シアノ、ニトロ、ニトロソ、アジド、オキソ、
置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、
ヒドロキシ、置換若しくは非置換のアルコキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロサイクリルオキシ、
メルカプト、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のシクロアルキルチオ、置換若しくは非置換のシクロアルケニルチオ、置換若しくは非置換のアリールチオ、置換若しくは非置換のヘテロアリールチオ、置換若しくは非置換のヘテロサイクリルチオ、
カルボキシ、置換若しくは非置換のアルコキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のシクロアルキルオキシカルボニル、置換若しくは非置換のシクロアルケニルオキシカルボニル、置換若しくは非置換のアリールオキシカルボニル、置換若しくは非置換のヘテロアリールオキシカルボニル、置換若しくは非置換のヘテロサイクリルオキシカルボニル、置換若しくは非置換のカルバモイル、
ホルミル、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のシクロアルキルカルボニル、置換若しくは非置換のシクロアルケニルカルボニル、置換若しくは非置換のアリールカルボニル、置換若しくは非置換のヘテロアリールカルボニル、置換若しくは非置換のヘテロサイクリルカルボニル、
スルフィノ、スルホ、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のシクロアルキルスルホニル、置換若しくは非置換のシクロアルケニルスルホニル、置換若しくは非置換のアリールスルホニル、置換若しくは非置換のヘテロアリールスルホニル、置換若しくは非置換のヘテロサイクリルスルホニル、置換若しくは非置換のスルファモイル
または置換若しくは非置換のアミノである化合物。

Ｒ４がハロゲン、シアノ、オキソ、置換若しくは非置換のアルキル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のアルコキシまたは置換若しくは非置換のアリールオキシである化合物。

Ｒ４がハロゲン、シアノ、オキソ、置換若しくは非置換のアルキル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のアルコキシまたは置換若しくは非置換のアリールオキシ
（それぞれ置換基は、ハロゲン、シアノ、ニトロ、ニトロソ、アジド、オキソ、アルキル、ハロアルキル、アルケニル、アルキニル、ヒドロキシ、アルコキシ、ハロアルコキシ、アルケニルオキシ、メルカプト、アルキルチオ、アルケニルチオ、カルボキシ、アルコキシカルボニル、アルケニルオキシカルボニル、カルバモイル、ホルミル、アルキルカルボニル、アルケニルカルボニル、スルフィノ、スルホ、アルキルスルホニル、アルケニルスルホニル、スルファモイルおよびアミノから選ばれる１以上の基である）である化合物。

Ｒ４がハロゲン、シアノまたは置換若しくは非置換のアルキルである化合物。

Ｒ４がハロゲン、シアノまたは置換若しくは非置換のアルキル
（それぞれ置換基は、ハロゲン、シアノ、ニトロ、アジド、オキソ、アルキル、ハロアルキル、アルケニル、アルキニル、ヒドロキシ、アルコキシおよびハロアルコキシから選ばれる１以上の基である）である化合物。

Ｒ４がハロゲン、シアノ、アルキルである化合物。 R 4 is halogen, cyano, nitro, nitroso, azide, oxo,
Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
Hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl Oxy, substituted or unsubstituted heterocyclyloxy,
Mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, Substituted or unsubstituted heterocyclylthio,
Carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or Unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl,
Formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted hetero Arylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl,
Sulfino, sulfo, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted Or a substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amino.

A compound wherein R 4 is halogen, cyano, oxo, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted aryloxy.

R 4 is halogen, cyano, oxo, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy or substituted or unsubstituted aryloxy (the substituents are halogen, cyano, nitro, Nitroso, azide, oxo, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, haloalkoxy, alkenyloxy, mercapto, alkylthio, alkenylthio, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, carbamoyl, formyl, alkylcarbonyl, alkenylcarbonyl, And one or more groups selected from sulfino, sulfo, alkylsulfonyl, alkenylsulfonyl, sulfamoyl and amino).

A compound wherein R 4 is halogen, cyano or substituted or unsubstituted alkyl.

R 4 is halogen, cyano, or substituted or unsubstituted alkyl (the substituents are one or more groups selected from halogen, cyano, nitro, azide, oxo, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, and haloalkoxy, respectively) Compound).

A compound in which R 4 is halogen, cyano, or alkyl.
Ｒ５が水素または置換若しくは非置換のアルキルである化合物。

Ｒ５が水素または炭素数１～３のアルキルである化合物。

Ｒ５が水素である化合物。 A compound wherein R 5 is hydrogen or substituted or unsubstituted alkyl.

A compound wherein R 5 is hydrogen or alkyl having 1 to 3 carbon atoms.

A compound wherein R 5 is hydrogen.
ｍが１または２である化合物。

ｍが１である化合物。

ｎが０～２である化合物。

ｎが０または１である化合物。 A compound wherein m is 1 or 2.

A compound wherein m is 1.

A compound wherein n is 0-2.

A compound wherein n is 0 or 1.
Rがハロゲン、オキソ、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルである化合物。

ｐが０～２の整数である化合物。 A compound wherein R is halogen, oxo, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl.

A compound wherein p is an integer of 0-2.
Ｘが芳香族へテロ環または非芳香族へテロ環である化合物。

Ｘがインドール、ピロロピリジン、ピロロピリミジン、ピロロピラジン、イミダゾール、ピラゾール、ピロール、トリアゾール、ピリジン、イミダゾピリジンまたはベンゾイミダゾールである化合物。

Ｘがインドール、ピロロピリジン、ピロロピリミジン、ピロロピラジン、ピラゾール、ピロールまたはベンゾイミダゾールである化合物。

Ｘがピラゾールである化合物。

Ｘが以下から選択される基である化合物。
Figure JPOXMLDOC01-appb-C000016
（なお、シクロヘキサン、（Ｒ３）ｍおよび（Ｒ４）ｎからの結合手は上記環上の置換可能ないずれの原子に結合していてもよい。） A compound wherein X is an aromatic heterocycle or a non-aromatic heterocycle.

A compound in which X is indole, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, imidazole, pyrazole, pyrrole, triazole, pyridine, imidazopyridine or benzimidazole.

A compound wherein X is indole, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, pyrazole, pyrrole or benzimidazole.

A compound wherein X is pyrazole.

A compound in which X is a group selected from the following.
Figure JPOXMLDOC01-appb-C000016
(The bond from cyclohexane, (R 3 ) m, and (R 4 ) n may be bonded to any substitutable atom on the ring.)
式：
Figure JPOXMLDOC01-appb-C000017
で示される基が、
Figure JPOXMLDOC01-appb-C000018
（Ｘ’はシクロヘキサン環との結合手を環内の窒素原子の隣接位に有する芳香族ヘテロ環または非芳香族へテロ環である。）
で示される基である化合物。 formula:
Figure JPOXMLDOC01-appb-C000017
A group represented by
Figure JPOXMLDOC01-appb-C000018
(X ′ is an aromatic heterocycle or non-aromatic heterocycle having a bond to the cyclohexane ring adjacent to the nitrogen atom in the ring.)
The compound which is group shown by these.
式：
Figure JPOXMLDOC01-appb-C000019
で示される基が、式：
Figure JPOXMLDOC01-appb-C000020
で示される基である化合物。

式：
Figure JPOXMLDOC01-appb-C000021
で示される基が、式：
Figure JPOXMLDOC01-appb-C000022
で示される基である化合物。 formula:
Figure JPOXMLDOC01-appb-C000019
A group represented by the formula:
Figure JPOXMLDOC01-appb-C000020
The compound which is group shown by these.

formula:
Figure JPOXMLDOC01-appb-C000021
A group represented by the formula:
Figure JPOXMLDOC01-appb-C000022
The compound which is group shown by these.
　なお、式：
Figure JPOXMLDOC01-appb-C000023
で示される基は、以下の式で示される基と同意義である。
式：
Figure JPOXMLDOC01-appb-C000024
式：
Figure JPOXMLDOC01-appb-C000025
で示される基は、以下の式で示される基と同意義である。
式：
Figure JPOXMLDOC01-appb-C000026
 The formula:
Figure JPOXMLDOC01-appb-C000023
The group represented by is the same as the group represented by the following formula.
formula:
Figure JPOXMLDOC01-appb-C000024
formula:
Figure JPOXMLDOC01-appb-C000025
The group represented by is the same as the group represented by the following formula.
formula:
Figure JPOXMLDOC01-appb-C000026
　式（Ｉ）で示される化合物は、
式：
Figure JPOXMLDOC01-appb-C000027
（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）
で示される化合物、および／または
式：
Figure JPOXMLDOC01-appb-C000028
（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）
で示される化合物を意味する。特に好ましくは、
式：
Figure JPOXMLDOC01-appb-C000029
（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）
で示される化合物である。 The compound represented by the formula (I) is
formula:
Figure JPOXMLDOC01-appb-C000027
(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).)
And / or the formula:
Figure JPOXMLDOC01-appb-C000028
(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).)
Means a compound represented by Particularly preferably,
formula:
Figure JPOXMLDOC01-appb-C000029
(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).)
It is a compound shown by these.
　上記化合物は、以下のようにも記載できる。
Figure JPOXMLDOC01-appb-C000030
（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。） The above compounds can also be described as follows.
Figure JPOXMLDOC01-appb-C000030
(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).)
　本発明化合物は、各々の化合物の生成可能であり、製薬上許容される塩を包含する。「製薬上許容される塩」としては、例えば塩酸、硫酸、硝酸またはリン酸等の無機酸の塩；パラトルエンスルホン酸、メタンスルホン酸、シュウ酸またはクエン酸等の有機酸の塩；アンモニウム、トリメチルアンモニウムまたはトリエチルアンモニウム等の有機塩基の塩；ナトリウムまたはカリウム等のアルカリ金属の塩；およびカルシウムまたはマグネシウム等のアルカリ土類金属の塩等を挙げることができる。 The compound of the present invention is capable of producing each compound and includes pharmaceutically acceptable salts. “Pharmaceutically acceptable salts” include, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; salts of organic acids such as paratoluenesulfonic acid, methanesulfonic acid, oxalic acid or citric acid; ammonium, Examples include salts of organic bases such as trimethylammonium or triethylammonium; salts of alkali metals such as sodium or potassium; and salts of alkaline earth metals such as calcium or magnesium.
　本発明化合物は、その溶媒和物を包含する。好ましくは水和物、アルコール和物等が挙げられる。例えば、１水和物、２水和物、１アルコール和物、２アルコール和物等である。 The compound of the present invention includes its solvate. Preferable examples include hydrates and alcohol hydrates. For example, monohydrate, dihydrate, monoalcohol hydrate, dialcohol solvate and the like.
　本発明化合物が不斉炭素原子を有する場合には、ラセミ体、両対掌体および全ての立体異性体（幾何異性体、エピマー、鏡像異性体等）を含む。また、本発明化合物が二重結合を有する場合にＥ体およびＺ体が存在し得るときはそのいずれをも含む。 When the compound of the present invention has an asymmetric carbon atom, it includes racemates, both enantiomers and all stereoisomers (geometric isomers, epimers, enantiomers, etc.). Moreover, when this invention compound has a double bond, when E body and Z body may exist, both are included.
　本発明化合物のプロドラッグは本発明化合物の範囲に含まれる。本発明化合物のプロドラッグは本発明化合物の機能的誘導体であり、本発明化合物に生体内で容易に変換される。ゆえに、本発明「化合物」は、具体的に開示された化合物又は場合によっては具体的に開示されていない化合物ではあるがＮＰＹ　Ｙ５の関与する疾患の患者に投与した後に生体内で前記の具体的な化合物に変換する化合物を含む。適切なプロドラッグ誘導体の選択と製剤のための通常の手順は、例えばDesign of Prodrugs (ed.H.Bundgaard, Elsevier, 1985) に記述されている。 The prodrug of the compound of the present invention is included in the scope of the compound of the present invention. Prodrugs of the compounds of the present invention are functional derivatives of the compounds of the present invention and are easily converted into the compounds of the present invention in vivo. Therefore, the “compound” of the present invention is a specifically disclosed compound or a compound that is not specifically disclosed in some cases, but is administered to a patient with a disease involving NPY Y5 in vivo. Including compounds that convert to The usual procedures for selection and formulation of suitable prodrug derivatives are described, for example, in Design of Prodrugs ed (ed. H. Bundgaard, Elsevier, 1985).
　本発明化合物である式（Ｉ）で示される化合物は、例えば次の方法で合成することができる。
Figure JPOXMLDOC01-appb-C000031
（式中、Ｈａｌはハロゲン、その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

　化合物（ＩＩＩ－１）に、式：Ｒ１（Ｒ２）ＮＳＯ２Ｈａｌで示される化合物を反応させ、式（Ｉ）で示される化合物を得る。また、式（ＩＩＩ－２）で示される化合物に、式：Ｒ５Ｈａｌで示される化合物を反応させ、式（Ｉ）で示される化合物を得る。
　上記反応は、塩基を用いて行うことができる。塩基としては、ピリジン、トリエチルアミン、Ｎ‐メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム等を使用することができる。
　上記反応は、０℃～５０℃で数分～数時間反応させればよい。溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、ヘキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、アセトニトリル、それらの混合溶媒等を用いることができる。
　Ｘ上のＲ３やＲ４を保護して上記反応を行い、反応後に脱保護してもよい。 The compound represented by formula (I) which is the compound of the present invention can be synthesized, for example, by the following method.
Figure JPOXMLDOC01-appb-C000031
(In the formula, Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).)

Compound (III-1) is reacted with a compound represented by the formula: R 1 (R 2 ) NSO 2 Hal to obtain a compound represented by formula (I). Further, the compound represented by the formula (III-2) is reacted with a compound represented by the formula: R 5 Hal to obtain a compound represented by the formula (I).
The above reaction can be performed using a base. As the base, pyridine, triethylamine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride and the like can be used.
The above reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours. Use solvents such as tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixed solvents thereof. Can do.
The above reaction may be carried out while protecting R 3 and R 4 on X, and may be deprotected after the reaction.
　また、本発明化合物は、以下のように合成することができる。
Figure JPOXMLDOC01-appb-C000032
（式中、Ｈａｌはハロゲン、その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

　化合物（ＩＩＩ－１）に、式：Ｒ１（Ｒ２）ＮＳＯＨａｌで示される化合物を反応させ、化合物（ＩＩＩ－３）を得る。さらに、得られた化合物（ＩＩＩ－３）を酸化し、式（Ｉ）で示される化合物を得る。
　式：Ｒ１（Ｒ２）ＮＳＯＨａｌで示される化合物を使用する工程は、塩基存在下で行うことができる。塩基としては、ピリジン、トリエチルアミン、Ｎ－メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム等を使用することができる。
　上記反応は、０℃～５０℃で数分～数時間反応させればよい。溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、ヘキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、アセトニトリルおよびそれらの混合溶媒等を用いることができる。
　酸化工程は、酸化剤を用いて行うことができる。酸化剤としては、ｍ－クロロ過安息香酸、過酢酸、過酸化水素、過トリフルオロ酢酸、過ヨウ素酸ナトリウム、次亜塩素酸ナトリウム、過マンガン酸カリウム、タングステン酸ナトリウム等が挙げられる。
　Ｘ上のＲ３やＲ４を保護して上記反応を行い、反応後に脱保護してもよい。 The compound of the present invention can be synthesized as follows.
Figure JPOXMLDOC01-appb-C000032
(In the formula, Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).)

Compound (III-1) is reacted with a compound represented by the formula: R 1 (R 2 ) NSOHal to obtain compound (III-3). Further, the obtained compound (III-3) is oxidized to obtain a compound represented by the formula (I).
The step of using the compound represented by the formula: R 1 (R 2 ) NSOHal can be performed in the presence of a base. As the base, pyridine, triethylamine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used.
The above reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours. Use solvents such as tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixed solvents thereof. Can do.
The oxidation step can be performed using an oxidizing agent. Examples of the oxidizing agent include m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, pertrifluoroacetic acid, sodium periodate, sodium hypochlorite, potassium permanganate, and sodium tungstate.
The above reaction may be carried out while protecting R 3 and R 4 on X, and may be deprotected after the reaction.
　Ｘがピラゾールの場合、以下に示す合成法を利用して本発明化合物の中間体である化合物（Ｘ－４）を合成することができる。
Figure JPOXMLDOC01-appb-C000033
（式中、Ｈａｌはハロゲン、その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

工程Ａ
　目的化合物に対応する置換基Ｒ５を有する化合物（Ｘ－１）と式：Ｒ１（Ｒ２）ＮＳＯ２Ｈａｌで示される化合物を適当な溶媒中、塩基で処理し、化合物（Ｘ－２）を得る。０℃～５０℃で数分～数時間反応させればよい。
　溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン（塩化メチレン）、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、アセトニトリル、それらの混合溶媒等が使用可能である。好ましくは、ジクロロメタンである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。
　塩基としては、トリエチルアミン、ピリジン、Ｎ－メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム等を用いることができる。好ましくはトリエチルアミンである。化合物（Ｘ－１）に対して、１～５等量の塩基を用いるのが好ましい。

工程Ｂ
　化合物（Ｘ－２）を適当な溶媒中、塩基で処理し、化合物（Ｘ－３）を得る。０℃～５０℃で数分～数時間反応させればよい。
　塩基としては、水酸化バリウム、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等を用いることができる。好ましくは、水酸化ナトリウムである。
　溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、テトラヒドロフランおよび／またはエタノールである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。

工程Ｃ
　化合物（Ｘ－３）を適当な溶媒中、ハロゲン化剤で処理し、０℃～５０℃で数分～数時間反応させ、酸ハロゲン化物を得る。
　ハロゲン化剤としては、オキサリルクロリド、チオニルクロリド、チオニルブロミド、五塩化リン、オキシ塩化リン等が挙げられる。好ましくはオキサリルクロリドである。化合物（Ｘ－３）に対して、１～５等量のハロゲン化剤を用いるのが好ましい。また、触媒としてジメチルホルムアミドを加えても良い。
　溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジメチルアセタミド、Ｎ－メチルピロリドン、ジエチルエーテル、１，２－ジクロロエタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、塩化メチレンおよび／またはジメチルホルムアミドである。これらの溶媒は、ハロゲン化剤との組み合わせで適宜選択して使用すればよい。
　なお、ハロゲン化剤の代わりに、無水酢酸、メタンスルホニルクロリド、クロロ炭酸エチルを用いて、酸ハロゲン化物の代わりに活性エステルを得て、次の工程Ｄに使用してもよい。

工程Ｄ
　工程Ｃで得られた酸ハロゲン化物または活性エステルと酢酸エチルを適当な溶媒中、ルイス酸とＮ-アルキルイミダゾール存在下、－１００℃～０℃で数分～数時間反応させた後、塩基を加えると、化合物（Ｘ－４）を得る。
　ルイス酸としては、四塩化チタン、四塩化スズ、三塩化アルミニウム、三フッ化ホウ素エーテル錯体、三塩化ホウ素、トリメチルシリルトリフルオロメタンスルホナート（ＴＭＳＯＴｆ）、二塩化亜鉛等を用いることができる。好ましくは、四塩化チタンである。
　Ｎ－アルキルイミダゾールとしては、Ｎ－メチルイミダゾール、Ｎ－エチルイミダゾール等を用いることができる。好ましくは、Ｎ－メチルイミダゾールである。
　塩基としては、Ｎ，Ｎ’－ジイソプロピルエチルアミン、ジエチルアミン、トリエチルアミン、ピリジン、Ｎ－メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム等を用いることができる。好ましくは、Ｎ，Ｎ’－ジイソプロピルエチルアミンである。
　溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、塩化メチレンおよび／または酢酸エチルである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。 When X is pyrazole, the compound (X-4), which is an intermediate of the compound of the present invention, can be synthesized using the synthesis method shown below.
Figure JPOXMLDOC01-appb-C000033
(In the formula, Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).)

Process A
The compound (X-1) having the substituent R 5 corresponding to the target compound and the compound represented by the formula: R 1 (R 2 ) NSO 2 Hal are treated with a base in an appropriate solvent to give the compound (X-2) Get. The reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane (methylene chloride), toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixtures thereof A solvent or the like can be used. Preferably, it is dichloromethane. These solvents may be appropriately selected and used in combination with a base.
As the base, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Triethylamine is preferred. It is preferable to use 1 to 5 equivalents of a base relative to compound (X-1).

Process B
Compound (X-2) is treated with a base in a suitable solvent to give compound (X-3). The reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
As the base, barium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide or the like can be used. Sodium hydroxide is preferable.
As the solvent, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, mixed solvents thereof, etc. are used. Is possible. Tetrahydrofuran and / or ethanol are preferred. These solvents may be appropriately selected and used in combination with a base.

Process C
Compound (X-3) is treated with a halogenating agent in a suitable solvent and reacted at 0 ° C. to 50 ° C. for several minutes to several hours to obtain an acid halide.
Examples of the halogenating agent include oxalyl chloride, thionyl chloride, thionyl bromide, phosphorus pentachloride, phosphorus oxychloride and the like. Oxalyl chloride is preferred. It is preferable to use 1 to 5 equivalents of a halogenating agent relative to compound (X-3). Further, dimethylformamide may be added as a catalyst.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, Pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Methylene chloride and / or dimethylformamide are preferable. These solvents may be appropriately selected and used in combination with a halogenating agent.
Instead of the halogenating agent, an active ester may be obtained instead of the acid halide using acetic anhydride, methanesulfonyl chloride, or ethyl chlorocarbonate, and used in the next step D.

Process D
The acid halide or active ester obtained in Step C and ethyl acetate are reacted in a suitable solvent in the presence of Lewis acid and N-alkylimidazole at −100 ° C. to 0 ° C. for several minutes to several hours. Addition yields compound (X-4).
As the Lewis acid, titanium tetrachloride, tin tetrachloride, aluminum trichloride, boron trifluoride ether complex, boron trichloride, trimethylsilyl trifluoromethanesulfonate (TMSOTf), zinc dichloride, or the like can be used. Titanium tetrachloride is preferable.
As N-alkylimidazole, N-methylimidazole, N-ethylimidazole and the like can be used. N-methylimidazole is preferable.
As the base, N, N′-diisopropylethylamine, diethylamine, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. N, N′-diisopropylethylamine is preferred.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Preference is given to methylene chloride and / or ethyl acetate. These solvents may be appropriately selected and used in combination with a base.
　Ｘがピラゾールの場合、化合物（Ｘ－４）から以下に示す合成法を利用して、本発明化合物を合成することができる。
Figure JPOXMLDOC01-appb-C000034
（式中、Ｈａｌはハロゲン、Ｒ６はＲ３、Ｒ４またはＲ３若しくはＲ４に誘導できる基である。その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

工程Ｅ
　化合物（Ｘ－４）を適切な溶媒中、ヒドラジン（例えば、ヒドラジンモノハイドレート）と反応させ、化合物（Ｘ－５）を得る。０℃～１００℃で数分～数時間反応させればよい。
　溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、メタノールである。
　ヒドラジンのかわりに、式：ＮＨ２ＮＨＲ６で示される化合物を用いることもできる。この場合、ヒドラジン環に、ヒドロキシ基と同時にＲ６を導入することができる。

工程Ｆ
　定法により、化合物（Ｘ－５）を用いて、目的化合物に対応する置換基Ｒ３およびＲ４を付し、式（Ｉ）で示される化合物を得ることができる。 When X is pyrazole, the compound of the present invention can be synthesized from compound (X-4) using the synthesis method shown below.
Figure JPOXMLDOC01-appb-C000034
(In the formula, Hal is halogen, R 6 is a group derivable to R 3 , R 4 or R 3 or R 4. Each other symbol has the same meaning as each symbol in the compound represented by the formula (I). .)

Process E
Compound (X-4) is reacted with hydrazine (eg, hydrazine monohydrate) in a suitable solvent to give compound (X-5). The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Preferably, it is methanol.
Instead of hydrazine, a compound represented by the formula: NH 2 NHR 6 can also be used. In this case, R 6 can be introduced into the hydrazine ring simultaneously with the hydroxy group.

Process F
By a conventional method, the compound represented by the formula (I) can be obtained by attaching the substituents R 3 and R 4 corresponding to the target compound using the compound (X-5).
　また、化合物（Ｘ－４）から式（Ｉ）で示される化合物を得る方法としては、以下の方法を用いることもできる。

工程Ｇ
　化合物（Ｘ－４）と式：Ｈａｌ－Ｃ（＝Ｏ）－Ｒ６で示される化合物を適当な溶媒中、塩基で処理し、化合物（Ｘ－６）を得る。０℃～５０℃で数分～数時間反応させればよい。
　溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン（塩化メチレン）、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、アセトニトリル、それらの混合溶媒等が使用可能である。好ましくは、ジクロロメタンである。
　塩基としては、トリエチルアミン、ピリジン、Ｎ－メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム、金属ナトリウム等を用いることができる。好ましくはピリジンである。化合物（Ｘ－４）に対して、１～５等量の塩基を用いるのが好ましい。
　該工程は、活性化剤の存在下で行うこともできる。活性化剤としては、塩化マグネシウム、臭化マグネシウム、ヨウ化マグネシウム等を用いることができる。好ましくは、塩化マグネシウムである。化合物（Ｘ－４）に対して、１～５等量の活性化剤を用いるのが好ましい。

工程Ｈ
　化合物（Ｘ－６）を適当な溶媒中、塩基で処理し、化合物（Ｘ－７）を得る。０℃～５０℃で数分～数時間反応させればよい。
　溶媒としては、ジメチルスルホキシド、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン（塩化メチレン）、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、アセトニトリル、それらの混合溶媒等が使用可能である。好ましくは、ジメチルスルホキシドである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。
　塩基としては、トリエチルアミン、ピリジン、Ｎ－メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム等を用いることができる。好ましくは塩化ナトリウムである。化合物（Ｘ－６）に対して、１～５等量の塩基を用いるのが好ましい。

工程Ｉ
　化合物（Ｘ－７）を適切な溶媒中、ヒドラジン（例えば、ヒドラジンモノハイドレート）と反応させ、式（Ｉ）で示される化合物を得る。０℃～１００℃で数分～数時間反応させればよい。
　溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、メタノールである。 In addition, as a method for obtaining the compound represented by the formula (I) from the compound (X-4), the following method can also be used.

Process G
The compound (X-4) and the compound represented by the formula: Hal-C (═O) —R 6 are treated with a base in an appropriate solvent to obtain a compound (X-6). The reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane (methylene chloride), toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixtures thereof A solvent or the like can be used. Preferably, it is dichloromethane.
As the base, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, metallic sodium and the like can be used. Pyridine is preferred. It is preferable to use 1 to 5 equivalents of a base relative to compound (X-4).
The step can also be performed in the presence of an activator. As the activator, magnesium chloride, magnesium bromide, magnesium iodide and the like can be used. Preferably, it is magnesium chloride. It is preferable to use 1 to 5 equivalents of an activator with respect to compound (X-4).

Process H
Compound (X-6) is treated with a base in a suitable solvent to give compound (X-7). The reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
Solvents include dimethyl sulfoxide, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane (methylene chloride), toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, A mixed solvent thereof or the like can be used. Preferred is dimethyl sulfoxide. These solvents may be appropriately selected and used in combination with a base.
As the base, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Sodium chloride is preferred. It is preferable to use 1 to 5 equivalents of a base relative to compound (X-6).

Process I
Compound (X-7) is reacted with hydrazine (for example, hydrazine monohydrate) in an appropriate solvent to obtain a compound represented by formula (I). The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Preferably, it is methanol.
　なお、工程Ａにおいて、目的化合物に対応する置換基Ｒ５を有する化合物（Ｘ－１）のアミノ基を定法により保護し、式：
Figure JPOXMLDOC01-appb-C000035
（式中、Ｂは保護基、その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）
で示される化合物（Ｘａ－１）を得、工程Ｂ～工程Ｉを行うこともできる。
　保護基としては、ベンジルオキシカルボニル、ｔｅｒｔ－ブトキシカルボニル、フルオレニルメトキシカルボニル等が挙げられる。好ましくは、ベンジルオキシカルボニルである。 In Step A, the amino group of the compound (X-1) having the substituent R 5 corresponding to the target compound is protected by a conventional method, and the formula:
Figure JPOXMLDOC01-appb-C000035
(In the formula, B is a protecting group, and other symbols are the same as the symbols in the compound represented by formula (I).)
Compound (Xa-1) represented by the above can be obtained and Step B to Step I can also be carried out.
Examples of the protecting group include benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl and the like. Preferably, it is benzyloxycarbonyl.
　工程Ｉの後、定法により脱保護を行い、式：
Figure JPOXMLDOC01-appb-C000036
（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）
で示される化合物（Ｘａ－２）を得る。 After step I, deprotection is carried out by a conventional method, and the formula:
Figure JPOXMLDOC01-appb-C000036
(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).)
To obtain a compound (Xa-2) represented by the formula:
　化合物（Ｘａ－２）に式：Ｒ１（Ｒ２）－Ｎ－ＳＯ２－Ｈａｌで示される化合物を適当な溶媒中、塩基で処理し、式（Ｉ）で示される化合物を得ることができる。反応条件は工程Ａと同様である。 Compound (Xa-2) can be treated with a base represented by the formula: R 1 (R 2 ) —N—SO 2 -Hal in a suitable solvent with a base to obtain a compound represented by formula (I). . The reaction conditions are the same as in step A.
　なお、Ｘによっては、以下に示す合成法を利用して、本発明化合物の中間体である化合物（ＩＶ－４）を合成することができる。
Figure JPOXMLDOC01-appb-C000037
（式中、Ｈａｌはハロゲン、その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

工程 a
　目的化合物に対応する置換基Ｒ１、Ｒ２、Ｒ５を有する化合物（ＩＶ－１）（合成法はＷＯ２００７／１２５９５２に記載）とトリハロ酢酸ハライドおよびそのＮａ塩を適当な溶媒中、０℃～５０℃で数分～数時間反応させ、化合物（ＩＶ－２）を得る。
　溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジメチルアセタミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、ジメチルホルムアミドである。

工程ｂ
　化合物（ＩＶ－２）とスルホニルハライドを適当な溶媒中で、塩基存在下で反応させ、化合物（ＩＶ－３）を得る。０℃～１００℃で数分～数時間反応させればよい。
　スルホニルハライドとしては、ｐ－トルエンスルホニルクロリド、ベンゼンスルホニルクロリド、メタンスルホニルクロリド、トリフルオロメタンスルホニルクロリド等を用いることができる。
　塩基としては、トリエチルアミン、ピリジン、N-メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム等を用いることができる。好ましくはトリエチルアミンである。化合物（ＩＶ－２）に対して、１～５等量の塩基を用いるのが好ましい。
　溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジメチルアセタミド、N-メチルピロリドン、ジエチルエーテル、１，２－ジクロロエタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、アセトニトリル、それらの混合溶媒等が使用可能である。好ましくは、塩化メチレンである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。
　触媒としては、DABCO (1,4-Diazabicyclo[2,2,2]octane)、HCl、H2SO4、酢酸、CF3COOH、トルエンスルホン酸、ｐ－トルエンスルホン酸等が挙げられる。好ましくは、DABCOである。

工程c
　化合物（ＩＶ－３）を適当な溶媒中、塩基で処理し、化合物（ＩＶ－４）を得る。－５０℃～５０℃で数分～数時間反応させればよい。
　塩基としては、ｎ－ブチルリチウム、ｓｅｃ－ブチルリチウム、ｔｅｒｔ－ブチルリチウム、メチルリチウム、ヒドラジン、プロパンチオールリチウム塩等を用いることができる。強塩基が好ましく、例えば、ｎ－ブチルリチウム等が好ましい。
　溶媒としては、塩化メチレン、テトラヒドロフラン、ジエチルエーテル、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、ペンタン、ヘプタン、ジオキサン、アセトン等が使用可能である。好ましくは、テトラヒドロフランおよび／またはヘキサンである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。 Depending on X, compound (IV-4), which is an intermediate of the compound of the present invention, can be synthesized using the synthesis method shown below.
Figure JPOXMLDOC01-appb-C000037
(In the formula, Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).)

Process a
A compound (IV-1) having substituents R 1 , R 2 , R 5 corresponding to the target compound (the synthesis method is described in WO2007 / 125595), trihaloacetic acid halide and its Na salt in an appropriate solvent at 0 ° C. to Reaction is performed at 50 ° C. for several minutes to several hours to obtain compound (IV-2).
Solvents include tetrahydrofuran, dimethylformamide, dimethylacetamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, Acetonitrile, water, a mixed solvent thereof or the like can be used. Preferred is dimethylformamide.

Step b
Compound (IV-2) and sulfonyl halide are reacted in a suitable solvent in the presence of a base to obtain compound (IV-3). The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
As the sulfonyl halide, p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride and the like can be used.
As the base, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Triethylamine is preferred. It is preferable to use 1 to 5 equivalents of a base relative to compound (IV-2).
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, Pentane, heptane, dioxane, acetone, acetonitrile, a mixed solvent thereof and the like can be used. Preferably, it is methylene chloride. These solvents may be appropriately selected and used in combination with a base.
As the catalyst, DABCO (1,4-Diazabicyclo [2,2,2 ] octane), HCl, H 2 SO 4, acetic acid, CF 3 COOH, toluenesulfonic acid, p- toluenesulfonic acid and the like. DABCO is preferable.

Process c
Compound (IV-3) is treated with a base in a suitable solvent to give compound (IV-4). The reaction may be performed at −50 ° C. to 50 ° C. for several minutes to several hours.
As the base, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium, hydrazine, propanethiol lithium salt and the like can be used. Strong bases are preferred, such as n-butyllithium.
As the solvent, methylene chloride, tetrahydrofuran, diethyl ether, toluene, benzene, xylene, cyclohexane, hexane, pentane, heptane, dioxane, acetone and the like can be used. Tetrahydrofuran and / or hexane are preferable. These solvents may be appropriately selected and used in combination with a base.
　Ｘがインドールの場合、本発明化合物は、以下のように合成することができる。
Figure JPOXMLDOC01-appb-C000038
（式中、Ｈａｌはハロゲン、その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

工程ｄ
　化合物（Ｖ－１）に適当な溶媒中、Ｎ－ブロモスクシンイミドを加え、化合物（Ｖ－２）を得る。－５０℃～室温で数分～数時間反応させればよい。
　溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、ジクロロメタンおよび／またはメタノールである。

工程ｅ
　化合物（Ｖ－２）に適当な溶媒中、ハロゲノ炭酸エチルを加え、化合物（Ｖ－３）を得る。０℃～１００℃で数分～数時間反応させればよい。
　溶媒としてはテトラヒドロフラン、ジメチルホルムアミド、ジメチルアセタミド、Ｎ-メチルピロリドン、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、ピリジン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能であるが、無溶媒でも実施可能である。好ましくは、テトラヒドロフランおよび／またはピリジンである。
　塩基の存在下で行ってもよい。塩基としては、ピリジン、Ｎ-メチルモルホリン、ジメチルアニリン等を使用することができる。 When X is indole, the compound of the present invention can be synthesized as follows.
Figure JPOXMLDOC01-appb-C000038
(In the formula, Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).)

Step d
N-bromosuccinimide is added to compound (V-1) in a suitable solvent to give compound (V-2). The reaction may be performed at −50 ° C. to room temperature for several minutes to several hours.
As the solvent, tetrahydrofuran, dimethylformamide, dichloromethane, toluene, benzene, xylene, cyclohexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, mixed solvents thereof, etc. are used. Is possible. Preferred is dichloromethane and / or methanol.

Process e
Compound (V-3) is obtained by adding ethyl halogenocarbonate to compound (V-2) in a suitable solvent. The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
Solvents include tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, dichloromethane, toluene, benzene, pyridine, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, Acetone, methanol, ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used, but the present invention can also be performed without a solvent. Tetrahydrofuran and / or pyridine are preferable.
The reaction may be performed in the presence of a base. As the base, pyridine, N-methylmorpholine, dimethylaniline and the like can be used.
工程ｆ
　化合物（Ｖ－３）と化合物（ＩＶ－４）を適当な溶媒中、塩基存在下で反応させ、化合物（Ｖ－４）を得る。０℃～１００℃で数分～数時間反応させればよい。
　塩基としては、トリエチルアミン、ＤＢＵ、炭酸ナトリウム、炭酸カリウム、水酸化バリウム、水酸化ナトリウム、水酸化カリウム等を用いることができる。好ましくは、トリエチルアミン、炭酸カリウム等である。
　溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジメチルアセタミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、プロパノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、ジメチルホルムアミドである。
　触媒としては、Pd(PPh3)4 (テトラキストリフェニルホスフィンパラジウム)、PdCl2(PPh3)2 (ジクロロビストリフェニルホスフィンパラジウム)、Pd(DBA) (ビスジベンジリデンアセトンパラジウム)、ヨウ化銅、DABCO等が挙げられる。好ましくは、ジクロロビストリフェニルホスフィンパラジウムおよび／またはヨウ化銅である。

工程ｇ
　化合物（Ｖ－４）を適当な溶媒中、塩基で処理し、化合物（Ｉ－３）を得る。０℃～１００℃で数分～数時間反応させればよい。
　塩基としては、テトラブチルアンモニウムフルオリド、トリエチルアミン、ピリジン、Ｎ-メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム、炭酸カリウム、炭酸ナトリウム、ヒドラジン、プロパンチオールリチウム塩等を用いることができる。好ましくはテトラブチルアンモニウムフルオリドである。
　溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、テトラヒドロフランである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。 Process f
Compound (V-3) and compound (IV-4) are reacted in a suitable solvent in the presence of a base to obtain compound (V-4). The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
As the base, triethylamine, DBU, sodium carbonate, potassium carbonate, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Preferred are triethylamine, potassium carbonate and the like.
Solvents include tetrahydrofuran, dimethylformamide, dimethylacetamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, Propanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Preferred is dimethylformamide.
Examples of the catalyst include Pd (PPh3) 4 (tetrakistriphenylphosphine palladium), PdCl2 (PPh3) 2 (dichlorobistriphenylphosphine palladium), Pd (DBA) (bisdibenzylideneacetone palladium), copper iodide, DABCO and the like. It is done. Preferred is dichlorobistriphenylphosphine palladium and / or copper iodide.

Process g
Compound (V-4) is treated with a base in a suitable solvent to give compound (I-3). The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
Use as bases tetrabutylammonium fluoride, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, hydrazine, propanethiol lithium salt, etc. Can do. Tetrabutylammonium fluoride is preferred.
Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, etc. A mixed solvent or the like can be used. Tetrahydrofuran is preferable. These solvents may be appropriately selected and used in combination with a base.
　Ｘがピロロピリミジンの場合、本発明化合物は、以下のように合成することができる。
Figure JPOXMLDOC01-appb-C000039
（式中、Ｈａｌはハロゲン、その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

工程ｈ
　化合物（ＶＩ－１）を適当な溶媒中、塩基の存在下で、シアノギ酸エチルと反応させることにより、化合物（ＶＩ－２）を得る。－１００℃～０℃で数分～数時間反応させればよい。
　塩基としては、リチウムジイソプロピルアミン、リチウムテトラメチルピペリジド、ｎ－ブチルリチウム、ｓｅｃ－ブチルリチウム、ｔｅｒｔ－ブチルリチウム、メチルリチウム、メチルリチウム等を用いることができる。好ましくは、リチウムジイソプロピルアミンである。
　溶媒としては、テトラヒドロフラン、ジエチルエーテル、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、ペンタン、ヘプタン、ジオキサン、それらの混合溶媒等が使用可能である。好ましくは、テトラヒドロフランである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。

工程ｉ
　化合物（ＶＩ－２）を適当な溶媒中、塩基で処理し、化合物（ＶＩ－３）を得る。０℃～５０℃で数分～数時間反応させればよい。
　塩基としては、水酸化バリウム、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等を用いることができる。好ましくは、水酸化ナトリウムである。
　溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、エタノールである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。 When X is pyrrolopyrimidine, the compound of the present invention can be synthesized as follows.
Figure JPOXMLDOC01-appb-C000039
(In the formula, Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).)

Process h
Compound (VI-2) is obtained by reacting compound (VI-1) with ethyl cyanoformate in a suitable solvent in the presence of a base. The reaction may be performed at −100 ° C. to 0 ° C. for several minutes to several hours.
As the base, lithium diisopropylamine, lithium tetramethylpiperidide, n-butyllithium, sec-butyllithium, tert-butyllithium, methyllithium, methyllithium, or the like can be used. Lithium diisopropylamine is preferable.
As the solvent, tetrahydrofuran, diethyl ether, toluene, benzene, xylene, cyclohexane, hexane, pentane, heptane, dioxane, a mixed solvent thereof or the like can be used. Tetrahydrofuran is preferable. These solvents may be appropriately selected and used in combination with a base.

Step i
Compound (VI-2) is treated with a base in a suitable solvent to give compound (VI-3). The reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
As the base, barium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide or the like can be used. Sodium hydroxide is preferable.
As the solvent, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, mixed solvents thereof, etc. are used. Is possible. Preferably, it is ethanol. These solvents may be appropriately selected and used in combination with a base.
工程ｊ
　化合物（ＶＩ－３）を適当な溶媒中、塩基で処理し、ジフェニルリン酸アジドと反応させることにより、化合物（ＶＩ－４）を得る。０℃～１００℃で数分～数時間反応させればよい。
　塩基としては、ジイソプロピルアミン、トリエチルアミン、ジメチルアミノピリジン等を用いることができる。好ましくは、トリエチルアミンである。
　溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、クロロホルム、ジオキサン、アセトン、アセトニトリル、ブタノール、それらの混合溶媒等が使用可能である。好ましくは、ｔ－ブタノールである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。

工程ｋ
　化合物（ＶＩ－４）と化合物（ＩＶ－４）を適当な溶媒中、塩基の存在下で反応させ、化合物（ＶＩ－５）を得る。０℃～１００℃で数分～数時間反応させればよい。反応条件は、工程ｆと同様である。

工程ｌ
　化合物（ＶＩ－５）を適当な溶媒中、塩基で処理し、化合物（Ｉ－４）を得る。０℃～１００℃で数分～数時間反応させればよい。
　塩基としては、１，８－ジアザビシクロ［５，４，０］－７－ウンデセン、テトラブチルアンモニウムフルオリド、トリエチルアミン、ピリジン、N-メチルモルホリン、ジメチルアニリン、金属アルコキシド等を用いることができる。好ましくは１，８－ジアザビシクロ［５，４，０］－７－ウンデセンである。
　溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、メタノールおよび／または水である。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。
　上記工程ｈ～ｌの化合物（ＶＩ－１）、（ＶＩ－２）、（ＶＩ－３）、（ＶＩ－４）、（ＶＩ－５）において、窒素原子の位置や数が異なる化合物を用いることにより、Ｘが各種の芳香族ヘテロ環である式（Ｉ）で示される化合物を合成することができる。 Step j
Compound (VI-4) is obtained by treating compound (VI-3) with a base in a suitable solvent and reacting with diphenylphosphoric acid azide. The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
As the base, diisopropylamine, triethylamine, dimethylaminopyridine and the like can be used. Triethylamine is preferable.
As the solvent, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, chloroform, dioxane, acetone, acetonitrile, butanol, a mixed solvent thereof or the like can be used. T-butanol is preferable. These solvents may be appropriately selected and used in combination with a base.

Process k
Compound (VI-4) and compound (IV-4) are reacted in an appropriate solvent in the presence of a base to obtain compound (VI-5). The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours. The reaction conditions are the same as in step f.

Process l
Compound (VI-5) is treated with a base in a suitable solvent to give compound (I-4). The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
As the base, 1,8-diazabicyclo [5,4,0] -7-undecene, tetrabutylammonium fluoride, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, metal alkoxide and the like can be used. 1,8-diazabicyclo [5,4,0] -7-undecene is preferred.
As the solvent, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used. is there. Methanol and / or water are preferred. These solvents may be appropriately selected and used in combination with a base.
In the compounds (VI-1), (VI-2), (VI-3), (VI-4), and (VI-5) in steps h to l, compounds having different nitrogen atom positions and numbers are used. Thus, the compound represented by the formula (I) in which X is various aromatic heterocycles can be synthesized.
　Ｘがピロールの場合、本発明化合物は、以下のように合成することができる。
Figure JPOXMLDOC01-appb-C000040
（式中、Ｙは式（Ｉ）のＲ３、Ｒ４または水素を示す。その他各記号は式（Ｉ）で示される化合物における各記号と同意義である。）

工程ｍ
　目的化合物に対応する置換基Ｒ１、Ｒ２、Ｒ５を有する化合物（ＶＩＩ－１）（合成法はＷＯ２００１／０３７８２６に記載）を適当な溶媒中、脱水剤で処理し、０℃～５０℃で数分～数時間反応させて、酸ハロゲン化物に変換した後、さらに、Ｎ，Ｏ－ジメチルヒドロキシアミン塩酸塩を加え、適当な溶媒中、塩基存在下、０℃～５０℃で数分～数時間反応させ、化合物（ＶＩＩ－２）を得る。
　脱水剤としては、オキサリルクロリド、チオニルクロリド、五塩化リン、オキシ塩化リン、無水酢酸、メタンスルホニルクロリド、クロロ炭酸エチル等が挙げられる。好ましくはオキサリルクロリドである。化合物（ＶＩＩ－１）に対して、１～５等量の脱水剤を用いるのが好ましい。また、触媒としてジメチルホルムアミドを加えても良い。
　塩基としては、トリエチルアミン、ピリジン、Ｎ－メチルモルホリン、ジメチルアニリン、炭酸カリウム、炭酸ナトリウム、水酸化バリウム、水酸化ナトリウム、水酸化カリウム等を用いることができる。好ましくはトリエチルアミンである。
　溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジメチルアセタミド、Ｎ－メチルピロリドン、ジエチルエーテル、１，２－ジクロロエタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、塩化メチレンおよび／またはジメチルホルムアミドである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。

工程ｎ
　化合物（ＶＩＩ－２）で示される化合物を適当な溶媒中、メチル化試薬で処理し、化合物（ＶＩＩ－３）を得る。－８０℃～１００℃で数分～数時間反応させればよい。
　メチル化試薬としては、メチルマグネシウムブロミド、メチルマグネシウムクロリド、メチルマグネシウムヨージド、メチルリチウムを用いることができる。好ましくは、メチルマグネシウムブロミド、メチルマグネシウムクロリドである。化合物（ＶＩＩ－２）に対して、１～５等量のグリニャール試薬を用いるのが好ましい。
　溶媒としては、テトラヒドロフラン、ジエチルエーテル、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、ペンタン、ヘプタン、ジオキサン、それらの混合溶媒等が使用可能である。好ましくは、テトラヒドロフランおよび／またはジエチルエーテルである。これらの溶媒は、メチル化試薬との組み合わせで適宜選択して使用すればよい。 When X is pyrrole, the compound of the present invention can be synthesized as follows.
Figure JPOXMLDOC01-appb-C000040
(In the formula, Y represents R 3 , R 4 or hydrogen in formula (I). Other symbols are the same as those in the compound represented by formula (I).)

Process m
A compound (VII-1) having a substituent R 1 , R 2 , or R 5 corresponding to the target compound (the synthesis method is described in WO2001 / 037826) is treated with a dehydrating agent in an appropriate solvent, and 0 ° C. to 50 ° C. The reaction mixture is reacted for several minutes to several hours to convert it into an acid halide, and further, N, O-dimethylhydroxyamine hydrochloride is added, and in a suitable solvent at 0 ° C. to 50 ° C. in the presence of a base for several minutes to Reaction is performed for several hours to obtain compound (VII-2).
Examples of the dehydrating agent include oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, acetic anhydride, methanesulfonyl chloride, ethyl chlorocarbonate and the like. Oxalyl chloride is preferred. It is preferable to use 1 to 5 equivalents of a dehydrating agent relative to compound (VII-1). Further, dimethylformamide may be added as a catalyst.
As the base, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, potassium carbonate, sodium carbonate, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Triethylamine is preferred.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, Pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Methylene chloride and / or dimethylformamide are preferable. These solvents may be appropriately selected and used in combination with a base.

Process n
The compound represented by compound (VII-2) is treated with a methylating reagent in an appropriate solvent to obtain compound (VII-3). The reaction may be performed at −80 ° C. to 100 ° C. for several minutes to several hours.
As the methylating reagent, methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, or methyllithium can be used. Preferred are methylmagnesium bromide and methylmagnesium chloride. It is preferable to use 1 to 5 equivalents of a Grignard reagent relative to compound (VII-2).
As the solvent, tetrahydrofuran, diethyl ether, toluene, benzene, xylene, cyclohexane, hexane, pentane, heptane, dioxane, a mixed solvent thereof or the like can be used. Tetrahydrofuran and / or diethyl ether are preferred. These solvents may be appropriately selected and used in combination with a methylating reagent.
工程ｏ
　化合物（ＶＩＩ－３）と目的化合物に対応する置換基Ｒ３を有するアルデヒドを適当な溶媒中、塩基で処理し、化合物（ＶＩＩ－４）を得る。０℃～１００℃で数分～数時間反応させればよい。
　塩基としては、トリエチルアミン、ピリジン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム、ブチルリチウム、ＬＤＡ、ナトリウムメトキシド等を用いることができる。好ましくは水酸化ナトリウムである。
　溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジメチルアセタミド、Ｎ－メチルピロリドン、ジエチルエーテル、１，２－ジクロロエタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、ペンタン、ヘプタン、ジオキサン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、メタノールである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。

工程ｐ
　化合物（ＶＩＩ－４）とニトロメタンを適当な溶媒中、塩基で処理し、化合物（ＶＩＩ－５）を得る。０℃～１００℃で数分～数時間反応させればよい。
　塩基としては、テトラブチルアンモニウムフルオリド、フッ化カリウム、フッ化セシウム、ジエチルアミン、トリエチルアミン、ピリジン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム等を用いることができる。好ましくはジエチルアミンである。
　溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、メタノールである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。 Process o
Compound (VII-3) and an aldehyde having a substituent R 3 corresponding to the target compound are treated with a base in an appropriate solvent to obtain compound (VII-4). The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
As the base, triethylamine, pyridine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, butyllithium, LDA, sodium methoxide and the like can be used. Sodium hydroxide is preferred.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, pentane, heptane, dioxane, methanol, Ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Preferably, it is methanol. These solvents may be appropriately selected and used in combination with a base.

Process p
Compound (VII-4) and nitromethane are treated with a base in an appropriate solvent to obtain compound (VII-5). The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
As the base, tetrabutylammonium fluoride, potassium fluoride, cesium fluoride, diethylamine, triethylamine, pyridine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Preferred is diethylamine.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, Those mixed solvents can be used. Preferably, it is methanol. These solvents may be appropriately selected and used in combination with a base.
工程ｑ
　化合物（ＶＩＩ－５）を適当な溶媒中、塩基で０℃～１００℃で数分～数時間処理し、さらに、メタノールで０℃～６５℃で数分～数時間処理した後、酸で処理することにより、化合物（ＶＩＩ－６）を得る。
　塩基としては、ジエチルアミン、トリエチルアミン、ピリジン、Ｎ-メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム等を用いることができる。好ましくは、水酸化カリウムである。
　酸としては、濃塩酸、濃硫酸、濃硝酸等を用いることができる。好ましくは、濃硫酸である。
　溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、１，２－ジクロロエタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、プロパノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、メタノールおよび／またはテトラヒドロフランである。これらの溶媒は、塩基や酸との組み合わせで適宜選択して使用すればよい。

工程ｒ
　化合物（ＶＩＩ－６）を適当な溶媒中、酢酸アンモニウムと反応させ、化合物（Ｉ－５）を得る。室温～１５０℃で数分～数時間反応させればよい。
　溶媒としては、酢酸、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジメチルアセタミド、N-メチルピロリドン、ジエチルエーテル、ジイソプロピルエーテル、１，２－ジクロロエタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、プロパノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、酢酸である。 Process q
Compound (VII-5) is treated with a base at 0 ° C. to 100 ° C. for several minutes to several hours in a suitable solvent, further treated with methanol at 0 ° C. to 65 ° C. for several minutes to several hours, and then treated with acid. Thus, compound (VII-6) is obtained.
As the base, diethylamine, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Preferably, it is potassium hydroxide.
As the acid, concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid and the like can be used. Preferably, it is concentrated sulfuric acid.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, Ethanol, propanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Methanol and / or tetrahydrofuran are preferred. These solvents may be appropriately selected and used in combination with a base or an acid.

Process r
Compound (VII-6) is reacted with ammonium acetate in a suitable solvent to give compound (I-5). The reaction may be performed at room temperature to 150 ° C. for several minutes to several hours.
Solvents include acetic acid, methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, diisopropyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, acetic acid Ethyl, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, propanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Preferably, it is acetic acid.
　Ｘがイミダゾールの場合、本発明化合物は、以下のように合成することができる。
Figure JPOXMLDOC01-appb-C000041
（式中、Ｈａｌはハロゲン、ＹおよびＺはそれぞれ式（Ｉ）のＲ３、Ｒ４または水素を示す。その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

工程ｓ
　目的化合物に対応するＲ３を有する化合物（ＶＩＩＩ－１）とテトラブチルアンモニウムハライドを適当な溶媒中、１００℃～２００℃で(場合によってはマイクロウェーブ反応装置を用いて)数分～数時間反応させ、化合物（ＶＩＩＩ－２）を得る。
　溶媒としては、酢酸、塩化メチレン、テトラヒドロフラン、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、メタノール、エタノール、アセトニトリル、それらの混合溶媒等が使用可能である。好ましくは、アセトニトリルである。

工程ｔ
　化合物（ＶＩＩＩ－２）を適当な溶媒中、ヘキサメチレンテトラミンと反応させることにより、化合物（ＶＩＩＩ－３）を得る。室温～１００℃で数分～数時間反応させればよい。
　溶媒としては、酢酸、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、アセトニトリル、それらの混合溶媒等が使用可能である。好ましくは、クロロホルムである。 When X is imidazole, the compound of the present invention can be synthesized as follows.
Figure JPOXMLDOC01-appb-C000041
(In the formula, Hal represents halogen, Y and Z each represent R 3 , R 4 or hydrogen in formula (I). The other symbols have the same meanings as those in the compound represented by formula (I). )

Process s
Reaction of compound (VIII-1) having R 3 corresponding to the target compound and tetrabutylammonium halide in a suitable solvent at 100 ° C. to 200 ° C. (possibly using a microwave reactor) for several minutes to several hours To give compound (VIII-2).
Solvents include acetic acid, methylene chloride, tetrahydrofuran, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, methanol, ethanol, acetonitrile, and mixtures thereof A solvent or the like can be used. Acetonitrile is preferred.

Process t
Compound (VIII-3) is obtained by reacting compound (VIII-2) with hexamethylenetetramine in a suitable solvent. The reaction may be performed at room temperature to 100 ° C. for several minutes to several hours.
Solvents include acetic acid, methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, those A mixed solvent or the like can be used. Preferably, it is chloroform.
工程ｕ
　化合物（ＶＩＩＩ－３）を適当な溶媒中、酸と反応させ、化合物（ＶＩＩＩ－４）を得る。室温～１００℃で数分～数時間反応させればよい。
　酸としては、濃塩酸、濃硫酸、濃硝酸等を用いることができる。好ましくは濃塩酸である。
　溶媒としては、酢酸、塩化メチレン、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、ペンタン、ヘプタン、ジオキサン、メタノール、エタノール、アセトニトリル、それらの混合溶媒等が使用可能である。好ましくは、エタノールである。

工程ｖ
　目的化合物に対応する置換基Ｒ１、Ｒ２、Ｒ５を有する化合物（ＶＩＩ－１）と化合物（ＶＩＩＩ－４）を反応させることによって、化合物（ＶＩＩＩ-５）を得る。反応条件は、上記工程ｍと同様である。

工程ｗ
　化合物（ＶＩＩＩ-５）を上記工程ｒと同様の方法に付せば、化合物（Ｉ－６）を得ることができる。 Step u
Compound (VIII-3) is reacted with an acid in an appropriate solvent to give compound (VIII-4). The reaction may be performed at room temperature to 100 ° C. for several minutes to several hours.
As the acid, concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid and the like can be used. Concentrated hydrochloric acid is preferred.
As the solvent, acetic acid, methylene chloride, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, pentane, heptane, dioxane, methanol, ethanol, acetonitrile, a mixed solvent thereof or the like can be used. Preferably, it is ethanol.

Process v
Compound (VIII-5) is obtained by reacting compound (VII-1) having substituents R 1 , R 2 and R 5 corresponding to the target compound and compound (VIII-4). The reaction conditions are the same as in step m above.

Process w
Compound (I-6) can be obtained by subjecting compound (VIII-5) to the same method as in step r above.
　Ｘがトリアゾールの場合、本発明化合物は、以下のように合成することができる。
Figure JPOXMLDOC01-appb-C000042

（式中、Ｙは式（Ｉ）のＲ３、Ｒ４または水素を示す。その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

工程ｘ
　目的化合物に対応する置換基Ｒ３、Ｒ４を有する化合物（ＩＸ－１）を適切な溶媒中、ハロゲノメチルと反応させ、化合物（ＩＸ－２）で示される化合物を得る。０℃～１００℃で数分～数時間反応させればよい。
　溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、アセトニトリルである。

工程ｙ
　目的化合物に対応する置換基Ｒ１、Ｒ２、Ｒ５を有する化合物（ＶＩＩ－１）を適当な溶媒中、脱水剤で処理し、０℃～５０℃で数分～数時間反応させ、さらに、ヒドラジン一水和物を加え、適当な溶媒中、０℃～５０℃で数分～数時間反応させ、化合物（ＩＸ-３）を得る。
　脱水剤としては、カルボニルジイミダゾール、ジシクロヘキシルカルボジイミド、トリフルオロベンゼンボロニックアシッド、ビス（ビストリメチルシリルアミノ）スズ等が挙げられる。好ましくはカルボニルジイミダゾールである。化合物（ＶＩＩ－１）に対して、１～５等量の脱水剤を用いるのが好ましい。
　溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、テトラヒドロフランである。

工程ｚ
　化合物（Ｘ-３）と化合物（Ｘ－２）を適切な溶媒中、塩基で処理することによって、化合物（ＶＩ－７）を得る。５０℃～１５０℃で数分～数時間反応させればよい。
　塩基としては、ジエチルアミン、トリエチルアミン、ピリジン、N-メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム、ヒドラジン、プロパンチオールリチウム塩等を用いることができる。好ましくは、トリエチルアミンである。
　溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、エタノールである。
　Ｘが上記に示した芳香族ヘテロ環以外の環であっても、有機化学の知識を用いて、Ｘが各種の芳香族ヘテロ環または非芳香族へテロ環である化合物についても、製造することができる。
　Ｒ１およびＲ５が隣接する窒素原子と一緒になって置換若しくは非置換の含窒素非芳香族ヘテロ環を形成している化合物についても、以下のように合成することができる。
Figure JPOXMLDOC01-appb-C000043
（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。式中のベンゼン環は置換基を有していてもよいし、ベンゼン環の代わりに他の環であってもよい。）
　化合物（Ｘ－１）とＨ２ＮＳＯ２ＮＨ２を塩基の存在下で反応させ、化合物（Ｉ－８）を得る。塩基としては、ピリジンなどを用いることができる。 When X is triazole, the compound of the present invention can be synthesized as follows.
Figure JPOXMLDOC01-appb-C000042

(In the formula, Y represents R 3 , R 4 or hydrogen in formula (I). Each other symbol has the same meaning as each symbol in the compound represented by formula (I).)

Process x
Compound (IX-1) having substituents R 3 and R 4 corresponding to the target compound is reacted with halogenomethyl in a suitable solvent to obtain a compound represented by compound (IX-2). The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Acetonitrile is preferred.

Process y
The compound (VII-1) having substituents R 1 , R 2 , R 5 corresponding to the target compound is treated with a dehydrating agent in a suitable solvent, reacted at 0 ° C. to 50 ° C. for several minutes to several hours, Then, hydrazine monohydrate is added and reacted in an appropriate solvent at 0 ° C. to 50 ° C. for several minutes to several hours to obtain compound (IX-3).
Examples of the dehydrating agent include carbonyldiimidazole, dicyclohexylcarbodiimide, trifluorobenzeneboronic acid, bis (bistrimethylsilylamino) tin, and the like. Preferred is carbonyldiimidazole. It is preferable to use 1 to 5 equivalents of a dehydrating agent relative to compound (VII-1).
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Tetrahydrofuran is preferable.

Step z
Compound (VI-7) is obtained by treating compound (X-3) and compound (X-2) with a base in a suitable solvent. The reaction may be performed at 50 ° C. to 150 ° C. for several minutes to several hours.
As the base, diethylamine, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, hydrazine, propanethiol lithium salt and the like can be used. Triethylamine is preferable.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Preferably, it is ethanol.
Even if X is a ring other than the aromatic heterocycle shown above, using the knowledge of organic chemistry, also producing compounds in which X is various aromatic heterocycles or non-aromatic heterocycles Can do.
A compound in which R 1 and R 5 together with the adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle can also be synthesized as follows.
Figure JPOXMLDOC01-appb-C000043
(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I). The benzene ring in the formula may have a substituent, or another ring instead of the benzene ring. It may be.)
Compound (I-1) is reacted with H 2 NSO 2 NH 2 in the presence of a base to give compound (I-8). As the base, pyridine or the like can be used.
　上記の工程において、以下の中間体は有用である。
　式：
Figure JPOXMLDOC01-appb-C000044
（式中、Ｒ５は水素または置換若しくは非置換のアルキルである。好ましくは、Ｒ５が水素である。その他各記号は式（Ｉ）で示される化合物における各記号と同意義である。）で示される化合物。なお、シクロヘキサン環に置換している－≡は、式：－Ｃ≡ＣＨで示される基を表す。 In the above steps, the following intermediates are useful.
formula:
Figure JPOXMLDOC01-appb-C000044
(In the formula, R 5 is hydrogen or substituted or unsubstituted alkyl. Preferably, R 5 is hydrogen. Other symbols are as defined in the compound represented by formula (I).) A compound represented by Note that —≡ substituted on the cyclohexane ring represents a group represented by the formula: —C≡CH.
　式：
Figure JPOXMLDOC01-appb-C000045
（式中、Ｒ５は水素または置換若しくは非置換のアルキルである。その他各記号は式（Ｉ）で示される化合物における各記号と同意義である。好ましくは、Ｒ５が水素である。）で示される化合物。 formula:
Figure JPOXMLDOC01-appb-C000045
(In the formula, R 5 is hydrogen or substituted or unsubstituted alkyl. The other symbols have the same meanings as those in the compound represented by formula (I). Preferably, R 5 is hydrogen.) A compound represented by
　式：
Figure JPOXMLDOC01-appb-C000046
（式中、Ｒ５は水素または置換若しくは非置換のアルキルであり、Ｒ８は置換若しくは非置換のアルキルである。好ましくは、Ｒ５が水素であり、Ｒ８がメチル、エチル、イソプロピルまたはｔｅｒｔ－ブチルである。その他各記号は式（Ｉ）で示される化合物における各記号と同意義である。）で示される化合物。 formula:
Figure JPOXMLDOC01-appb-C000046
Wherein R 5 is hydrogen or substituted or unsubstituted alkyl and R 8 is substituted or unsubstituted alkyl. Preferably, R 5 is hydrogen and R 8 is methyl, ethyl, isopropyl or tert -Butyl, and other symbols are the same as the symbols in the compound represented by formula (I).
　式：
Figure JPOXMLDOC01-appb-C000047
（式中、Ｒ５は水素または置換若しくは非置換のアルキルである。好ましくは、Ｒ５が水素である。その他各記号は式（Ｉ）で示される化合物における各記号と同意義である。）で示される化合物。 formula:
Figure JPOXMLDOC01-appb-C000047
(In the formula, R 5 is hydrogen or substituted or unsubstituted alkyl. Preferably, R 5 is hydrogen. Other symbols are as defined in the compound represented by formula (I).) A compound represented by
　本発明化合物はＮＰＹ　Ｙ５の関与する疾患全般、例えば、摂食障害、肥満症、神経性食欲昂進症、性的障害、生殖障害、鬱病、癲癇発作、高血圧、脳溢血、鬱血心不全または睡眠障害に有効に作用するが、特に肥満症の予防および／または治療並びに肥満症における体重管理に有用である。また、肥満がリスクファクターとなる疾患、例えば糖尿病、高血圧、高脂血症、動脈硬化、急性冠症候群等の予防および／または治療に対しても有効である。
　さらに、本発明化合物は、ＮＰＹ　Ｙ５受容体拮抗作用のみならず、医薬としての有用性を備えており、下記いずれか、あるいは全ての優れた特徴を有している。
ａ）ＣＹＰ酵素（例えば、ＣＹＰ１Ａ２、ＣＹＰ２Ｃ９、ＣＹＰ３Ａ４等) に対する阻害作用が弱い。
ｂ）薬物代謝酵素の誘導を起こしにくい。
ｃ）高いバイオアベイラビリティー、適度なクリアランス等良好な薬物動態を示す。
ｄ）貧血誘発作用等の毒性が低い。
ｅ）代謝安定性が高い。
ｆ）高いＹ５受容体選択性を有している。
ｇ）水溶性が高い。
ｈ）脳移行性が高い。
ｉ）生殖毒性（例えば、催奇形性等）を起こさない。
ｊ）消化管障害（例えば、出血性腸炎、消化管潰瘍、消化管出血等）を起こさない。 The compounds of the present invention are effective for all diseases involving NPY Y5, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension, cerebral hyperemia, congestive heart failure or sleep disorders It is particularly useful for the prevention and / or treatment of obesity and weight management in obesity. It is also effective for the prevention and / or treatment of diseases in which obesity is a risk factor, such as diabetes, hypertension, hyperlipidemia, arteriosclerosis, and acute coronary syndrome.
Furthermore, the compound of the present invention has not only an NPY Y5 receptor antagonistic action but also a usefulness as a medicine, and has any or all of the following excellent features.
a) The inhibitory action against CYP enzymes (for example, CYP1A2, CYP2C9, CYP3A4, etc.) is weak.
b) It is difficult to induce drug metabolizing enzymes.
c) Good pharmacokinetics such as high bioavailability and moderate clearance.
d) Low toxicity such as anemia-inducing action.
e) High metabolic stability.
f) High Y5 receptor selectivity.
g) High water solubility.
h) High brain transferability.
i) Does not cause reproductive toxicity (eg, teratogenicity).
j) Does not cause gastrointestinal disorders (for example, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).
　さらに、本発明化合物はＮＰＹ　Ｙ１およびＹ２受容体に対する親和性は低く、高いＹ５受容体選択性を有している。ＮＰＹは末梢で持続性の血管収縮作用を惹起するが、この作用は主としてＹ１受容体を介している。Ｙ５受容体はこのような作用に全く関与しないことから、末梢血管収縮に基づく副作用を誘発する可能性は低く、本発明化合物を有効成分とする医薬組成物は安全な医薬として好適に用いることが可能であると考えられる。 Furthermore, the compound of the present invention has low affinity for NPY Y1 and Y2 receptors and high Y5 receptor selectivity. NPY induces a sustained vasoconstrictive action in the periphery, but this action is mainly mediated by the Y1 receptor. Since the Y5 receptor is not involved in such an action at all, the possibility of inducing side effects based on peripheral vasoconstriction is low, and a pharmaceutical composition containing the compound of the present invention as an active ingredient can be preferably used as a safe medicine. It is considered possible.
　本発明化合物を有効成分とする医薬組成物は、摂食を抑制して抗肥満効果を示すものである。そのため、消化吸収を阻害することによって抗肥満効果を示す薬剤に見られるような消化不良等の副作用や、抗肥満効果を示すセロトニントランスポーター阻害剤のような抗鬱作用等の中枢性副作用を発現しないことは該医薬組成物の特長の一つである。 The pharmaceutical composition containing the compound of the present invention as an active ingredient suppresses food intake and exhibits an anti-obesity effect. Therefore, side effects such as indigestion as seen in drugs that exhibit anti-obesity effects by inhibiting digestion and absorption, and central side effects such as antidepressant effects such as serotonin transporter inhibitors that exhibit anti-obesity effects Not doing so is one of the features of the pharmaceutical composition.
　本発明の医薬組成物を投与する場合、経口的、非経口的のいずれの方法でも投与することができる。経口投与は常法に従って錠剤、顆粒剤、散剤、カプセル剤、丸剤、液剤、シロップ剤、バッカル剤または舌下剤等の通常用いられる剤型に調製して投与すればよい。非経口投与は、例えば筋肉内投与、静脈内投与等の注射剤、坐剤、経皮吸収剤、吸入剤等、通常用いられるいずれの剤型でも好適に投与することができる。本発明に係る化合物は経口吸収性が高いため、経口剤として好適に使用できる。 When administering the pharmaceutical composition of the present invention, it can be administered either orally or parenterally. Oral administration may be prepared and administered in a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods. For parenteral administration, any commonly used dosage forms such as injections such as intramuscular administration and intravenous administration, suppositories, percutaneous absorption agents, inhalants and the like can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.
　本発明化合物の有効量にその剤型に適した賦形剤、結合剤、湿潤剤、崩壊剤、滑沢剤、希釈剤等の各種医薬用添加剤を必要に応じて混合し医薬組成物とすることができる。注射剤の場合には適当な担体と共に滅菌処理を行なって製剤とすればよい。 Various pharmaceutical additives such as excipients, binders, wetting agents, disintegrants, lubricants, diluents and the like suitable for the dosage form are mixed with an effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition. can do. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.
　賦形剤としては乳糖、白糖、ブドウ糖、デンプン、炭酸カルシウムまたは結晶セルロ－ス等が挙げられる。結合剤としてはメチルセルロ－ス、カルボキシメチルセルロ－ス、ヒドロキシプロピルセルロ－ス、ゼラチンまたはポリビニルピロリドン等が挙げられる。崩壊剤としてはカルボキシメチルセルロ－ス、カルボキシメチルセルロ－スナトリウム、デンプン、アルギン酸ナトリウム、カンテン末またはラウリル硫酸ナトリウム等が挙げられる。滑沢剤としてはタルク、ステアリン酸マグネシウムまたはマクロゴ－ル等が挙げられる。坐剤の基剤としてはカカオ脂、マクロゴ－ルまたはメチルセルロ－ス等を用いることができる。また、液剤または乳濁性、懸濁性の注射剤として調製する場合には通常使用されている溶解補助剤、懸濁化剤、乳化剤、安定化剤、保存剤、等張剤等を適宜添加しても良い。経口投与の場合には嬌味剤、芳香剤等を加えても良い。 Excipients include lactose, sucrose, glucose, starch, calcium carbonate, crystalline cellulose and the like. Examples of the binder include methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin, and polyvinyl pyrrolidone. Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose sodium, starch, sodium alginate, agar powder or sodium lauryl sulfate. Examples of the lubricant include talc, magnesium stearate, and macrogol. As a suppository base, cacao butter, macrogol, methyl cellulose or the like can be used. In addition, when preparing as liquid or emulsion or suspension injections, commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. are added as appropriate. You may do it. In the case of oral administration, flavoring agents, fragrances and the like may be added.
　本発明の医薬組成物の投与量は、患者の年齢、体重、疾病の種類や程度、投与経路等を考慮した上で設定することが望ましいが、成人に経口投与する場合、通常０．０５～１００ｍｇ／ｋｇ／日であり、好ましくは０．１～１０ｍｇ／ｋｇ／日の範囲内である。非経口投与の場合には投与経路により大きく異なるが、通常０．００５～１０ｍｇ／ｋｇ／日であり、好ましくは０．０１～１ｍｇ／ｋｇ／日の範囲内である。これを１日１回～数回に分けて投与すれば良い。 The dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
　本発明の医薬組成物は他の抗肥満薬（肥満症や肥満症における体重管理等に用いることのできる薬剤）と組み合わせて用いることもできる。また、本発明の医薬組成物の投与療法は、既知の食事療法、薬物療法、運動等と組み合わせて用いることもできる。
　例えば、以下の方法も本発明の範囲内である。
　本発明化合物、その製薬上許容される塩またはそれらの溶媒和物と併用して、肥満若しくは肥満関連疾患の予防若しくは治療又は肥満における体重管理のために用いられる薬剤を投与することを特徴とする、肥満若しくは肥満関連疾患の予防若しくは治療又は肥満における体重管理の方法。
　本発明化合物、その製薬上許容される塩またはそれらの溶媒和物の投与による予防または治療を受けている患者に、肥満若しくは肥満関連疾患の予防若しくは治療又は肥満における体重管理のために用いられる薬剤を投与することを特徴とする、肥満若しくは肥満関連疾患の予防若しくは治療又は肥満における体重管理の方法。
　肥満若しくは肥満関連疾患の予防若しくは治療又は肥満における体重管理のために用いられる薬剤としては、食欲抑制作用を有する化合物（フェンフルラミン及びフルオキセチン等の選択的セロトニン再取り込み阻害剤；マジンドール等）、栄養素の消化吸収抑制作用を有する化合物（糖類吸収抑制作用を有する化合物（アカルボース、ボグリボース等のα‐グルコシダーゼ阻害剤；ダパグリフロジン、レモグリフロジン、ＫＧＴ－１０７５等のＳＧＬＴ－２阻害剤等）、脂肪吸収抑制作用を有する化合物（リパーゼ阻害剤（胃リパーゼ阻害作用を有する化合物；オルリスタット、リプスタチン、パンクリシン、セチリスタット等の膵リパーゼ阻害作用を有する化合物等）、コレスチラミン、コレスチラミド等の胆汁酸吸着レジン等）、５ＨＴトランスポーター阻害剤、ＮＥトランスポーター阻害剤、ＣＢ－１アンタゴニスト／インバースアゴニスト、グレリンアンタゴニスト、Ｈ３アンタゴニスト／インバースアゴニスト、ＭＣＨ　Ｒ１アンタゴニスト、ＭＣＨ　Ｒ２アゴニスト／アンタゴニスト、ＮＰＹ　Ｙ１受容体 アンタゴニスト、ＮＰＹ　Ｙ２受容体アゴニスト、ＮＰＹ　Ｙ４受容体アゴニスト、ＮＰＹ　Ｙ５受容体アンタゴニスト、ｍＧｌｕＲ５アンタゴニスト、レプチン、レプチンアゴニスト、レプチン誘導体、オピオイドアンタゴニスト、オレキシンアンタゴニスト、ＢＲＳ３アゴニスト、ＣＣＫ－Ａアゴニスト、ＣＮＴＦ、ＣＮＴＦアゴニスト、ＣＮＴＦ誘導体、ＧＨＳアゴニスト、５ＨＴ２Ｃアゴニスト、Ｍｃ４ｒアゴニスト、モノアミン再取り込み阻害剤、ＧＬＰ－１アゴニスト、ＵＣＰ－１、２及び３活性剤、β３アゴニスト、甲状腺ホルモンβアゴニスト、ＰＤＥ阻害剤、ＦＡＳ阻害剤、ＤＧＡＴ１阻害剤、ＤＧＡＴ２阻害剤、ＡＣＣ２阻害剤、グルココルチコイドアンタゴニスト、アシル－エストロゲン、脂肪酸トランスポーター阻害剤、ジカルボン酸トランスポーター阻害剤等が挙げられる。 The pharmaceutical composition of the present invention can also be used in combination with other anti-obesity drugs (agents that can be used for weight management in obesity and obesity). Moreover, the administration therapy of the pharmaceutical composition of the present invention can also be used in combination with known diet therapy, drug therapy, exercise and the like.
For example, the following methods are also within the scope of the present invention.
In combination with the compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof, a drug used for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity is administered. A method for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity;
Drugs used for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity to patients undergoing prevention or treatment by administration of the compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof A method for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity, which comprises administering
Examples of drugs used for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity include compounds having anorectic effect (selective serotonin reuptake inhibitors such as fenfluramine and fluoxetine; mazindol, etc.), nutrients A compound having an inhibitory action on digestion and absorption (compounds having an inhibitory action on sugar absorption (α-glucosidase inhibitors such as acarbose and voglibose; SGLT-2 inhibitors such as dapagliflozin, remogliflozin and KGT-1075); Compounds (lipase inhibitors (compounds having gastric lipase inhibitory action; compounds having pancreatic lipase inhibitory action such as orlistat, lipstatin, pancricin, cetiristat, etc.), bile acid adsorption resins such as cholestyramine, cholestyramide, etc.), 5H Transporter inhibitor, NE transporter inhibitor, CB-1 antagonist / inverse agonist, ghrelin antagonist, H3 antagonist / inverse agonist, MCH R1 antagonist, MCH R2 agonist / antagonist, NPY Y1 receptor antagonist, NPY Y2 receptor agonist, NPY Y4 receptor agonist, NPY Y5 receptor antagonist, mGluR5 antagonist, leptin, leptin agonist, leptin derivative, opioid antagonist, orexin antagonist, BRS3 agonist, CCK-A agonist, CNTF, CNTF agonist, CNTF derivative, GHS agonist, 5HT2C agonist , Mc4r agonist, monoamine reuptake inhibitor, GLP-1 Gonists, UCP-1, 2 and 3 activators, β3 agonists, thyroid hormone β agonists, PDE inhibitors, FAS inhibitors, DGAT1 inhibitors, DGAT2 inhibitors, ACC2 inhibitors, glucocorticoid antagonists, acyl-estrogens, fatty acid trans Examples include a porter inhibitor and a dicarboxylic acid transporter inhibitor.
　以下に実施例を示し、本発明をさらに詳しく説明するが、これらは本発明を限定するものではない。
　また、本明細書中で用いる略号は以下の意味を表す。
Ｍｅ：メチル
Ｅｔ：エチル
Ｐｒ：プロピル
Ｂｕ：ブチル
ＴＨＦ：テトラヒドロフラン
ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド
ＤＭＡ：ジメチルアセトアミド
ＤＭＳＯ：ジメチルスルホキシド
ＴＭＳＯＴｆ：トリメチルシリルトリフラート
Ｃｂｚ：ベンジルオキシカルボニル
ＮＭＭ：Ｎ－メチルモルホリン
ＮＩＳ：Ｎ-ヨードスクシンイミド The present invention will be described in more detail with reference to the following examples, but these are not intended to limit the present invention.
Moreover, the symbol used in this specification represents the following meaning.
Me: methyl Et: ethyl Pr: propyl Bu: butyl THF: tetrahydrofuran DMF: N, N-dimethylformamide DMA: dimethylacetamide DMSO: dimethyl sulfoxide TMSOTf: trimethylsilyl triflate Cbz: benzyloxycarbonyl NMM: N-methylmorpholine NIS: N- Iodosuccinimide
実施例１　化合物Ｉａ－１の合成
第１工程
Figure JPOXMLDOC01-appb-C000048
　化合物１(10 g, 48.1 mmol)に塩化メチレン(50 ml)を加えた後、氷冷下でジメチルスルファモイルクロリド (10.4 ml, 96.0 mmol)とトリエチルアミン(26.7 ml , 193 mmol)を加え、氷冷下のまま４時間攪拌した。反応液を水へあけ、酢酸エチルで抽出した。有機層を水洗し、更に飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去することにより化合物２を得た。
1H-NMR (CDCl3) δ: 4.39 (1.0H, d, J = 7.60 Hz), 4.11 (2.0H, q, J = 7.1 Hz), 3.20-3.11 (1.0H, m), 2.97 (6.0H, s), 2.25-2.12 (3.0H, m), 2.03 (2.0H, br-d, J = 15.7 Hz), 1.56-1.46 (2.0H, m), 1.30-1.20 (5.0H, m).

第２工程
Figure JPOXMLDOC01-appb-C000049
　化合物２をエタノール(15 ml)とテトラヒドロフラン(30 ml)に溶解させた後、水10mlに溶解した水酸化ナトリウム(2.89 g, 72.2 mmol)を加え、５時間室温で攪拌した。有機溶媒の一部を減圧留去した後、反応液を希塩酸水へあけ、酸性とし、クロロホルムで抽出した。有機層を水洗し、更に飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去することにより化合物３を定量的に得た。

第３工程
Figure JPOXMLDOC01-appb-C000050
　化合物３ (10.7 g, 42.7 mmol)に塩化メチレン(50 ml)を加えた後、氷冷下でオキザリルクロリド(3.85 ml, 44.0 mmol)とＮ，Ｎ’－ジメチルホルムアミド(0.1 ml, 1.28 mmol)を加えた。室温で１時間攪拌した後、反応液を減圧下濃縮して酸クロリドを得た。
　Ｎ－メチルイミダゾール(4.09 ml, 51.3 mmol)の塩化メチレン(50 ml)－酢酸エチル(6.70 mL, 68.4 mmol)溶液に、-60℃で酸クロリド(42.7 mmol)の塩化メチレン(50 ml)溶液を加え、さらに同温度で四塩化チタン(15.6 ml, 141 mmol)を滴下し、30分間攪拌した。反応液にＮ，Ｎ’－ジイソプロピルエチルアミン(26.9 ml, 154 mmol)を加え、-40℃で40分間攪拌した後、水を加え、酢酸エチルで抽出した。有機層を水洗し、更に飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製し、化合物４ (9.61 g, 収率70%)を得た。
1H-NMR (CDCl3) δ: 4.19 (2.0H, q, J = 7.1 Hz), 4.12 (1.0H, d, J = 8.1 Hz), 3.47 (2.0H, s), 3.19-3.11 (1.0H, m), 2.79 (6.0H, s), 2.47-2.39 (1.0H, m), 2.19-2.16 (2.0H, m), 1.99 (2.0H, br-d, J = 13.69 Hz), 1.51-1.40 (2.0H, m), 1.31-1.19 (5.0H,m). Example 1 First Step of Synthesis of Compound Ia-1
Figure JPOXMLDOC01-appb-C000048
Methylene chloride (50 ml) was added to compound 1 (10 g, 48.1 mmol), and then dimethylsulfamoyl chloride (10.4 ml, 96.0 mmol) and triethylamine (26.7 ml, 193 mmol) were added under ice-cooling. The mixture was stirred for 4 hours with cooling. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound 2.
1 H-NMR (CDCl 3 ) δ: 4.39 (1.0H, d, J = 7.60 Hz), 4.11 (2.0H, q, J = 7.1 Hz), 3.20-3.11 (1.0H, m), 2.97 (6.0H , s), 2.25-2.12 (3.0H, m), 2.03 (2.0H, br-d, J = 15.7 Hz), 1.56-1.46 (2.0H, m), 1.30-1.20 (5.0H, m).

Second step
Figure JPOXMLDOC01-appb-C000049
Compound 2 was dissolved in ethanol (15 ml) and tetrahydrofuran (30 ml), sodium hydroxide (2.89 g, 72.2 mmol) dissolved in 10 ml of water was added, and the mixture was stirred at room temperature for 5 hours. After part of the organic solvent was distilled off under reduced pressure, the reaction solution was poured into dilute hydrochloric acid, acidified, and extracted with chloroform. The organic layer was washed with water, further washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain Compound 3 quantitatively.

Third step
Figure JPOXMLDOC01-appb-C000050
Methylene chloride (50 ml) was added to compound 3 (10.7 g, 42.7 mmol), and then oxalyl chloride (3.85 ml, 44.0 mmol) and N, N′-dimethylformamide (0.1 ml, 1.28 mmol) were added under ice cooling. Was added. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure to obtain acid chloride.
To a solution of N-methylimidazole (4.09 ml, 51.3 mmol) in methylene chloride (50 ml) -ethyl acetate (6.70 mL, 68.4 mmol) was added a solution of acid chloride (42.7 mmol) in methylene chloride (50 ml) at -60 ° C. In addition, titanium tetrachloride (15.6 ml, 141 mmol) was further added dropwise at the same temperature, followed by stirring for 30 minutes. N, N′-diisopropylethylamine (26.9 ml, 154 mmol) was added to the reaction mixture, and the mixture was stirred at −40 ° C. for 40 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 4 (9.61 g, yield 70%).
1 H-NMR (CDCl 3 ) δ: 4.19 (2.0H, q, J = 7.1 Hz), 4.12 (1.0H, d, J = 8.1 Hz), 3.47 (2.0H, s), 3.19-3.11 (1.0H , m), 2.79 (6.0H, s), 2.47-2.39 (1.0H, m), 2.19-2.16 (2.0H, m), 1.99 (2.0H, br-d, J = 13.69 Hz), 1.51-1.40 (2.0H, m), 1.31-1.19 (5.0H, m).
第４工程
Figure JPOXMLDOC01-appb-C000051
　塩化マグネシウム(1.48 g, 15.6 mmol)に塩化メチレン(20 ml)を加えた後、化合物４(5.0 g, 15.6 mmol)を加えた。この懸濁液に氷冷下にてピリジン(2.52 ml, 31.2 mmol)を加え、15分間攪拌した。その後、氷冷下のまま3-フルオロベンゾイルクロリド(1.90ml, 15.6 mmol)の塩化メチレン(5 ml)溶液を加えた後、室温で４時間攪拌した。反応液を希塩酸水へあけ、酸性とし酢酸エチルで抽出した。有機層を水洗し更に飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去することにより化合物５(6.68 g, 収率97%)を得た。

第５工程
Figure JPOXMLDOC01-appb-C000052
　化合物５ (6.68 g, 15.1 mmol)にジメチルスルホキシド(25ml)を加えた後、塩化ナトリウム(970 mg, 16.6 mmol)と水(0.54ml, 30.2 mmol)を加え、140℃で1時間攪拌した。反応液を水へあけ酢酸エチルで抽出した。有機層を水、飽和塩化ナトリウム水溶液で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製し、化合物６ (942 mg, 収率17%)を得た。
1H-NMR (CDCl3) δ: 7.65 (1.0H, d, J = 7.6 Hz), 7.57 (1.0H, d, J = 9.6 Hz), 7.45-7.40 (1.0H, m), 7.24-7.20 (1.0H, m), 6.13 (1.0H, s), 4.07 (1.0H, d, J = 8.1 Hz), 3.25-3.18 (1.0H, m), 2.81 (6.0H, s), 2.31-2.17 (3.0H, m), 2.02 (2.0H, br-d, J = 13.2 Hz), 1.64-1.55 (2.0H, m), 1.34-1.24 (2.0H, m).

第６工程
Figure JPOXMLDOC01-appb-C000053
　化合物６ (433 mg, 1.17 mmol)にメタノール(6 ml)を加えた後、ヒドラジン一水和物(0.068 ml, 1.40 mmol)を加え、室温で４時間攪拌した。反応液を水へあけ酢酸エチルで抽出した。有機層を水、飽和塩化ナトリウム水溶液で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製し、化合物Ｉａ－１(320 mg, 収率75%)を得た。
1H-NMR (CDCl3) δ: 7.49-7.33 (3.0H, m), 7.01 (1.0H, td, J = 8.4, 2.5 Hz), 4.14 (1.0H, d, J = 7.6 Hz), 3.30-3.23 (1.0H, m), 2.82 (6.0H, s), 2.68-2.62 (1.0H, m), 2.18 (4.0H, dd, J = 42.6, 13.2 Hz), 1.58 (2.0H, q, J = 13.0 Hz), 1.36 (2.0H, q, J = 12.5 Hz). Fourth step
Figure JPOXMLDOC01-appb-C000051
Methylene chloride (20 ml) was added to magnesium chloride (1.48 g, 15.6 mmol), and then compound 4 (5.0 g, 15.6 mmol) was added. Pyridine (2.52 ml, 31.2 mmol) was added to this suspension under ice cooling, and the mixture was stirred for 15 minutes. Thereafter, a solution of 3-fluorobenzoyl chloride (1.90 ml, 15.6 mmol) in methylene chloride (5 ml) was added with ice cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into dilute hydrochloric acid, acidified and extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound 5 (6.68 g, yield 97%).

5th process
Figure JPOXMLDOC01-appb-C000052
Dimethyl sulfoxide (25 ml) was added to compound 5 (6.68 g, 15.1 mmol), sodium chloride (970 mg, 16.6 mmol) and water (0.54 ml, 30.2 mmol) were added, and the mixture was stirred at 140 ° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 6 (942 mg, yield 17%).
1 H-NMR (CDCl 3 ) δ: 7.65 (1.0H, d, J = 7.6 Hz), 7.57 (1.0H, d, J = 9.6 Hz), 7.45-7.40 (1.0H, m), 7.24-7.20 ( 1.0H, m), 6.13 (1.0H, s), 4.07 (1.0H, d, J = 8.1 Hz), 3.25-3.18 (1.0H, m), 2.81 (6.0H, s), 2.31-2.17 (3.0 H, m), 2.02 (2.0H, br-d, J = 13.2 Hz), 1.64-1.55 (2.0H, m), 1.34-1.24 (2.0H, m).

6th process
Figure JPOXMLDOC01-appb-C000053
Methanol (6 ml) was added to compound 6 (433 mg, 1.17 mmol), hydrazine monohydrate (0.068 ml, 1.40 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound Ia-1 (320 mg, yield 75%).
1 H-NMR (CDCl 3 ) δ: 7.49-7.33 (3.0H, m), 7.01 (1.0H, td, J = 8.4, 2.5 Hz), 4.14 (1.0H, d, J = 7.6 Hz), 3.30- 3.23 (1.0H, m), 2.82 (6.0H, s), 2.68-2.62 (1.0H, m), 2.18 (4.0H, dd, J = 42.6, 13.2 Hz), 1.58 (2.0H, q, J = 13.0 Hz), 1.36 (2.0H, q, J = 12.5 Hz).
実施例２　化合物Ｉａ－９及び化合物ＩＩａ－３の合成
第１工程
Figure JPOXMLDOC01-appb-C000054
　化合物１ (10 g, 48.1 mmol)にアセトニトリル(40 ml)と水(20 ml)を加えた後、氷冷下でベンジルオキシカルボニルクロリド (8.25 ml, 57.8 mmol)とトリエチルアミン(26.7 ml , 193 mmol)を加え、氷冷下のまま４時間攪拌した。反応液を希塩酸水へあけ、酸性とし、酢酸エチルで抽出した。有機層を水洗し、更に飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去することにより化合物８ (11.9 g, 収率81%)を得た。
1H-NMR (CDCl3) δ: 7.36-7.31 (5.0H, m), 5.09 (2.0H, s), 4.12 (2.0H, q, J = 7.1 Hz), 2.21 (1.0H, tt, J = 12.2, 3.5 Hz), 2.10-2.00 (4.0H, m), 1.59-1.49 (2.0H, m), 1.24 (3.0H, t, J = 7.1 Hz), 1.14 (2.0H, q, J = 12.5 Hz).

第２工程
Figure JPOXMLDOC01-appb-C000055
　化合物８(14.7 g, 48.1 mmol)をエタノール(60 ml)とテトラヒドロフラン(30 ml)に溶解させた後、2規定水酸化ナトリウム水溶液(120 ml, 240 mmol)を加え、室温で4時間攪拌した。反応液を希塩酸水へあけ、酸性とし、クロロホルムで抽出し、有機層を水洗し、更に飽和食塩水で洗浄した。この時目的物の一部が結晶として析出したため、それらを濾取した。濾液の有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去することにより結晶を得た。先に濾取した結晶と合わせ、酢酸エチル―ヘキサンの混合溶媒から再結晶精製することで、化合物９ (5.49 g, 収率41%)を得た。
1H-NMR (DMSO-d6) δ: 7.38-7.29 (5.0H, m), 7.19 (1H, d, J = 8.1 Hz), 4.99 (2.0H, s), 3.25-3.22 (1.0H, m), 2.12-2.06 (1.0H, m), 1.90-1.82 (4.0H, m), 1.33 (2.0H, dd, J = 25.1, 10.4 Hz), 1.17 (2.0H, q, J = 11.3 Hz). Example 2 Synthesis of Compound Ia-9 and Compound IIa-3 First Step
Figure JPOXMLDOC01-appb-C000054
Acetonitrile (40 ml) and water (20 ml) were added to compound 1 (10 g, 48.1 mmol), and then benzyloxycarbonyl chloride (8.25 ml, 57.8 mmol) and triethylamine (26.7 ml, 193 mmol) under ice-cooling. And stirred for 4 hours with ice cooling. The reaction solution was poured into dilute hydrochloric acid, acidified, and extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound 8 (11.9 g, yield 81%).
1 H-NMR (CDCl 3 ) δ: 7.36-7.31 (5.0H, m), 5.09 (2.0H, s), 4.12 (2.0H, q, J = 7.1 Hz), 2.21 (1.0H, tt, J = 12.2, 3.5 Hz), 2.10-2.00 (4.0H, m), 1.59-1.49 (2.0H, m), 1.24 (3.0H, t, J = 7.1 Hz), 1.14 (2.0H, q, J = 12.5 Hz ).

Second step
Figure JPOXMLDOC01-appb-C000055
Compound 8 (14.7 g, 48.1 mmol) was dissolved in ethanol (60 ml) and tetrahydrofuran (30 ml), 2N aqueous sodium hydroxide solution (120 ml, 240 mmol) was added, and the mixture was stirred at room temperature for 4 hr. The reaction solution was poured into dilute hydrochloric acid, acidified, extracted with chloroform, the organic layer was washed with water, and further washed with saturated brine. At this time, some of the target product was precipitated as crystals, and they were collected by filtration. The organic layer of the filtrate was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain crystals. Compound 9 (5.49 g, yield 41%) was obtained by combining with the crystals collected earlier and recrystallizing from a mixed solvent of ethyl acetate-hexane.
1 H-NMR (DMSO-d 6 ) δ: 7.38-7.29 (5.0H, m), 7.19 (1H, d, J = 8.1 Hz), 4.99 (2.0H, s), 3.25-3.22 (1.0H, m ), 2.12-2.06 (1.0H, m), 1.90-1.82 (4.0H, m), 1.33 (2.0H, dd, J = 25.1, 10.4 Hz), 1.17 (2.0H, q, J = 11.3 Hz).
第３工程
Figure JPOXMLDOC01-appb-C000056
　化合物９ (3.00 g, 10.8 mmol)に塩化メチレン(50 ml)を加えた後、氷冷下でオキザリルクロリド(0.975 ml, 11.1 mmol)とＮ，Ｎ’－ジメチルホルムアミド(0.025 ml, 0.325 mmol)を加えた。室温で１時間攪拌した後、反応液を減圧下濃縮して酸クロリドを得た。
　Ｎ－メチルイミダゾール(1.04 ml, 13.0 mmol)の塩化メチレン(50 ml)－酢酸エチル(1.69 mL, 17.3 mmol)溶液に、-60℃で酸クロリド(10.8 mmol)の塩化メチレン(50 ml)溶液を加え、さらに同温度で四塩化チタン(3.94 ml, 35.7 mmol)を滴下し、30分間攪拌した。反応液にN,N’-ジイソプロピルエチルアミン(6.80 ml, 38.9 mmol)を加え、-40℃で40分間攪拌した後、水を加え、酢酸エチルで抽出した。有機層を水洗し、更に飽和食塩水で洗浄して、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製し、化合物１０ (1.75 g, 収率47%)を得た。
1H-NMR (CDCl3) δ: 7.37-7.31 (5.0H, m), 5.08 (2.0H, s), 4.70 (1.0H, d, J = 5.6 Hz), 4.19 (2.0H, q, J = 7.10 Hz), 3.47-3.44 (3.0H, m), 2.45-2.39 (1.0H, m), 2.12 (2.0H, br-d, J = 10.1 Hz), 1.97 (2.0H, br-d, J = 13.2 Hz), 1.52-1.42 (2.0H, br-d, J = 13.7 Hz), 1.29-1.24 (3.0H, m), 1.15 (2.0H, dd, J = 24.8, 9.6 Hz).

第４工程
Figure JPOXMLDOC01-appb-C000057
　塩化マグネシウム(1.03 g, 10.8 mmol)に塩化メチレン(20 ml)を加えた後、化合物１０(3.12 g, 8.98 mmol)を加えた。この懸濁液に氷冷下にてピリジン(1.45 ml, 18.0 mmol)を加え、15分間攪拌した。その後、氷冷下のまま3-フルオロベンゾイルクロリド(1.31 ml, 10.8 mmol)の塩化メチレン(5 ml)溶液を加えた後、室温で２時間攪拌した。反応液を希塩酸水へあけ、酸性とし、酢酸エチルで抽出した。有機層を水洗し、更に飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製し、化合物１１ (3.04 g, 収率72%)を得た。

第５工程
Figure JPOXMLDOC01-appb-C000058
　化合物１１ (3.04 g, 6.47 mmol)にジメチルスルホキシド(20ml)を加えた後、塩化ナトリウム(416 mg, 7.12 mmol)と水(0.23ml, 13.0 mmol)を加え、140℃で1時間攪拌した。反応液を水へあけ、酢酸エチルで抽出した。有機層を水、飽和塩化ナトリウム水溶液で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製し、β-ジケトンを定量的(2.57 g)に得た。
　得られたβ-ジケトン(2.57 g, 6.47 mmol)にメタノール(30 ml)を加えた後、ヒドラジン一水和物(0.377 ml, 7.76 mmol)を加え、室温で２時間攪拌した。反応液を水へあけ、酢酸エチルで抽出した。有機層を水、飽和塩化ナトリウム水溶液で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製し、化合物１２ (1.41g, 収率55%)を得た。
1H-NMR (DMSO-d6) δ: 12.67 (0.9H, s), 7.59-7.24 (9.0H, m), 7.08 (1.0H, s), 6.53 (1.0H, s), 5.02 (2.0H, s), 3.38-3.34 (1.0H, m), 2.61-2.55 (1.0H, s), 2.01-1.90 (4.0H, m), 1.50-1.29 (4.0H, m).

第６工程
Figure JPOXMLDOC01-appb-C000059
　化合物１２ (1.41 g, 3.58 mmol)にメタノール(50ml)を加えた後、水酸化パラジウム触媒(282 mg, 2.01 mmol)を加え、常圧室温にて3時間攪拌しながら水素添加反応を行なった。反応液をセライト濾過した後、濾液の溶媒を減圧下留去し、残渣をジオキサン(50 ml)に再度溶解した。氷冷下にて４規定塩酸のジオキサン溶液(1.34 ml, 5.38 mmol)を加え30分間攪拌した後、溶媒を減圧下留去することにより化合物１３を定量的(1.06 g)に得た。
1H-NMR (DMSO-d6) δ: 7.61-7.54 (2.0H, m), 7.43 (1.0H, dd, J = 14.2, 8.1 Hz), 7.11 (1.0H, td, J = 8.4, 2.5 Hz), 6.57 (1.0H, s), 3.03 (1.0H, br-s), 2.61 (1.0H, t, J = 8.4 Hz), 2.05 (4.0H, br-d, J = 8.6 Hz), 1.55-1.42 (4.0H, m). Third step
Figure JPOXMLDOC01-appb-C000056
Methylene chloride (50 ml) was added to compound 9 (3.00 g, 10.8 mmol), and then oxalyl chloride (0.975 ml, 11.1 mmol) and N, N′-dimethylformamide (0.025 ml, 0.325 mmol) were added under ice cooling. Was added. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure to obtain acid chloride.
To a solution of N-methylimidazole (1.04 ml, 13.0 mmol) in methylene chloride (50 ml) -ethyl acetate (1.69 mL, 17.3 mmol) is added a solution of acid chloride (10.8 mmol) in methylene chloride (50 ml) at -60 ° C. In addition, titanium tetrachloride (3.94 ml, 35.7 mmol) was further added dropwise at the same temperature, followed by stirring for 30 minutes. N, N′-diisopropylethylamine (6.80 ml, 38.9 mmol) was added to the reaction mixture, and the mixture was stirred at −40 ° C. for 40 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 10 (1.75 g, yield 47%).
1 H-NMR (CDCl 3 ) δ: 7.37-7.31 (5.0H, m), 5.08 (2.0H, s), 4.70 (1.0H, d, J = 5.6 Hz), 4.19 (2.0H, q, J = 7.10 Hz), 3.47-3.44 (3.0H, m), 2.45-2.39 (1.0H, m), 2.12 (2.0H, br-d, J = 10.1 Hz), 1.97 (2.0H, br-d, J = 13.2 Hz), 1.52-1.42 (2.0H, br-d, J = 13.7 Hz), 1.29-1.24 (3.0H, m), 1.15 (2.0H, dd, J = 24.8, 9.6 Hz).

Fourth step
Figure JPOXMLDOC01-appb-C000057
Methylene chloride (20 ml) was added to magnesium chloride (1.03 g, 10.8 mmol), and then compound 10 (3.12 g, 8.98 mmol) was added. Pyridine (1.45 ml, 18.0 mmol) was added to this suspension under ice cooling, and the mixture was stirred for 15 minutes. Thereafter, a solution of 3-fluorobenzoyl chloride (1.31 ml, 10.8 mmol) in methylene chloride (5 ml) was added with ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into dilute hydrochloric acid, acidified, and extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 11 (3.04 g, yield 72%).

5th process
Figure JPOXMLDOC01-appb-C000058
Dimethyl sulfoxide (20 ml) was added to compound 11 (3.04 g, 6.47 mmol), sodium chloride (416 mg, 7.12 mmol) and water (0.23 ml, 13.0 mmol) were added, and the mixture was stirred at 140 ° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain β-diketone quantitatively (2.57 g).
Methanol (30 ml) was added to the obtained β-diketone (2.57 g, 6.47 mmol), hydrazine monohydrate (0.377 ml, 7.76 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 12 (1.41 g, yield 55%).
1 H-NMR (DMSO-d 6 ) δ: 12.67 (0.9H, s), 7.59-7.24 (9.0H, m), 7.08 (1.0H, s), 6.53 (1.0H, s), 5.02 (2.0H , s), 3.38-3.34 (1.0H, m), 2.61-2.55 (1.0H, s), 2.01-1.90 (4.0H, m), 1.50-1.29 (4.0H, m).

6th process
Figure JPOXMLDOC01-appb-C000059
Methanol (50 ml) was added to compound 12 (1.41 g, 3.58 mmol), palladium hydroxide catalyst (282 mg, 2.01 mmol) was added, and a hydrogenation reaction was performed with stirring at normal pressure and room temperature for 3 hours. The reaction solution was filtered through Celite, and then the solvent of the filtrate was distilled off under reduced pressure. The residue was dissolved again in dioxane (50 ml). Under ice-cooling, 4N hydrochloric acid in dioxane (1.34 ml, 5.38 mmol) was added and stirred for 30 minutes, and then the solvent was distilled off under reduced pressure to obtain compound 13 quantitatively (1.06 g).
1 H-NMR (DMSO-d 6 ) δ: 7.61-7.54 (2.0H, m), 7.43 (1.0H, dd, J = 14.2, 8.1 Hz), 7.11 (1.0H, td, J = 8.4, 2.5 Hz ), 6.57 (1.0H, s), 3.03 (1.0H, br-s), 2.61 (1.0H, t, J = 8.4 Hz), 2.05 (4.0H, br-d, J = 8.6 Hz), 1.55- 1.42 (4.0H, m).
第７工程
Figure JPOXMLDOC01-appb-C000060
　2-クロロエタノール(0.374 ml, 5.58 mmol)にアセトニトリル(20 ml)を加えた後、氷冷下でクロロスルホニルイソシアナート (0.484 ml, 5.58 mmol)を加え、同温度にて30分間攪拌し、反応活性種を得た。
　化合物１３(1.50 g, 5.07 mmol)にアセトニトリル(100 ml)を加えた後、氷冷下でN-メチルモルフォリン(2.79 ml, 25.4 mmol)を加え、さらに同温度にて上記で調製した反応活性種を滴下した。室温で３時間攪拌後、反応液の溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィにより精製し、化合物Ｉａ－９ (1.68g, 収率81%)を得た。
1H-NMR (DMSO-d6) δ: 12.7(1H, s), 8.45 (1H, s), 7.50 (3H, m), 7.07 (1H, s), 6.52 (1H, s), 4.39 (2.6H, t, J = 7.60 Hz), 3.96 (2.6H, t, J = 7.6 Hz), 3.36 (1H, m), 2.63 (1H,m)), 1.97 (4H,m), 1.43 (4H, m).

第８工程
Figure JPOXMLDOC01-appb-C000061
　化合物Ｉａ－９ (50.0 mg, 0.122 mmol)にジオキサン(5 ml)を加えた後、プロパン-1-アミン(0.012 ml, 0.147 mmol)、トリエチルアミン(0.051 ml, 0.367 mmol)、トリメチルシリルトリフラート(0.015 ml, 0.122 mmol)を順次加え、80℃で8時間攪拌した。反応液を水へあけ酢酸エチルで抽出した。有機層を水、飽和塩化ナトリウム水溶液で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製し、化合物ＩＩａ－３ (33.0 mg, 収率71%)を得た。
1H-NMR (DMSO-d6) δ: 12.67 (0.8H, s), 7.57 (2.0H, m), 7.42 (1.0H, m), 7.08 (1.0H, m), 6.80 (1.0H, m), 6.73 (1.0H,m), 6.53 (0.9H, s), 3.00 (1.0H, m), 2.78 (2.0H, q, J = 6.76 Hz), 2.57 (1.0H,m), 2.00 (4.0H,m), 1.52-1.29 (6.0H, m), 0.87 (3.0H, t, J = 7.60 Hz). 7th process
Figure JPOXMLDOC01-appb-C000060
Acetonitrile (20 ml) was added to 2-chloroethanol (0.374 ml, 5.58 mmol), then chlorosulfonyl isocyanate (0.484 ml, 5.58 mmol) was added under ice cooling, and the mixture was stirred at the same temperature for 30 min. Active species were obtained.
Acetonitrile (100 ml) was added to compound 13 (1.50 g, 5.07 mmol), then N-methylmorpholine (2.79 ml, 25.4 mmol) was added under ice cooling, and the reaction activity prepared above at the same temperature. Seeds were dripped. After stirring at room temperature for 3 hours, the solvent of the reaction solution was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound Ia-9 (1.68 g, yield 81%).
1 H-NMR (DMSO-d 6 ) δ: 12.7 (1H, s), 8.45 (1H, s), 7.50 (3H, m), 7.07 (1H, s), 6.52 (1H, s), 4.39 (2.6 H, t, J = 7.60 Hz), 3.96 (2.6H, t, J = 7.6 Hz), 3.36 (1H, m), 2.63 (1H, m)), 1.97 (4H, m), 1.43 (4H, m ).

8th step
Figure JPOXMLDOC01-appb-C000061
After adding dioxane (5 ml) to compound Ia-9 (50.0 mg, 0.122 mmol), propan-1-amine (0.012 ml, 0.147 mmol), triethylamine (0.051 ml, 0.367 mmol), trimethylsilyl triflate (0.015 ml, 0.122 mmol) was sequentially added, and the mixture was stirred at 80 ° C. for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound IIa-3 (33.0 mg, yield 71%).
1 H-NMR (DMSO-d 6 ) δ: 12.67 (0.8H, s), 7.57 (2.0H, m), 7.42 (1.0H, m), 7.08 (1.0H, m), 6.80 (1.0H, m ), 6.73 (1.0H, m), 6.53 (0.9H, s), 3.00 (1.0H, m), 2.78 (2.0H, q, J = 6.76 Hz), 2.57 (1.0H, m), 2.00 (4.0 H, m), 1.52-1.29 (6.0H, m), 0.87 (3.0H, t, J = 7.60 Hz).
実施例３
第１工程
Figure JPOXMLDOC01-appb-C000062
（Ｒ１およびＲ２はそれぞれ独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリールまたは置換若しくは非置換のヘテロサイクリルであり、
Ｒ１およびＲ２は隣接する窒素原子と一緒になって置換若しくは非置換の含窒素芳香族ヘテロ環または置換若しくは非置換の含窒素非芳香族ヘテロ環を形成してもよい。）
　化合物１６ (１当量)をジオキサンに溶解させ、Ｎ-ヨードスクシンイミド(1.2当量)を加え80℃で数時間攪拌する。その後、反応液をチオ硫酸ナトリウム水溶液へあけ酢酸エチルで抽出する。有機層を水洗し無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去することで化合物１７を得る。

第２工程
Figure JPOXMLDOC01-appb-C000063
（Ｒ１およびＲ２は前記と同意義である。）
　化合物１７(1当量)、亜鉛粉末(0.2当量)、青酸亜鉛(0.6当量) をジメチルアセトアミドに溶解させ、窒素気流下Pd(PtBu3)2(0.1当量)を加え95℃で数時間攪拌する。その後、反応液を水へあけ酢酸エチルで抽出する。有機層を水洗し無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製することで目的物１８を得る。
　これら化合物１６～１８も本発明化合物である。 Example 3
First step
Figure JPOXMLDOC01-appb-C000062
(R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl;
R 1 and R 2 may be combined with an adjacent nitrogen atom to form a substituted or unsubstituted nitrogen-containing aromatic heterocyclic ring or a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic ring. )
Compound 16 (1 equivalent) is dissolved in dioxane, N-iodosuccinimide (1.2 equivalent) is added, and the mixture is stirred at 80 ° C. for several hours. The reaction mixture is then poured into an aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain Compound 17.

Second step
Figure JPOXMLDOC01-appb-C000063
(R 1 and R 2 are as defined above.)
Compound 17 (1 eq), zinc powder (0.2 eq), zinc cyanide (0.6 eq) are dissolved in dimethylacetamide, Pd (P t Bu 3 ) 2 (0.1 eq) is added under a nitrogen stream, and the mixture is stirred at 95 ° C. for several hours. To do. The reaction mixture is then poured into water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel chromatography to obtain the desired product 18.
These compounds 16 to 18 are also compounds of the present invention.
　以下、同様にして式（Ｉ）で示される化合物を合成することができる。
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000084

Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000087
 Hereinafter, the compound represented by the formula (I) can be synthesized in the same manner.
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000084

Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000087
Ia-1
1H-NMR (CDCl3) δ: 7.49-7.33 (2.9H, m), 7.01 (1.0H, td, J = 8.36, 2.53 Hz), 4.14 (1.0H, d, J = 7.60 Hz), 3.30-3.23 (1.1H, m), 2.82 (5.9H, s), 2.68-2.62 (1.2H, m), 2.18 (4.5H, dd, J = 42.58, 13.18 Hz), 1.58 (2.2H, q, J = 13.01 Hz), 1.36 (2.2H, q, J = 12.50 Hz).

Ia-2
1H-NMR (CDCl3) δ: 7.54 (1.0H, t, J = 9.38 Hz), 7.43 (1.0H, s), 7.18 (1.0H, dt, J = 14.53, 5.07 Hz), 6.29 (1.0H, s), 4.04 (1.0H, d, J = 8.11 Hz), 3.29-3.25 (1.1H, m), 2.82 (6.2H, s), 2.68-2.62 (1.2H, m), 2.24 (2.2H, d, J = 13.18 Hz), 2.12 (2.2H, d, J = 12.67 Hz), 1.58 (6.1H, dd, J = 23.83, 11.66 Hz), 1.37 (2.8H, dd, J = 24.59, 9.38 Hz).

Ia-3
1H-NMR (CDCl3) δ: 7.83 (0.9H, s), 7.55 (1.3H, dd, J = 12.42, 8.36 Hz), 7.46 (1.0H, d, J = 8.11 Hz), 6.33 (0.9H, s), 4.06 (1.1H, d, J = 7.60 Hz), 3.28 (1.0H, dt, J = 13.01, 4.82 Hz), 2.82 (5.9H, s), 2.65 (1.1H, dd, J = 13.43, 10.39 Hz), 2.18 (4.2H, dd, J = 48.67, 11.66 Hz), 1.58 (7.4H, dd, J = 24.08, 11.41 Hz), 1.37 (3.2H, dd, J = 24.33, 9.63 Hz).

Ia-4
1H-NMR (CDCl3) δ: 7.49-7.33 (3H, m), 7.02 (1H,m), 6.34 (1H, s), 4.21 (1H, d, J = 8.11 Hz), 3.28 (1H, m), 2.85 (3H, s), 2.64 (1H, m), 2.34 (1H, m), 2.24 (2H, br-d, J = 11.66 Hz), 2.13 (2H, br-d, J = 13.18 Hz), 1.59 (2H, m), 1.39 (2H,m), 0.76 (4.H, m).

Ia-5
1H-NMR (CDCl3) δ: 7.41 (3H,m), 7.00 (1.0H, m), 6.34 (1H, s), 4.47 (1H, t, J = 7.86 Hz), 4.13 (1H, d, J = 8.11 Hz), 3.65 (1H, t, J = 7.86 Hz), 3.31-3.20 (5H, m), 2.63 (1H, m), 2.17 (4H, m), 1.58 (2H,m), 1.36 (2H, m), 1.20 (6H, t, J = 7.10 Hz). Ia-1
1 H-NMR (CDCl 3 ) δ: 7.49-7.33 (2.9H, m), 7.01 (1.0H, td, J = 8.36, 2.53 Hz), 4.14 (1.0H, d, J = 7.60 Hz), 3.30- 3.23 (1.1H, m), 2.82 (5.9H, s), 2.68-2.62 (1.2H, m), 2.18 (4.5H, dd, J = 42.58, 13.18 Hz), 1.58 (2.2H, q, J = 13.01 Hz), 1.36 (2.2H, q, J = 12.50 Hz).

Ia-2
1 H-NMR (CDCl 3 ) δ: 7.54 (1.0H, t, J = 9.38 Hz), 7.43 (1.0H, s), 7.18 (1.0H, dt, J = 14.53, 5.07 Hz), 6.29 (1.0H , s), 4.04 (1.0H, d, J = 8.11 Hz), 3.29-3.25 (1.1H, m), 2.82 (6.2H, s), 2.68-2.62 (1.2H, m), 2.24 (2.2H, d, J = 13.18 Hz), 2.12 (2.2H, d, J = 12.67 Hz), 1.58 (6.1H, dd, J = 23.83, 11.66 Hz), 1.37 (2.8H, dd, J = 24.59, 9.38 Hz) .

Ia-3
1 H-NMR (CDCl 3 ) δ: 7.83 (0.9H, s), 7.55 (1.3H, dd, J = 12.42, 8.36 Hz), 7.46 (1.0H, d, J = 8.11 Hz), 6.33 (0.9H , s), 4.06 (1.1H, d, J = 7.60 Hz), 3.28 (1.0H, dt, J = 13.01, 4.82 Hz), 2.82 (5.9H, s), 2.65 (1.1H, dd, J = 13.43 , 10.39 Hz), 2.18 (4.2H, dd, J = 48.67, 11.66 Hz), 1.58 (7.4H, dd, J = 24.08, 11.41 Hz), 1.37 (3.2H, dd, J = 24.33, 9.63 Hz).

Ia-4
1 H-NMR (CDCl 3 ) δ: 7.49-7.33 (3H, m), 7.02 (1H, m), 6.34 (1H, s), 4.21 (1H, d, J = 8.11 Hz), 3.28 (1H, m ), 2.85 (3H, s), 2.64 (1H, m), 2.34 (1H, m), 2.24 (2H, br-d, J = 11.66 Hz), 2.13 (2H, br-d, J = 13.18 Hz) , 1.59 (2H, m), 1.39 (2H, m), 0.76 (4.H, m).

Ia-5
1 H-NMR (CDCl 3 ) δ: 7.41 (3H, m), 7.00 (1.0H, m), 6.34 (1H, s), 4.47 (1H, t, J = 7.86 Hz), 4.13 (1H, d, J = 8.11 Hz), 3.65 (1H, t, J = 7.86 Hz), 3.31-3.20 (5H, m), 2.63 (1H, m), 2.17 (4H, m), 1.58 (2H, m), 1.36 ( 2H, m), 1.20 (6H, t, J = 7.10 Hz).
Ia-6
1H-NMR (CDCl3) δ: 7.46-7.37 (3.1H, m), 7.01 (1.0H, td, J = 8.24, 2.20 Hz), 6.35 (1.0H, s), 4.06-4.05 (1.1H, br m), 3.24 (5.3H, dq, J = 10.00, 5.00 Hz), 2.66-2.63 (1.2H, m), 2.23-2.12 (4.9H, m), 1.66-1.55 (10.6H, m), 1.38-1.29 (4.2H, m).

Ia-7
1H-NMR (CDCl3) δ: 7.49-7.34 (3H, m), 7.02 (1H, t, J = 8.36 Hz), 6.35 (1.0H, s), 4.28 (1.0H, d, J = 8.62 Hz), 4.16 (2.0H, s), 3.32 (1.0H, m), 2.98 (3H, s), 2.66 (1H, m), 2.28 (2H, d, J = 10.65 Hz), 2.15 (2H, d, J = 12.67 Hz), 1.60 (2H, m), 1.43 (2H, m).

Ia-8
1H-NMR (CDCl3) δ: 7.41 (3H,m), 7.01 (1.0H, t, J = 8.36 Hz), 6.35 (1.0H, s), 4.18 (1.0H, d, J = 8.11 Hz), 3.50 (2H, t, J = 6.59 Hz), 3.30 (1.0H, m), 2.94 (3H, s), 2.72-2.63 (3H, m), 2.24 (2H, d, J = 12.67 Hz), 2.14 (2H, d, J = 12.17 Hz), 1.61 (2H, dd, J = 24.59, 12.42 Hz), 1.38 (2H, dd, J = 26.11, 11.41 Hz).

Ia-9
1H-NMR (DMSO-d6) δ: 12.7(1H, s), 8.45 (1H, s), 7.50 (3H, m), 7.07 (1H, s), 6.52 (1H, s), 4.39 (2.6H, t, J = 7.60 Hz), 3.96 (2.6H, t, J = 7.6 Hz), 3.36 (1H, m), 2.63 (1H,m)), 1.97 (4H,m), 1.43 (4H, m)

Ia-10
1H-NMR (CDCl3) δ: 7.42 (3.0H, m), 7.01 (1.0H, m), 6.35 (1.0H, s), 4.00 (1.0H, d, J = 8.11 Hz), 3.77 (4.0H, t, J = 4.56 Hz), 3.32-3.28 (1.0H, m), 3.21 (4.0H, t, J = 4.56 Hz), 2.66 (1.0H,m), 2.25 (2.0H, m), 2.14 (2.0H, m), 1.61 (2.0H, m), 1.40 (2.0H, m). Ia-6
1 H-NMR (CDCl 3 ) δ: 7.46-7.37 (3.1H, m), 7.01 (1.0H, td, J = 8.24, 2.20 Hz), 6.35 (1.0H, s), 4.06-4.05 (1.1H, br m), 3.24 (5.3H, dq, J = 10.00, 5.00 Hz), 2.66-2.63 (1.2H, m), 2.23-2.12 (4.9H, m), 1.66-1.55 (10.6H, m), 1.38 -1.29 (4.2H, m).

Ia-7
1 H-NMR (CDCl 3 ) δ: 7.49-7.34 (3H, m), 7.02 (1H, t, J = 8.36 Hz), 6.35 (1.0H, s), 4.28 (1.0H, d, J = 8.62 Hz ), 4.16 (2.0H, s), 3.32 (1.0H, m), 2.98 (3H, s), 2.66 (1H, m), 2.28 (2H, d, J = 10.65 Hz), 2.15 (2H, d, J = 12.67 Hz), 1.60 (2H, m), 1.43 (2H, m).

Ia-8
1 H-NMR (CDCl 3 ) δ: 7.41 (3H, m), 7.01 (1.0H, t, J = 8.36 Hz), 6.35 (1.0H, s), 4.18 (1.0H, d, J = 8.11 Hz) , 3.50 (2H, t, J = 6.59 Hz), 3.30 (1.0H, m), 2.94 (3H, s), 2.72-2.63 (3H, m), 2.24 (2H, d, J = 12.67 Hz), 2.14 (2H, d, J = 12.17 Hz), 1.61 (2H, dd, J = 24.59, 12.42 Hz), 1.38 (2H, dd, J = 26.11, 11.41 Hz).

Ia-9
1 H-NMR (DMSO-d 6 ) δ: 12.7 (1H, s), 8.45 (1H, s), 7.50 (3H, m), 7.07 (1H, s), 6.52 (1H, s), 4.39 (2.6 H, t, J = 7.60 Hz), 3.96 (2.6H, t, J = 7.6 Hz), 3.36 (1H, m), 2.63 (1H, m)), 1.97 (4H, m), 1.43 (4H, m )

Ia-10
1 H-NMR (CDCl 3 ) δ: 7.42 (3.0H, m), 7.01 (1.0H, m), 6.35 (1.0H, s), 4.00 (1.0H, d, J = 8.11 Hz), 3.77 (4.0 H, t, J = 4.56 Hz), 3.32-3.28 (1.0H, m), 3.21 (4.0H, t, J = 4.56 Hz), 2.66 (1.0H, m), 2.25 (2.0H, m), 2.14 (2.0H, m), 1.61 (2.0H, m), 1.40 (2.0H, m).
Ia-11
1H-NMR (CDCl3) δ: 7.47-7.35 (3.0H, m), 7.01 (1.0H, m), 6.36 (1.0H, s), 4.19 (1.0H, d, J = 8.11 Hz), 3.82 (2.0H, q, J = 8.62 Hz), 3.27 (1.0H, m), 2.99 (3H, s), 2.66 (1.0H,m), 2.23 (2.0H,m), 2.12 (2.0H, m), 1.59 (2.0H, m), 1.38 (2.0H, m).

Ia-12
1H-NMR (DMSO-d6) δ: 12.67 (0.9H, s), 7.56 (2.0H, t, J = 13.43 Hz), 7.40-7.30 (7H, m), 7.09 (1.0H, s), 6.54 (1.0H, s), 4.22 (2.0H, s), 3.11-3.07 (1.0H, m), 2.58 (1.0H, m), 2.00 (4.0H, m), 1.43 (4.0H, m).

Ia-13
1H-NMR (CDCl3) δ: 7.49-7.35 (3.0H, m), 7.02 (1.0H, d, J = 6.59 Hz), 6.35 (1.0H, s), 4.46 (1.0H, d, J = 8.11 Hz), 3.50 (2.0H, t, J = 6.59 Hz), 3.30 (3.0H,m), 2.69 (3.0H, m), 2.17 (4.0H,m), 1.58 (2.0H, m), 1.33 (5.0H, m).

Ia-14
1H-NMR (CDCl3) δ: 7.49 (1.0H, d, J = 7.60 Hz), 7.37 (7.0H, m), 7.01 (1.0H, m), 6.35 (1.0H, s), 4.41 (2.0H, s), 4.13 (1.0H, d, J = 8.11 Hz), 3.22 (3.0H, m), 2.63 (1.0H, tt, J = 12.17, 3.46 Hz), 2.14 (4.0H, dd, J = 26.87, 12.17 Hz), 1.54 (2.0H, dd, J = 25.35, 10.65 Hz), 1.32 (2.0H, dd, J = 26.36, 11.66 Hz), 1.16 (3.0H, t, J = 7.10 Hz).

Ia-15
1H-NMR (DMSO-d6) δ: 12.67 (1.0H, s), 7.56 (3.0H, m), 7.42 (1.0H, dd, J = 13.43, 5.83 Hz), 7.09 (1.0H, t, J = 8.11 Hz), 6.51 (1.0H, s), 3.45 (4.0H, t, J = 6.59 Hz), 3.10 (1.0H, m), 2.82 (4.0H, t, J = 6.84 Hz), 2.58 (1.0H, m), 2.01 (4.0H, m), 1.42 (4.0H, m).

Ia-16
1H-NMR (DMSO-d6) δ: 12.67 (0.9H, s), 7.61-7.41 (3.0H, m), 7.09 (1.0H, t, J = 7.60 Hz), 6.77-6.70 (2.0H, m), 6.54 (1.0H, s), 3.07-3.00 (1.0H, m), 2.59 (2.0H, d, J = 6.59 Hz), 2.01 (4.0H, br-t, J = 10.90 Hz), 1.48-1.28 (4.0H, m), 0.88 (9.0H, s). Ia-11
1 H-NMR (CDCl 3 ) δ: 7.47-7.35 (3.0H, m), 7.01 (1.0H, m), 6.36 (1.0H, s), 4.19 (1.0H, d, J = 8.11 Hz), 3.82 (2.0H, q, J = 8.62 Hz), 3.27 (1.0H, m), 2.99 (3H, s), 2.66 (1.0H, m), 2.23 (2.0H, m), 2.12 (2.0H, m) , 1.59 (2.0H, m), 1.38 (2.0H, m).

Ia-12
1 H-NMR (DMSO-d 6 ) δ: 12.67 (0.9H, s), 7.56 (2.0H, t, J = 13.43 Hz), 7.40-7.30 (7H, m), 7.09 (1.0H, s), 6.54 (1.0H, s), 4.22 (2.0H, s), 3.11-3.07 (1.0H, m), 2.58 (1.0H, m), 2.00 (4.0H, m), 1.43 (4.0H, m).

Ia-13
1 H-NMR (CDCl 3 ) δ: 7.49-7.35 (3.0H, m), 7.02 (1.0H, d, J = 6.59 Hz), 6.35 (1.0H, s), 4.46 (1.0H, d, J = 8.11 Hz), 3.50 (2.0H, t, J = 6.59 Hz), 3.30 (3.0H, m), 2.69 (3.0H, m), 2.17 (4.0H, m), 1.58 (2.0H, m), 1.33 (5.0H, m).

Ia-14
1 H-NMR (CDCl 3 ) δ: 7.49 (1.0H, d, J = 7.60 Hz), 7.37 (7.0H, m), 7.01 (1.0H, m), 6.35 (1.0H, s), 4.41 (2.0 H, s), 4.13 (1.0H, d, J = 8.11 Hz), 3.22 (3.0H, m), 2.63 (1.0H, tt, J = 12.17, 3.46 Hz), 2.14 (4.0H, dd, J = 26.87, 12.17 Hz), 1.54 (2.0H, dd, J = 25.35, 10.65 Hz), 1.32 (2.0H, dd, J = 26.36, 11.66 Hz), 1.16 (3.0H, t, J = 7.10 Hz).

Ia-15
1 H-NMR (DMSO-d 6 ) δ: 12.67 (1.0H, s), 7.56 (3.0H, m), 7.42 (1.0H, dd, J = 13.43, 5.83 Hz), 7.09 (1.0H, t, J = 8.11 Hz), 6.51 (1.0H, s), 3.45 (4.0H, t, J = 6.59 Hz), 3.10 (1.0H, m), 2.82 (4.0H, t, J = 6.84 Hz), 2.58 ( 1.0H, m), 2.01 (4.0H, m), 1.42 (4.0H, m).

Ia-16
1 H-NMR (DMSO-d 6 ) δ: 12.67 (0.9H, s), 7.61-7.41 (3.0H, m), 7.09 (1.0H, t, J = 7.60 Hz), 6.77-6.70 (2.0H, m), 6.54 (1.0H, s), 3.07-3.00 (1.0H, m), 2.59 (2.0H, d, J = 6.59 Hz), 2.01 (4.0H, br-t, J = 10.90 Hz), 1.48 -1.28 (4.0H, m), 0.88 (9.0H, s).
IIa-1
1H-NMR (DMSO-d6) δ: 8.31 (0.6H, s), 7.57 (2.0H, m), 7.42 (1.0H, m), 7.08 (1.0H, m), 6.86 (1.0H, d, J = 7.60 Hz), 6.61 (1.0H, d, J = 5.07 Hz), 6.52 (1.0H, s), 2.99 (1.0H, m), 2.57 (1.0H, m), 2.46 (3.0H, d, J = 4.56 Hz), 2.00 (4.0H, m), 1.39 (4.0 H, dq, J = 44.10, 12.25 Hz).

IIa-2
1H-NMR (DMSO-d6) δ: 12.68 (0.7H, s), 7.56 (2.0H, m), 7.42 (1.0H, q, J = 7.27 Hz), 7.09 (1.0H, t, J = 8.11 Hz), 6.82 (1.0H, d, J = 7.60 Hz), 6.71 (1.0H, t, J = 5.83 Hz), 6.54 (1.0H, s), 2.99 (1.0H, m), 2.89-2.82 (2.0H, m), 2.57 (1.0H, m), 2.00 (4.0H, m), 1.39 (4.0H, m), 1.07 (3.8H, t, J = 7.35 Hz).

IIa-3
1H-NMR (DMSO-d6) δ: 12.67 (0.8H, s), 7.57 (2.0H, m), 7.42 (1.0H, m), 7.08 (1.0H, m), 6.80 (1.0H, m), 6.73 (1.0H,m), 6.53 (0.9H, s), 3.00 (1.0H, m), 2.78 (2.0H, q, J = 6.76 Hz), 2.57 (1.0H,m), 2.00 (4.0H,m), 1.52-1.29 (6.0H, m), 0.87 (3.0H, t, J = 7.60 Hz).

IIa-4
1H-NMR (DMSO-d6) δ: 12.67 (0.9H, s), 7.51 (3.0H, m), 7.08 (1.0H, m), 6.70 (2.0H, m), 6.53 (1.0H, s), 3.00 (1.0H, br-s), 2.54 (2.0H, m), 2.01 (4.0H, m), 1.50-1.32 (4.0H, m), 1.11 (6.0H, d, J = 6.08 Hz).

IIa-5
1H-NMR (DMSO-d6) δ: 12.68 (0.9H, s), 7.61-7.42 (3.0H, m), 7.11 (2.0H, m), 6.94 (1.0H, d, J = 7.10 Hz), 6.53 (1.0H, s), 3.06-3.02 (1.0H, m), 2.58 (1.0H, t, J = 10.39 Hz), 2.30 (1.0H, td, J = 6.34, 2.37 Hz), 2.05 (4.0H, m), 1.50-1.31 (4.0H, m), 0.53 (4.0H, m). IIa-1
1 H-NMR (DMSO-d 6 ) δ: 8.31 (0.6H, s), 7.57 (2.0H, m), 7.42 (1.0H, m), 7.08 (1.0H, m), 6.86 (1.0H, d , J = 7.60 Hz), 6.61 (1.0H, d, J = 5.07 Hz), 6.52 (1.0H, s), 2.99 (1.0H, m), 2.57 (1.0H, m), 2.46 (3.0H, d , J = 4.56 Hz), 2.00 (4.0H, m), 1.39 (4.0 H, dq, J = 44.10, 12.25 Hz).

IIa-2
1 H-NMR (DMSO-d 6 ) δ: 12.68 (0.7H, s), 7.56 (2.0H, m), 7.42 (1.0H, q, J = 7.27 Hz), 7.09 (1.0H, t, J = 8.11 Hz), 6.82 (1.0H, d, J = 7.60 Hz), 6.71 (1.0H, t, J = 5.83 Hz), 6.54 (1.0H, s), 2.99 (1.0H, m), 2.89-2.82 ( 2.0H, m), 2.57 (1.0H, m), 2.00 (4.0H, m), 1.39 (4.0H, m), 1.07 (3.8H, t, J = 7.35 Hz).

IIa-3
1 H-NMR (DMSO-d 6 ) δ: 12.67 (0.8H, s), 7.57 (2.0H, m), 7.42 (1.0H, m), 7.08 (1.0H, m), 6.80 (1.0H, m ), 6.73 (1.0H, m), 6.53 (0.9H, s), 3.00 (1.0H, m), 2.78 (2.0H, q, J = 6.76 Hz), 2.57 (1.0H, m), 2.00 (4.0 H, m), 1.52-1.29 (6.0H, m), 0.87 (3.0H, t, J = 7.60 Hz).

IIa-4
1 H-NMR (DMSO-d 6 ) δ: 12.67 (0.9H, s), 7.51 (3.0H, m), 7.08 (1.0H, m), 6.70 (2.0H, m), 6.53 (1.0H, s ), 3.00 (1.0H, br-s), 2.54 (2.0H, m), 2.01 (4.0H, m), 1.50-1.32 (4.0H, m), 1.11 (6.0H, d, J = 6.08 Hz) .

IIa-5
1 H-NMR (DMSO-d 6 ) δ: 12.68 (0.9H, s), 7.61-7.42 (3.0H, m), 7.11 (2.0H, m), 6.94 (1.0H, d, J = 7.10 Hz) , 6.53 (1.0H, s), 3.06-3.02 (1.0H, m), 2.58 (1.0H, t, J = 10.39 Hz), 2.30 (1.0H, td, J = 6.34, 2.37 Hz), 2.05 (4.0 H, m), 1.50-1.31 (4.0H, m), 0.53 (4.0H, m).
IIa-6
1H-NMR (DMSO-d6) δ: 12.67 (0.8H, s), 7.57 (2.0H, dd, J = 25.85, 8.62 Hz), 7.42 (1.0H, t, J = 7.86 Hz), 7.08 (1.0H, t, J = 8.62 Hz), 6.77 (2.0H, dd, J = 6.59, 3.55 Hz), 6.53 (1.0H, s), 3.48 (1.0H, m), 3.02-2.99 (1.0H, m), 2.57 (1.0H, m), 2.01 (4.0H, m), 1.81 (2.0H, m), 1.61 (2.0H, m), 1.37 (10.0H, m).

IIa-7
1H-NMR (DMSO-d6) δ: 12.63 (0.8H, s), 9.65 (1.0H, s), 7.50 (4.0H, m), 7.28 (2.1H, t, J = 7.86 Hz), 7.17 (2.0H, d, J = 7.60 Hz), 7.07 (1.0H, s), 6.98 (1.0H, t, J = 7.35 Hz), 6.50 (1.0, s), 3.05 (1.0H, dt, J = 13.52, 4.44 Hz), 2.55 (1.0H, m), 1.93 (2.0H, d, J = 11.66 Hz), 1.83 (2.0H, d, J = 10.65 Hz), 1.38 (2.0H, q, J = 12.67 Hz), 1.25 (2.0H, dd, J = 22.31, 12.67 Hz).

IIa-8
1H-NMR (DMSO-d6) δ: 9.42 (1.0H, s), 7.50 (6.0H, m), 7.15 (4.0H, m), 6.52 (1.0H, s), 3.15-3.12 (1.0H, m), 2.56 (1.0H, m), 1.93 (4.0H, dd, J = 25.85, 12.17 Hz), 1.47-1.26 (4.0H, m).

IIa-9
1H-NMR (DMSO-d6) δ: 12.67 (1.0H, s), 7.50 (3.0H, ddd, J = 64.89, 20.53, 8.11 Hz), 7.08 (1.0H, t, J = 7.60 Hz), 6.81 (1.0H, d, J = 7.10 Hz), 6.71 (1.0H, t, J = 5.58 Hz), 6.53 (1.0H, s), 3.04-2.97 (1.0H, m), 2.81 (2.0H, q, J = 6.76 Hz), 2.58 (1.0H, t, J = 11.91 Hz), 2.00 (4.0H, m), 1.49-1.27 (8.0H, m), 0.88 (3.0H, t, J = 7.35 Hz).

IIa-10
1H-NMR (DMSO-d6) δ: 12.67 (0.8H, s), 7.57 (2.0H, dd, J = 27.88, 9.12 Hz), 7.41 (1.0H, dd, J = 14.45, 7.35 Hz), 7.08 (1.0H, t, J = 8.62 Hz), 6.81 (1.0H, d, J = 7.60 Hz), 6.71 (1.0H, t, J = 5.32 Hz), 6.52 (1.0H, s), 2.99 (1.0H, dq, J = 14.83, 3.55 Hz), 2.80 (2.0H, q, J = 6.76 Hz), 2.58 (1.0H, t, J = 11.41 Hz), 2.00 (4.0H, d, J = 10.14 Hz), 1.46-1.26 (10.0H, m), 0.87 (3.0H, t, J = 6.59 Hz). IIa-6
1 H-NMR (DMSO-d 6 ) δ: 12.67 (0.8H, s), 7.57 (2.0H, dd, J = 25.85, 8.62 Hz), 7.42 (1.0H, t, J = 7.86 Hz), 7.08 ( 1.0H, t, J = 8.62 Hz), 6.77 (2.0H, dd, J = 6.59, 3.55 Hz), 6.53 (1.0H, s), 3.48 (1.0H, m), 3.02-2.99 (1.0H, m ), 2.57 (1.0H, m), 2.01 (4.0H, m), 1.81 (2.0H, m), 1.61 (2.0H, m), 1.37 (10.0H, m).

IIa-7
1 H-NMR (DMSO-d 6 ) δ: 12.63 (0.8H, s), 9.65 (1.0H, s), 7.50 (4.0H, m), 7.28 (2.1H, t, J = 7.86 Hz), 7.17 (2.0H, d, J = 7.60 Hz), 7.07 (1.0H, s), 6.98 (1.0H, t, J = 7.35 Hz), 6.50 (1.0, s), 3.05 (1.0H, dt, J = 13.52 , 4.44 Hz), 2.55 (1.0H, m), 1.93 (2.0H, d, J = 11.66 Hz), 1.83 (2.0H, d, J = 10.65 Hz), 1.38 (2.0H, q, J = 12.67 Hz ), 1.25 (2.0H, dd, J = 22.31, 12.67 Hz).

IIa-8
1 H-NMR (DMSO-d 6 ) δ: 9.42 (1.0H, s), 7.50 (6.0H, m), 7.15 (4.0H, m), 6.52 (1.0H, s), 3.15-3.12 (1.0H , m), 2.56 (1.0H, m), 1.93 (4.0H, dd, J = 25.85, 12.17 Hz), 1.47-1.26 (4.0H, m).

IIa-9
1 H-NMR (DMSO-d 6 ) δ: 12.67 (1.0H, s), 7.50 (3.0H, ddd, J = 64.89, 20.53, 8.11 Hz), 7.08 (1.0H, t, J = 7.60 Hz), 6.81 (1.0H, d, J = 7.10 Hz), 6.71 (1.0H, t, J = 5.58 Hz), 6.53 (1.0H, s), 3.04-2.97 (1.0H, m), 2.81 (2.0H, q , J = 6.76 Hz), 2.58 (1.0H, t, J = 11.91 Hz), 2.00 (4.0H, m), 1.49-1.27 (8.0H, m), 0.88 (3.0H, t, J = 7.35 Hz) .

IIa-10
1 H-NMR (DMSO-d 6 ) δ: 12.67 (0.8H, s), 7.57 (2.0H, dd, J = 27.88, 9.12 Hz), 7.41 (1.0H, dd, J = 14.45, 7.35 Hz), 7.08 (1.0H, t, J = 8.62 Hz), 6.81 (1.0H, d, J = 7.60 Hz), 6.71 (1.0H, t, J = 5.32 Hz), 6.52 (1.0H, s), 2.99 (1.0 H, dq, J = 14.83, 3.55 Hz), 2.80 (2.0H, q, J = 6.76 Hz), 2.58 (1.0H, t, J = 11.41 Hz), 2.00 (4.0H, d, J = 10.14 Hz) , 1.46-1.26 (10.0H, m), 0.87 (3.0H, t, J = 6.59 Hz).
IIa-11
1H-NMR (DMSO-d6) δ: 12.67 (1.0H, s), 7.57 (2.0, dd, J = 26.87, 8.62 Hz), 7.41 (1.0H, dd, J = 14.19, 7.10 Hz), 7.08 (1.0H, s), 6.78 (2.0H, dd, J = 15.46, 6.84 Hz), 6.53 (1.0H, s), 3.01 (1.0H, tt, J = 10.65, 3.89 Hz), 2.64-2.55 (3.0H, m), 2.00 (4.0H, t, J = 4.31 Hz), 1.77-1.67 (1.0H, m), 1.38 (4.0H, dq, J = 45.62, 11.74 Hz), 0.88 (6.0H, d, J = 6.60 Hz)

IIa-12
1H-NMR (DMSO-d6) δ: 12.67 (0.8H, s), 7.57 (2.0H, dd, J = 27.63, 9.38 Hz), 7.41 (1.0H, dd, J = 14.19, 7.60 Hz), 7.08 (1.0H, s), 6.87-6.78 (2.0H, m), 6.53 (1.0H, s), 3.04-3.00 (1.0H, m), 2.71 (2.0H, t, J = 6.34 Hz), 2.57 (1.0H, t, J = 10.90 Hz), 2.02-1.98 (4.0H, m), 1.39 (4.0H, dq, J = 49.81, 12.34 Hz), 0.98-0.92 (1.0H, m), 0.43 (2.0H, q, J = 6.08 Hz), 0.17 (2.0H, q, J = 4.90 Hz).

IIa-13
1H-NMR (DMSO-d6) δ: 12.68 (0.9H, s), 7.74 (1.0H, s), 7.57 (2.0H, dd, J = 26.87, 8.62 Hz), 7.41 (1.0H, dd, J = 14.45, 7.35 Hz), 7.16-7.06 (2.0H, m), 6.53 (1.0H, s), 3.61 (2.0H, ddd, J = 15.84, 9.76, 6.46 Hz), 3.04 (1.0H, tt, J = 11.41, 3.46 Hz), 2.58 (1.0H, t, J = 11.66 Hz), 2.01 (4.0H, t, J = 9.12 Hz), 1.39 (4.0H, dq, J = 47.40, 11.74 Hz).

IIa-14
1H-NMR (DMSO-d6) δ: 12.68 (0.8H, s), 7.62-7.41 (4.0H, m), 7.10 (2.0H, d, J = 7.1 Hz), 6.53 (1.0H, s), 6.19-5.89 (1.0H, m), 3.27-3.17 (2.0H, m), 3.08-3.00 (1.0H, m), 2.62-2.56 (1.0H, m), 2.02-2.00 (4.0H, m), 1.50-1.29 (4.0H, m).

IIa-15
1H-NMR (DMSO-d6) δ: 12.68 (0.7H, s), 7.56 (2.0H, m), 7.42 (1.0H, m), 7.12 (3.0H,m), 6.52 (1.0H, s), 3.06 (3.0H, m), 2.69 (2.0H, t, J = 6.59 Hz), 2.58 (1.0H, t, J = 11.15 Hz), 2.02 (4.0H, t, J = 11.15 Hz), 1.39 (4.0H, dq, J = 45.37, 11.74 Hz). IIa-11
1 H-NMR (DMSO-d 6 ) δ: 12.67 (1.0H, s), 7.57 (2.0, dd, J = 26.87, 8.62 Hz), 7.41 (1.0H, dd, J = 14.19, 7.10 Hz), 7.08 (1.0H, s), 6.78 (2.0H, dd, J = 15.46, 6.84 Hz), 6.53 (1.0H, s), 3.01 (1.0H, tt, J = 10.65, 3.89 Hz), 2.64-2.55 (3.0 H, m), 2.00 (4.0H, t, J = 4.31 Hz), 1.77-1.67 (1.0H, m), 1.38 (4.0H, dq, J = 45.62, 11.74 Hz), 0.88 (6.0H, d, (J = 6.60 Hz)

IIa-12
1 H-NMR (DMSO-d 6 ) δ: 12.67 (0.8H, s), 7.57 (2.0H, dd, J = 27.63, 9.38 Hz), 7.41 (1.0H, dd, J = 14.19, 7.60 Hz), 7.08 (1.0H, s), 6.87-6.78 (2.0H, m), 6.53 (1.0H, s), 3.04-3.00 (1.0H, m), 2.71 (2.0H, t, J = 6.34 Hz), 2.57 (1.0H, t, J = 10.90 Hz), 2.02-1.98 (4.0H, m), 1.39 (4.0H, dq, J = 49.81, 12.34 Hz), 0.98-0.92 (1.0H, m), 0.43 (2.0 H, q, J = 6.08 Hz), 0.17 (2.0H, q, J = 4.90 Hz).

IIa-13
1 H-NMR (DMSO-d 6 ) δ: 12.68 (0.9H, s), 7.74 (1.0H, s), 7.57 (2.0H, dd, J = 26.87, 8.62 Hz), 7.41 (1.0H, dd, J = 14.45, 7.35 Hz), 7.16-7.06 (2.0H, m), 6.53 (1.0H, s), 3.61 (2.0H, ddd, J = 15.84, 9.76, 6.46 Hz), 3.04 (1.0H, tt, J = 11.41, 3.46 Hz), 2.58 (1.0H, t, J = 11.66 Hz), 2.01 (4.0H, t, J = 9.12 Hz), 1.39 (4.0H, dq, J = 47.40, 11.74 Hz).

IIa-14
1 H-NMR (DMSO-d 6 ) δ: 12.68 (0.8H, s), 7.62-7.41 (4.0H, m), 7.10 (2.0H, d, J = 7.1 Hz), 6.53 (1.0H, s) , 6.19-5.89 (1.0H, m), 3.27-3.17 (2.0H, m), 3.08-3.00 (1.0H, m), 2.62-2.56 (1.0H, m), 2.02-2.00 (4.0H, m) , 1.50-1.29 (4.0H, m).

IIa-15
1 H-NMR (DMSO-d 6 ) δ: 12.68 (0.7H, s), 7.56 (2.0H, m), 7.42 (1.0H, m), 7.12 (3.0H, m), 6.52 (1.0H, s ), 3.06 (3.0H, m), 2.69 (2.0H, t, J = 6.59 Hz), 2.58 (1.0H, t, J = 11.15 Hz), 2.02 (4.0H, t, J = 11.15 Hz), 1.39 (4.0H, dq, J = 45.37, 11.74 Hz).
IIa-16
1H-NMR (DMSO-d6) δ: 12.67 (0.9H, s), 7.61-7.41 (3.0H, m), 7.09 (1.0H, t, J = 7.60 Hz), 6.77-6.70 (2.0H, m), 6.54 (1.0H, s), 3.07-3.00 (1.0H, m), 2.59 (2.0H, d, J = 6.59 Hz), 2.01 (4.0H, br-t, J = 10.90 Hz), 1.48-1.28 (4.0H, m), 0.88 (9.0H, s).

IIa-18
1H-NMR (DMSO-d6) δ: 12.68 (0.8H, s), 9.65 (1.0H, s), 7.61-7.39 (4.0H, m), 7.09 (1.0H, t, J = 7.9 Hz), 6.53 (1.0H, s), 3.64 (3.0H, s), 3.11-3.06 (1.0H, m), 2.58-2.54 (1.0H, m), 2.00-1.97 (4.0H, m), 1.48-1.31 (4.0H, m).

IIa-19
1H-NMR (DMSO-d6) δ: 12.67 (1.0H, s), 9.51 (1.0H, s), 7.62-7.38 (4.0H, m), 7.08 (1.0H, t, J = 7.9 Hz), 6.52 (1.0H, s), 3.87 (2.0H, q, J = 7.1 Hz), 3.12-3.06 (1.0H, m), 2.59-2.54 (1.0H, m), 1.99 (4.0H, br-d, J = 10.7 Hz), 1.45-1.24 (4.0H, m), 1.15 (3.0H, t, J = 7.1 Hz).

IIa-20
1H-NMR (DMSO-d6) δ: 12.67 (0.8H, s), 9.33 (0.9H, s), 7.61-7.40 (4.0H,m), 7.08 (1.0H, t, J = 7.4 Hz), 6.53 (1.0H, s), 4.06-4.00 (1.0H, m), 3.14-3.07 (1.0H, m), 2.59-2.53 (1.0H, d, J = 12.2 Hz), 2.00-1.98 (4.0H, m), 1.48-1.31 (4.0H, m), 1.14 (6.0H, d, J = 6.08 Hz). IIa-16
1 H-NMR (DMSO-d 6 ) δ: 12.67 (0.9H, s), 7.61-7.41 (3.0H, m), 7.09 (1.0H, t, J = 7.60 Hz), 6.77-6.70 (2.0H, m), 6.54 (1.0H, s), 3.07-3.00 (1.0H, m), 2.59 (2.0H, d, J = 6.59 Hz), 2.01 (4.0H, br-t, J = 10.90 Hz), 1.48 -1.28 (4.0H, m), 0.88 (9.0H, s).

IIa-18
1 H-NMR (DMSO-d 6 ) δ: 12.68 (0.8H, s), 9.65 (1.0H, s), 7.61-7.39 (4.0H, m), 7.09 (1.0H, t, J = 7.9 Hz) , 6.53 (1.0H, s), 3.64 (3.0H, s), 3.11-3.06 (1.0H, m), 2.58-2.54 (1.0H, m), 2.00-1.97 (4.0H, m), 1.48-1.31 (4.0H, m).

IIa-19
1 H-NMR (DMSO-d 6 ) δ: 12.67 (1.0H, s), 9.51 (1.0H, s), 7.62-7.38 (4.0H, m), 7.08 (1.0H, t, J = 7.9 Hz) , 6.52 (1.0H, s), 3.87 (2.0H, q, J = 7.1 Hz), 3.12-3.06 (1.0H, m), 2.59-2.54 (1.0H, m), 1.99 (4.0H, br-d , J = 10.7 Hz), 1.45-1.24 (4.0H, m), 1.15 (3.0H, t, J = 7.1 Hz).

IIa-20
1 H-NMR (DMSO-d 6 ) δ: 12.67 (0.8H, s), 9.33 (0.9H, s), 7.61-7.40 (4.0H, m), 7.08 (1.0H, t, J = 7.4 Hz) , 6.53 (1.0H, s), 4.06-4.00 (1.0H, m), 3.14-3.07 (1.0H, m), 2.59-2.53 (1.0H, d, J = 12.2 Hz), 2.00-1.98 (4.0H , m), 1.48-1.31 (4.0H, m), 1.14 (6.0H, d, J = 6.08 Hz).
IIa-23
1H-NMR (DMSO-d6) δ: 12.56 (1.0H, s), 7.74-6.71 (7.0H, m), 6.45 (1.0H, s), 3.00 (1.0H, s), 2.78 (2.0H, m), 2.57 (1.0H, m), 2.00 (4.0H, m), 1.41 (6.0H, m), 0.87 (3.0H, t, J = 7.35 Hz).

IIa-32
1H-NMR (DMSO-d6) δ: 12.67 (1.0H, s), 7.59-7.09 (4.0H, m), 6.68 (2.0H, m), 6.54 (1.0H, s), 3.06 (2.0H, m), 2.57 (1.0H, s), 2.00 (4.0H, d, J = 13.69 Hz), 1.48-1.31 (6.0H, m), 1.09 (3.0H, d, J = 6.59 Hz), 0.86 (3.0H, t, J = 7.35 Hz).

IIa-33
1H-NMR (DMSO-d6) δ: 12.66 (1.0H, s), 7.41-7.77 (3.0H, m), 6.47-6.59 (3.0H, m), 3.05 (1.0H, m), 2.57 (1.0H, m), 2.02 (4.0H, m), 1.37 (13.0H, m).

IIb-2
1H-NMR (DMSO-d6) δ: 12.69 (1.0H, s), 7.75 (2.0H, m), 7.36 (2.0H, m), 6.76-6.55 (3.0H, m), 3.28 (1.0H, m), 2.99 (1.0H, m), 2.57 (1.0H, m), 2.01 (4.0H, m), 1.47-1.31 (4.0H, m), 1.11 (6.0H, d, J = 6.59 Hz).

IIb-10
1H-NMR (DMSO-d6) δ: 12.81 (1.0H, s), 7.11 (6.0H, m), 3.28 (1.0H, m), 3.00 (1.0H, m), 2.67 (1.0H, m), 1.99 (4.0H, m), 1.57 (2.0H, m), 1.34 (2.0H, m), 1.11 (6.0H, d, J = 6.59 Hz).

IIb-12
H-NMR (DMSO-d6) δ: 13.79 (1.0H, s), 7.71-7.56 (3.0H, m), 7.33 (1.0H, m), 6.71-6.82 (2.0H, m), 3.29 (1.0H, m), 3.03 (1.0H, m), 2.79 (1.0H, m), 2.02 (4.0H, m), 1.66 (2.0H, m), 1.36 (2.0H, m), 1.11 (6.0H, d, J = 6.59 Hz).

IIb-65
1H-NMR (DMSO-d6) δ: 12.67 (1.0H, s), 7.42-7.77 (3.0H, m), 6.76-6.52 (3.0H, m), 3.27 (1.0H, m), 3.00 (1.0H, m), 2.57 (1.0H, m), 2.00 (4.0H, m), 1.37 (4.0H, m), 1.11 (6.0H, d, J = 6.59 Hz).

IIb-66
H-NMR (DMSO-d6) δ: 12.77 (1.0H, s), 7.44 (2.0H, d, J = 7.10 Hz), 7.10 (1.0H, m), 6.76-6.61 (3.0H, m), 3.27 (1.0H, m), 3.01 (1.0H, m), 2.58 (1.0H, m), 1.99 (4.0H, m), 1.39 (4.0H, m), 1.11 (6.0H, d, J = 6.59 Hz).

IIc-2 
1H-NMR (DMSO-d6) δ: 12.69 (1.0H, s), 7.32-7.79 (4.0H, m), 6.54-6.81 (3.0H, m), 2.99 (1.0H, m), 2.78 (2.0H, q, J = 6.76 Hz), 2.57 (1.0H, m), 1.99 (4.0H, m), 1.41 (6.0H, m), 0.87 (3.0H, t, J = 7.35 Hz).

IIc-10
1H-NMR (DMSO-d6) δ: 12.82 (1.0H, s), 7.46-7.56 (3.0H, m), 7.18 (1.0H, m), 6.84-6.73 (2.0H, m), 3.00 (1.0H, m), 2.77 (2.0H, q, J = 6.76 Hz), 2.65 (1.0H, m), 1.98 (4.0H, m), 1.58-1.32 (6.0H, m), 0.87 (3.0H, t, J = 7.35 Hz).

IIc-12
1H-NMR (DMSO-d6) δ: 13.77 (1.0H, s), 7.56-7.71 (3.0H, m), 7.32 (1.0H, m), 6.88-6.77 (2.0H, m), 3.05-3.01 (1.0H, m), 2.78 (3.0H, m), 2.01 (4.0H, m), 1.66 (2.0H, m), 1.38 (4.0H, m), 0.88 (3.0H, t, J = 7.35 Hz).

IIc-55
1H-NMR (DMSO-d6) δ: 12.67 (1.0H, s), 7.42-7.59 (3.0H, m), 7.08 (1.0H, m), 6.48-6.60 (3.0H, m), 3.04 (1.0H, m), 2.57 (1.0H, m), 2.03 (4.0H, m), 1.47-1.24 (13.0H, m).

IIc-65
1H-NMR (DMSO-d6) δ: 12.67 (1.0H, s), 7.77-7.44 (3.0H, m), 6.52-6.81 (3.0H, m), 2.99 (1.0H, m), 2.77 (2.0H, m), 2.56 (1.0H, m), 2.00 (4.0H, m), 1.40 (6.0H, m), 0.87 (3.0H, t, J = 7.35 Hz).

IIc-66
1H-NMR (DMSO-d6) δ: 12.77 (1.0H, s), 7.44 (2.0H, d, J = 7.10 Hz), 7.11 (1.0H, m), 6.81-6.61 (3.0H, m), 2.99 (1.0H, m), 2.77 (2.0H, m), 2.57 (1.0H, m), 2.00 (4.0H, m), 1.40 (6.0H, m), 0.87 (3.0H, t, J = 7.35 Hz). IIa-23
1 H-NMR (DMSO-d 6 ) δ: 12.56 (1.0H, s), 7.74-6.71 (7.0H, m), 6.45 (1.0H, s), 3.00 (1.0H, s), 2.78 (2.0H , m), 2.57 (1.0H, m), 2.00 (4.0H, m), 1.41 (6.0H, m), 0.87 (3.0H, t, J = 7.35 Hz).

IIa-32
1 H-NMR (DMSO-d 6 ) δ: 12.67 (1.0H, s), 7.59-7.09 (4.0H, m), 6.68 (2.0H, m), 6.54 (1.0H, s), 3.06 (2.0H , m), 2.57 (1.0H, s), 2.00 (4.0H, d, J = 13.69 Hz), 1.48-1.31 (6.0H, m), 1.09 (3.0H, d, J = 6.59 Hz), 0.86 ( (3.0H, t, J = 7.35 Hz).

IIa-33
1 H-NMR (DMSO-d 6 ) δ: 12.66 (1.0H, s), 7.41-7.77 (3.0H, m), 6.47-6.59 (3.0H, m), 3.05 (1.0H, m), 2.57 ( 1.0H, m), 2.02 (4.0H, m), 1.37 (13.0H, m).

IIb-2
1 H-NMR (DMSO-d 6 ) δ: 12.69 (1.0H, s), 7.75 (2.0H, m), 7.36 (2.0H, m), 6.76-6.55 (3.0H, m), 3.28 (1.0H , m), 2.99 (1.0H, m), 2.57 (1.0H, m), 2.01 (4.0H, m), 1.47-1.31 (4.0H, m), 1.11 (6.0H, d, J = 6.59 Hz) .

IIb-10
1 H-NMR (DMSO-d 6 ) δ: 12.81 (1.0H, s), 7.11 (6.0H, m), 3.28 (1.0H, m), 3.00 (1.0H, m), 2.67 (1.0H, m ), 1.99 (4.0H, m), 1.57 (2.0H, m), 1.34 (2.0H, m), 1.11 (6.0H, d, J = 6.59 Hz).

IIb-12
H-NMR (DMSO-d 6 ) δ: 13.79 (1.0H, s), 7.71-7.56 (3.0H, m), 7.33 (1.0H, m), 6.71-6.82 (2.0H, m), 3.29 (1.0 H, m), 3.03 (1.0H, m), 2.79 (1.0H, m), 2.02 (4.0H, m), 1.66 (2.0H, m), 1.36 (2.0H, m), 1.11 (6.0H, d, J = 6.59 Hz).

IIb-65
1 H-NMR (DMSO-d 6 ) δ: 12.67 (1.0H, s), 7.42-7.77 (3.0H, m), 6.76-6.52 (3.0H, m), 3.27 (1.0H, m), 3.00 ( 1.0H, m), 2.57 (1.0H, m), 2.00 (4.0H, m), 1.37 (4.0H, m), 1.11 (6.0H, d, J = 6.59 Hz).

IIb-66
H-NMR (DMSO-d 6 ) δ: 12.77 (1.0H, s), 7.44 (2.0H, d, J = 7.10 Hz), 7.10 (1.0H, m), 6.76-6.61 (3.0H, m), 3.27 (1.0H, m), 3.01 (1.0H, m), 2.58 (1.0H, m), 1.99 (4.0H, m), 1.39 (4.0H, m), 1.11 (6.0H, d, J = 6.59 Hz).

IIc-2
1 H-NMR (DMSO-d 6 ) δ: 12.69 (1.0H, s), 7.32-7.79 (4.0H, m), 6.54-6.81 (3.0H, m), 2.99 (1.0H, m), 2.78 ( 2.0H, q, J = 6.76 Hz), 2.57 (1.0H, m), 1.99 (4.0H, m), 1.41 (6.0H, m), 0.87 (3.0H, t, J = 7.35 Hz).

IIc-10
1 H-NMR (DMSO-d 6 ) δ: 12.82 (1.0H, s), 7.46-7.56 (3.0H, m), 7.18 (1.0H, m), 6.84-6.73 (2.0H, m), 3.00 ( 1.0H, m), 2.77 (2.0H, q, J = 6.76 Hz), 2.65 (1.0H, m), 1.98 (4.0H, m), 1.58-1.32 (6.0H, m), 0.87 (3.0H, t, J = 7.35 Hz).

IIc-12
1 H-NMR (DMSO-d 6 ) δ: 13.77 (1.0H, s), 7.56-7.71 (3.0H, m), 7.32 (1.0H, m), 6.88-6.77 (2.0H, m), 3.05- 3.01 (1.0H, m), 2.78 (3.0H, m), 2.01 (4.0H, m), 1.66 (2.0H, m), 1.38 (4.0H, m), 0.88 (3.0H, t, J = 7.35 Hz).

IIc-55
1 H-NMR (DMSO-d 6 ) δ: 12.67 (1.0H, s), 7.42-7.59 (3.0H, m), 7.08 (1.0H, m), 6.48-6.60 (3.0H, m), 3.04 ( 1.0H, m), 2.57 (1.0H, m), 2.03 (4.0H, m), 1.47-1.24 (13.0H, m).

IIc-65
1 H-NMR (DMSO-d 6 ) δ: 12.67 (1.0H, s), 7.77-7.44 (3.0H, m), 6.52-6.81 (3.0H, m), 2.99 (1.0H, m), 2.77 ( 2.0H, m), 2.56 (1.0H, m), 2.00 (4.0H, m), 1.40 (6.0H, m), 0.87 (3.0H, t, J = 7.35 Hz).

IIc-66
1 H-NMR (DMSO-d 6 ) δ: 12.77 (1.0H, s), 7.44 (2.0H, d, J = 7.10 Hz), 7.11 (1.0H, m), 6.81-6.61 (3.0H, m) , 2.99 (1.0H, m), 2.77 (2.0H, m), 2.57 (1.0H, m), 2.00 (4.0H, m), 1.40 (6.0H, m), 0.87 (3.0H, t, J = 7.35 Hz).
試験例１－１　マウスＮＰＹ　Ｙ５受容体に対する親和性
　マウスＮＰＹ　Ｙ５受容体をコードするｃＤＮＡ配列（Ｂｉｏｃｈｉｍ．　Ｂｉｏｐｈｙｓ．　Ａｃｔａ　１３２８：　８３－８９，　１９９７参照）を、発現ベクター　ｐＭＥ１８Ｓ（Ｔａｋｅｂｅ　ｅｔ　ａｌ．　Ｍｏｌ．　Ｃｅｌｌ．　Ｂｉｏｌ．　８，　４６６－４７２）にクローニングした。得られた発現ベクターを、ＬｉｐｏｆｅｃｔＡＭＩＮＥ試薬（商標、インビトロジェン社）を用いて、使用説明書にしたがって宿主細胞ＣＨＯにトランスフェクションし、ＮＰＹ　Ｙ５受容体安定発現細胞を得た。
　マウスＮＰＹ　Ｙ５受容体を発現させたＣＨＯ細胞から調製した膜標品を、本発明に係る化合物及び３０，０００ｃｐｍの［１２５Ｉ］ペプタイドＹＹ（終濃度６０ｐＭ：ＧＥ　ヘルスケア社製）とともに、アッセイ緩衝液（０．１％　牛血清アルブミンを含む２０ｍＭ　ＨＥＰＥＳ－Ｈａｎｋｓ緩衝液、ｐＨ７．４）中で、２５℃、２時間インキュベーションした後、１％　ポリエチレンイミン処理したグラスフィルターＧＦ／Ｃにて濾過した。５０ｍＭ　Ｔｒｉｓ－ＨＣｌ緩衝液、ｐＨ７．４にて洗浄後、ガンマカウンターにてグラスフィルター上の放射活性を求めた。非特異的結合は２００ｎＭペプタイドＹＹ存在下で測定し、特異的ペプタイドＹＹ結合に対する被検化合物の５０％阻害濃度（ＩＣ５０値）を求めた［Ｉｎｕｉ，　Ａ．　ｅｔ　ａｌ．　Ｅｎｄｏｃｒｉｎｏｌｏｇｙ　１３１，　２０９０－２０９６（１９９２）参照］。結果を表１に示す。
　本発明に係る化合物は、マウスＮＰＹ　Ｙ５受容体に対するペプタイドＹＹ（ＮＰＹと同族物質）の結合を阻害した。即ち本化合物は、マウスＮＰＹ　Ｙ５受容体に対して親和性を示した。
Figure JPOXMLDOC01-appb-T000088
 Test Example 1-1 Affinity for Mouse NPY Y5 Receptor A cDNA sequence encoding the mouse NPY Y5 receptor (see Biochim. Biophys. Acta 1328: 83-89, 1997) was expressed in the expression vector pME18S (Takebe et al. Mol. Cell.Biol.8, 466-472). The obtained expression vector was transfected into a host cell CHO using LipofectAMINE reagent (trademark, Invitrogen) according to the instruction manual, and NPY Y5 receptor stably expressing cells were obtained.
Membrane preparations prepared from CHO cells expressing mouse NPY Y5 receptor were assay buffer together with the compounds of the present invention and 30,000 cpm [ 125 I] peptide YY (final concentration 60 pM: manufactured by GE Healthcare). The solution was incubated in a solution (20 mM HEPES-Hanks buffer containing 0.1% bovine serum albumin, pH 7.4) at 25 ° C. for 2 hours, and then filtered through a glass filter GF / C treated with 1% polyethyleneimine. After washing with 50 mM Tris-HCl buffer, pH 7.4, the radioactivity on the glass filter was determined with a gamma counter. Non-specific binding was measured in the presence of 200 nM peptide YY, and the 50% inhibitory concentration (IC 50 value) of the test compound for specific peptide YY binding was determined [Inui, A. et al. et al. Endocrinology 131, 2090-2096 (1992)]. The results are shown in Table 1.
The compound according to the present invention inhibited the binding of peptide YY (NPY and homologous substances) to the mouse NPY Y5 receptor. That is, this compound showed affinity for the mouse NPY Y5 receptor.
Figure JPOXMLDOC01-appb-T000088
試験例１－２　ヒトＮＰＹ　Ｙ５受容体に対する親和性
　ヒトＮＰＹ　Ｙ５受容体をコードするｃＤＮＡ配列（ＷＯ９６／１６５４２号参照）を、発現ベクター　ｐＭＥ１８Ｓ（Ｔａｋｅｂｅ　ｅｔ　ａｌ．　Ｍｏｌ．　Ｃｅｌｌ．　Ｂｉｏｌ．　８，　４６６－４７２）にクローニングする。得られた発現ベクターを、ＬｉｐｏｆｅｃｔＡＭＩＮＥ試薬（商標、インビトロジェン社）を用いて、使用説明書にしたがって宿主細胞ＣＨＯにトランスフェクションし、ＮＰＹ　Ｙ５受容体安定発現細胞を得る。
　ヒトＮＰＹ　Ｙ５受容体を発現させたＣＨＯ細胞から調製した膜標品を、本発明に係る化合物及び３０，０００ｃｐｍの［１２５Ｉ］ペプタイドＹＹ（終濃度６０ｐＭ：ＧＥ　ヘルスケア社製）とともに、アッセイ緩衝液（０．１％　牛血清アルブミンを含む２０　ｍＭ　ＨＥＰＥＳ－Ｈａｎｋｓ緩衝液、ｐＨ７．４）中で、２５℃、２時間インキュベーションした後、１％ポリエチレンイミン処理したグラスフィルターＧＦ／Ｃにて濾過する。５０ｍＭ　Ｔｒｉｓ－ＨＣｌ緩衝液、ｐＨ７．４にて洗浄後、ガンマカウンターにてグラスフィルター上の放射活性を求める。非特異的結合は２００　ｎＭペプタイドＹＹ存在下で測定し、特異的ペプタイドＹＹ結合に対する被検化合物の５０％阻害濃度（ＩＣ５０値）を求める［Ｉｎｕｉ，　Ａ．　ｅｔ　ａｌ．　Ｅｎｄｏｃｒｉｎｏｌｏｇｙ　１３１，　２０９０－２０９６（１９９２）参照］。 Test Example 1-2 Affinity for Human NPY Y5 Receptor A cDNA sequence encoding the human NPY Y5 receptor (see WO96 / 16542) was expressed in the expression vector pME18S (Takebe et al. Mol. Cell. Biol. 8, 466- 472). The obtained expression vector is transfected into a host cell CHO using LipofectAMINE reagent (trademark, Invitrogen) according to the instruction manual to obtain NPY Y5 receptor stably expressing cells.
Membrane preparation prepared from CHO cells expressing human NPY Y5 receptor was assay buffer together with the compound of the present invention and 30,000 cpm [ 125 I] peptide YY (final concentration 60 pM: manufactured by GE Healthcare). Incubate in a liquid (20 mM HEPES-Hanks buffer containing 0.1% bovine serum albumin, pH 7.4) at 25 ° C. for 2 hours, and then filter through a glass filter GF / C treated with 1% polyethyleneimine. . After washing with 50 mM Tris-HCl buffer, pH 7.4, the radioactivity on the glass filter is determined with a gamma counter. Non-specific binding is measured in the presence of 200 nM peptide YY, and the 50% inhibitory concentration (IC 50 value) of the test compound for specific peptide YY binding is determined [Inui, A. et al. et al. Endocrinology 131, 2090-2096 (1992)].
試験例２　ラットおよびマウス脳移行性評価
　カセットドージング法（Ｄｒｕｇ．Ｍｅｔａｂ．Ｄｉｓｐｏｓ．（２００１）；　２９，　９５７－９６６参照）を用いて、ラット（Ｃｒｌ；ＣＤ（ＳＤ），　♂，　８ｗｅｅｋｓ）については静脈内投与（０．５ｍｇ／ｍＬ／ｋｇ）３０分後、マウス（Ｊｃｌ；Ｃ５７ＢＬ／６Ｊ，　♂，　８ｗｅｅｋｓ）については経口投与（２ｍｇ／１０ｍＬ／ｋｇ）３時間または５時間後の血漿および脳内濃度から、脳移行性（脳／血漿分配係数；Ｋｐ）を評価した。 Test Example 2 Rat and Mouse Brain Migration Evaluation Using the cassette dosing method (Drug. Metab. Dispos. (2001); 29, 957-966), rat (Crl; CD (SD), ♂, 8weeks) 30 minutes after intravenous administration (0.5 mg / mL / kg), for mice (Jcl; C57BL / 6J, Ｊ, 8weeks), plasma and brain 3 hours or 5 hours after oral administration (2 mg / 10 mL / kg) From the concentration, brain transferability (brain / plasma partition coefficient; Kp) was evaluated.
試験例３　ラットにおける薬物動態評価
　カセットドージング法を用いて、ラット（Ｃｒｌ；ＣＤ（ＳＤ），　♂，　８ｗｅｅｋｓ）静脈内投与（０．５ｍｇ／ｍＬ／ｋｇ）後の血漿中濃度推移から、半減期（ｔ１／２）および全身クリアランス（ＣＬｔｏｔ）を評価した。 Test Example 3 Pharmacokinetic Evaluation in Rats Using the cassette dosing method, the half-life was determined from the change in plasma concentration after intravenous administration (0.5 mg / mL / kg) in rats (Crl; CD (SD), ♂, 8 weeks). (T1 / 2) and systemic clearance (CLtot) were evaluated.
試験例４　ＣＨＯ細胞におけるｃＡＭＰ生成抑制作用
　ヒトＮＰＹ　Ｙ５受容体を発現させたＣＨＯ細胞を、２．５ｍＭイソブチルメチルキサンチン（ＳＩＧＭＡ社）存在下で３７℃、２０分間インキュベーションした後、本発明に係る化合物を添加し５分間インキュベーションし、その後５０ｎＭＮＰＹおよび１０μＭフォルスコリン（Ｓｉｇｍａ社）を加えて３０分間インキュベーションした。１Ｎ　ＨＣｌを添加して反応を停止した後、上清中のｃＡＭＰ量をＥＩＡ　ｋｉｔ（Ａｍｅｒｓｈａｍ　ＬＩＦＥ　ＳＩＥＮＣＥ社製）を用いて測定した。フォルスコリン刺激によるｃＡＭＰ生成に対するＮＰＹの抑制作用を１００％とし、このＮＰＹ作用に対する本発明に係る化合物の５０％阻害濃度（ＩＣ５０値）を求めた。
Figure JPOXMLDOC01-appb-T000089
 Test Example 4 cAMP Production Inhibitory Action in CHO Cells After CHO cells expressing human NPY Y5 receptor were incubated at 37 ° C. for 20 minutes in the presence of 2.5 mM isobutylmethylxanthine (SIGMA), the compounds according to the present invention Was added and incubated for 5 minutes, after which 50 nMNPY and 10 μM forskolin (Sigma) were added and incubated for 30 minutes. After stopping the reaction by adding 1N HCl, the amount of cAMP in the supernatant was measured using EIA kit (manufactured by Amersham LIFE SIENCE). The inhibitory action of NPY on cAMP production by forskolin stimulation was taken as 100%, and the 50% inhibitory concentration (IC 50 value) of the compound according to the present invention for this NPY action was determined.
Figure JPOXMLDOC01-appb-T000089
試験例５　ＮＰＹ　Ｙ５受容体選択性
　Ｙ１発現細胞（ｈｕｍａｎ　ｎｅｕｒｏｂｌａｓｔｏｍａ，　ＳＫ－Ｎ－ＭＣ）膜標品およびＹ２発現細胞（ｈｕｍａｎ　ｎｅｕｒｏｂｌａｓｔｏｍａ，　ＳＭＳ－ＫＡＮ）膜標品を使用して試験例１－２と同様の方法で試験を行い、本発明に係る化合物のＮＰＹ　Ｙ１受容体およびＮＰＹ　Ｙ２受容体に対する親和性を測定する。その結果により、本発明に係る化合物がＮＰＹ　Ｙ５受容体選択性を有していることを確認することができる。 Test Example 5 NPY Y5 Receptor Selectivity Test Example 1-2 and Y1-expressing cell (human neuroblastoma, SK-N-MC) membrane sample and Y2-expressing cell (human neuroblastoma, SMS-KAN) membrane sample were used. The test is performed in the same manner, and the affinity of the compound of the present invention for the NPY Y1 receptor and the NPY Y2 receptor is measured. As a result, it can be confirmed that the compound according to the present invention has NPY Y5 receptor selectivity.
試験例６　摂食抑制作用
　エーテル麻酔下、雄性Ｃ５７ＢＬ／６Ｊマウス（１２－１４　週齢、２５－３０ｇ）の外後頭稜から鼻背部まで正中に沿って皮膚を切開し、頭蓋骨上部を露出させた。露出部ｂｒｅｇｍａ　よりｌａｍｂｄａに向かって約　１　ｍｍ後方、正中線から左側に約１ｍｍの位置に電気ドリルを用いて直径約１ｍｍの穴を開けた。麻酔から覚醒後のマウスに０．５％ヒドロキシプロピルメチルセルロース（信越化学株式会社製）水溶液あるいはこの水溶液に懸濁した被検物質を強制経口投与し、投与１時間後、ＮＰＹ　Ｙ５受容体特異的アゴニスト（［　ｃＰＰ１－７，ＮＰＹ１９－２３，Ａｌａ３１，Ａｉｂ３２，Ｇｌｎ３４］－ｈＰａｎｃｒｅａｔｉｃ　Ｐｏｌｙｐｅｐｔｉｄｅ：Ｔｏｃｒｉｓ社製）０．１ｎｍｏｌを先に設けた頭部開口部よりカニューレを用いて注入した。注入２時間後および４時間後にマウスの摂食量を測定し、０．５％ヒドロキシプロピルメチルセルロース溶液投与群と被検物質投与群との間の摂餌量の差を調査した。その結果、本発明化合物を１２．５　ｍｇ／ｋｇの用量で投与した場合、０．５％ヒドロキシプロピルメチルセルロースを投与した場合と比較して摂食量が有意に抑制された。
　例えば化合物Ｉａ－３　１２．５　ｍｇ／ｋｇの用量で投与した群（Ａ群）の注入２時間後および４時間後の摂食量はそれぞれ０．２８±０．０５ｇ、０．５７±０．０８ｇであった。一方、０．５％ヒドロキシプロピルメチルセルロース溶液投与群（Ｂ群）の注入２時間後および４時間後の摂食量はそれぞれ０．６２±０．０６ｇ、１．３７±０．０８ｇであった。また、ＮＰＹ　Ｙ５受容体特異的アゴニストを注入しない０．５％ヒドロキシプロピルメチルセルロース溶液投与群（Ｃ群）の摂食量は０．１０±０．０３ｇ、０．１３±０．０２ｇであり、Ｃ群の値をＡ，Ｂ群から差し引いて換算すれば、Ａ群における注入２時間後および４時間後のＢ群に対する摂食抑制率はそれぞれ６５．１％，　６４．１％になる。 Test Example 6 Feeding Inhibitory Action Under ether anesthesia, skin was incised along the midline from the external occipital crest to the back of the nose of male C57BL / 6J mice (12-14 weeks old, 25-30 g) to expose the upper skull . A hole having a diameter of about 1 mm was formed using an electric drill at a position about 1 mm rearward from the exposed part bregma toward lamda, about 1 mm from the midline to the left side. A 0.5% hydroxypropylmethylcellulose aqueous solution (manufactured by Shin-Etsu Chemical Co., Ltd.) or a test substance suspended in this aqueous solution is forcibly orally administered to mice after waking up from anesthesia, and NPY Y5 receptor-specific agonist 1 hour after administration ([CPP 1-7 , NPY 19-23 , Ala 31 , Aib 32 , Gln 34 ] -hPanalytic Polypeptide: manufactured by Tocris Co.) 0.1 nmol was injected from the head opening previously provided using a cannula. The food intake of mice was measured 2 hours and 4 hours after the injection, and the difference in food intake between the group administered with 0.5% hydroxypropylmethylcellulose solution and the group administered with the test substance was investigated. As a result, when the compound of the present invention was administered at a dose of 12.5 mg / kg, the amount of food intake was significantly suppressed compared to the case where 0.5% hydroxypropylmethylcellulose was administered.
For example, in the group (Group A) administered at a dose of 12.5 mg / kg of Compound Ia-3, the food intake after 2 hours and 4 hours after injection was 0.28 ± 0.05 g and 0.57 ± 0.08 g, respectively. Met. On the other hand, the amount of food consumed 2 hours and 4 hours after injection in the 0.5% hydroxypropylmethylcellulose solution administration group (Group B) was 0.62 ± 0.06 g and 1.37 ± 0.08 g, respectively. In addition, the amount of food consumed in the 0.5% hydroxypropylmethylcellulose solution administration group (Group C) in which no NPY Y5 receptor-specific agonist was injected was 0.10 ± 0.03 g, 0.13 ± 0.02 g, and Group C If the value of A is subtracted from the A and B groups and converted, the feeding suppression rates for the B group at 2 hours and 4 hours after the injection in the A group are 65.1% and 64.1%, respectively.
試験例７　ＣＹＰ阻害試験
　市販のプールドヒト肝ミクロソームを用いて、ヒト主要ＣＹＰ５分子種（ＣＹＰ１Ａ２、２Ｃ９、２Ｃ１９、２Ｄ６、３Ａ４）の典型的基質代謝反応として７－エトキシレゾルフィンのＯ－脱エチル化（ＣＹＰ１Ａ２）、トルブタミドのメチル－水酸化（ＣＹＰ２Ｃ９）、メフェニトインの４’－水酸化（ＣＹＰ２Ｃ１９）、　デキストロメトルファンのＯ脱メチル化（ＣＹＰ２Ｄ６）、テルフェナジンの水酸化（ＣＹＰ３Ａ４）を指標とし、それぞれの代謝物生成量が被検化合物によって阻害される程度を評価した。 Test Example 7 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) The degree to which the metabolite production was inhibited by the test compound was evaluated.
　反応条件は以下のとおり：基質、０．５　μｍｏｌ／Ｌ　エトキシレゾルフィン（ＣＹＰ１Ａ２）、１００　μｍｏｌ／Ｌ　トルブタミド（ＣＹＰ２Ｃ９）、５０　μｍｏｌ／Ｌ　Ｓ－メフェニトイン（ＣＹＰ２Ｃ１９）、５μｍｏｌ／Ｌ　デキストロメトルファン（ＣＹＰ２Ｄ６）、１　μｍｏｌ／Ｌ　テルフェナジン（ＣＹＰ３Ａ４）；反応時間、１５分；反応温度、３７℃；酵素、プールドヒト肝ミクロソーム　０．２ｍｇ　タンパク質／ｍＬ；被検薬物濃度、１、５、１０、２０　μｍｏｌ／Ｌ（４点）。 The reaction conditions are as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan ( CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsomes 0.2 mg protein / mL; test drug concentration 1, 5, 10, 20 μmol / L (4 points).
　９６穴プレートに反応溶液として、５０ｍＭ　Ｈｅｐｅｓ　緩衝液中に各５種の基質、ヒト肝ミクロソーム、被検薬物を上記組成で加え、補酵素であるＮＡＤＰＨを添加して、指標とする代謝反応を開始し、３７℃、１５分間反応した後、メタノール／アセトニトリル＝１／１（ｖ／ｖ）溶液を添加することで反応を停止した。３０００ｒｐｍ、１５分間の遠心操作後、遠心上清中のレゾルフィン（ＣＹＰ１Ａ２代謝物）を蛍光マルチラベルカウンタで、トルブタミド水酸化体　（ＣＹＰ２Ｃ９代謝物）、メフェニトイン４’水酸化体（ＣＹＰ２Ｃ１９代謝物）、デキストロルファン（ＣＹＰ２Ｄ６代謝物）、テルフェナジンアルコール体（ＣＹＰ３Ａ４代謝物）をＬＣ／ＭＳ／ＭＳで定量した。 As a reaction solution in a 96-well plate, 5 kinds of each substrate, human liver microsome, and test drug are added in the above composition in 50 mM Hepes buffer solution, and NADPH as a coenzyme is added to start a metabolic reaction as an index. The mixture was reacted at 37 ° C. for 15 minutes, and then the reaction was stopped by adding a methanol / acetonitrile = 1/1 (v / v) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant of the centrifugation was analyzed with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite), Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.
　薬物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、被検薬物溶液を加えたそれぞれの濃度での残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出した。
　結果を以下に示す。
化合物Ｉａ－１：５種　＞２０μＭ
化合物Ｉａ－４：５種　＞２０μＭ
化合物ＩＩａ－６：５種　＞２０μＭ
化合物ＩＩａ－１１：５種　＞２０μＭ
化合物ＩＩｂ－１０：５種　＞１５μＭ　　
化合物ＩＩｂ－６６　：５種　＞２０μＭ
化合物ＩＩｃ－１０：５種　＞１６μＭ　　
化合物ＩＩｃ－６６　：５種　＞２０μＭ The control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution added was calculated. The IC 50 was calculated by inverse estimation using a logistic model.
The results are shown below.
Compound Ia-1: 5 species> 20 μM
Compound Ia-4: 5 species> 20 μM
Compound IIa-6: 5 species> 20 μM
Compound IIa-11: 5 species> 20 μM
Compound IIb-10: 5 species> 15 μM
Compound IIb-66: 5 types> 20 μM
Compound IIc-10: 5 species> 16 μM
Compound IIc-66: 5 types> 20 μM
試験例８　代謝安定性について
　ヒト肝ミクロソームによる代謝安定性評価：トリス塩酸バッファー（ｐＨ７．４）中にＮＡＤＰＨ（終濃度１ｍＭ，酸化的代謝の場合）、肝ミクロソーム（終濃度０．５　ｍｇ　ｐｒｏｔｅｉｎ／ｍｌ）および各化合物（終濃度２μＭ）を添加し、３７℃で０分および３０分間反応させた。グルクロン酸抱合の場合は、ＮＡＤＰＨに代えてＵＤＰＧＡ（終濃度５ｍＭ）を添加した。反応液の倍量のアセトニトリル／メタノール＝１／１（ｖ／ｖ）を添加し反応を停止した後、その遠心上清中の化合物をＨＰＬＣで測定した。０分および３０分の値の比較から代謝反応による消失量を算出し、本発明化合物の代謝安定性を確認した。
　以下に化合物濃度０．５μＭでの残存率を示す。
化合物Ｉａ－１：８７．４％
化合物Ｉａ－１１：７６．４％
化合物ＩＩａ－３：９２．７％
化合物ＩＩａ－５：９９．３％
化合物ＩＩａ－３３：１００％
化合物ＩＩｂ－１０：９７．７％
化合物ＩＩｂ－６５：９１．０％
化合物ＩＩｃ－１０：９２．４％
化合物ＩＩｃ－６６：９２．３％ Test Example 8 Metabolic stability Metabolic stability evaluation by human liver microsomes: NADPH (final concentration 1 mM, in the case of oxidative metabolism), liver microsomes (final concentration 0.5 mg protein / in) in Tris-HCl buffer (pH 7.4) ml) and each compound (final concentration 2 μM) were added and reacted at 37 ° C. for 0 and 30 minutes. In the case of glucuronidation, UDPGA (final concentration 5 mM) was added instead of NADPH. After the reaction was stopped by adding acetonitrile / methanol = 1/1 (v / v) twice the amount of the reaction solution, the compound in the centrifugal supernatant was measured by HPLC. The amount of disappearance due to metabolic reaction was calculated from the comparison of the values of 0 minute and 30 minutes, and the metabolic stability of the compound of the present invention was confirmed.
The remaining rate at a compound concentration of 0.5 μM is shown below.
Compound Ia-1: 87.4%
Compound Ia-11: 76.4%
Compound IIa-3: 92.7%
Compound IIa-5: 99.3%
Compound IIa-33: 100%
Compound IIb-10: 97.7%
Compound IIb-65: 91.0%
Compound IIc-10: 92.4%
Compound IIc-66: 92.3%
試験例９　粉末溶解度試験
　９６ウェルプレートに検体を適量入れ、ＪＰ－１液（塩化ナトリウム２．０ｇ、塩酸７．０ｍＬに水を加えて１０００ｍＬとする）、ＪＰ－２液（ｐＨ６．８のリン酸塩緩衝液５００ｍＬに水５００ｍＬを加える）、２０ｍｍｏｌ／Ｌ　ＴＣＡ（タウロコール酸ナトリウム）／ＪＰ－２液（ＴＣＡ　１．０８ｇにＪＰ－２液を加え１００ｍＬとする）を２００μＬずつ添加する。試験液添加後に溶解した場合には、適宜原末を追加する。密閉し３７℃で１時間振とうする。濾過し、各濾液１００μＬにメタノール１００μＬを添加して２倍希釈を行う。希釈倍率は、必要に応じて変更する。気泡および析出物がないかを確認し、密閉して振とうする。絶対検量線法によりＨＰＬＣを用いて定量を行う。 Test Example 9 Powder Solubility Test An appropriate amount of specimen was placed in a 96-well plate, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid was added to make 1000 mL), JP-2 solution (pH 6.8 phosphorus) 200 mL of water is added to 500 mL of the acid buffer, and 20 mmol / L TCA (sodium taurocholate) / JP-2 solution (JP2 solution is added to 1.08 g of TCA to make 100 mL). When dissolving after adding the test solution, add bulk powder as appropriate. Seal and shake at 37 ° C. for 1 hour. Filter, add 100 μL of methanol to 100 μL of each filtrate and dilute 2 times. Change the dilution factor as necessary. Check for bubbles and deposits, seal and shake. Quantification is performed using HPLC by the absolute calibration curve method.
製剤例
　以下に示す製剤例は例示にすぎないものであり、発明の範囲を何ら限定することを意図するものではない。
製剤例１　錠剤
　　化合物（Ｉ）　　　　　　　　　１５ｍｇ
　　デンプン　　　　　　　　　　　１５ｍｇ
　　乳糖　　　　　　　　　　　　　１５ｍｇ
　　結晶性セルロース　　　　　　　１９ｍｇ
　　ポリビニルアルコール　　　　　　３ｍｇ
　　蒸留水　　　　　　　　　　　　３０ｍｌ
　　ステアリン酸カルシウム　　　　　３ｍｇ
　ステアリン酸カルシウム以外の成分を均一に混合し、破砕造粒して乾燥し、適当な大きさの顆粒剤とする。次にステアリン酸カルシウムを添加して圧縮成形して錠剤とする。 Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1 Tablet Compound (I) 15 mg
Starch 15mg
Lactose 15mg
Crystalline cellulose 19mg
Polyvinyl alcohol 3mg
30ml distilled water
Calcium stearate 3mg
Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
製剤例２　カプセル剤
　　化合物（Ｉ）　　　　　　　　　１０ｍｇ
　　ステアリン酸マグネシウム　　　１０ｍｇ
　　乳糖　　　　　　　　　　　　　８０ｍｇ
を均一に混合して粉末または細粒状として散剤をつくる。それをカプセル容器に充填してカプセル剤とする。 Formulation Example 2 Capsule Compound (I) 10 mg
Magnesium stearate 10mg
Lactose 80mg
Are mixed uniformly to make a powder as a fine powder or powder. It is filled into a capsule container to form a capsule.
製剤例３　顆粒剤
　　化合物（Ｉ）　　　　　　　　　　　３０ｇ
　　乳糖　　　　　　　　　　　　　　２６５ｇ
　　ステアリン酸マグネシウム　　　　　　５ｇ
　よく混合し、圧縮成型した後、粉砕、整粒し、篩別して適当な大きさの顆粒剤とする。 Formulation Example 3 Granules Compound (I) 30 g
Lactose 265g
Magnesium stearate 5g
After mixing well, compression molding, pulverizing, sizing, and sieving to make granules of appropriate size.
　以上の試験例から明らかなように、本発明化合物はＮＰＹ　Ｙ５受容体拮抗作用を示す。従って、本発明化合物は摂食障害、肥満症、神経性食欲昂進症、性的障害、生殖障害、鬱病、癲癇発作、高血圧、脳溢血、鬱血心不全、睡眠障害等の予防または治療のための医薬として非常に有用である。また、本発明化合物は有効な摂食抑制作用を示すことから、肥満症における体重管理、体重減量、体重減量後の体重維持のために非常に有用である。さらに、肥満がリスクファクターとなる疾患、例えば糖尿病、高血圧、高脂血症、動脈硬化、急性冠症候群等の治療または予防のための医薬として非常に有用である。 As is clear from the above test examples, the compound of the present invention exhibits NPY Y5 receptor antagonistic action. Therefore, the compound of the present invention is used as a medicament for the prevention or treatment of eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension, cerebral hyperemia, congestive heart failure, sleep disorders, etc. Very useful. In addition, since the compound of the present invention exhibits an effective anti-feeding action, it is very useful for weight management, weight loss, and weight maintenance after weight loss in obesity. Furthermore, it is very useful as a medicament for treating or preventing diseases in which obesity is a risk factor, such as diabetes, hypertension, hyperlipidemia, arteriosclerosis, and acute coronary syndrome.

Claims (16)

  1. 式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
    （式中、
    Ｒ１およびＲ２はそれぞれ独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリールまたは置換若しくは非置換のヘテロサイクリルであり、
    Ｒ１およびＲ２は隣接する窒素原子と一緒になって置換若しくは非置換の含窒素芳香族ヘテロ環または置換若しくは非置換の含窒素非芳香族ヘテロ環を形成してもよく、または
    Ｒ１およびＲ５は隣接する窒素原子と一緒になって置換若しくは非置換の含窒素非芳香族ヘテロ環を形成してもよく、
    Ｘは芳香族ヘテロ環または非芳香族へテロ環であり、
    Ｒ３はそれぞれ独立して、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリールまたは置換若しくは非置換のヘテロサイクリルであり、
    Ｒ４はそれぞれ独立して、ハロゲン、シアノ、ニトロ、ニトロソ、アジド、オキソ、
    置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、
    ヒドロキシ、置換若しくは非置換のアルコキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロサイクリルオキシ、
    メルカプト、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のシクロアルキルチオ、置換若しくは非置換のシクロアルケニルチオ、置換若しくは非置換のアリールチオ、置換若しくは非置換のヘテロアリールチオ、置換若しくは非置換のヘテロサイクリルチオ、
    カルボキシ、置換若しくは非置換のアルコキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のシクロアルキルオキシカルボニル、置換若しくは非置換のシクロアルケニルオキシカルボニル、置換若しくは非置換のアリールオキシカルボニル、置換若しくは非置換のヘテロアリールオキシカルボニル、置換若しくは非置換のヘテロサイクリルオキシカルボニル、置換若しくは非置換のカルバモイル、
    ホルミル、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のシクロアルキルカルボニル、置換若しくは非置換のシクロアルケニルカルボニル、置換若しくは非置換のアリールカルボニル、置換若しくは非置換のヘテロアリールカルボニル、置換若しくは非置換のヘテロサイクリルカルボニル、
    スルフィノ、スルホ、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のシクロアルキルスルホニル、置換若しくは非置換のシクロアルケニルスルホニル、置換若しくは非置換のアリールスルホニル、置換若しくは非置換のヘテロアリールスルホニル、置換若しくは非置換のヘテロサイクリルスルホニル、置換若しくは非置換のスルファモイルまたは置換若しくは非置換のアミノであり、
    Ｒ５は水素、置換若しくは非置換のアルキルまたは置換若しくは非置換のアリールであり、
    ｍは０～２の整数であり、
    ｎは０～５の整数であり、
    Ｒはそれぞれ独立して、ハロゲン、オキソ、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルであり、
    ｐは０～２の整数である）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＮＰＹＹ５受容体拮抗作用を有する医薬組成物。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
    (Where
    R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl,
    R 1 and R 2 together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing aromatic heterocycle or a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, or R 1 and R 5 together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle,
    X is an aromatic heterocycle or a non-aromatic heterocycle,
    Each R 3 is independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl;
    Each R 4 is independently halogen, cyano, nitro, nitroso, azide, oxo,
    Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
    Hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl Oxy, substituted or unsubstituted heterocyclyloxy,
    Mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, Substituted or unsubstituted heterocyclylthio,
    Carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or Unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl,
    Formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted hetero Arylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl,
    Sulfino, sulfo, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted A heteroarylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amino,
    R 5 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
    m is an integer from 0 to 2,
    n is an integer from 0 to 5,
    Each R is independently halogen, oxo, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
    p is an integer of 0 to 2, and a pharmaceutical composition having an NPYY5 receptor antagonistic action, comprising a compound represented by the formula: pharmaceutically acceptable salts thereof or solvates thereof.
  2. 式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000002
    （式中、
    Ｒ１およびＲ２はそれぞれ独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリールまたは置換若しくは非置換のヘテロサイクリルであり、
    Ｒ１およびＲ２は隣接する窒素原子と一緒になって置換若しくは非置換の含窒素芳香族ヘテロ環または置換若しくは非置換の含窒素非芳香族ヘテロ環を形成してもよく、または
    Ｒ１およびＲ５は隣接する窒素原子と一緒になって置換若しくは非置換の含窒素非芳香族ヘテロ環を形成してもよく、
    Ｘは芳香族へテロ環または非芳香族ヘテロ環であり、
    Ｒ３はそれぞれ独立して、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリールまたは置換若しくは非置換のヘテロサイクリルであり、
    Ｒ４はそれぞれ独立して、ハロゲン、シアノ、ニトロ、ニトロソ、アジド、オキソ、
    置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、
    ヒドロキシ、置換若しくは非置換のアルコキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロサイクリルオキシ、
    メルカプト、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のシクロアルキルチオ、置換若しくは非置換のシクロアルケニルチオ、置換若しくは非置換のアリールチオ、置換若しくは非置換のヘテロアリールチオ、置換若しくは非置換のヘテロサイクリルチオ、
    カルボキシ、置換若しくは非置換のアルコキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のシクロアルキルオキシカルボニル、置換若しくは非置換のシクロアルケニルオキシカルボニル、置換若しくは非置換のアリールオキシカルボニル、置換若しくは非置換のヘテロアリールオキシカルボニル、置換若しくは非置換のヘテロサイクリルオキシカルボニル、置換若しくは非置換のカルバモイル、
    ホルミル、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のシクロアルキルカルボニル、置換若しくは非置換のシクロアルケニルカルボニル、置換若しくは非置換のアリールカルボニル、置換若しくは非置換のヘテロアリールカルボニル、置換若しくは非置換のヘテロサイクリルカルボニル、
    スルフィノ、スルホ、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のシクロアルキルスルホニル、置換若しくは非置換のシクロアルケニルスルホニル、置換若しくは非置換のアリールスルホニル、置換若しくは非置換のヘテロアリールスルホニル、置換若しくは非置換のヘテロサイクリルスルホニル、置換若しくは非置換のスルファモイルまたは置換若しくは非置換のアミノであり、
    Ｒ５は水素、置換若しくは非置換のアルキルまたは置換若しくは非置換のアリールであり、
    ｍは０～２の整数であり、
    ｎは０～５の整数であり、
    Ｒはそれぞれ独立して、ハロゲン、オキソ、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルであり、
    ｐは０～２の整数である）で示される化合物（但し、以下の化合物を除く。
    Figure JPOXMLDOC01-appb-C000003
    ）、
    その製薬上許容される塩またはそれらの溶媒和物。     Formula (I):
    Figure JPOXMLDOC01-appb-C000002
    (Where
    R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl,
    R 1 and R 2 together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing aromatic heterocycle or a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, or R 1 and R 5 together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle,
    X is an aromatic heterocycle or a non-aromatic heterocycle,
    Each R 3 is independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl;
    Each R 4 is independently halogen, cyano, nitro, nitroso, azide, oxo,
    Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
    Hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl Oxy, substituted or unsubstituted heterocyclyloxy,
    Mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, Substituted or unsubstituted heterocyclylthio,
    Carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or Unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl,
    Formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted hetero Arylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl,
    Sulfino, sulfo, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted A heteroarylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amino,
    R 5 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
    m is an integer from 0 to 2,
    n is an integer from 0 to 5,
    Each R is independently halogen, oxo, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
    p is an integer of 0 to 2 (excluding the following compounds).
    Figure JPOXMLDOC01-appb-C000003
    ),
    The pharmaceutically acceptable salt or solvate thereof.
  3. Ｘがインドール、ピロロピリジン、ピロロピリミジン、ピロロピラジン、イミダゾール、ピラゾール、ピロール、トリアゾール、ピリジン、イミダゾピリジンまたはベンゾイミダゾールである、請求項２記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound according to claim 2, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein X is indole, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, imidazole, pyrazole, pyrrole, triazole, pyridine, imidazopyridine or benzimidazole. object.
  4. Ｘがピラゾールである、請求項２記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound according to claim 2, wherein X is pyrazole, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  5. 式：
    Figure JPOXMLDOC01-appb-C000004
    で示される基が、
    Figure JPOXMLDOC01-appb-C000005
    で示される基であり、
    ｎが０または１である、
    請求項２記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。     formula:
    Figure JPOXMLDOC01-appb-C000004
    A group represented by
    Figure JPOXMLDOC01-appb-C000005
    A group represented by
    n is 0 or 1;
    The compound according to claim 2, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  6. ｍが１である、請求項２～５いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound according to any one of claims 2 to 5, wherein m is 1, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  7. Ｒ１およびＲ２がそれぞれ独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキルまたは置換若しくは非置換のアリールである、請求項２～５いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl. Or a pharmaceutically acceptable salt or solvate thereof.
  8. Ｒ２が置換若しくは非置換のアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキルまたは置換若しくは非置換のアリールである、請求項２～５いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound according to any one of claims 2 to 5, wherein R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, or a pharmaceutically acceptable salt thereof Salts or solvates thereof.
  9. Ｒ１が水素または置換若しくは非置換のアルキルであり、
    Ｒ２が置換若しくは非置換のアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキルまたは置換若しくは非置換のアリールである、請求項２～５いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。     R 1 is hydrogen or substituted or unsubstituted alkyl;
    The compound according to any one of claims 2 to 5, wherein R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, or a pharmaceutically acceptable salt thereof Salts or solvates thereof.
  10. Ｒ１およびＲ２が隣接する窒素原子と一緒になって置換若しくは非置換の含窒素非芳香族ヘテロ環を形成している、請求項２～５いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound according to any one of claims 2 to 5, wherein R 1 and R 2 together with the adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, and a pharmaceutically acceptable salt thereof. Salts or solvates thereof.
  11. Ｒ３がそれぞれ独立して、置換または非置換のフェニルである、
    請求項２～５いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。     Each R 3 is independently substituted or unsubstituted phenyl;
    The compound according to any one of claims 2 to 5, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  12. Ｒ４がそれぞれ独立して、ハロゲン、シアノまたは置換若しくは非置換のアルキルである、請求項２～５いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound according to any one of claims 2 to 5, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein each R 4 is independently halogen, cyano, or substituted or unsubstituted alkyl.
  13. 請求項２～１２のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を有効成分とする医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 2 to 12, its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.
  14. ＮＰＹ　Ｙ５受容体拮抗作用を有する、請求項１３記載の医薬組成物。 The pharmaceutical composition according to claim 13, which has an NPY Y5 receptor antagonistic action.
  15. 請求項２～１２のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、ＮＰＹ　Ｙ５の関与する疾患の治療または予防方法。 A method for treating or preventing a disease involving NPY Y5, which comprises administering the compound according to any one of claims 2 to 12, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  16. ＮＰＹ　Ｙ５受容体の関与する疾患を治療または予防するための、請求項２～１２のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound according to any one of claims 2 to 12, its pharmaceutically acceptable salt, or a solvate thereof, for treating or preventing a disease involving NPY Y5 receptor.
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Publication number Priority date Publication date Assignee Title
US8815271B2 (en) 2010-11-03 2014-08-26 Dow Agrosciences, Llc. Pesticidal compositions and processes related thereto
US9024031B1 (en) 2014-08-19 2015-05-05 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
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US9029554B1 (en) 2013-10-17 2015-05-12 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9029555B1 (en) 2014-07-31 2015-05-12 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9029556B1 (en) 2014-07-31 2015-05-12 Dow Argosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
CN104628656A (en) * 2015-02-11 2015-05-20 佛山市赛维斯医药科技有限公司 Symmetric cyclohexanecarboxamide type double-target-point inhibitor containing pyrimidine structure and application
CN104649981A (en) * 2015-02-11 2015-05-27 佛山市赛维斯医药科技有限公司 Symmetrical cyclohexane carboxylic acid benzyl amide SGLT2/SGLT1 double-target inhibitor with pyrimidine structure as well as preparation method and application of symmetrical cyclohexane carboxylic acid benzyl amide SGLT2/SGLT1 double-target inhibitor
CN104649980A (en) * 2015-02-11 2015-05-27 佛山市赛维斯医药科技有限公司 Symmetrical cyclohexane carboxylic acid amide SGLT2/SGLT1 double-target inhibitor with pyrimidine structure as well as preparation method and application of symmetrical cyclohexane carboxylic acid amide SGLT2/SGLT1 double-target inhibitor
US9044017B2 (en) 2013-10-17 2015-06-02 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
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US9085552B1 (en) 2014-09-12 2015-07-21 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9102655B2 (en) 2013-10-17 2015-08-11 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9102654B2 (en) 2013-10-17 2015-08-11 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9108946B2 (en) 2013-10-17 2015-08-18 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9137998B2 (en) 2013-10-22 2015-09-22 Dow Agrosciences Llc Pesticidal compositions and related methods
US9144241B2 (en) 2013-10-22 2015-09-29 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
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US9199964B1 (en) 2014-07-31 2015-12-01 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
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US9497966B2 (en) 2013-10-22 2016-11-22 Dow Agrosciences Llc Pesticidal compositions and related methods
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US9591857B2 (en) 2012-04-27 2017-03-14 Dow Agrosciences Llc Pesticidal compositions and processes related thereto
US9655365B2 (en) 2011-10-26 2017-05-23 Dow Agrosciences Llc Pesticidal compositions and processes related thereto
US9708288B2 (en) 2012-04-27 2017-07-18 Dow Agrosciences Llc Pesticidal compositions and processes related thereto
US9788546B2 (en) 2013-10-22 2017-10-17 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9788545B2 (en) 2013-10-22 2017-10-17 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9801383B2 (en) 2013-10-22 2017-10-31 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
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US9808008B2 (en) 2013-10-22 2017-11-07 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US10100033B2 (en) 2016-12-29 2018-10-16 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US10233155B2 (en) 2016-12-29 2019-03-19 Dow Agrosciences Llc Processes for the preparation of pesticide compounds
US11724982B2 (en) 2014-10-10 2023-08-15 The Research Foundation For The State University Of New York Trifluoromethoxylation of arenes via intramolecular trifluoromethoxy group migration

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002326983A (en) * 2001-03-01 2002-11-15 Pfizer Prod Inc Beta 3 agonist and use thereof
JP2003505376A (en) * 1999-07-21 2003-02-12 藤沢薬品工業株式会社 Benzimidazolone derivatives and their use as phosphodiesterase inhibitors
WO2004052862A1 (en) * 2002-12-10 2004-06-24 Ono Pharmaceutical Co., Ltd. Nitrogen-containing heterocyclic compounds and medicinal use thereof
JP2006508117A (en) * 2002-11-12 2006-03-09 ノバルティス アクチエンゲゼルシャフト 4-Amino-5-phenyl-7-cyclohexyl-pyrrolo [2,3-d] pyrimidine derivatives
JP2007510717A (en) * 2003-11-12 2007-04-26 エルジー・ライフ・サイエンシーズ・リミテッド Melanocortin receptor agonist
WO2009131096A1 (en) * 2008-04-21 2009-10-29 塩野義製薬株式会社 Compound having npy y5 receptor antagonist activity
WO2010096462A1 (en) * 2009-02-17 2010-08-26 Enanta Pharmaceuticals, Inc Linked diimidazole derivatives

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003505376A (en) * 1999-07-21 2003-02-12 藤沢薬品工業株式会社 Benzimidazolone derivatives and their use as phosphodiesterase inhibitors
JP2002326983A (en) * 2001-03-01 2002-11-15 Pfizer Prod Inc Beta 3 agonist and use thereof
JP2006508117A (en) * 2002-11-12 2006-03-09 ノバルティス アクチエンゲゼルシャフト 4-Amino-5-phenyl-7-cyclohexyl-pyrrolo [2,3-d] pyrimidine derivatives
WO2004052862A1 (en) * 2002-12-10 2004-06-24 Ono Pharmaceutical Co., Ltd. Nitrogen-containing heterocyclic compounds and medicinal use thereof
JP2007510717A (en) * 2003-11-12 2007-04-26 エルジー・ライフ・サイエンシーズ・リミテッド Melanocortin receptor agonist
WO2009131096A1 (en) * 2008-04-21 2009-10-29 塩野義製薬株式会社 Compound having npy y5 receptor antagonist activity
WO2010096462A1 (en) * 2009-02-17 2010-08-26 Enanta Pharmaceuticals, Inc Linked diimidazole derivatives

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Publication number Priority date Publication date Assignee Title
US8815271B2 (en) 2010-11-03 2014-08-26 Dow Agrosciences, Llc. Pesticidal compositions and processes related thereto
US9422278B2 (en) 2010-11-03 2016-08-23 Dow Agrosciences Llc Pesticidal compositions and processes related thereto
US10093670B2 (en) 2011-07-15 2018-10-09 Shionogi & Co., Ltd. Azabenzimidazole derivative having AMPK-activating activity
US9567330B2 (en) 2011-07-15 2017-02-14 Shionogi & Co., Ltd. Azabenzimidazole derivative having AMPK-activating activity
US9655365B2 (en) 2011-10-26 2017-05-23 Dow Agrosciences Llc Pesticidal compositions and processes related thereto
US9282739B2 (en) 2012-04-27 2016-03-15 Dow Agrosciences Llc Pesticidal compositions and processes related thereto
US9708288B2 (en) 2012-04-27 2017-07-18 Dow Agrosciences Llc Pesticidal compositions and processes related thereto
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US9434712B2 (en) 2013-10-17 2016-09-06 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
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US9102655B2 (en) 2013-10-17 2015-08-11 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
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US10233155B2 (en) 2016-12-29 2019-03-19 Dow Agrosciences Llc Processes for the preparation of pesticide compounds

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