WO2012020725A1 - Heterocyclic derivative having npy y5 receptor antagonism - Google Patents

Heterocyclic derivative having npy y5 receptor antagonism Download PDF

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WO2012020725A1
WO2012020725A1 PCT/JP2011/068032 JP2011068032W WO2012020725A1 WO 2012020725 A1 WO2012020725 A1 WO 2012020725A1 JP 2011068032 W JP2011068032 W JP 2011068032W WO 2012020725 A1 WO2012020725 A1 WO 2012020725A1
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substituted
unsubstituted
formula
compound
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直樹 神山
顕 行正
祐二 西浦
友亮 田村
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塩野義製薬株式会社
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/08Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/30Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08Radicals containing only hydrogen and carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/10Radicals substituted by halogen atoms or nitro radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14Radicals substituted by nitrogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

Definitions

  • the present invention relates to a novel heterocyclic derivative having NPY Y5 receptor antagonistic activity and useful as a pharmaceutical, particularly as an anti-obesity drug.
  • Obesity is defined as the accumulation of excess fat or adipose tissue in the body relative to lean body mass, and is recognized as the main risk factor for health problems.
  • the body mass index (BMI) is a simple index of the height-weight ratio that is commonly used to classify an adult (over 15 years old) group or individual as overweight or obese. It is defined as the body weight (kg / m 2 ) expressed in kilograms divided by the height squared in meters. According to the World Health Organization, BMI of 25 kg / m 2 or more is “overweight” and 30 kg / m 2 or more is “obese”. On the other hand, the Japanese Obesity Society designates BMI of 25 kg / m 2 or more as “obesity”.
  • 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. In previous reports, NPY has been found to have feeding promoting action, anticonvulsant action, learning promoting action, anti-anxiety action, anti-stress 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.
  • Non-Patent Document 5 a pharmaceutical composition having an NPY receptor antagonistic action is a preventive or therapeutic agent for various diseases involving the NPY receptor as described above.
  • subtypes Y1, Y2, Y3, Y4, Y5, and Y6 have been discovered for NPY receptors (see Non-Patent Document 6).
  • 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 7 to 9).
  • Patent Documents 1 and 2 and Non-Patent Document 1 include the formula: A benzimidazole derivative having an NPY Y5 receptor antagonistic activity having a group represented by formula (2) at the 2-position is disclosed.
  • Patent Document 3 discloses a benzimidazole derivative having an SCD inhibitory action.
  • the document discloses 6- (cyclopropylsulfonyl) -2- (2′-fluorobiphenyl-4-yl) -1) -1H-benzimidazole (Example 2 of the document).
  • Patent Document 4 discloses a benzimidazole derivative having an anticancer activity.
  • Patent Document 5 discloses a benzimidazole derivative having an ATP-sensitive potassium channel inhibitory action.
  • Patent Document 6 discloses a benzimidazole derivative having a protein kinase inhibitory action.
  • the document includes 2- (4-amino-1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-yl) -N, N-diethyl-1H-benzo [d].
  • Imidazole-5-sulfonamide (Example 59 of that document) is disclosed.
  • Patent Document 7 discloses a benzimidazole derivative having a substituted phenyl-substituted sulfamoyl group at the 5-position, which acts on tyrosine kinase.
  • Patent Documents 8 and 9 disclose benzimidazole derivatives having an unsubstituted sulfamoyl group at the 5-position.
  • Patent Documents 10 to 14 and Non-Patent Documents 2 to 4 disclose benzimidazole derivatives having a methanesulfonyl group at the 5-position.
  • Patent Document 15 discloses a benzimidazole derivative having a benzylsulfamoyl group at the 5-position.
  • Non-Patent Document 2 discloses a benzimidazole derivative having a phenylsulfamoyl group at the 5-position.
  • the nitrogen atom on the benzimidazole ring is substituted with a methyl group.
  • Patent Documents 3 to 15 and Non-Patent Documents 2 to 4 do not describe NPY Y5 receptor antagonistic action.
  • An object of the present invention is to provide a novel heterocyclic 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 eating 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.
  • substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group is substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino It may be.
  • X is —SO 2 —
  • Y 1 is ⁇ C (—H) —
  • Y 3 is ⁇ C (—H) —
  • Z is —N ⁇
  • R 2 is cyclopropyl
  • R 11 and R 12 are hydrogen
  • R 4 is phenyl
  • n is 1
  • R 5 is 2-fluorophenyl
  • X is —N (—Et) —SO 2 —
  • Y 1 is ⁇ C (—H) —
  • Y 3 is ⁇ C ( -H)-
  • R 2 is ethyl
  • R 11 is amino
  • R 12 is hydrogen
  • R 4 is piperidin-4-yl
  • n is 1
  • R 5 is 7H-pyrrolo [2,3-d] -pyrimidin-4-yl.
  • R 6 is hydrogen or substituted or unsubstituted alkyl, or R 6 together with the adjacent nitrogen atom together with R 2 may form a substituted or unsubstituted heterocycle.
  • the above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group is substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino It may be.
  • X is —N (—Et) —SO 2 —
  • Y 1 is ⁇ C (—H) —
  • Y 3 is ⁇ C (— H) —
  • Z is —N ⁇
  • R 2 is ethyl
  • R 11 is amino
  • R 12 is hydrogen
  • R 4 is piperidin-4-yl
  • n is 1.
  • R 5 is 7H-pyrrolo [2,3-d] -pyrimidin-4-yl.
  • a pharmaceutical composition having an NPY Y5 receptor antagonistic action comprising the compound according to any one of (1) to (12) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group is substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino It may be.
  • R 4 is a substituted or unsubstituted non-aromatic heterocyclic group, n is 1.
  • a pharmaceutically acceptable salt thereof, or a solvate thereof a pharmaceutical composition having an NPY Y5 receptor antagonistic action.
  • n is 1, and R 5 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted non-aromatic heterocycle
  • 17. The pharmaceutical composition according to the above (16), wherein n is 1, and R 5 is a substituted or unsubstituted non-aromatic heterocyclic group.
  • n is 1, R 5 is cyano, substituted or unsubstituted alkyl or a group represented by the formula: —O—R 10 , and R 10 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl
  • (19) The pharmaceutical composition according to any one of the above (15) to (18), wherein R 4 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • X is —SO 2 — or —N (—R 6 ) —SO 2 —
  • Y 1 is ⁇ C (—R 8 ) —
  • Y 2 is —C (—R 3 ) ⁇
  • (21) For use in prevention and / or treatment of obesity or weight management in obesity for use in combination with the pharmaceutical composition according to any one of (13) to (20) above, which comprises a compound having an anti-obesity action Pharmaceutical composition.
  • a method for preventing and / or treating obesity which comprises administering a compound represented by the formula (I) described in (15) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a method for weight management in obesity comprising administering the compound represented by the formula (I) described in (15) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the compound of the present invention exhibits NPY Y5 receptor antagonistic action, and is associated with drugs, particularly 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, sleep disorder and the like.
  • drugs particularly NPY Y5
  • NPY Y5 receptor antagonistic action 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, sleep disorder and the like.
  • 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 the treatment or prevention of diseases in which obesity is a risk factor, such as
  • the present invention relates to a compound of formula (I): (Where X is —SO 2 —, —N (—R 6 ) —SO 2 — or —SO 2 —N (—R 7 ) —, Y 1 is ⁇ C (—R 8 ) — or ⁇ N—, Y 2 is —C (—R 3 ) ⁇ or —N ⁇ , Y 3 is ⁇ C (—R 1 ) — or ⁇ N—, Z is —C (—R 9 ) ⁇ or —N ⁇ , R 1 , R 3 , R 8 , R 9 , R 11 and R 12 are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsub
  • Formula (I) In the compound represented by the formula (1), when Z is —N ⁇ , it means any of the following structures (Ia) or (Ib). (In the formula, each symbol has the same meaning as the symbol used in the compound represented by formula (I).)
  • X is —SO 2 —, —N (—R 6 ) —SO 2 — or —SO 2 —N (—R 7 ) —.
  • R 6 may be combined with R 2 and the adjacent nitrogen atom to form a substituted or unsubstituted heterocycle
  • R 7 is combined with R 2 and the adjacent nitrogen atom and —SO 2 —.
  • a substituted or unsubstituted heterocyclic ring may be formed.
  • X is preferably —SO 2 —, —N (—R 6 ) —SO 2 —, and more preferably —SO 2 —.
  • R 6 and R 2 together with the adjacent nitrogen atom form a substituted or unsubstituted heterocycle.
  • the compound represented by the formula (I) is represented by the following formula (Ic).
  • the “heterocycle” may be aromatic or non-aromatic.
  • a ring atom may contain a nitrogen atom, an oxygen atom, or a sulfur atom.
  • a 3- to 8-membered non-aromatic or aromatic heterocyclic ring is preferable.
  • other rings may be condensed. For example, 1 to 3 3 to 8 membered carbocyclic or heterocyclic rings may be condensed.
  • the “heterocycle” is preferably a 5- to 7-membered non-aromatic or aromatic heterocycle, or a ring in which a 5- to 7-membered carbon ring or heterocycle is condensed.
  • the formula: Preferred examples of the group represented by are exemplified by the following groups, or groups in which one 5-membered or 6-membered carbocyclic or heterocyclic ring is condensed to these groups. These groups may be substituted at any substitutable position. Particularly preferably, Alternatively, these are groups in which a benzene ring or a cyclohexane ring is condensed.
  • the compound represented by formula (I) is represented by the following formula (Id): Indicated by (In the formula, each symbol is as defined above.)
  • the “heterocycle” may contain a nitrogen atom, an oxygen atom, or a sulfur atom in addition to the nitrogen atom and the sulfur atom shown in the above formula as constituent atoms of the ring. Preferably, it is a 3- to 8-membered non-aromatic heterocyclic ring. Further, other rings may be condensed. For example, 1 to 3 3 to 8 membered carbocyclic or heterocyclic rings may be condensed.
  • heterocycle is preferably a 5- to 7-membered non-aromatic heterocycle, or a ring in which a 5- to 7-membered carbon ring or heterocycle is condensed.
  • group represented by are exemplified by the following groups, or groups in which one 5-membered or 6-membered carbocyclic or heterocyclic ring is condensed to these groups. These groups may be substituted at any substitutable position.
  • Y 1 is ⁇ C (—R 8 ) — or ⁇ N—. Preferred is ⁇ C (—R 8 ) —, and particularly preferred is ⁇ C (—H) —.
  • Y 3 is ⁇ C (—R 1 ) — or ⁇ N—.
  • Preferred is ⁇ C (—R 1 ) —, and particularly preferred is ⁇ C (—H) —.
  • R 1 , R 3 , R 8 , R 9 , R 11 and R 12 are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by the formula: —O—R 10 ,
  • R 1 , R 3 , R 8 , R 9 , R 11 and R 12 include hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted Substituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted Substituted sulfamoyl, group represented by the formula: —O—R 10 , group represented by the formula: —O—C ( ⁇ O) —R 10 , group represented by the formula: —C ( ⁇ O) —R 10 , A group represented by the formula: —C ( ⁇ O) —
  • Particularly preferred substituents for R 1 are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano.
  • Particularly preferred substituents for R 3 are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano.
  • Particularly preferred substituents for R 8 are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano.
  • Particularly preferred substituents for R 9 are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano.
  • substituents for R 11 are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano, a group represented by the formula: —O—R 10 .
  • Further preferred substituents are hydrogen, hydroxy, fluorine, chlorine, cyano, methyl, isopropyloxy, trifluoromethyloxy, phenoxy and the like.
  • Preferred substituents for R 12 are hydrogen, hydroxy, halogen, cyano, and a group represented by the formula: —O—R 10 .
  • Further preferred substituents are hydrogen, hydroxy, fluorine, chlorine, cyano, isopropyloxy, trifluoromethyloxy, phenoxy and the like.
  • haloalkyl and haloalkyloxy include a group in which 1 to 5 (preferably 1 to 3) halogens are substituted on the alkyl part of alkyl and alkyloxy.
  • 1 to 5 preferably 1 to 3
  • R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino.
  • R 10 include substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted A non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl or a substituted or unsubstituted sulfamoyl. Further preferred embodiments include isopropyl, trifluoromethyl, phenyl and the like.
  • R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl.
  • Preferred embodiments of R 2 are substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted cycloalkyl, and particularly preferably substituted or unsubstituted alkyl.
  • a substituted or unsubstituted alkyl having 2 to 10 carbon atoms is preferable, an alkyl having 2 to 4 carbon atoms is particularly preferable, and an alkyl having 3 or 4 carbon atoms is more preferable.
  • methyl, ethyl, propyl, tert-butyl, trifluoromethyl, trifluoromethyl, trifluoropropyl and the like can be mentioned. More preferred are ethyl, propyl, tert-butyl, trifluoroethyl, trifluoropropyl and the like.
  • R 2 is alkyl having 1 or 2 carbon atoms
  • substituted methyl and substituted ethyl are preferable.
  • methyl substituted with 1 to 3 halogens and ethyl substituted with 1 to 3 halogens are preferred.
  • R 4 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group.
  • R 4 are substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, particularly preferably Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted non-aromatic heterocyclic group.
  • R 4 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or a substituted or unsubstituted non-aromatic heterocyclic group, 1 or 2 oxo, thioxo or substituted or unsubstituted imino May be substituted.
  • oxo, thioxo or imino are substituted with carbon atoms or sulfur atoms constituting the ring.
  • a cyclic group having —C ( ⁇ O) —, —S ( ⁇ O) —, —S ( ⁇ O) 2 —, —C ( ⁇ S) —, —C ( ⁇ NH) — in the ring.
  • the imino may have a substituent.
  • R 4 substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted non-aromatic heterocyclic group is R 5
  • any number of substitutable substituents may be present at any substitutable position.
  • substituents are halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R 10 , group represented by formula: —O—C ( ⁇ O) —R 10 , formula: — A
  • R 5 is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R 10 , group represented by formula: —O—C ( ⁇ O) —R 10 , formula: —
  • R 10 has the same meaning as described above.
  • Preferred embodiments of R 5 include cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or An unsubstituted non-aromatic heterocyclic group or a group represented by the formula: —O—R 10 (wherein R 10 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl).
  • substituted or unsubstituted cycloalkyl substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group.
  • substituted or unsubstituted aryl or substituted or unsubstituted non-aromatic heterocyclic group is preferable.
  • R 5 is preferably substituted next to the adjacent position of the bond of R 4 (the bond that substitutes for the condensed ring).
  • R 4 when R 4 is substituted or unsubstituted phenyl or substituted or unsubstituted 6-membered monocyclic heteroaryl, R 5 is substituted at the meta position of the bond of the phenyl or 6-membered monocyclic heteroaryl. Is preferred.
  • R 4 is a substituted or unsubstituted non-aromatic heterocyclic group
  • R 5 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Ring system substituents such as heteroaryl, substituted or unsubstituted non-aromatic heterocyclic groups are preferred.
  • R 4 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
  • R 5 is in addition to the above ring system substituents, cyano, substituted or unsubstituted alkyl, formula: —O—R 10
  • R 6 and R 7 are hydrogen or substituted or unsubstituted alkyl. Preferably, it is hydrogen.
  • R 6 may be combined with an adjacent nitrogen atom together with R 2 to form a substituted or unsubstituted heterocycle.
  • R 7 may be combined with the adjacent nitrogen atom and —SO 2 — together with R 2 to form a substituted or unsubstituted heterocycle.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Alkyl means a straight 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.
  • alkyl for R 2
  • methyl, ethyl, propyl, isopropyl and tert-butyl are preferable.
  • alkyl having 2 to 10 carbon atoms for R 2 , ethyl, propyl, isopropyl and tert-butyl are preferable.
  • Alkenyl means a straight or branched hydrocarbon group having 2 to 10 carbon atoms having one or more double bonds at any 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 straight or branched hydrocarbon group having 2 to 10 carbon atoms having one or more triple bonds at an arbitrary 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 and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic saturated hydrocarbon groups.
  • Examples of the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • cycloalkyl having 3 to 6 carbon atoms and cycloalkyl having 5 or 6 carbon atoms are preferable.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclohexyl and the like.
  • ring condensed with the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms examples include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring, Cyclopentene ring) and the like, and non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.).
  • non-aromatic carbocycles eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.)
  • non-aromatic heterocycles for example, piperidine ring, piperazine ring, morpholine ring, etc
  • the bond is assumed to come from a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms.
  • the following groups are also exemplified by cycloalkyl and are included in cycloalkyl. These groups may be substituted at any substitutable position.
  • “Cycloalkenyl” is a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic unsaturated aliphatic hydrocarbon groups. Means.
  • Examples of the cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl.
  • cycloalkenyl having 3 to 6 carbon atoms and cycloalkenyl having 5 or 6 carbon atoms are preferable.
  • Examples of the ring condensed with the C3-C8 cyclic unsaturated aliphatic hydrocarbon group include carbocycles (aromatic carbocycles (eg, benzene ring, naphthalene ring etc.), non-aromatic carbocycles (eg cycloalkane ring).
  • aromatic carbocycles eg, benzene ring, naphthalene ring etc.
  • non-aromatic carbocycles eg cycloalkane ring
  • cyclohexane ring, cyclopentane ring, etc. examples include cycloalkene ring (example: cyclohexene ring, cyclopentene ring, etc.)), heterocycle (aromatic heterocycle (pyridine ring, pyrimidine ring, pyrrole ring, imidazole ring, etc.)) And non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.)
  • the bond is assumed to come from a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms. .
  • the following groups are also exemplified as cycloalkenyl and are included in cycloalkenyl. These groups may be substituted at any substitutable position.
  • Aryl is a monocyclic or polycyclic aromatic carbocyclic group, and a group obtained by further condensing one or two 3- to 8-membered rings to these monocyclic or polycyclic aromatic carbocyclic groups.
  • Examples of the monocyclic or polycyclic aromatic carbocyclic group include phenyl, naphthyl, anthryl, and phenanthryl. Particularly preferred is phenyl.
  • Rings condensed with monocyclic or polycyclic aromatic carbocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring). And non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring).
  • the bond is assumed to come from a monocyclic or polycyclic aromatic carbocyclic group.
  • the following groups are also exemplified as aryl and are included in aryl. These groups may be substituted at any substitutable position.
  • aryl in R 4
  • phenyl is preferable.
  • aryl in R 5
  • phenyl is preferable.
  • Heteroaryl means a monocyclic or polycyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring, and monocyclic or polycyclic A group obtained by further condensing one or two 3- to 8-membered rings on an aromatic heterocyclic group.
  • a 5- or 6-membered heteroaryl is particularly preferable.
  • pyrrolyl imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl
  • examples include oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and the like.
  • the “polycyclic aromatic heterocyclic group” is particularly preferably a heteroaryl fused with a 5- or 6-membered ring, such as indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, Naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotria Bicyclic aromatic heterocyclic groups such as zolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyra
  • any ring may have a bond.
  • Rings condensed with monocyclic or polycyclic aromatic heterocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene).
  • a non-aromatic heterocyclic ring for example, a piperidine ring, a piperazine ring, a morpholine ring, etc.
  • the bond is assumed to be from a monocyclic or polycyclic aromatic heterocyclic group.
  • heteroaryl groups are also exemplified as heteroaryl, and are included in heteroaryl. These groups may be substituted at any substitutable position.
  • heteroaryl in R 4 , pyridyl, pyrazolyl and the like are preferable.
  • Non-aromatic heterocyclic group means a non-aromatic heterocyclic group having one or more hetero atoms arbitrarily selected from O, S and N in the ring, and these non-aromatic heterocyclic groups This means a group in which one or two 3- to 8-membered rings are condensed to the formula group. It contains a monocyclic non-aromatic heterocyclic group or a polycyclic non-aromatic heterocyclic group.
  • ⁇ 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.
  • any ring may have a bond.
  • the following groups are also included in the non-aromatic heterocyclic group.
  • non-aromatic heterocyclic group in R 4 , tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, morpholinyl, dihydropyridinyl and the like are preferable.
  • non-aromatic heterocyclic group in R 4 , piperidinyl, morpholino, morpholinyl and the like are preferable.
  • a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group is substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino Also good.
  • substituents of “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl” or “substituted alkyl having 2 to 10 carbon atoms” include halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or Unsubstituted amino, carboxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group , Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by the formula: —O—R 10 , represented by the formula: —O—
  • substituents of “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl” or “substituted alkyl having 2 to 10 carbon atoms” include halogen, cyano, carboxy and the like.
  • Preferred substituents of “substituted alkyl” include halogen.
  • a preferable substituent of “substituted alkyl having 2 to 10 carbon atoms” includes halogen.
  • Substituted cycloalkyl “substituted cycloalkenyl”, “substituted aryl”, “substituted heteroaryl”, “substituted non-aromatic heterocyclic group”, “R 6 and R 2 together with the adjacent nitrogen atom”
  • Substituents of “substituted heterocycle formed” or “substituted heterocycle formed by combining R 7 and R 2 together with the adjacent nitrogen atom and —SO 2 —” include halogen, hydroxy, mercapto, nitro, Nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstitute
  • Substituted or unsubstituted cycloalkyl “substituted or unsubstituted cycloalkenyl”, “substituted or unsubstituted non-aromatic heterocyclic group”, “R 6 and R 2 together with the adjacent nitrogen atom Or a substituted or unsubstituted heterocyclic ring formed by R 7 and R 2 together with the adjacent nitrogen atom and —SO 2 — ”can be substituted. Any position may be substituted with oxo, thioxo or substituted or unsubstituted imino.
  • substituted cycloalkyl Preferred “substituted cycloalkyl”, “substituted cycloalkenyl”, “substituted aryl”, “substituted heteroaryl”, “substituted non-aromatic heterocyclic group”, “R 6 and R 2 together with the adjacent nitrogen atom”
  • Substituents of “substituted heterocycle formed” or “substituted heterocycle formed by combining R 7 and R 2 together with the adjacent nitrogen atom and —SO 2 —” include halogen, alkyl, haloalkyl, Examples include alkyloxy and haloalkyloxy.
  • Preferred substituents of “substituted aryl” include halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy and the like.
  • a preferable substituent of the “substituted non-aromatic heterocyclic group” includes halogen.
  • R 11 and R 12 are each independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, a group represented by the formula: —O—R 10 , a group represented by the formula: —O—C ( ⁇ O) —R 10 , A group represented by the formula: —C ( ⁇ O) —R 10 , a group represented by the formula:
  • Formula (Ih) And the pharmaceutically acceptable salt thereof, or a solvate thereof, includes the following (Ih-A) or (Ih-B).
  • R 11 and R 12 are each independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, a group represented by the formula: —O—R 10 , a group represented by the formula: —O—C ( ⁇ O) —R 10 , A group represented by the formula: —C ( ⁇ O) —R 10 , a group represented by the formula:
  • R 11 and R 12 are each independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, a group represented by the formula: —O—R 10 , a group represented by the formula: —O—C ( ⁇ O) —R 10 , A group represented by the formula: —C ( ⁇ O) —R 10 , a group represented by the formula:
  • R 11 and R 12 are each independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, a group represented by the formula: —O—R 10 , a group represented by the formula: —O—C ( ⁇ O) —R 10 , A group represented by the formula: —C ( ⁇ O) —R 10 , a group represented by the formula:
  • Formula (Io) And the pharmaceutically acceptable salts thereof, or the solvates thereof include the following embodiments (Io-A) to (Io-B).
  • R 11 and R 12 are each independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, a group represented by the formula: —O—R 10 , a group represented by the formula: —O—C ( ⁇ O) —R 10 , A group represented by the formula: —C ( ⁇ O) —R 10 , a group represented by the formula:
  • the compounds of the present invention include pharmaceutically acceptable salts of the respective compounds.
  • basic salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt , Triethanolamine salt, brocaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt and other aliphatic amine salts; N, N-dibenzylethylenediamine, venetamine salt and other aralkylamine salts; pyridine salt, picoline salt, quinoline salt, isoquinoline Heterocyclic aromatic amine salts such as salts; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyl
  • the acid salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate and ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate; Examples include acidic amino acids such as aspartate and glutamate. In particular, when Z is —N ⁇ , the compound of the present invention can be used as these acid salts.
  • the compounds of the present invention include solvates thereof.
  • the solvate means a solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof, and examples thereof include alcohol (eg, ethanol) solvate and hydrate. Examples of the hydrate include monohydrate, dihydrate and the like.
  • the compound of the present invention has an asymmetric carbon atom, it includes racemates, both enantiomers and all stereoisomers (geometric isomers, epimers, enantiomers, etc.).
  • this invention compound has a double bond, when E body and Z body can exist, both are included. Prodrugs of the compounds of the invention are within the scope of the 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 the specific compound is administered in vivo after being administered to a patient with a disease involving NPY Y5. Including compounds that convert to Conventional procedures for selection and formulation of suitable prodrug derivatives are described, for example, in Design of Prodrugs (ed. H. Bundgaard, Elsevier, 1985).
  • One or more hydrogen, carbon or other atoms of the compounds of the present invention may be replaced with an isotope of hydrogen, carbon or other atoms.
  • the compound represented by the formula (I) includes all radiolabeled compounds of the compound represented by the formula (I).
  • Such “radiolabeled”, “radiolabeled” etc. of compounds of formula (I) are each encompassed by the present invention and are useful as research and / or diagnostic tools in metabolic pharmacokinetic studies and binding assays It is.
  • isotopes examples include 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine are included, such as 35 S, 18 F and 36 Cl.
  • the radiolabeled compound of the present invention can be prepared by methods well known in the art.
  • the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium.
  • This method comprises reacting a precursor of which the compound of formula (I) is appropriately halogen-substituted with tritium gas in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. May be included.
  • a suitable catalyst such as Pd / C
  • Suitable methods for preparing other tritium labeled compounds include Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). 14C-labeled compounds can be prepared by using raw materials having 14 C carbon.
  • this invention compound can be manufactured based on the knowledge of organic chemistry also by methods other than the synthesis method shown below. (In the formula, each symbol has the same meaning as described above. Hal means halogen.)
  • the compound represented by the formula (III) is produced from the compound represented by the formula (II) via a diazonium salt.
  • the diazonium salt can be produced by reacting the compound represented by the formula (II) with NaNO 2 and HCl.
  • a reaction solvent water, a mixed solvent of water and alcohol (for example, methanol) can be used.
  • the diazonium salt can be reacted with a copper halide (for example, copper bromide, copper chloride, copper iodide, etc.) to produce a compound represented by the formula (III).
  • the reaction can be carried out at 0 ° C. to room temperature. It can also be heated to 40-60 ° C.
  • the compound represented by formula (I) is produced from the compound represented by formula (III).
  • the compound represented by the formula (I) can be produced by reacting a compound having a reactive amino group (—NH—) in the ring with the halogen of the compound represented by the formula (III).
  • the substituent on R 4 may be introduced prior to step 2 or after step 2.
  • As the reaction solvent acetonitrile, tetrahydrofuran, toluene, benzene, 2-propanol, etc.
  • the reaction can also be performed at room temperature. Moreover, you may heat suitably, seeing the progress of reaction. For example, it can be performed by heating to 100 to 120 ° C. in acetonitrile. It can be performed under microwave irradiation.
  • the compound represented by the formula (III) is useful as a synthetic intermediate for the compound represented by the formula (I).
  • the compound represented by the formula (II) used in the above step 1 can be produced as follows. (In the formula, X is —SO 2 —, and other symbols are as defined above. Pro represents an amino-protecting group.)
  • the —S— group of the compound represented by the formula (IV) is oxidized to produce the compound represented by the formula (V).
  • the oxidizing agent mCPBA (metachloroperbenzoic acid), KMnO 4 (potassium permanganate), Oxone, NaIO 4 (sodium periodate), NaBO 3 (sodium perborate), hydrogen peroxide, etc. may be used. it can.
  • the reaction solvent dichloromethane, chloroform, acetonitrile, acetone, water and the like can be used. The reaction can be performed at room temperature, or may be appropriately heated while watching the progress of the reaction.
  • the amino protecting group of the compound represented by formula (IV) is removed to produce the compound represented by formula (II).
  • the amino protecting group a methoxycarbonyl group, tert-butoxycarbonyl group, 9-fluorenylmethoxycarbonyl, trichloroethoxycarbonyl and the like can be used. What is necessary is just to select deprotection conditions suitably according to a protecting group. For example, the protecting group may be eliminated under alkaline conditions.
  • the compound of formula (VI) is represented by the formula:
  • the compound represented by formula (VII) is produced by reacting the compound represented by formula (II) in the presence of a base and performing amidation.
  • a base As the reaction solvent, dichloromethane, dimethylformamide, tetrahydrofuran, 1-methylpyrrolidin-2-one, N, N-dimethylacetamide, acetonitrile and the like can be used.
  • the base triethylamine, pyridine, dimethylaminopyridine, N, N-diisopropylethylamine and the like can be used.
  • HATU (2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium) can be used as a condensing agent.
  • Step 6 the compound represented by the formula (VII) is cyclized to produce the compound represented by the formula (I).
  • the reaction can be carried out at 100 to 150 ° C. using acetic acid, hydrochloric acid, sulfuric acid, paratoluenesulfonic acid, 10-camphorsulfonic acid and the like as the reaction solvent.
  • Steps 5 and 6 are shown as compounds having a group represented by the formula: —X—R 2 , but are similar to steps 5 and 6 using a compound having a group represented by —S—R 2.
  • the reaction may be carried out, followed by oxidation of -S-.
  • the substituent on R 4 may be introduced after Step 5 or 6 or may be introduced prior to Step 5.
  • the compound represented by the formula (VII) is useful as a synthetic intermediate for the compound represented by the formula (I).
  • the compound represented by the formula (I) can also be produced by the following steps.
  • X is —SO 2 —, and other symbols have the same meanings as described above, and Hal means halogen.
  • Step 7 the compound represented by the formula (VIII) is reacted with a compound having a reactive amino group (—NH—) in the ring to produce a compound represented by the formula (IX).
  • This step can be performed according to step 2.
  • the reaction can be carried out in the presence of DIEA (N, N-diisopropylethylamine), triethylamine or the like.
  • the reaction can be performed at room temperature or by heating to 150 to 200 ° C.
  • As the reaction solvent IPA (isopropyl alcohol), dioxane, toluene, tetrahydrofuran, ethanol, 1-methylpyrrolidin-2-one, N, N-dimethylformamide and the like can be used.
  • Process 8 In this step, a compound represented by the formula (IX) is reacted with a compound represented by the formula: R 2 SH (wherein R 2 is as defined above) to produce a compound represented by the formula (X).
  • R 2 is as defined above
  • Pd 2 (dba) 3 tris (dibenzylideneacetone) dipalladium (0)
  • Pd (OAc) 2 palladium acetate
  • copper iodide Pd (PPh 3 ) 4 (tetrakistriphenylphosphine palladium, etc.
  • DIEA N, N-diisopropylethylamine
  • DOX dioxane
  • the reaction can be performed at room temperature or by heating to 100 to 120 ° C. This step can be performed under microwave irradiation.
  • R 2 SH wherein R 2 is as defined above
  • R 2 SSR 2 wherein R 2 is as defined above
  • R 2 SH (wherein R 2 is as defined above)
  • R 2 S ( ⁇ O) O—R for example, R is 2-
  • a compound having —S ( ⁇ O) — can be produced using a compound represented by (naphthylmethyl), and then oxidized to produce a compound represented by formula (I).
  • the base n-butyllithium, sec-butyllithium, or tert-butyllithium can be used.
  • —NH— of the condensed ring of the formula (IX) may be protected with an SEM group (2- (trimethylsilyl) ethoxymethyl group). The SEM group can be removed by heating in the presence of TBAF (tetrabutylammonium fluoride).
  • Step 9 the —S— group of the compound represented by the formula (X) is oxidized to produce the compound represented by the formula (I).
  • This step can be performed according to step 3.
  • the substituent on R 4 may be introduced after each of steps 7 to 9, or may be introduced prior to step 7.
  • the compound represented by the formula (X) is useful as a synthetic intermediate for the compound represented by the formula (I).
  • Step 10 Suzuki reaction is performed on the compound represented by the formula (III) using Pd (PPh 3 ) 4 (tetrakis (triphenylphosphine) palladium) and CS 2 CO 3 (cesium carbonate) in the presence of RB (OH) 2. And a step for producing a compound represented by the formula (I).
  • Step 11 the compound represented by the formula (VI) is reacted with CDI (N, N′-carbodiimidazole) to produce the compound represented by the formula (XI).
  • CDI N, N′-carbodiimidazole
  • XI the compound represented by the formula (XI)
  • dimethylformamide, 1-methylpyrrolidin-2-one, N, N-dimethylacetamide, dichloromethane, toluene and the like can be used.
  • the reaction can be performed at room temperature, and may be appropriately heated.
  • Step 12 the compound represented by the formula (XI) is reacted with a halogenating agent to produce the compound represented by the formula (III).
  • a halogenating agent phosphorus oxychloride or the like can be used.
  • Step 13 the compound represented by the formula (XII) is reacted with the compound represented by the formula (XIII) to produce the compound represented by the formula (XIV).
  • This step can be performed in the presence of a base.
  • a base NaHMDS (sodium bis (trimethylsilyl) amide) or the like can be used.
  • the amount of the base 1.0 to 1.5 equivalents can be used with respect to the compound represented by (XIII).
  • As the reaction solvent tetrahydrofuran or the like can be used.
  • Step 14 the nitro group of the compound represented by the formula (XIV) is reduced to produce the compound represented by the formula (XV).
  • This step can be performed using a nitro group reduction reaction known in organic chemistry.
  • this step can be performed using Na 2 S 2 O 4 (sodium hydrosulfite) as a reducing agent.
  • Na 2 S 2 O 4 sodium hydrosulfite
  • the solvent methanol, ethanol, tetrahydrofuran, or a mixed solvent of these and water can be used.
  • the reaction can be carried out at room temperature or may be heated to 50-80 ° C.
  • Step 15 A step of producing a compound represented by the formula (XVI) by introducing a group represented by the formula: —C ( ⁇ O) —OR (wherein R is alkyl) into the amino group of the compound represented by the formula (XV). It is.
  • a compound represented by Hal—C ( ⁇ O) —OR can be used.
  • ethyl chlorocarbonate and ethyl chlorocarbonate can be used.
  • This step can be performed in the presence of a base.
  • pyridine, dimethylaminopyridine, triethylamine and the like can be used.
  • As the reaction solvent tetrahydrofuran, N, N-dimethylformamide and the like can be used. This step can be performed at room temperature or may be heated to 50 to 80 ° C.
  • Step 16 the compound represented by the formula (IX) is produced from the compound represented by the formula (XVI).
  • This step can be performed in the presence of TBAF (tetrabutylammonium fluoride). TBAF can be used in an amount of 2 to 3 equivalents based on the compound represented by the formula (XVI).
  • As the reaction solvent tetrahydrofuran, N, N-dimethylformamide and the like can be used.
  • This step can be performed at room temperature or may be heated to 50 to 80 ° C.
  • the compound represented by the formula (IX) thus obtained can be led to the compound represented by the formula (I) through steps 8 and 9. Therefore, the compound represented by the formula (IX) is useful as a synthetic intermediate for the compound represented by the formula (I).
  • the compound represented by the formula (I) thus obtained can be purified by crystallization in various solvents.
  • Solvents used include alcohol (methanol, ethanol, isopropyl alcohol, n-butanol, etc.), ether (diethyl ether, diisopropyl ether, etc.), acetic acid methyl ester, acetic acid ethyl ester, chloroform, methylene chloride, tetrahydrofuran, N, N— Examples thereof include dimethylformamide, toluene, benzene, xylene, acetonitrile, hexane, dioxane, dimethoxyethane, water or a mixed solvent thereof. After dissolving in these solvents under heating to remove impurities, the temperature may be gradually lowered and the precipitated solid or crystals may be collected by filtration.
  • the compounds of the present invention prevent NPY Y5 related diseases in general, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension, cerebral hyperemia, congestive heart failure or sleep disorders And / or effective treatment. 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, dyslipidemia, 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.
  • High metabolic stability e. High water solubility.
  • g) Does not cause gastrointestinal disorders (eg, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).
  • the compound of the present invention is particularly excellent in the point b).
  • the compound of the present invention has low affinity for NPY Y1 and Y2 receptors and has 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, it is unlikely to induce side effects based on peripheral vasoconstriction, and the compound of the present invention considered to have high Y5 receptor selectivity is used as an active ingredient.
  • the pharmaceutical composition to be used can be suitably used as a safe medicine.
  • 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, and crystalline cellulose.
  • 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.
  • lubricant include talc, magnesium stearate, and macrogol.
  • cacao butter, macrogol, methyl cellulose or the like can be used.
  • 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).
  • agents that can be used for weight management in obesity and obesity agents that can be used for weight management in obesity and obesity.
  • a pharmaceutical composition containing a compound having an anti-obesity action in combination with the compound of the present invention it can be used for prevention and / or treatment of obesity, weight management in obesity, and the like.
  • the pharmaceutical composition containing the compound of the present invention can be used in combination with a pharmaceutical composition containing a compound having an anti-obesity action for the prevention and / or treatment of obesity or weight management in obesity. it can.
  • the administration therapy of the pharmaceutical composition of the present invention can be used in combination with diet therapy, drug therapy, exercise and the like.
  • Pancreatic lipase inhibitor Orlistat, cetiristat.
  • Gastrointestinal function regulator 6-chloro-2-phenyl-8,8a-dihydro-indenol [1,2-d] thiazol-3a-ol.
  • Serotonin 2C agonist lorcaserine hydrochloride.
  • Carboxypeptidase inhibitor Formula: A compound represented by GPR119 agonist: Formula: A compound represented by Cannabinoid CB1 receptor antagonist: rimonabant hydrochloride.
  • Neurokinin NK3 receptor antagonist rimonabant hydrochloride.
  • Monoamine uptake inhibitor sibutramine hydrochloride.
  • Selective antagonist of melanin-concentrating hormone MCH receptor (SLC-1): Formula: A compound represented by Stearoyl coenzyme A desaturase-1 inhibitor: Formula: A compound represented by Noradrenaline and dopamine reuptake inhibitors: Tesofensin.
  • a combination of bupropion, a noradrenaline and dopamine reuptake inhibitor, and naltrexone, an opioid receptor antagonist, a combination of fentamine, which has an NE secretion-promoting action, and topiramate, a GABA agonist also contain compounds having an anti-obesity effect Exemplified as a pharmaceutical composition.
  • Tetrahydrofuran (1.5 ml) and a 1 mol / L tetrahydrofuran solution (2.25 ml, 2.25 mmol) of tetrabutylammonium fluoride were added to the resulting residue, and the mixture was slightly stirred at 60 ° C. for 4 hours.
  • the solvent was distilled off under reduced pressure, ethyl acetate was added, washed with water 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 15 (106.7 mg, yield 40.8%).
  • Second step Compound 25 (969 mg, 5.44 mmol) obtained in the first step was dissolved in THF (5 ml), cooled to 0 ° C., triethylamine (0.904 ml, 6.52 mmol) and mesyl chloride (0.508 ml, 6.52 mmol) were added. The reaction was carried out at 0 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off.
  • N, N-dimethylformamide (5 ml) was added to the resulting residue, and then sodium cyanide (400 mg, 8.16 mmol) and tetrabutylammonium iodide (201 mg, 0.554 mmol) were added.
  • the mixture was reacted at 100 ° C. for 8 hours and cooled to room temperature. Water was added and extracted with ethyl acetate, and the organic layer was washed with water. After drying over magnesium sulfate, the solvent was distilled off and the residue was purified by column chromatography to obtain the title compound 26 (346 mg, yield 34%).
  • Example 8 Synthesis of Compound (I-15) First Step N, N-dimethylformamide (5.0 ml), triethylamine (0.570 ml, 4.11 mmol) and 6-chloronicotinic acid (5.0 ml) were added to 4- (propylthio) benzene-1,2-diamine 19 (500 mg, 2.74 mmol) under a nitrogen stream. 432 mg, 2.74 mmol) was added. HATU (1252 mg, 3.29 mmol) was added under ice cooling, and the mixture was vigorously stirred for 1 hour with ice cooling.
  • Example 10 Synthesis of Compound (I-43) Dimethyl sulfoxide (0.4 ml) and acetonitrile (0.4 ml) were added to compound I-9 (8.8 mg, 0.023 mmol) under a nitrogen stream. Selectflour (9.51 mg, 0.026 mmol) was added under ice-cooling, and the mixture was slightly stirred for 1 hour with ice-cooling. Thereafter, the mixture was slightly stirred at room temperature for 1 hour and further stirred at 50 ° C. for 1 hour. Selectflour (9.51 mg, 0.026 mmol, further 19.02 mg, 0.052 mmol) was added, and the reaction was performed at 50 ° C.
  • Example 13 Synthesis of Compound (I-58) First Step Dichloromethane (50 ml) was added to albendazole 53 (5 g, 18.8 mmol), then mCPBA (10.4 ml, 96.0 mmol) was added under ice cooling, and the mixture was stirred for 30 minutes with ice cooling. The reaction solution was neutralized by adding a saturated aqueous sodium hydrogen carbonate solution. The solid precipitated at this time was collected by filtration and dried to obtain a sulfone compound.
  • Example 14 Synthesis of Compound (I-59,75) First Step After 2-propanol (15 ml) was added to chloride 57 (3.0 g, 13.0 mmol), 2-phenylmorpholine hydrochloride (2.59 g, 13.0 mmol) and diisopropylethylamine (4.50 ml, 26.0 mmol) were added under ice cooling. added. Microwave was irradiated for 30 minutes under the condition of 180 ° C. Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain Compound 58 quantitatively.
  • Second step After adding 1,4-dioxane (10 ml) to compound 58 (1.0 g, 2.79 mmol) obtained in the first step, diisopropylethylamine (1.46 ml, 8.37 mmol), Pd2 (dba) 3 (256 mg, 0.279 mmol), Xantphos (323 mg, 0.558 mmol) and ethanethiol (0.204 ml, 2.79 mmol) were added. Microwave was irradiated for 1 hour at 150 ° C. Thereafter, the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate.
  • Example 16 Synthesis of Compound (I-63) After adding 1,4-dioxane (2 ml) and water (0.2 ml) to compound 55 (70 mg, 0.231 mmol), boronic acid (17.6 mg, 0.231 mmol), cesium carbonate (113 mg, 8.37 mmol) and Pd (PPh3) 4 (256 mg, 0.279 mmol) was added. Microwave was irradiated for 20 minutes at 180 ° C. Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 64 (60 mg, yield 68%).
  • Example 18 Synthesis of Compound (I-68) First Step NMP (0.25 ml), 2-propanol (0.5 ml) and amine 68 (65 mg, 0, 247 mmol) were added to compound 55 (75 mg, 0.247 mmol) and reacted at 180 ° C. for 1 hour under microwave irradiation. The reaction solution was poured into a 10% aqueous citric acid solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by column chromatography to obtain an amine adduct (79 mg).
  • Example 19 Synthesis of Compound 72 (I-71) First Step Diamine 5 (1 g, 4.16 mmol) was dissolved in N, N-dimethylformamide (10 ml) and carbonyldiimidazole (743 mg, 4.58 mmol) was added. After reacting overnight at room temperature, the reaction solution was poured into a 2 mol / L aqueous hydrochloric acid solution. After extraction with ethyl acetate, the extract was washed with saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain the target compound 70 (897 mg, 81% yield).
  • Example 20 Synthesis of Compound (I-72) First Step Reaction was carried out in the same manner as in Step 1 of Example Compound I-2 to give compound 73.
  • Example 23 Synthesis of Compound 86 (I-78) First Step
  • the target product 82 (yield 93.3%) was obtained by the same reaction as in the first step of Example compound (I-1).
  • Second step The target product 83 (yield 93%) was obtained by the same reaction as in the second step of Example compound (I-1).
  • Third step The target compound 84 (79%) was obtained by the same reaction as in the first step of Example compound (I-73).
  • Example 24 Synthesis of Compound (I-76) First Step Compound 84 (22 mg, 0.06 mmol) obtained in the third step of Example compound (I-78) was added to Pd2 (dba) 3 (22 mg, 0.06 mmol), Ru-phos (1.8 mg, 0.0006 mmol), t -Butoxy sodium (17.3 mg, 0.18 mmol) was added with dioxane and amine hydrochloride (10 mg, 0.066 mmol) and reacted under microwave irradiation at 100 ° C. for 30 minutes, 120 ° C. for 30 minutes, and further at 140 ° C. for 30 minutes. .
  • the target product 87 (12.1 mg, 45% yield) was obtained by distilling off the solvent and purifying by column chromatography.
  • Example 25 Synthesis of Compound (I-79) First Step The target compound 89 (44% yield) was obtained by the same reaction as in the 1st and 2nd steps of Example compound (I-74). LCMS; 479.90 (M + H)
  • Example 26 Synthesis of Compound (I-80) First Step After sulfonyl chloride 90 (7 g, 27.3 mmol) was dissolved in THF (70 ml), morpholine (7.14 ml, 82 mmol) was added and stirred at room temperature for 20 minutes. Water and 2 mol / L hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated, and the residue was purified by column chromatography to give compound 91 (3.72 g, yield 44%).
  • Second step Compound 91 (3.6 g, 11.8 mmol) obtained in the first step was dissolved in acetonitrile (36 ml), and triethylamine (1.96 ml, 14.1 mmol) and benzylamine (2.13 ml, 14.12 mmol) were added. Stir for hours.
  • Examples of combinations of Y 1 , Y 2 , Y 3 , and Z in the compounds of the present invention include the combinations described in Tables 22 and 23 below.
  • R 2 and X in the compounds of the present invention include the combinations described in Tables 24 and 25 below.
  • R 4 in the compound of the present invention examples include the examples described in Table 26 below.
  • (VI) to (XVIII) mean the same groups as those corresponding to R 4 of the compounds represented by formulas (VI) to (XVIII).
  • R 5 in the compound of the present invention examples include combinations described in Table 27 below.
  • R 11 in the compound of the present invention examples include combinations described in Table 28 below.
  • R 12 in the compound of the present invention examples include the combinations described in Table 29 below.
  • Test Example 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)]. The results are shown in Table 30.
  • 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 2 Affinity for human NPY Y5 receptor
  • a cDNA sequence encoding human NPY Y5 receptor was expressed in expression vector pME18S (Takebe et al. Mol. Cell. Biol. 8, 466-472). Cloning into 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).
  • Test Example 3 Rat Brain Migration Evaluation Intravenous to rats (Crl; CD (SD), ⁇ , 8weeks) using the cassette dosing method (Drug. Metab. Dispos. (2001); see 29, 957-966) From the plasma and brain concentration 30 minutes after administration (0.5 mg / mL / kg), brain transferability (brain / plasma partition coefficient; Kp) was evaluated. As a result, the compound of the present invention showed good brain migration. For example, Compound I-82 had a brain Kp: 0.49.
  • Test Example 4 Evaluation of transferability to mouse brain Oral administration to mice (Jcl; C57BL / 6J, ⁇ , 8weeks) using a cassette dosing method (Drug. Metab. Dispos. (2001); see 29, 957-966) 2 mg / 10 mL / kg) From the plasma and brain concentrations after 3 or 5 hours, the brain transferability (brain / plasma partition coefficient; Kp) can be evaluated.
  • Test Example 5 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. As a result, the compound of the present invention showed good pharmacokinetics such as high bioavailability and appropriate clearance.
  • Test Example 6 Inhibition of cAMP production in CHO cells CHO cells expressing human NPY Y5 receptor were incubated at 37 ° C. for 20 minutes in the presence of 2.5 mM isobutylmethylxanthine (SIGMA), and then the compound 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
  • Test Example 7 NPY Y5 Receptor Selectivity Test Examples 1-2 and Y1-expressing cells (human neuroblastoma, SK-N-MC) membrane preparation and Y2-expressing cells (human neuroblastoma, SMS-KAN) membrane preparation 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 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 8 Feeding Inhibitory Action Under ether anesthesia, skin was incised along the midline from the outer 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 the mice was measured 2 hours and 4 hours after the injection, and the difference in food intake between the 0.5% hydroxypropylmethylcellulose solution administration group and the test substance administration group was investigated.
  • the compound of the present invention was administered at a dose of 25 mg / kg, the amount of food intake was significantly suppressed as compared with the case where 0.5% hydroxypropylmethylcellulose was administered.
  • the food intake after 2 hours and 4 hours after injection was 0.28 ⁇ 0.04 g and 0.45 ⁇ 0.09 g, respectively. .
  • the amount of food intake 2 hours and 4 hours after injection in the 0.5% hydroxypropylmethylcellulose solution administration group (Group B) was 0.63 ⁇ 0.06 g and 1.22 ⁇ 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 ⁇ 0.07 g, 0.17 ⁇ 0.06 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 2 hours and 4 hours after the injection in the A group are 65.9% and 74.2%, respectively.
  • Test Example 9 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of major human 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.
  • CYP3A4 Fluorescence MBI Test is a test for examining the enhancement of CYP3A4 inhibition of a compound by metabolic reaction, using 7-benzyloxytrifluoromethylcoumarin (7-BFC) using E. coli-expressed CYP3A4 as an enzyme.
  • 7-benzyloxytrifluoromethylcoumarin (7-BFC) using E. coli-expressed CYP3A4 as an enzyme.
  • HFC 7-hydroxytrifluoromethylcoumarin
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); test drug concentration, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • 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 case where the difference in IC 50 values was 5 ⁇ M or more was designated as (+), and the case where it was 3 ⁇ M or less was designated as ( ⁇ ).
  • 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.

Abstract

The purpose of the present invention is to find a novel compound having NPY Y5 receptor antagonism. A compound represented by formula (I) was found to have NPY Y5 receptor antagonism. (I) (In the formula, X represents -SO2- or the like; Y1 represents =C(-R8)- or the like; Y2 represents -C(-R3)= or the like; Y3 represents =C(-R1)- or the like; Z represents -N= or the like; R1, R3, R8, R9, R11, and R12 each independently represent hydrogen or the like; R2 represents a substituted or unsubstituted alkyl group or the like; R4 represents a substituted or unsubstituted aryl group or the like; and R5 represents a substituted or unsubstituted aryl group or the like; and n represents 1 or the like.)

Description

NPY Y5受容体拮抗作用を有するヘテロ環誘導体Heterocyclic derivatives having NPY Y5 receptor antagonistic activity
 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なヘテロ環誘導体に関する。 The present invention relates to a novel heterocyclic derivative having NPY Y5 receptor antagonistic activity and useful as a pharmaceutical, particularly as an anti-obesity drug.
 肥満は除脂肪体重に対して体内に過剰な脂肪あるいは脂肪組織が蓄積した状態と定義されており、健康問題の主なリスクファクターと認識されている。身体質量指数(BMI)は成人(15歳以上)の集団あるいは個人を過体重や肥満に分類する際に共通して使用されている身長体重比の単純指数である。メートルで表す身長の二乗で割ったキログラムで表す体重(kg/m)として定義されている。世界保健機関では、BMIが25kg/m以上を「過体重」、30kg/m以上を「肥満」としている。一方で、日本肥満学会ではBMIが25kg/m以上を「肥満」としている。なぜなら、糖尿病や脂質異常症を含む肥満関連疾患の数がBMIに応じて増加する、そしてその疾患の数の平均値がBMIが25kg/mにおいて1.0以上になるためである。世界保健機関による2005年の調査では、世界中で、約16億人が過体重、少なくとも4億人が肥満であるとされている。肥満は主に身体的活動や日常生活における消費に対するカロリー摂取の割合の増加によってもたらされる。近年の高脂肪、高糖分含有食物の摂取増加により肥満者数は増加しており、2015年には世界中で、7億人以上が肥満と診断されると予想されている。 Obesity is defined as the accumulation of excess fat or adipose tissue in the body relative to lean body mass, and is recognized as the main risk factor for health problems. The body mass index (BMI) is a simple index of the height-weight ratio that is commonly used to classify an adult (over 15 years old) group or individual as overweight or obese. It is defined as the body weight (kg / m 2 ) expressed in kilograms divided by the height squared in meters. According to the World Health Organization, BMI of 25 kg / m 2 or more is “overweight” and 30 kg / m 2 or more is “obese”. On the other hand, the Japanese Obesity Society designates BMI of 25 kg / m 2 or more as “obesity”. This is because the number of obesity-related diseases including diabetes and dyslipidemia increases according to BMI, and the average value of the number of diseases becomes 1.0 or more at a BMI of 25 kg / m 2 . According to a 2005 survey by the World Health Organization, around 1.6 billion people worldwide are overweight and at least 400 million are obese. Obesity is mainly caused by an increase in the ratio of caloric intake to physical activity and consumption in daily life. The number of obese people is increasing due to an increase in the intake of high fat and high sugar content foods in recent years, and it is predicted that more than 700 million people will be diagnosed with obesity worldwide in 2015.
 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はヒト及び動物の中枢神経系及び末梢組織に広く分布している。
 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5参照)。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又は治療薬となる。
 NPY受容体には、現在までにY1、Y2、Y3、Y4、Y5及びY6のサブタイプが発見されている(非特許文献6参照)。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7~9参照)。
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.
In previous reports, NPY has been found to have feeding promoting action, anticonvulsant action, learning promoting action, anti-anxiety action, anti-stress 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 5). Therefore, a pharmaceutical composition having an NPY receptor antagonistic action is a preventive or therapeutic agent for various diseases involving the NPY receptor as described above.
To date, subtypes Y1, Y2, Y3, Y4, Y5, and Y6 have been discovered for NPY receptors (see Non-Patent Document 6). 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 7 to 9).
特許文献1及び2、非特許文献1には、式:
Figure JPOXMLDOC01-appb-C000004

で示される基を2位に有する、NPY Y5受容体拮抗作用を有するベンゾイミダゾール誘導体が開示されている。
Patent Documents 1 and 2 and Non-Patent Document 1 include the formula:
Figure JPOXMLDOC01-appb-C000004

A benzimidazole derivative having an NPY Y5 receptor antagonistic activity having a group represented by formula (2) at the 2-position is disclosed.
特許文献3には、SCD阻害作用を有するベンズイミダゾール誘導体が開示されている。該文献には、6-(シクロプロピルスルホニル)-2-(2’-フルオロビフェニル-4-イル)-1)-1H-ベンズイミダゾール(該文献の実施例2)が開示されている。
特許文献4には、抗癌作用を有するベンズイミダゾール誘導体が開示されている。特許文献5には、ATP感受性カリウムチャンネル阻害作用を有するベンズイミダゾール誘導体が開示されている。
特許文献6には、プロテインキナーゼ阻害作用を有するベンズイミダゾール誘導体が開示されている。該文献には、2-(4-アミノ-1-(7H-ピロロ[2,3-d]ピリミジン-4-イル)ピペリジン-4-イル)-N,N-ジエチル-1H-ベンゾ[d]イミダゾール-5-スルホンアミド(該文献の実施例59)が開示されている。
 特許文献7には、チロシンキナーゼに作用する、5位に置換フェニル置換スルファモイル基を有するベンズイミダゾール誘導体が開示されている。特許文献8及び9には、5位に非置換スルファモイル基を有するベンズイミダゾール誘導体が開示されている。
Patent Document 3 discloses a benzimidazole derivative having an SCD inhibitory action. The document discloses 6- (cyclopropylsulfonyl) -2- (2′-fluorobiphenyl-4-yl) -1) -1H-benzimidazole (Example 2 of the document).
Patent Document 4 discloses a benzimidazole derivative having an anticancer activity. Patent Document 5 discloses a benzimidazole derivative having an ATP-sensitive potassium channel inhibitory action.
Patent Document 6 discloses a benzimidazole derivative having a protein kinase inhibitory action. The document includes 2- (4-amino-1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-yl) -N, N-diethyl-1H-benzo [d]. Imidazole-5-sulfonamide (Example 59 of that document) is disclosed.
Patent Document 7 discloses a benzimidazole derivative having a substituted phenyl-substituted sulfamoyl group at the 5-position, which acts on tyrosine kinase. Patent Documents 8 and 9 disclose benzimidazole derivatives having an unsubstituted sulfamoyl group at the 5-position.
 特許文献10~14、非特許文献2~4には、5位にメタンスルホニル基を有するベンズイミダゾール誘導体が開示されている。特許文献15には、5位にベンジルスルファモイル基を有するベンズイミダゾール誘導体が開示されている。非特許文献2には、5位にフェニルスルファモイル基を有するベンズイミダゾール誘導体が開示されている。特許文献10~15、非特許文献2~4に記載のベンズイミダゾール誘導体は、ベンズイミダゾール環上の窒素原子がメチル基で置換されている。 Patent Documents 10 to 14 and Non-Patent Documents 2 to 4 disclose benzimidazole derivatives having a methanesulfonyl group at the 5-position. Patent Document 15 discloses a benzimidazole derivative having a benzylsulfamoyl group at the 5-position. Non-Patent Document 2 discloses a benzimidazole derivative having a phenylsulfamoyl group at the 5-position. In the benzimidazole derivatives described in Patent Documents 10 to 15 and Non-Patent Documents 2 to 4, the nitrogen atom on the benzimidazole ring is substituted with a methyl group.
 特許文献3~15、非特許文献2~4には、NPY Y5受容体拮抗作用については記載されていない。 Patent Documents 3 to 15 and Non-Patent Documents 2 to 4 do not describe NPY Y5 receptor antagonistic action.
国際公開第2008/137270International Publication No. 2008/137270 国際公開第2002/048152International Publication No. 2002/045152 国際公開第2009/129625International Publication No. 2009/129625 国際公開第2009/007390International Publication No. 2009/007390 国際公開第2008/148468International Publication No. 2008/148468 国際公開第2008/075109International Publication No. 2008/075109 国際公開第2007/056155International Publication No. 2007/056155 国際公開第2004/069160International Publication No. 2004/069160 国際公開第2001/002369International Publication No. 2001/002369 特開昭56-74154JP 56-74154 特開昭55-106264JP 55-106264 特開昭55-82162JP 55-82162 特開昭55-71757JP-A-55-71757 特開昭54-160379JP 54-160379 特開昭53-105529JP 53-105529 A
 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のヘテロ環誘導体を提供することにある。 An object of the present invention is to provide a novel heterocyclic 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、該化合物が強い摂食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、代謝安定性及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 eating 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-C000005

(式中、
Xは-SO-または-N(-R)-SO-であり、
は=C(-R)-または=N-であり、
は-C(-R)=または-N=であり、
は=C(-R)-または=N-であり、
Zは-C(-R)=または-N=であり、
、R、R、R、R11及びR12はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
10は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
は置換もしくは非置換の炭素数2~10のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルであり、
は置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基であり、
は置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基であり、
nは1であり、
は水素または置換もしくは非置換のアルキルであり、またはRはRと共に隣接する窒素原子と一緒になって置換もしくは非置換の複素環を形成していてもよい。上記の置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換の非芳香族複素環式基は、1または2個のオキソ、チオキソまたは置換もしくは非置換のイミノで置換されていてもよい。ただし、Xが-SO-であり、Yが=C(-H)-であり、Yが-C(-H)=であり、Yが=C(-H)-であり、Zが-N=であり、Rがシクロプロピルであり、R11及びR12が水素であり、Rがフェニルであり、nが1であり、かつRが2-フルオロフェニルである場合、及び、Xが-N(-Et)-SO-であり、Yが=C(-H)-であり、Yが-C(-H)=であり、Yが=C(-H)-であり、Zが-N=であり、Rがエチルであり、R11がアミノであり、R12が水素であり、Rがピペリジン-4-イルであり、nが1であり、かつRが7H-ピロロ[2,3-d]-ピリミジン-4-イルである場合を除く。)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。
(2)
式(I):
Figure JPOXMLDOC01-appb-C000006

(式中、
Xは-SO-または-N(-R)-SO-であり、
は=C(-R)-または=N-であり、
は-C(-R)=または-N=であり、
は=C(-R)-または=N-であり、
Zは-C(-R)=または-N=であり、
、R、R、R、R11及びR12はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
10は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルであり、
は置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基であり、
は置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基であり、
nは1であり、
ただし、Rが置換もしくは非置換のフェニルまたは置換もしくは非置換の6員単環ヘテロアリールである場合、Rは該フェニルまたは6員単環ヘテロアリールのメタ位に置換している、
は水素または置換もしくは非置換のアルキルであり、またはRはRと共に隣接する窒素原子と一緒になって置換もしくは非置換の複素環を形成していてもよい。上記の置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換の非芳香族複素環式基は、1または2個のオキソ、チオキソまたは置換もしくは非置換のイミノで置換されていてもよい。ただし、Xが-N(-Et)-SO-であり、Yが=C(-H)-であり、Yが-C(-H)=であり、Yが=C(-H)-であり、Zが-N=であり、Rがエチルであり、R11がアミノであり、R12が水素であり、Rがピペリジン-4-イルであり、nが1であり、かつRが7H-ピロロ[2,3-d]-ピリミジン-4-イルである場合を除く。)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。
(3)
が置換もしくは非置換の非芳香族複素環式基である、上記(1)または(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)
が置換もしくは非置換のフェニルであり、かつRが該フェニルのメタ位に置換している、上記(1)または(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)
が置換もしくは非置換の5員単環ヘテロアリールである、上記(1)または(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)
が置換もしくは非置換の6員単環ヘテロアリールであり、かつRが該ヘテロアリールのメタ位に置換している、上記(1)または(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。
(7)
が置換もしくは非置換の非芳香族複素環式基である、上記(1)~(6)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。
(8)
Xが-SO-である、上記(1)~(7)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。
(9)
が置換もしくは非置換の炭素数2~10のアルキルである、上記(1)~(8)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。
(10)
Xが-N(-R)-SO-であり、RがRと共に隣接する窒素原子と一緒になって置換もしくは非置換の複素環を形成している、上記(1)~(7)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。
(11)
が=C(-R)-であり、Yが-C(-R)=であり、かつYが=C(-R)-である、上記(1)~(10)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。
(12)
Zが-N=である、上記(1)~(11)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。
(13)
上記(1)~(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含有する医薬組成物。
(14)
上記(1)~(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含有する、NPY Y5受容体拮抗作用を有する医薬組成物。
(15)
式(I):
Figure JPOXMLDOC01-appb-C000007

(式中、
Xは-SO-、-N(-R)-SO-または-SO-N(-R)-であり、
は=C(-R)-または=N-であり、
は-C(-R)=または-N=であり、
は=C(-R)-または=N-であり、
Zは-C(-R)=または-N=であり、
、R、R、R、R11及びR12はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
10は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルであり、
は置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基であり、
はハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
nは0または1であり、
及びRは水素または置換もしくは非置換のアルキルであり、またはRはRと共に隣接する窒素原子と一緒になって置換もしくは非置換の複素環を形成していてもよく、RはRと共に隣接する窒素原子及び-SO-と一緒になって置換もしくは非置換の複素環を形成していてもよい。
上記の置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換の非芳香族複素環式基は、1または2個のオキソ、チオキソまたは置換もしくは非置換のイミノで置換されていてもよい。ただし、Rが置換もしくは非置換の非芳香族複素環式基である場合、nは1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NPY Y5受容体拮抗作用を有する医薬組成物。
(16)
nが1であり、Rが置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基である、上記(15)記載の医薬組成物。
(17)
nが1であり、Rが置換もしくは非置換の非芳香族複素環式基である、上記(16)記載の医薬組成物。
(18)
nが1であり、Rがシアノ、置換もしくは非置換のアルキルまたは式:-O-R10で示される基であり、R10が置換もしくは非置換のアルキルまたは置換もしくは非置換のアリールである、上記(15)記載の医薬組成物。
(19)
が置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリールである、上記(15)~(18)のいずれかに記載の医薬組成物。
(20)
Xが-SO-または-N(-R)-SO-であり、Yが=C(-R)-であり、Yが-C(-R)=であり、Yが=C(-R)-であり、かつZが-N=である、上記(15)~(19)のいずれかに記載の医薬組成物。
(21)
抗肥満作用を有する化合物を含有する、上記(13)~(20)のいずれかに記載の医薬組成物と併用するための、肥満症の予防および/または治療用、または肥満症における体重管理用の医薬組成物。
That is, the present invention relates to the following.
(1)
Formula (I):
Figure JPOXMLDOC01-appb-C000005

(Where
X is —SO 2 — or —N (—R 6 ) —SO 2 —,
Y 1 is ═C (—R 8 ) — or ═N—,
Y 2 is —C (—R 3 ) ═ or —N═,
Y 3 is ═C (—R 1 ) — or ═N—,
Z is —C (—R 9 ) ═ or —N═,
R 1 , R 3 , R 8 , R 9 , R 11 and R 12 are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by the formula: —O—R 10 , formula: A group represented by —O—C (═O) —R 10 , represented by the formula: —C (═O) —R 10 A group represented by the formula: —C (═O) —O—R 10 , a group represented by the formula: —S—R 10 , a group represented by the formula: —SO 2 —R 10 or a formula: A group represented by O—SO 2 —R 10 ;
R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
R 2 is substituted or unsubstituted alkyl having 2 to 10 carbon atoms, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
R 4 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group,
R 5 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group,
n is 1,
R 6 is hydrogen or substituted or unsubstituted alkyl, or R 6 together with the adjacent nitrogen atom together with R 2 may form a substituted or unsubstituted heterocycle. The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group is substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino It may be. However, X is —SO 2 —, Y 1 is ═C (—H) —, Y 2 is —C (—H) =, and Y 3 is ═C (—H) —, When Z is —N═, R 2 is cyclopropyl, R 11 and R 12 are hydrogen, R 4 is phenyl, n is 1, and R 5 is 2-fluorophenyl , And X is —N (—Et) —SO 2 —, Y 1 is ═C (—H) —, Y 2 is —C (—H) =, and Y 3 is ═C ( -H)-, Z is -N =, R 2 is ethyl, R 11 is amino, R 12 is hydrogen, R 4 is piperidin-4-yl, and n is 1 And R 5 is 7H-pyrrolo [2,3-d] -pyrimidin-4-yl. ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
(2)
Formula (I):
Figure JPOXMLDOC01-appb-C000006

(Where
X is —SO 2 — or —N (—R 6 ) —SO 2 —,
Y 1 is ═C (—R 8 ) — or ═N—,
Y 2 is —C (—R 3 ) ═ or —N═,
Y 3 is ═C (—R 1 ) — or ═N—,
Z is —C (—R 9 ) ═ or —N═,
R 1 , R 3 , R 8 , R 9 , R 11 and R 12 are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by the formula: —O—R 10 , formula: A group represented by —O—C (═O) —R 10 , represented by the formula: —C (═O) —R 10 A group represented by the formula: —C (═O) —O—R 10 , a group represented by the formula: —S—R 10 , a group represented by the formula: —SO 2 —R 10 or a formula: A group represented by O—SO 2 —R 10 ;
R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
R 4 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group,
R 5 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group,
n is 1,
Provided that when R 4 is substituted or unsubstituted phenyl or substituted or unsubstituted 6-membered monocyclic heteroaryl, R 5 is substituted at the meta position of the phenyl or 6-membered monocyclic heteroaryl.
R 6 is hydrogen or substituted or unsubstituted alkyl, or R 6 together with the adjacent nitrogen atom together with R 2 may form a substituted or unsubstituted heterocycle. The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group is substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino It may be. However, X is —N (—Et) —SO 2 —, Y 1 is ═C (—H) —, Y 2 is —C (—H) =, and Y 3 is ═C (— H) —, Z is —N═, R 2 is ethyl, R 11 is amino, R 12 is hydrogen, R 4 is piperidin-4-yl, and n is 1. Except when R 5 is 7H-pyrrolo [2,3-d] -pyrimidin-4-yl. ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
(3)
The compound according to the above (1) or (2), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 4 is a substituted or unsubstituted non-aromatic heterocyclic group.
(4)
R 4 is substituted or unsubstituted phenyl, and R 5 is substituted at the meta position of the phenyl, the compound according to the above (1) or (2), a pharmaceutically acceptable salt thereof, or their Solvate.
(5)
The compound according to (1) or (2), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 4 is a substituted or unsubstituted 5-membered monocyclic heteroaryl.
(6)
The compound according to the above (1) or (2), wherein R 4 is substituted or unsubstituted 6-membered monocyclic heteroaryl and R 5 is substituted at the meta position of the heteroaryl, its pharmaceutically acceptable Salts, or solvates thereof.
(7)
The compound according to any one of the above (1) to (6), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 5 is a substituted or unsubstituted non-aromatic heterocyclic group.
(8)
The compound according to any one of the above (1) to (7), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein X is —SO 2 —.
(9)
The compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 2 is substituted or unsubstituted alkyl having 2 to 10 carbon atoms.
(10)
(1) to (1) wherein X is —N (—R 6 ) —SO 2 —, and R 6 together with the adjacent nitrogen atom together with R 2 forms a substituted or unsubstituted heterocyclic ring. The compound according to any one of 7), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(11)
(1) to (10) above, wherein Y 1 is ═C (—R 8 ) —, Y 2 is —C (—R 3 ) =, and Y 3 is ═C (—R 1 ) —. ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
(12)
The compound according to any one of the above (1) to (11), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Z is —N═.
(13)
A pharmaceutical composition comprising the compound according to any one of (1) to (12) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(14)
A pharmaceutical composition having an NPY Y5 receptor antagonistic action, comprising the compound according to any one of (1) to (12) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(15)
Formula (I):
Figure JPOXMLDOC01-appb-C000007

(Where
X is —SO 2 —, —N (—R 6 ) —SO 2 — or —SO 2 —N (—R 7 ) —,
Y 1 is ═C (—R 8 ) — or ═N—,
Y 2 is —C (—R 3 ) ═ or —N═,
Y 3 is ═C (—R 1 ) — or ═N—,
Z is —C (—R 9 ) ═ or —N═,
R 1 , R 3 , R 8 , R 9 , R 11 and R 12 are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by the formula: —O—R 10 , formula: A group represented by —O—C (═O) —R 10 , represented by the formula: —C (═O) —R 10 A group represented by the formula: —C (═O) —O—R 10 , a group represented by the formula: —S—R 10 , a group represented by the formula: —SO 2 —R 10 or a formula: A group represented by O—SO 2 —R 10 ;
R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
R 4 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group,
R 5 is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R 10 , group represented by formula: —O—C (═O) —R 10 , formula: —C (= O) group represented by -R 10, wherein: -C (= O) groups represented by -O-R 10, wherein: -S-R Groups represented by 0, the formula: or a group represented by the formula represented by -SO 2 -R 10: is a group represented by -O-SO 2 -R 10,
n is 0 or 1;
R 6 and R 7 are hydrogen or substituted or unsubstituted alkyl, or R 6 together with the adjacent nitrogen atom together with R 2 may form a substituted or unsubstituted heterocycle, R 7 May combine with R 2 and the adjacent nitrogen atom and —SO 2 — to form a substituted or unsubstituted heterocycle.
The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group is substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino It may be. However, when R 4 is a substituted or unsubstituted non-aromatic heterocyclic group, n is 1. ), A pharmaceutically acceptable salt thereof, or a solvate thereof, a pharmaceutical composition having an NPY Y5 receptor antagonistic action.
(16)
n is 1, and R 5 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted non-aromatic heterocycle The pharmaceutical composition according to the above (15), which is a formula group.
(17)
The pharmaceutical composition according to the above (16), wherein n is 1, and R 5 is a substituted or unsubstituted non-aromatic heterocyclic group.
(18)
n is 1, R 5 is cyano, substituted or unsubstituted alkyl or a group represented by the formula: —O—R 10 , and R 10 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl The pharmaceutical composition according to (15) above.
(19)
The pharmaceutical composition according to any one of the above (15) to (18), wherein R 4 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
(20)
X is —SO 2 — or —N (—R 6 ) —SO 2 —, Y 1 is ═C (—R 8 ) —, Y 2 is —C (—R 3 ) ═, Y The pharmaceutical composition according to any one of the above (15) to (19), wherein 3 is = C (-R 1 )-and Z is -N =.
(21)
For use in prevention and / or treatment of obesity or weight management in obesity for use in combination with the pharmaceutical composition according to any one of (13) to (20) above, which comprises a compound having an anti-obesity action Pharmaceutical composition.
(22)
肥満症の予防および/または治療用である、上記(13)~(20)のいずれかに記載の医薬組成物。
(23)
肥満症における体重管理用である上記(13)~(20)のいずれかに記載の医薬組成物。
(24)
上記(15)記載の式(I)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投与することを特徴とする、肥満症の予防および/または治療方法。
(25)
上記(15)記載の式(I)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投与することを特徴とする、肥満症における体重管理方法。
(26)
肥満症の予防および/または治療のための、上記(15)記載の式(I)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。
(27)
肥満症における体重管理のための、上記(15)記載の式(I)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。
(28)
抗肥満作用を有する化合物を含有する医薬組成物を、上記(13)~(20)のいずれかに記載の医薬組成物と併用することを特徴とする、肥満症の予防および/または治療方法。
(29)
抗肥満作用を有する化合物を含有する医薬組成物を、上記(13)~(20)のいずれかに記載の医薬組成物と併用することを特徴とする、肥満症における体重管理方法。
(30)
式(III):
Figure JPOXMLDOC01-appb-C000008

(式中、各記号は上記(1)と同意義であり、Halはハロゲンを意味する。)
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。
(31)
式(VII):
Figure JPOXMLDOC01-appb-C000009

(式中、各記号は上記(1)と同意義である。)
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。
(32)
式(X):
Figure JPOXMLDOC01-appb-C000010

(式中、各記号は上記(1)と同意義である。)
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。
(33)
上記(1)~(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製造方法。
(34)
上記(1)~(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結晶化することを特徴とする、上記(33)記載の製造方法。
(35)
上記(30)~(32)のいずれかの化合物を用いる工程を含むことを特徴とする、上記(33)記載の製造方法。
(22)
The pharmaceutical composition according to any one of the above (13) to (20), which is used for prevention and / or treatment of obesity.
(23)
The pharmaceutical composition according to any one of (13) to (20), which is used for weight management in obesity.
(24)
A method for preventing and / or treating obesity, which comprises administering a compound represented by the formula (I) described in (15) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(25)
A method for weight management in obesity, comprising administering the compound represented by the formula (I) described in (15) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(26)
The compound represented by the formula (I) according to the above (15), a pharmaceutically acceptable salt thereof, or a solvate thereof for the prevention and / or treatment of obesity.
(27)
The compound represented by the formula (I) according to the above (15), a pharmaceutically acceptable salt thereof, or a solvate thereof for weight management in obesity.
(28)
A method for preventing and / or treating obesity, comprising using a pharmaceutical composition containing a compound having an anti-obesity action in combination with the pharmaceutical composition according to any one of (13) to (20) above.
(29)
A method for weight management in obesity, comprising using a pharmaceutical composition containing a compound having an anti-obesity action in combination with the pharmaceutical composition according to any one of (13) to (20) above.
(30)
Formula (III):
Figure JPOXMLDOC01-appb-C000008

(In the formula, each symbol is as defined in (1) above, and Hal means halogen.)
Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(31)
Formula (VII):
Figure JPOXMLDOC01-appb-C000009

(In the formula, each symbol has the same meaning as (1) above.)
Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(32)
Formula (X):
Figure JPOXMLDOC01-appb-C000010

(In the formula, each symbol has the same meaning as (1) above.)
Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(33)
A method for producing the compound according to any one of the above (1) to (12), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(34)
The method according to (33) above, wherein the compound according to any one of (1) to (12), a pharmaceutically acceptable salt thereof, or a solvate thereof is crystallized.
(35)
The production method according to (33) above, which comprises a step of using any one of the compounds (30) to (32).
 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、鬱血心不全又は睡眠障害等の治療又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、脂質異常症、動脈硬化、急性冠症候群等の治療又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 action, and is associated with drugs, particularly 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, sleep disorder and the like. 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 the treatment or prevention of diseases in which obesity is a risk factor, such as diabetes, hypertension, dyslipidemia, arteriosclerosis, and acute coronary syndromes.
 以下に本発明を説明する。本発明は、式(I):
Figure JPOXMLDOC01-appb-C000011

(式中、
Xは-SO-、-N(-R)-SO-または-SO-N(-R)-であり、
は=C(-R)-または=N-であり、
は-C(-R)=または-N=であり、
は=C(-R)-または=N-であり、
Zは-C(-R)=または-N=であり、
、R、R、R、R11及びR12はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
10は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルであり、
は置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基であり、
はハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-Rで示される基、式:-O-C(=O)-Rで示される基、式:-C(=O)-Rで示される基、式:-C(=O)-O-Rで示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
nは0または1であり、
及びRは水素または置換もしくは非置換のアルキルであり、またはRはRと共に隣接する窒素原子と一緒になって置換もしくは非置換の複素環を形成していてもよく、RはRと共に隣接する窒素原子及び-SO-と一緒になって置換もしくは非置換の複素環を形成していてもよい。
上記の置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換の非芳香族複素環式基は、1または2個のオキソ、チオキソまたは置換もしくは非置換のイミノで置換されていてもよい。ただし、Rが置換もしくは非置換の非芳香族複素環式基である場合、nは1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に関する。
The present invention will be described below. The present invention relates to a compound of formula (I):
Figure JPOXMLDOC01-appb-C000011

(Where
X is —SO 2 —, —N (—R 6 ) —SO 2 — or —SO 2 —N (—R 7 ) —,
Y 1 is ═C (—R 8 ) — or ═N—,
Y 2 is —C (—R 3 ) ═ or —N═,
Y 3 is ═C (—R 1 ) — or ═N—,
Z is —C (—R 9 ) ═ or —N═,
R 1 , R 3 , R 8 , R 9 , R 11 and R 12 are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by the formula: —O—R 10 , formula: A group represented by —O—C (═O) —R 10 , represented by the formula: —C (═O) —R 10 A group represented by the formula: —C (═O) —O—R 10 , a group represented by the formula: —S—R 10 , a group represented by the formula: —SO 2 —R 10 or a formula: A group represented by O—SO 2 —R 10 ;
R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
R 4 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group,
R 5 is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R, group represented by formula: —O—C (═O) —R, formula: —C (═O) a group represented by -R, wherein: -C (= O) groups represented by -O-R, wherein: a group represented by -S-R 10, : Or a group represented by the formula represented by -SO 2 -R 10: is a group represented by -O-SO 2 -R 10,
n is 0 or 1;
R 6 and R 7 are hydrogen or substituted or unsubstituted alkyl, or R 6 together with the adjacent nitrogen atom together with R 2 may form a substituted or unsubstituted heterocycle, R 7 May combine with R 2 and the adjacent nitrogen atom and —SO 2 — to form a substituted or unsubstituted heterocycle.
The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group is substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino It may be. However, when R 4 is a substituted or unsubstituted non-aromatic heterocyclic group, n is 1. ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
式(I):
Figure JPOXMLDOC01-appb-C000012

で示される化合物において、Zが-N=の場合、以下の(Ia)または(Ib)のいずれの構造をも意味する。
Figure JPOXMLDOC01-appb-C000013

(式中、各記号は、式(I)で示される化合物で使用されている記号と同意義である。)
Formula (I):
Figure JPOXMLDOC01-appb-C000012

In the compound represented by the formula (1), when Z is —N═, it means any of the following structures (Ia) or (Ib).
Figure JPOXMLDOC01-appb-C000013

(In the formula, each symbol has the same meaning as the symbol used in the compound represented by formula (I).)
式(I)で示される化合物において、Xが-N(-R)-SO-の場合に、RがRと共に隣接する窒素原子と一緒になって置換もしくは非置換の複素環を形成していているとき、式(I)で示される化合物は、以下の式(Ic)で示される。なお、Xが-N(-R)-SO-である場合、窒素原子がRに結合するものとする。
Figure JPOXMLDOC01-appb-C000014

(式中、各記号は、式(I)で示される化合物で使用されている記号と同意義である。)
In the compound represented by the formula (I), when X is —N (—R 6 ) —SO 2 —, R 6 together with R 2 together with the adjacent nitrogen atom forms a substituted or unsubstituted heterocyclic ring. When formed, the compound of formula (I) is represented by the following formula (Ic). Note that when X is —N (—R 6 ) —SO 2 —, a nitrogen atom is bonded to R 2 .
Figure JPOXMLDOC01-appb-C000014

(In the formula, each symbol has the same meaning as the symbol used in the compound represented by formula (I).)
式(I)で示される化合物において、Xが-SO-N(-R)-の場合に、RがRと共に隣接する窒素原子及び-SO-と一緒になって置換もしくは非置換の複素環を形成しているとき、式(I)で示される化合物は、以下の式(Id)で示される。なお、Xが-SO-N(-R)-である場合、硫黄原子がRに結合するものとする。
Figure JPOXMLDOC01-appb-C000015

(式中、各記号は、式(I)で示される化合物で使用されている記号と同意義である。)
 式(I):
Figure JPOXMLDOC01-appb-C000016

で示される化合物としては、特に、以下の態様が好ましい。なお、以下の式(Ie)~(Iv)において、各記号は、式(I)で示される化合物で使用されている記号と同意義である。
Figure JPOXMLDOC01-appb-C000017

Figure JPOXMLDOC01-appb-C000018

Figure JPOXMLDOC01-appb-C000019

Figure JPOXMLDOC01-appb-C000020

Figure JPOXMLDOC01-appb-C000021

Figure JPOXMLDOC01-appb-C000022

Figure JPOXMLDOC01-appb-C000023

Figure JPOXMLDOC01-appb-C000024

Figure JPOXMLDOC01-appb-C000025

Figure JPOXMLDOC01-appb-C000026

Figure JPOXMLDOC01-appb-C000027

Figure JPOXMLDOC01-appb-C000028

Figure JPOXMLDOC01-appb-C000029

Figure JPOXMLDOC01-appb-C000030

Figure JPOXMLDOC01-appb-C000031

Figure JPOXMLDOC01-appb-C000032

Figure JPOXMLDOC01-appb-C000033

Figure JPOXMLDOC01-appb-C000034
In the compound represented by the formula (I), when X is —SO 2 —N (—R 7 ) —, R 7 together with R 2 together with the adjacent nitrogen atom and —SO 2 — is substituted or non-substituted. When a substituted heterocyclic ring is formed, the compound represented by the formula (I) is represented by the following formula (Id). Note that when X is —SO 2 —N (—R 7 ) —, a sulfur atom is bonded to R 2 .
Figure JPOXMLDOC01-appb-C000015

(In the formula, each symbol has the same meaning as the symbol used in the compound represented by formula (I).)
Formula (I):
Figure JPOXMLDOC01-appb-C000016

As the compound represented by the following, the following embodiments are particularly preferable. In the following formulas (Ie) to (Iv), each symbol has the same meaning as that used in the compound represented by formula (I).
Figure JPOXMLDOC01-appb-C000017

Figure JPOXMLDOC01-appb-C000018

Figure JPOXMLDOC01-appb-C000019

Figure JPOXMLDOC01-appb-C000020

Figure JPOXMLDOC01-appb-C000021

Figure JPOXMLDOC01-appb-C000022

Figure JPOXMLDOC01-appb-C000023

Figure JPOXMLDOC01-appb-C000024

Figure JPOXMLDOC01-appb-C000025

Figure JPOXMLDOC01-appb-C000026

Figure JPOXMLDOC01-appb-C000027

Figure JPOXMLDOC01-appb-C000028

Figure JPOXMLDOC01-appb-C000029

Figure JPOXMLDOC01-appb-C000030

Figure JPOXMLDOC01-appb-C000031

Figure JPOXMLDOC01-appb-C000032

Figure JPOXMLDOC01-appb-C000033

Figure JPOXMLDOC01-appb-C000034
 上記式(I)、(Ia)~(Iv)において使用されている各記号について、説明する。
 Xは-SO-、-N(-R)-SO-または-SO-N(-R)-である。RはRと共に隣接する窒素原子と一緒になって置換もしくは非置換の複素環を形成していてもよく、RはRと共に隣接する窒素原子及び-SO-と一緒になって置換もしくは非置換の複素環を形成していてもよい。Xとして、好ましくは、-SO-、-N(-R)-SO-であり、さらに好ましくは、-SO-である。
 Xが-N(-R)-SO-である場合、RがRと共に隣接する窒素原子と一緒になって置換もしくは非置換の複素環を形成している場合が好ましい。
Each symbol used in the above formulas (I), (Ia) to (Iv) will be described.
X is —SO 2 —, —N (—R 6 ) —SO 2 — or —SO 2 —N (—R 7 ) —. R 6 may be combined with R 2 and the adjacent nitrogen atom to form a substituted or unsubstituted heterocycle, and R 7 is combined with R 2 and the adjacent nitrogen atom and —SO 2 —. A substituted or unsubstituted heterocyclic ring may be formed. X is preferably —SO 2 —, —N (—R 6 ) —SO 2 —, and more preferably —SO 2 —.
When X is —N (—R 6 ) —SO 2 —, it is preferable that R 6 and R 2 together with the adjacent nitrogen atom form a substituted or unsubstituted heterocycle.
 RがRと共に隣接する窒素原子と一緒になって置換もしくは非置換の複素環を形成していている場合、式(I)で示される化合物は、以下の式(Ic)で示される。
Figure JPOXMLDOC01-appb-C000035

(式中、各記号は前記と同意義である。)
 上記「複素環」は、芳香族であってもよく、非芳香族であってもよい。また、環の構成原子に上記式に示された窒素原子以外に、窒素原子、酸素原子、硫黄原子を含んでいてもよい。好ましくは、3~8員の非芳香族、または芳香族の複素環である。また、他の環が縮合していてもよい。たとえば、1~3個の3~8員の炭素環または複素環が縮合していてもよい。上記「複素環」としては、好ましくは、5~7員の非芳香族または芳香族の複素環、またはそれらに5~7員の炭素環または複素環が縮合した環である。たとえば、式:
Figure JPOXMLDOC01-appb-C000036

で示される基の好ましい態様としては、以下の基、またはこれらの基に1個の5員または6員の炭素環または複素環が縮合した基が例示される。なお、これらの基は置換可能な任意の位置で置換されていてもよい。
Figure JPOXMLDOC01-appb-C000037

Figure JPOXMLDOC01-appb-C000038

 特に好ましくは、

 または、これらにベンゼン環またはシクロヘキサン環が縮合した基である。
When R 6 and R 2 together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic ring, the compound represented by the formula (I) is represented by the following formula (Ic).
Figure JPOXMLDOC01-appb-C000035

(In the formula, each symbol is as defined above.)
The “heterocycle” may be aromatic or non-aromatic. Further, in addition to the nitrogen atom represented by the above formula, a ring atom may contain a nitrogen atom, an oxygen atom, or a sulfur atom. A 3- to 8-membered non-aromatic or aromatic heterocyclic ring is preferable. Further, other rings may be condensed. For example, 1 to 3 3 to 8 membered carbocyclic or heterocyclic rings may be condensed. The “heterocycle” is preferably a 5- to 7-membered non-aromatic or aromatic heterocycle, or a ring in which a 5- to 7-membered carbon ring or heterocycle is condensed. For example, the formula:
Figure JPOXMLDOC01-appb-C000036

Preferred examples of the group represented by are exemplified by the following groups, or groups in which one 5-membered or 6-membered carbocyclic or heterocyclic ring is condensed to these groups. These groups may be substituted at any substitutable position.
Figure JPOXMLDOC01-appb-C000037

Figure JPOXMLDOC01-appb-C000038

Particularly preferably,

Alternatively, these are groups in which a benzene ring or a cyclohexane ring is condensed.
 RがRと共に隣接する窒素原子及び-SO-と一緒になって置換もしくは非置換の複素環を形成している場合、式(I)で示される化合物は、以下の式(Id)で示される。
Figure JPOXMLDOC01-appb-C000040

(式中、各記号は前記と同意義である。)
 上記「複素環」は、環の構成原子に上記式に示された窒素原子及び硫黄原子以外に、窒素原子、酸素原子、硫黄原子を含んでいてもよい。好ましくは、3~8員の非芳香族複素環である。また、他の環が縮合していてもよい。たとえば、1~3個の3~8員の炭素環または複素環が縮合していてもよい。上記「複素環」としては、好ましくは、5~7員の非芳香族複素環、またはそれらに5~7員の炭素環または複素環が縮合した環である。たとえば、式:
Figure JPOXMLDOC01-appb-C000041

で示される基の好ましい態様としては、以下の基、またはこれらの基に1個の5員または6員の炭素環または複素環が縮合した基が例示される。なお、これらの基は置換可能な任意の位置で置換されていてもよい。
Figure JPOXMLDOC01-appb-C000042
When R 7 together with R 2 and the adjacent nitrogen atom and —SO 2 — form a substituted or unsubstituted heterocycle, the compound represented by formula (I) is represented by the following formula (Id): Indicated by
Figure JPOXMLDOC01-appb-C000040

(In the formula, each symbol is as defined above.)
The “heterocycle” may contain a nitrogen atom, an oxygen atom, or a sulfur atom in addition to the nitrogen atom and the sulfur atom shown in the above formula as constituent atoms of the ring. Preferably, it is a 3- to 8-membered non-aromatic heterocyclic ring. Further, other rings may be condensed. For example, 1 to 3 3 to 8 membered carbocyclic or heterocyclic rings may be condensed. The “heterocycle” is preferably a 5- to 7-membered non-aromatic heterocycle, or a ring in which a 5- to 7-membered carbon ring or heterocycle is condensed. For example, the formula:
Figure JPOXMLDOC01-appb-C000041

Preferred examples of the group represented by are exemplified by the following groups, or groups in which one 5-membered or 6-membered carbocyclic or heterocyclic ring is condensed to these groups. These groups may be substituted at any substitutable position.
Figure JPOXMLDOC01-appb-C000042
 Yは=C(-R)-または=N-である。好ましくは、=C(-R)-であり、特に好ましくは、=C(-H)-である。
 Yは-C(-R)=または-N=である。好ましくは、-C(-R)=であり、特に好ましくは、-C(-H)=である。
 Yは=C(-R)-または=N-である。好ましくは、=C(-R)-であり、特に好ましくは、=C(-H)-である。
 Zは-C(-R)=または-N=である。好ましくは、-N=である。Zが-C(-R)=の場合、好ましくは、-C(-H)=である。
Y 1 is ═C (—R 8 ) — or ═N—. Preferred is ═C (—R 8 ) —, and particularly preferred is ═C (—H) —.
Y 2 is —C (—R 3 ) ═ or —N═. -C (-R 3 ) = is preferable, and -C (-H) = is particularly preferable.
Y 3 is ═C (—R 1 ) — or ═N—. Preferred is ═C (—R 1 ) —, and particularly preferred is ═C (—H) —.
Z is —C (—R 9 ) ═ or —N═. Preferably, -N =. When Z is -C (-R 9 ) =, preferably -C (-H) =.
 R、R、R、R、R11及びR12はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基または式:-SO-R10で示される基である。
、R、R、R、R11及びR12の好ましい態様としては、水素、ハロゲン、ヒドロキシ、シアノ、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基または式:-SO-R10で示される基である。
 Rとして特に好ましい置換基は、水素、アルキル、ヒドロキシ、ハロゲン、ハロアルキル、ハロアルキルオキシ、シアノである。
 Rとして特に好ましい置換基は、水素、アルキル、ヒドロキシ、ハロゲン、ハロアルキル、ハロアルキルオキシ、シアノである。
 Rとして特に好ましい置換基は、水素、アルキル、ヒドロキシ、ハロゲン、ハロアルキル、ハロアルキルオキシ、シアノである。
 Rとして特に好ましい置換基は、水素、アルキル、ヒドロキシ、ハロゲン、ハロアルキル、ハロアルキルオキシ、シアノである。
 R11として特に好ましい置換基は、水素、アルキル、ヒドロキシ、ハロゲン、ハロアルキル、ハロアルキルオキシ、シアノ、式:-O-R10で示される基である。さらに好ましい置換基は、水素、ヒドロキシ、フッ素、塩素、シアノ、メチル、イソプロピルオキシ、トリフルオロメチルオキシ、フェノキシ等である。
 R12として好ましい置換基は、水素、ヒドロキシ、ハロゲン、シアノ、式:-O-R10で示される基である。さらに好ましい置換基は、水素、ヒドロキシ、フッ素、塩素、シアノ、イソプロピルオキシ、トリフルオロメチルオキシ、フェノキシ等である。
 ここで、ハロアルキル及びハロアルキルオキシは、アルキル及びアルキルオキシのアルキル部分に、1~5個(好ましくは、1~3個)のハロゲンが置換した基を包含する。
好ましくは
R 1 , R 3 , R 8 , R 9 , R 11 and R 12 are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by the formula: —O—R 10 , formula: A group represented by —O—C (═O) —R 10 , represented by the formula: —C (═O) —R 10 A group represented by the formula: —C (═O) —O—R 10 , a group represented by the formula: —S—R 10 or a group represented by the formula: —SO 2 —R 10 .
Preferred embodiments of R 1 , R 3 , R 8 , R 9 , R 11 and R 12 include hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted Substituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted Substituted sulfamoyl, group represented by the formula: —O—R 10 , group represented by the formula: —O—C (═O) —R 10 , group represented by the formula: —C (═O) —R 10 , A group represented by the formula: —C (═O) —O—R 10 or a group represented by the formula: —SO 2 —R 10 .
Particularly preferred substituents for R 1 are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano.
Particularly preferred substituents for R 3 are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano.
Particularly preferred substituents for R 8 are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano.
Particularly preferred substituents for R 9 are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano.
Particularly preferred substituents for R 11 are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano, a group represented by the formula: —O—R 10 . Further preferred substituents are hydrogen, hydroxy, fluorine, chlorine, cyano, methyl, isopropyloxy, trifluoromethyloxy, phenoxy and the like.
Preferred substituents for R 12 are hydrogen, hydroxy, halogen, cyano, and a group represented by the formula: —O—R 10 . Further preferred substituents are hydrogen, hydroxy, fluorine, chlorine, cyano, isopropyloxy, trifluoromethyloxy, phenoxy and the like.
Here, haloalkyl and haloalkyloxy include a group in which 1 to 5 (preferably 1 to 3) halogens are substituted on the alkyl part of alkyl and alkyloxy.
Preferably
 R10は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノである。
 R10の好ましい態様としては、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のスルファモイルである。さらに好ましい態様としては、イソプロピル、トリフルオロメチル、フェニル等である。
R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino.
Preferred embodiments of R 10 include substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted A non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl or a substituted or unsubstituted sulfamoyl. Further preferred embodiments include isopropyl, trifluoromethyl, phenyl and the like.
 Rは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルである。
 Rの好ましい態様としては、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニルまたは置換もしくは非置換のシクロアルキルであり、特に好ましくは、置換もしくは非置換のアルキルである。「置換もしくは非置換のアルキル」中でも、炭素数2~10の置換もしくは非置換のアルキルが好ましく、特に、炭素数2~4のアルキルが好ましく、さらには、炭素数3または4のアルキルが好ましい。例えば、メチル、エチル、プロピル、tert-ブチル、トリフルオロメチル、トリフルオロメチル、トリフルオロプロピル等が挙げられる。さらに好ましくは、エチル、プロピル、tert-ブチル、とリフルオロエチル、トリフルオロプロピル等が挙げられる。
 また、Rが炭素数1または2のアルキルの場合、置換されたメチル、置換されたエチルが好ましい。たとえば、1~3個のハロゲンで置換されたメチルや、1~3個のハロゲンで置換されたエチルが好ましい。
R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl.
Preferred embodiments of R 2 are substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted cycloalkyl, and particularly preferably substituted or unsubstituted alkyl. Among the “substituted or unsubstituted alkyl”, a substituted or unsubstituted alkyl having 2 to 10 carbon atoms is preferable, an alkyl having 2 to 4 carbon atoms is particularly preferable, and an alkyl having 3 or 4 carbon atoms is more preferable. For example, methyl, ethyl, propyl, tert-butyl, trifluoromethyl, trifluoromethyl, trifluoropropyl and the like can be mentioned. More preferred are ethyl, propyl, tert-butyl, trifluoroethyl, trifluoropropyl and the like.
When R 2 is alkyl having 1 or 2 carbon atoms, substituted methyl and substituted ethyl are preferable. For example, methyl substituted with 1 to 3 halogens and ethyl substituted with 1 to 3 halogens are preferred.
 Rは置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基である。
 Rの好ましい態様としては、置換もしくは非置換のシクロアルキル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基であり、特に好ましくは、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基である。例えば、シクロヘキシル、ピロリジル、ピペラジニル、ピペリジニル、テトラヒドロピリジニル、モルホリニル、モルホリノ、テトラヒドロフラニル、フェニル、ピラゾリル等が挙げられる。
 Rが置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換の非芳香族複素環式基である場合、1または2個のオキソ、チオキソまたは置換もしくは非置換のイミノで置換されていてもよい。これらのオキソ、チオキソまたはイミノは環を構成する炭素原子、硫黄原子に置換する。この場合、-C(=O)-、-S(=O)-、-S(=O)-、-C(=S)-、-C(=NH)-を環内に有する環式基を意味する。当該イミノは置換基を有していてもよい。
 Rの置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基は、R、R11、R12以外にも、置換可能な任意の位置に、置換可能な任意の数の置換基を有していてもよい。これらの置換基は、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基から選択される。ここで、R10は前記と同意義である。
R 4 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group.
Preferred embodiments of R 4 are substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, particularly preferably Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted non-aromatic heterocyclic group. Examples include cyclohexyl, pyrrolidyl, piperazinyl, piperidinyl, tetrahydropyridinyl, morpholinyl, morpholino, tetrahydrofuranyl, phenyl, pyrazolyl and the like.
When R 4 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or a substituted or unsubstituted non-aromatic heterocyclic group, 1 or 2 oxo, thioxo or substituted or unsubstituted imino May be substituted. These oxo, thioxo or imino are substituted with carbon atoms or sulfur atoms constituting the ring. In this case, a cyclic group having —C (═O) —, —S (═O) —, —S (═O) 2 —, —C (═S) —, —C (═NH) — in the ring. Means group. The imino may have a substituent.
R 4 substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted non-aromatic heterocyclic group is R 5 In addition to R 11 and R 12 , any number of substitutable substituents may be present at any substitutable position. These substituents are halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R 10 , group represented by formula: —O—C (═O) —R 10 , formula: — A group represented by C (═O) —R 10 , a group represented by the formula: —C (═O) —O—R 10 , a formula : Selected from a group represented by —S—R 10 , a group represented by formula: —SO 2 —R 10 or a group represented by formula: —O—SO 2 —R 10 . Here, R 10 has the same meaning as described above.
 Rはハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基である。ここで、R10は前記と同意義である。
 Rの好ましい態様としては、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基または式:-O-R10(式中、R10は置換もしくは非置換のアルキルまたは置換もしくは非置換のアリール)で示される基である。特に好ましくは、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基である。その中でも、置換もしくは非置換のアリールまたは置換もしくは非置換の非芳香族複素環式基が好ましい。例えば、ヒドロキシ、フッ素、塩素、シアノ、メチル、イソプロピルオキシ、トリフルオロメチルオキシ、フェノキシ、tert-ブチルオキシカルボニル、ジメチルモルホリニル、ジフルオロピペリジニル、ベンゾイル、フェニル、クロロフェニル、フルオロフェニル、メチルオキシフェニル、トリフルオロメチルフェニル、トリフルオロメチルオキシフェニル等が挙げられる。
 Rは、Rの結合手(縮合環に置換する結合手)の隣接位の隣に置換する場合が好ましい。たとえば、Rが置換もしくは非置換のフェニルまたは置換もしくは非置換の6員単環ヘテロアリールである場合、Rは該フェニルまたは6員単環ヘテロアリールの該結合手のメタ位に置換しているときが好ましい。
 Rが置換もしくは非置換の非芳香族複素環式基である場合、Rは置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基などの環系の置換基が好ましい。
 Rが置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリールである場合、Rは上記の環系の置換基に加え、シアノ、置換もしくは非置換のアルキル、式:-O-R10(式中、R10は置換もしくは非置換のアルキルまたは置換もしくは非置換のアリール)で示される基も好ましい。
R 5 is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R 10 , group represented by formula: —O—C (═O) —R 10 , formula: —C (= O) group represented by -R 10, wherein: -C (= O) groups represented by -O-R 10, wherein: -S-R Groups represented by 0, the formula: or a group represented by the formula represented by -SO 2 -R 10: is a group represented by -O-SO 2 -R 10. Here, R 10 has the same meaning as described above.
Preferred embodiments of R 5 include cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or An unsubstituted non-aromatic heterocyclic group or a group represented by the formula: —O—R 10 (wherein R 10 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl). Particularly preferred are substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group. Of these, substituted or unsubstituted aryl or substituted or unsubstituted non-aromatic heterocyclic group is preferable. For example, hydroxy, fluorine, chlorine, cyano, methyl, isopropyloxy, trifluoromethyloxy, phenoxy, tert-butyloxycarbonyl, dimethylmorpholinyl, difluoropiperidinyl, benzoyl, phenyl, chlorophenyl, fluorophenyl, methyloxyphenyl , Trifluoromethylphenyl, trifluoromethyloxyphenyl, and the like.
R 5 is preferably substituted next to the adjacent position of the bond of R 4 (the bond that substitutes for the condensed ring). For example, when R 4 is substituted or unsubstituted phenyl or substituted or unsubstituted 6-membered monocyclic heteroaryl, R 5 is substituted at the meta position of the bond of the phenyl or 6-membered monocyclic heteroaryl. Is preferred.
When R 4 is a substituted or unsubstituted non-aromatic heterocyclic group, R 5 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Ring system substituents such as heteroaryl, substituted or unsubstituted non-aromatic heterocyclic groups are preferred.
When R 4 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, R 5 is in addition to the above ring system substituents, cyano, substituted or unsubstituted alkyl, formula: —O—R 10 A group represented by the formula (wherein R 10 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl) is also preferred.
 nは0または1である。好ましくは、1である。
 R及びRは水素または置換もしくは非置換のアルキルである。好ましくは、水素である。RはRと共に隣接する窒素原子と一緒になって置換もしくは非置換の複素環を形成していてもよい。RはRと共に隣接する窒素原子及び-SO-と一緒になって置換もしくは非置換の複素環を形成していてもよい。
n is 0 or 1. Preferably, 1.
R 6 and R 7 are hydrogen or substituted or unsubstituted alkyl. Preferably, it is hydrogen. R 6 may be combined with an adjacent nitrogen atom together with R 2 to form a substituted or unsubstituted heterocycle. R 7 may be combined with the adjacent nitrogen atom and —SO 2 — together with R 2 to form a substituted or unsubstituted heterocycle.
 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、又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、臭素及びヨウ素を包含する。 “Halogen” includes fluorine, chlorine, bromine and iodine.
 「アルキル」とは、炭素数1~10の直鎖又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。
 Rにおける「アルキル」としては、メチル、エチル、プロピル、イソプロピル、tert-ブチルが好ましい。
 Rにおける「炭素数2から10のアルキル」としては、エチル、プロピル、イソプロピル、tert-ブチルが好ましい。
“Alkyl” means a straight 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.
As the “alkyl” for R 2 , methyl, ethyl, propyl, isopropyl and tert-butyl are preferable.
As the “alkyl having 2 to 10 carbon atoms” for R 2 , ethyl, propyl, isopropyl and tert-butyl are preferable.
 「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の直鎖又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 any 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の直鎖状又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 straight or branched hydrocarbon group having 2 to 10 carbon atoms having one or more triple bonds at an arbitrary 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、及びこれらの環状飽和炭化水素基にさらに3~8員の環が1または2個縮合した基を意味する。炭素数3~8の環状飽和炭化水素基としては、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、シクロオクチルが挙げられる。特に、炭素数3~6のシクロアルキル、炭素数5または6のシクロアルキルが好ましい。
 Rにおける「シクロアルキル」としては、シクロプロピル、シクロブチル、シクロへキシル等が挙げられる。
 炭素数3~8の環状飽和炭化水素基に縮合する環としては、非芳香族炭素環(例えば、シクロアルカン環(例:シクロヘキサン環、シクロペンタン環など)、シクロアルケン環(例:シクロヘキセン環、シクロペンテン環)など)、非芳香族複素環(例えば、ピペリジン環、ピペラジン環、モルホリン環など)が挙げられる。なお、結合手は、炭素数3~8の環状飽和炭化水素基から出ているものとする。
 例えば、以下の基もシクロアルキルに例示され、シクロアルキルに含まれる。なお、これらの基は置換可能な任意の位置で置換されていてもよい。
Figure JPOXMLDOC01-appb-C000043

Figure JPOXMLDOC01-appb-C000044

Figure JPOXMLDOC01-appb-C000045
“Cycloalkyl” means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic saturated hydrocarbon groups. Examples of the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In particular, cycloalkyl having 3 to 6 carbon atoms and cycloalkyl having 5 or 6 carbon atoms are preferable.
Examples of “cycloalkyl” for R 4 include cyclopropyl, cyclobutyl, cyclohexyl and the like.
Examples of the ring condensed with the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring, Cyclopentene ring) and the like, and non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.). The bond is assumed to come from a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms.
For example, the following groups are also exemplified by cycloalkyl and are included in cycloalkyl. These groups may be substituted at any substitutable position.
Figure JPOXMLDOC01-appb-C000043

Figure JPOXMLDOC01-appb-C000044

Figure JPOXMLDOC01-appb-C000045
 「シクロアルケニル」とは、炭素数3~8個の環状不飽和脂肪族炭化水素基、及びこれらの環状不飽和脂肪族炭化水素基にさらに3~8員の環が1または2個縮合した基を意味する。炭素数3~8個の環状不飽和脂肪族炭化水素基としては、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などが挙げられる。特に、炭素数3~6のシクロアルケニル、炭素数5または6のシクロアルケニルが好ましい。
 炭素数3~8の環状不飽和脂肪族炭化水素基に縮合する環としては、炭素環(芳香族炭素環(例えば、ベンゼン環、ナフタレン環など)、非芳香族炭素環(例えば、シクロアルカン環(例:シクロヘキサン環、シクロペンタン環など)、シクロアルケン環(例:シクロヘキセン環、シクロペンテン環など)など))、複素環(芳香族複素環(ピリジン環、ピリミジン環、ピロール環、イミダゾール環など)、非芳香族複素環(例えば、ピペリジン環、ピペラジン環、モルホリン環など)が挙げられる。なお、結合手は、炭素数3~8の環状不飽和脂肪族炭化水素基から出ているものとする。
 例えば、以下の基もシクロアルケニルとして例示され、シクロアルケニルに含まれる。なお、これらの基は置換可能な任意の位置で置換されていてもよい。
Figure JPOXMLDOC01-appb-C000046

Figure JPOXMLDOC01-appb-C000047

Figure JPOXMLDOC01-appb-C000048

Figure JPOXMLDOC01-appb-C000049
“Cycloalkenyl” is a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic unsaturated aliphatic hydrocarbon groups. Means. Examples of the cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. In particular, cycloalkenyl having 3 to 6 carbon atoms and cycloalkenyl having 5 or 6 carbon atoms are preferable.
Examples of the ring condensed with the C3-C8 cyclic unsaturated aliphatic hydrocarbon group include carbocycles (aromatic carbocycles (eg, benzene ring, naphthalene ring etc.), non-aromatic carbocycles (eg cycloalkane ring). (Example: cyclohexane ring, cyclopentane ring, etc.), cycloalkene ring (example: cyclohexene ring, cyclopentene ring, etc.)), heterocycle (aromatic heterocycle (pyridine ring, pyrimidine ring, pyrrole ring, imidazole ring, etc.)) And non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.) The bond is assumed to come from a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms. .
For example, the following groups are also exemplified as cycloalkenyl and are included in cycloalkenyl. These groups may be substituted at any substitutable position.
Figure JPOXMLDOC01-appb-C000046

Figure JPOXMLDOC01-appb-C000047

Figure JPOXMLDOC01-appb-C000048

Figure JPOXMLDOC01-appb-C000049
 「アリール」とは、単環又は多環の芳香族炭素環式基、及びこれらの単環又は多環の芳香族炭素環式基にさらに3~8員の環が1または2個縮合した基を意味する。単環又は多環の芳香族炭素環式基としては、例えば、フェニル、ナフチル、アントリル、フェナントリルが挙げられる。特にフェニルが好ましい。
 単環又は多環の芳香族炭素環式基に縮合する環としては、非芳香族炭素環(例えば、シクロアルカン環(例:シクロヘキサン環、シクロペンタン環など)、シクロアルケン環(例:シクロヘキセン環、シクロペンテン環など)など)、非芳香族複素環(例えば、ピペリジン環、ピペラジン環、モルホリン環など)が挙げられる。なお、結合手は、単環又は多環の芳香族炭素環式基から出ているものとする。
 例えば、以下の基もアリールとして例示され、アリールに含まれる。なお、これらの基は置換可能な任意の位置で置換されていてもよい。
Figure JPOXMLDOC01-appb-C000050

Figure JPOXMLDOC01-appb-C000051

 Rにおける「アリール」としては、フェニルが好ましい。
 Rにおける「アリール」としては、フェニルが好ましい。
“Aryl” is a monocyclic or polycyclic aromatic carbocyclic group, and a group obtained by further condensing one or two 3- to 8-membered rings to these monocyclic or polycyclic aromatic carbocyclic groups. Means. Examples of the monocyclic or polycyclic aromatic carbocyclic group include phenyl, naphthyl, anthryl, and phenanthryl. Particularly preferred is phenyl.
Rings condensed with monocyclic or polycyclic aromatic carbocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring). And non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring). The bond is assumed to come from a monocyclic or polycyclic aromatic carbocyclic group.
For example, the following groups are also exemplified as aryl and are included in aryl. These groups may be substituted at any substitutable position.
Figure JPOXMLDOC01-appb-C000050

Figure JPOXMLDOC01-appb-C000051

As the “aryl” in R 4 , phenyl is preferable.
As the “aryl” in R 5 , phenyl is preferable.
 「ヘテロアリール」とは、O、S及びNから任意に選択されるヘテロ原子を環内に1以上有する単環又は多環の芳香族へテロ環式基、及びこれらの単環又は多環の芳香族へテロ環式基にさらに3~8員の環が1または2個縮合した基を意味する。
 「単環の芳香族ヘテロ環式基」としては、特に5員または6員のヘテロアリールが好ましく、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、チエニルなどが挙げられる。
 「多環の芳香族ヘテロ環式基」としては、特に5員または6員の環が縮合したヘテロアリールが好ましく、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。
 単環又は多環の芳香族へテロ環式基に縮合する環としては、非芳香族炭素環(例えば、シクロアルカン環(例:シクロヘキサン環、シクロペンタン環など)、シクロアルケン環(例:シクロヘキセン環、シクロペンテン環など)など)、非芳香族複素環(例えば、ピペリジン環、ピペラジン環、モルホリン環など)が挙げられる。なお、結合手は、単環又は多環の芳香族へテロ環式基から出ているものとする。
 例えば、以下の基もヘテロアリールとして例示され、ヘテロアリールに含まれる。なお、これらの基は置換可能な任意の位置で置換されていてもよい。
Figure JPOXMLDOC01-appb-C000052

Figure JPOXMLDOC01-appb-C000053

 Rにおける「ヘテロアリール」としては、ピリジル、ピラゾリル等が好ましい。
“Heteroaryl” means a monocyclic or polycyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring, and monocyclic or polycyclic A group obtained by further condensing one or two 3- to 8-membered rings on an aromatic heterocyclic group.
As the “monocyclic aromatic heterocyclic group”, a 5- or 6-membered heteroaryl is particularly preferable. For example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, Examples include oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and the like.
The “polycyclic aromatic heterocyclic group” is particularly preferably a heteroaryl fused with a 5- or 6-membered ring, such as indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, Naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotria Bicyclic aromatic heterocyclic groups such as zolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl; carbazolyl, Kurijiniru, xanthenyl, phenothiazinyl, phenoxathiinyl, cycloalkenyl, 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.
Rings condensed with monocyclic or polycyclic aromatic heterocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene). A non-aromatic heterocyclic ring (for example, a piperidine ring, a piperazine ring, a morpholine ring, etc.). The bond is assumed to be from a monocyclic or polycyclic aromatic heterocyclic group.
For example, the following groups are also exemplified as heteroaryl, and are included in heteroaryl. These groups may be substituted at any substitutable position.
Figure JPOXMLDOC01-appb-C000052

Figure JPOXMLDOC01-appb-C000053

As the “heteroaryl” in R 4 , pyridyl, pyrazolyl and the like are preferable.
 「非芳香族複素環式基」とは、O、S及び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、及びこれらの非芳香族へテロ環式基にさらに3~8員の環が1または2個縮合した基を意味する。
単環の非芳香族へテロ環式基または多環の非芳香族へテロ環式基を含有する。
 「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。
 例えば、以下の基も非芳香族複素環式基に含まれる。
Figure JPOXMLDOC01-appb-C000054

Figure JPOXMLDOC01-appb-C000055

Figure JPOXMLDOC01-appb-C000056

 Rにおける「非芳香族複素環式基」としては、テトラヒドロピラニル、ピロリジニル、ピペリジニル、ピペラジニル、モルホリノ、モルホリニル、ジヒドロピリジニル等が好ましい。
 Rにおける「非芳香族複素環式基」としては、ピペリジニル、モルホリノ、モルホリニル等が好ましい。
“Non-aromatic heterocyclic group” means a non-aromatic heterocyclic group having one or more hetero atoms arbitrarily selected from O, S and N in the ring, and these non-aromatic heterocyclic groups This means a group in which one or two 3- to 8-membered rings are condensed to the formula group.
It contains a monocyclic non-aromatic heterocyclic group or a polycyclic non-aromatic heterocyclic group.
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.
For example, the following groups are also included in the non-aromatic heterocyclic group.
Figure JPOXMLDOC01-appb-C000054

Figure JPOXMLDOC01-appb-C000055

Figure JPOXMLDOC01-appb-C000056

As the “non-aromatic heterocyclic group” in R 4 , tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, morpholinyl, dihydropyridinyl and the like are preferable.
As the “non-aromatic heterocyclic group” in R 4 , piperidinyl, morpholino, morpholinyl and the like are preferable.
 置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換の非芳香族複素環式基は、1または2個のオキソ、チオキソまたは置換もしくは非置換のイミノで置換されていてもよい。 A substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group is substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino Also good.
 「置換アルキル」、「置換アルケニル」、「置換アルキニル」または「置換の炭素数2~10のアルキル」の置換基としては、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基または式:-SO-R10で示される基(ここでR10は、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノ)が挙げられる。これらの置換基で、置換可能な任意の位置が1~数個、置換されていてもよい。
 好ましい「置換アルキル」、「置換アルケニル」、「置換アルキニル」または「置換の炭素数2~10のアルキル」の置換基としては、ハロゲン、シアノ、カルボキシ等が挙げられる。
 好ましい「置換アルキル」の置換基としては、ハロゲンが挙げられる。
 好ましい「置換の炭素数2~10のアルキル」の置換基としては、ハロゲンが挙げられる。
Examples of the substituent of “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl” or “substituted alkyl having 2 to 10 carbon atoms” include halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or Unsubstituted amino, carboxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group , Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by the formula: —O—R 10 , represented by the formula: —O—C (═O) —R 10 A group represented by the formula: —C (═O) —R 10 ; a group represented by the formula: —C (═O) —O—R 10 ; A group represented by the formula: —S—R 10 or a group represented by the formula: —SO 2 —R 10 (where R 10 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino). With these substituents, 1 to several arbitrary positions where substitution is possible may be substituted.
Preferred substituents of “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl” or “substituted alkyl having 2 to 10 carbon atoms” include halogen, cyano, carboxy and the like.
Preferred substituents of “substituted alkyl” include halogen.
A preferable substituent of “substituted alkyl having 2 to 10 carbon atoms” includes halogen.
 「置換シクロアルキル」、「置換シクロアルケニル」、「置換アリール」、「置換ヘテロアリール」、「置換非芳香族複素環式基」、「RとRが共に隣接する窒素原子と一緒になって形成する置換複素環」または「RとRが共に隣接する窒素原子及び-SO-と一緒になって形成する置換複素環」の置換基としては、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基または式:-SO-R10で示される基(ここでR10は、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノ)が挙げられる。これらの置換基で、置換可能な任意の位置が1~数個、置換されていてもよい。
 「置換もしくは非置換のシクロアルキル」、「置換もしくは非置換のシクロアルケニル」、「置換もしくは非置換の非芳香族複素環式基」、「RとRが共に隣接する窒素原子と一緒になって形成する置換もしくは非置換の複素環」または「RとRが共に隣接する窒素原子及び-SO-と一緒になって形成する置換もしくは非置換の複素環」は、置換可能な任意の位置がオキソ、チオキソまたは置換もしくは非置換のイミノで置換されていてもよい。
 好ましい「置換シクロアルキル」、「置換シクロアルケニル」、「置換アリール」、「置換ヘテロアリール」、「置換非芳香族複素環式基」、「RとRが共に隣接する窒素原子と一緒になって形成する置換複素環」または「RとRが共に隣接する窒素原子及び-SO-と一緒になって形成する置換複素環」の置換基としては、、ハロゲン、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ等が挙げられる。
 好ましい「置換アリール」の置換基としては、ハロゲン、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ等が挙げられる。
 好ましい「置換非芳香族複素環式基」の置換基としては、ハロゲンが挙げられる。
“Substituted cycloalkyl”, “substituted cycloalkenyl”, “substituted aryl”, “substituted heteroaryl”, “substituted non-aromatic heterocyclic group”, “R 6 and R 2 together with the adjacent nitrogen atom” Substituents of “substituted heterocycle formed” or “substituted heterocycle formed by combining R 7 and R 2 together with the adjacent nitrogen atom and —SO 2 —” include halogen, hydroxy, mercapto, nitro, Nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, a substituted or unsubstituted amidino formula: a group represented by -O-R 10, wherein: -O-C (= O) a group represented by —R 10 , a group represented by formula: —C (═O) —R 10 , a group represented by formula: —C (═O) —O—R 10 , a formula: —S—R group or the formula represented by 10: group (wherein R 10 represented by -SO 2 -R 10 are substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carba Yl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted amidino) can be mentioned. With these substituents, 1 to several arbitrary positions where substitution is possible may be substituted.
“Substituted or unsubstituted cycloalkyl”, “substituted or unsubstituted cycloalkenyl”, “substituted or unsubstituted non-aromatic heterocyclic group”, “R 6 and R 2 together with the adjacent nitrogen atom Or a substituted or unsubstituted heterocyclic ring formed by R 7 and R 2 together with the adjacent nitrogen atom and —SO 2 — ”can be substituted. Any position may be substituted with oxo, thioxo or substituted or unsubstituted imino.
Preferred “substituted cycloalkyl”, “substituted cycloalkenyl”, “substituted aryl”, “substituted heteroaryl”, “substituted non-aromatic heterocyclic group”, “R 6 and R 2 together with the adjacent nitrogen atom” Substituents of “substituted heterocycle formed” or “substituted heterocycle formed by combining R 7 and R 2 together with the adjacent nitrogen atom and —SO 2 —” include halogen, alkyl, haloalkyl, Examples include alkyloxy and haloalkyloxy.
Preferred substituents of “substituted aryl” include halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy and the like.
A preferable substituent of the “substituted non-aromatic heterocyclic group” includes halogen.
 「置換アミノ」、「置換カルバモイル」、「置換スルファモイル」、「置換アミジノ」または「置換イミノ」の置換基としては、ヒドロキシ、シアノ、ホルミル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-Rで示される基、式:-C(=O)-Rで示される基、式:-C(=O)-O-Rで示される基、または式:-SO-Rで示される基(ここでRは、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基)が挙げられる。これらの置換基で、置換可能な任意の位置が1~2個、置換されていてもよい。 As the substituent of “substituted amino”, “substituted carbamoyl”, “substituted sulfamoyl”, “substituted amidino” or “substituted imino”, hydroxy, cyano, formyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R, group represented by formula: —C (═O) —R, formula: -C (= O) groups represented by -O-R or the formula: is a group (wherein R represented by -SO 2 -R Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl or a substituted or unsubstituted non-aromatic heterocyclic group). With these substituents, 1 to 2 arbitrary positions where substitution is possible may be substituted.
 本発明化合物において、特に好ましい態様を以下に示す。
式(Ie):
Figure JPOXMLDOC01-appb-C000057

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において、以下の(Ie-A)または(Ie-B)で示される態様が挙げられる。
(Ie-A)
Xが-SO-であり、
が=C(-H)-であり、
が-C(-H)=であり、
が=C(-H)-であり、
Zが-C(-H)=であり、
11及びR12がそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
10が置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
が置換もしくは非置換の炭素数2~10のアルキルであり、
が置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基である、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。
(Ie-B)
Xが-SO-であり、
が=C(-H)-であり、
が-C(-H)=であり、
が=C(-H)-であり、
Zが-C(-H)=であり、
11及びR12がそれぞれ独立して、水素、ハロゲン、ヒドロキシ、シアノ、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
10が置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
が置換もしくは非置換の炭素数2~10のアルキルであり、
が置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリールである、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。
In the compound of the present invention, particularly preferred embodiments are shown below.
Formula (Ie):
Figure JPOXMLDOC01-appb-C000057

And the pharmaceutically acceptable salt thereof, or the solvate thereof, include the following embodiments represented by (Ie-A) or (Ie-B).
(Ie-A)
X is —SO 2 —;
Y 1 is = C (-H)-,
Y 2 is -C (-H) =,
Y 3 is = C (-H)-,
Z is -C (-H) =,
R 11 and R 12 are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocycle Formula group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R 10 , formula: —O—C (═O) —R 10 a group represented the formula: -C (= O) group represented by -R 10, wherein: -C (= O) - Group, represented by -R 10 formula: a group represented by -S-R 10, wherein: or a group represented by the formula represented by -SO 2 -R 10: is a group represented by -O-SO 2 -R 10,
R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
R 2 is substituted or unsubstituted alkyl having 2 to 10 carbon atoms,
The compound wherein R 5 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted non-aromatic heterocyclic group , A pharmaceutically acceptable salt thereof, or a solvate thereof.
(Ie-B)
X is —SO 2 —;
Y 1 is = C (-H)-,
Y 2 is -C (-H) =,
Y 3 is = C (-H)-,
Z is -C (-H) =,
R 11 and R 12 are each independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, a group represented by the formula: —O—R 10 , a group represented by the formula: —O—C (═O) —R 10 , A group represented by the formula: —C (═O) —R 10 , a group represented by the formula: —C (═O) —O—R 10 , a group represented by the formula: —S—R 10 , a formula: —SO group or the formula represented by 2 -R 10: is a group represented by -O-SO 2 -R 10,
R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
R 2 is substituted or unsubstituted alkyl having 2 to 10 carbon atoms,
A compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 5 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
 本発明化合物において、特に好ましい態様を以下に示す。
式(Ih):
Figure JPOXMLDOC01-appb-C000058

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において、以下の(Ih-A)または(Ih-B)で示される態様が挙げられる。
(Ih-A)
Xが-SO-であり、
が=C(-H)-であり、
が-C(-H)=であり、
が=C(-H)-であり、
Zが-C(-H)=であり、
11及びR12がそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
10が置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
が置換もしくは非置換の炭素数2~10のアルキルであり、
が置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基である、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。
(Ih-B)
Xが-SO-であり、
が=C(-H)-であり、
が-C(-H)=であり、
が=C(-H)-であり、
Zが-C(-H)=であり、
11及びR12がそれぞれ独立して、水素、ハロゲン、ヒドロキシ、シアノ、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
10が置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
が置換もしくは非置換の炭素数2~10のアルキルであり、
が置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリールである、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。
In the compound of the present invention, particularly preferred embodiments are shown below.
Formula (Ih):
Figure JPOXMLDOC01-appb-C000058

And the pharmaceutically acceptable salt thereof, or a solvate thereof, includes the following (Ih-A) or (Ih-B).
(Ih-A)
X is —SO 2 —;
Y 1 is = C (-H)-,
Y 2 is -C (-H) =,
Y 3 is = C (-H)-,
Z is -C (-H) =,
R 11 and R 12 are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocycle Formula group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R 10 , formula: —O—C (═O) —R 10 a group represented the formula: -C (= O) group represented by -R 10, wherein: -C (= O) - Group, represented by -R 10 formula: a group represented by -S-R 10, wherein: or a group represented by the formula represented by -SO 2 -R 10: is a group represented by -O-SO 2 -R 10,
R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
R 2 is substituted or unsubstituted alkyl having 2 to 10 carbon atoms,
The compound wherein R 5 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted non-aromatic heterocyclic group , A pharmaceutically acceptable salt thereof, or a solvate thereof.
(Ih-B)
X is —SO 2 —;
Y 1 is = C (-H)-,
Y 2 is -C (-H) =,
Y 3 is = C (-H)-,
Z is -C (-H) =,
R 11 and R 12 are each independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, a group represented by the formula: —O—R 10 , a group represented by the formula: —O—C (═O) —R 10 , A group represented by the formula: —C (═O) —R 10 , a group represented by the formula: —C (═O) —O—R 10 , a group represented by the formula: —S—R 10 , a formula: —SO group or the formula represented by 2 -R 10: is a group represented by -O-SO 2 -R 10,
R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
R 2 is substituted or unsubstituted alkyl having 2 to 10 carbon atoms,
A compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 5 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
 本発明化合物において、特に好ましい態様を以下に示す。
式(Ij):
Figure JPOXMLDOC01-appb-C000059

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において、以下の(Ij-A)または(Ij-B)で示される態様が挙げられる。
(Ij-A)
Xが-SO-であり、
が=C(-H)-であり、
が-C(-H)=であり、
が=C(-H)-であり、
Zが-C(-H)=であり、
11及びR12がそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
10が置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
が置換もしくは非置換の炭素数2~10のアルキルであり、
が置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基である、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。
(Ij-B)
Xが-SO-であり、
が=C(-H)-であり、
が-C(-H)=であり、
が=C(-H)-であり、
Zが-C(-H)=であり、
11及びR12がそれぞれ独立して、水素、ハロゲン、ヒドロキシ、シアノ、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
10が置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
が置換もしくは非置換の炭素数2~10のアルキルであり、
が置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリールである、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。
In the compound of the present invention, particularly preferred embodiments are shown below.
Formula (Ij):
Figure JPOXMLDOC01-appb-C000059

And the pharmaceutically acceptable salt thereof, or the solvate thereof, include the following embodiments (Ij-A) or (Ij-B).
(Ij-A)
X is —SO 2 —;
Y 1 is = C (-H)-,
Y 2 is -C (-H) =,
Y 3 is = C (-H)-,
Z is -C (-H) =,
R 11 and R 12 are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocycle Formula group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R 10 , formula: —O—C (═O) —R 10 a group represented the formula: -C (= O) group represented by -R 10, wherein: -C (= O) - Group, represented by -R 10 formula: a group represented by -S-R 10, wherein: or a group represented by the formula represented by -SO 2 -R 10: is a group represented by -O-SO 2 -R 10,
R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
R 2 is substituted or unsubstituted alkyl having 2 to 10 carbon atoms,
The compound wherein R 5 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted non-aromatic heterocyclic group , A pharmaceutically acceptable salt thereof, or a solvate thereof.
(Ij-B)
X is —SO 2 —;
Y 1 is = C (-H)-,
Y 2 is -C (-H) =,
Y 3 is = C (-H)-,
Z is -C (-H) =,
R 11 and R 12 are each independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, a group represented by the formula: —O—R 10 , a group represented by the formula: —O—C (═O) —R 10 , A group represented by the formula: —C (═O) —R 10 , a group represented by the formula: —C (═O) —O—R 10 , a group represented by the formula: —S—R 10 , a formula: —SO group or the formula represented by 2 -R 10: is a group represented by -O-SO 2 -R 10,
R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
R 2 is substituted or unsubstituted alkyl having 2 to 10 carbon atoms,
A compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 5 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
 本発明化合物において、特に好ましい態様を以下に示す。
式(Im):
Figure JPOXMLDOC01-appb-C000060

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において、以下の(Im-A)または(Im-B)で示される態様が挙げられる。
(Im-A)
Xが-SO-であり、
が=C(-H)-であり、
が-C(-H)=であり、
が=C(-H)-であり、
Zが-C(-H)=であり、
11及びR12がそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
10が置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
が置換もしくは非置換の炭素数2~10のアルキルであり、
が置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基である、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。
(Im-B)
Xが-SO-であり、
が=C(-H)-であり、
が-C(-H)=であり、
が=C(-H)-であり、
Zが-C(-H)=であり、
11及びR12がそれぞれ独立して、水素、ハロゲン、ヒドロキシ、シアノ、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
10が置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
が置換もしくは非置換の炭素数2~10のアルキルであり、
が置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリールである、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。
In the compound of the present invention, particularly preferred embodiments are shown below.
Formula (Im):
Figure JPOXMLDOC01-appb-C000060

And the pharmaceutically acceptable salt or solvate thereof include the following embodiments (Im-A) or (Im-B).
(Im-A)
X is —SO 2 —;
Y 1 is = C (-H)-,
Y 2 is -C (-H) =,
Y 3 is = C (-H)-,
Z is -C (-H) =,
R 11 and R 12 are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocycle Formula group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R 10 , formula: —O—C (═O) —R 10 a group represented the formula: -C (= O) group represented by -R 10, wherein: -C (= O) - Group, represented by -R 10 formula: a group represented by -S-R 10, wherein: or a group represented by the formula represented by -SO 2 -R 10: is a group represented by -O-SO 2 -R 10,
R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
R 2 is substituted or unsubstituted alkyl having 2 to 10 carbon atoms,
The compound wherein R 5 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted non-aromatic heterocyclic group , A pharmaceutically acceptable salt thereof, or a solvate thereof.
(Im-B)
X is —SO 2 —;
Y 1 is = C (-H)-,
Y 2 is -C (-H) =,
Y 3 is = C (-H)-,
Z is -C (-H) =,
R 11 and R 12 are each independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, a group represented by the formula: —O—R 10 , a group represented by the formula: —O—C (═O) —R 10 , A group represented by the formula: —C (═O) —R 10 , a group represented by the formula: —C (═O) —O—R 10 , a group represented by the formula: —S—R 10 , a formula: —SO group or the formula represented by 2 -R 10: is a group represented by -O-SO 2 -R 10,
R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
R 2 is substituted or unsubstituted alkyl having 2 to 10 carbon atoms,
A compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 5 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
 本発明化合物において、特に好ましい態様を以下に示す。
式(Io):
Figure JPOXMLDOC01-appb-C000061

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において、以下の(Io-A)~(Io-B)で示される態様が挙げられる。
(Io-A)
Xが-SO-であり、
が=C(-H)-であり、
が-C(-H)=であり、
が=C(-H)-であり、
Zが-C(-H)=であり、
11及びR12がそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
10が置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
が置換もしくは非置換の炭素数2~10のアルキルであり、
が置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基である、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。
(Io-B)
Xが-SO-であり、
が=C(-H)-であり、
が-C(-H)=であり、
が=C(-H)-であり、
Zが-C(-H)=であり、
11及びR12がそれぞれ独立して、水素、ハロゲン、ヒドロキシ、シアノ、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
10が置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
が置換もしくは非置換の炭素数2~10のアルキルであり、
が置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリールである、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。
In the compound of the present invention, particularly preferred embodiments are shown below.
Formula (Io):
Figure JPOXMLDOC01-appb-C000061

And the pharmaceutically acceptable salts thereof, or the solvates thereof include the following embodiments (Io-A) to (Io-B).
(Io-A)
X is —SO 2 —;
Y 1 is = C (-H)-,
Y 2 is -C (-H) =,
Y 3 is = C (-H)-,
Z is -C (-H) =,
R 11 and R 12 are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocycle Formula group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R 10 , formula: —O—C (═O) —R 10 a group represented the formula: -C (= O) group represented by -R 10, wherein: -C (= O) - Group, represented by -R 10 formula: a group represented by -S-R 10, wherein: or a group represented by the formula represented by -SO 2 -R 10: is a group represented by -O-SO 2 -R 10,
R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
R 2 is substituted or unsubstituted alkyl having 2 to 10 carbon atoms,
The compound wherein R 5 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted non-aromatic heterocyclic group , A pharmaceutically acceptable salt thereof, or a solvate thereof.
(Io-B)
X is —SO 2 —;
Y 1 is = C (-H)-,
Y 2 is -C (-H) =,
Y 3 is = C (-H)-,
Z is -C (-H) =,
R 11 and R 12 are each independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, a group represented by the formula: —O—R 10 , a group represented by the formula: —O—C (═O) —R 10 , A group represented by the formula: —C (═O) —R 10 , a group represented by the formula: —C (═O) —O—R 10 , a group represented by the formula: —S—R 10 , a formula: —SO group or the formula represented by 2 -R 10: is a group represented by -O-SO 2 -R 10,
R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
R 2 is substituted or unsubstituted alkyl having 2 to 10 carbon atoms,
A compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 5 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
 本発明化合物は、各々の化合物の製薬上許容される塩を包含する。塩基性塩として、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩;カルシウム塩、マグネシウム塩等のアルカリ土類金属塩;アンモニウム塩;トリメチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、エタノールアミン塩、ジエタノールアミン塩、トリエタノールアミン塩、ブロカイン塩、メグルミン塩、ジエタノールアミン塩またはエチレンジアミン塩等の脂肪族アミン塩;N,N-ジベンジルエチレンジアミン、ベネタミン塩等のアラルキルアミン塩;ピリジン塩、ピコリン塩、キノリン塩、イソキノリン塩等のヘテロ環芳香族アミン塩;テトラメチルアンモニウム塩、テトラエチルアモニウム塩、ベンジルトリメチルアンモニウム塩、ベンジルトリエチルアンモニウム塩、ベンジルトリブチルアンモニウム塩、メチルトリオクチルアンモニウム塩、テトラブチルアンモニウム塩等の第4級アンモニウム塩;アルギニン塩、リジン塩等の塩基性アミノ酸塩等が挙げられる。
 酸性塩としては、例えば、塩酸塩、硫酸塩、硝酸塩、リン酸塩、炭酸塩、炭酸水素塩、過塩素酸塩等の無機酸塩;酢酸塩、プロピオン酸塩、乳酸塩、マレイン酸塩、フマール酸塩、酒石酸塩、リンゴ酸塩、クエン酸塩、アスコルビン酸塩等の有機酸塩;メタンスルホン酸塩、イセチオン酸塩、ベンゼンスルホン酸塩、p-トルエンスルホン酸塩等のスルホン酸塩;アスパラギン酸塩、グルタミン酸塩等の酸性アミノ酸等が挙げられる。特に、Zが-N=のとき、本発明化合物をこれらの酸性塩として、用いることができる。
The compounds of the present invention include pharmaceutically acceptable salts of the respective compounds. Examples of basic salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt , Triethanolamine salt, brocaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt and other aliphatic amine salts; N, N-dibenzylethylenediamine, venetamine salt and other aralkylamine salts; pyridine salt, picoline salt, quinoline salt, isoquinoline Heterocyclic aromatic amine salts such as salts; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyl Examples include quaternary ammonium salts such as trioctylammonium salt and tetrabutylammonium salt; basic amino acid salts such as arginine salt and lysine salt.
Examples of the acid salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate and ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate; Examples include acidic amino acids such as aspartate and glutamate. In particular, when Z is —N═, the compound of the present invention can be used as these acid salts.
 本発明化合物は、その溶媒和物を包含する。溶媒和物とは、本発明化合物またはその製薬上許容される塩の溶媒和物を意味し、例えば、アルコール(例:エタノール)和物や水和物等が挙げられる。水和物としては、1水和物、2水和物等を挙げることができる。
 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、両対掌体及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体及びZ体が存在し得るときはそのいずれをも含む。
 本発明化合物のプロドラッグは本発明の範囲に含まれる。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 compounds of the present invention include solvates thereof. The solvate means a solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof, and examples thereof include alcohol (eg, ethanol) solvate and hydrate. Examples of the hydrate include monohydrate, dihydrate and the like.
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 can exist, both are included.
Prodrugs of the compounds of the invention are within the scope of the 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 the specific compound is administered in vivo after being administered to a patient with a disease involving NPY Y5. Including compounds that convert to Conventional procedures for selection and formulation of suitable prodrug derivatives are described, for example, in Design of Prodrugs (ed. H. Bundgaard, Elsevier, 1985).
 本発明の化合物の一つ以上の水素、炭素または他の原子は、水素、炭素または他の原子の同位体で置換され得る。
 例えば、式(I)で示される化合物は、式(I)で示される化合物のすべての放射性標識体を包含する。式(I)で示される化合物のそのような「放射性標識化」、「放射性標識体」などは、それぞれが本発明に包含され、代謝薬物動態研究ならびに結合アッセイにおける研究および/または診断ツールとして有用である。本発明の式(I)で示される化合物に組み込まれ得る同位体の例としては、それぞれH、H、13C、14C、15N、18O、17O、31P、32P、35S、18Fおよび36Clのように、水素、炭素、窒素、酸素、リン、硫黄、フッ素、および塩素が包含される。本発明の放射性標識化合物は、当該技術分野で周知の方法で調製できる。例えば、式(I)で示されるトリチウム標識化合物は、例えば、トリチウムを用いた触媒的脱ハロゲン化反応によって、式(I)で示される特定の化合物にトリチウムを導入することで調製できる。この方法は、適切な触媒、例えばPd/Cの存在下、塩基の存在または非存在下で、式(I)で示される化合物が適切にハロゲン置換された前駆体とトリチウムガスとを反応させることを包含してもよい。他のトリチウム標識化合物を調製するための適切な方法としては、Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987年)を参照にできる。14C-標識化合物は、14C炭素を有する原料を用いることによって調製できる。
One or more hydrogen, carbon or other atoms of the compounds of the present invention may be replaced with an isotope of hydrogen, carbon or other atoms.
For example, the compound represented by the formula (I) includes all radiolabeled compounds of the compound represented by the formula (I). Such “radiolabeled”, “radiolabeled” etc. of compounds of formula (I) are each encompassed by the present invention and are useful as research and / or diagnostic tools in metabolic pharmacokinetic studies and binding assays It is. Examples of isotopes that can be incorporated into the compound represented by the formula (I) of the present invention include 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine are included, such as 35 S, 18 F and 36 Cl. The radiolabeled compound of the present invention can be prepared by methods well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. This method comprises reacting a precursor of which the compound of formula (I) is appropriately halogen-substituted with tritium gas in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. May be included. Suitable methods for preparing other tritium labeled compounds include Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). 14C-labeled compounds can be prepared by using raw materials having 14 C carbon.
 以下に、本発明化合物の一般的な製造方法を説明する。なお、本発明化合物は以下に示す合成方法以外の方法でも、有機化学の知識に基づいて、製造することができる。
Figure JPOXMLDOC01-appb-C000062

(式中、各記号の意義は前記と同意義である。Halはハロゲンを意味する。)
Below, the general manufacturing method of this invention compound is demonstrated. In addition, this invention compound can be manufactured based on the knowledge of organic chemistry also by methods other than the synthesis method shown below.
Figure JPOXMLDOC01-appb-C000062

(In the formula, each symbol has the same meaning as described above. Hal means halogen.)
工程1
 式(II)で示される化合物からジアゾニウム塩を経由して、式(III)で示される化合物を製造する工程である。
 ジアゾニウム塩は、式(II)で示される化合物と、NaNO及びHClを反応させることにより、製造することができる。
 反応溶媒としては、水、水とアルコール(たとえば、メタノール)の混合溶媒を用いることができる。
 ジアゾニウム塩の形成後、ジアゾニウム塩にハロゲン化銅(たとえば、臭化銅、塩化銅、ヨウ化銅など)を反応させ、式(III)で示される化合物を製造することができる。 反応は、0℃から室温で行うことができる。また、40~60℃に加温することもできる。
Process 1
In this step, the compound represented by the formula (III) is produced from the compound represented by the formula (II) via a diazonium salt.
The diazonium salt can be produced by reacting the compound represented by the formula (II) with NaNO 2 and HCl.
As a reaction solvent, water, a mixed solvent of water and alcohol (for example, methanol) can be used.
After the formation of the diazonium salt, the diazonium salt can be reacted with a copper halide (for example, copper bromide, copper chloride, copper iodide, etc.) to produce a compound represented by the formula (III). The reaction can be carried out at 0 ° C. to room temperature. It can also be heated to 40-60 ° C.
工程2
 式(III)で示される化合物から、式(I)で示される化合物を製造する工程である。
 反応性のアミノ基(-NH-)を環内に有する化合物を、式(III)で示される化合物のハロゲンと反応させることにより、式(I)で示される化合物を製造することができる。R上の置換基は、工程2に先立ち導入しておいてもよいし、工程2の後に導入してもよい。
 反応溶媒として、アセトニトリル、テトラヒドロフラン、トルエン、ベンゼン、2-プロパノールなど)を用いることができる。
 反応は、室温でも行うことができる。また、反応の進行を見て、適宜加温してもよい。たとえば、アセトニトリル中で100~120℃に加温して行うことができる。
 マイクロウェーブの照射下で行うことができる。
 式(III)で示される化合物は、式(I)で示される化合物の合成中間体として有用である。
Process 2
In this step, the compound represented by formula (I) is produced from the compound represented by formula (III).
The compound represented by the formula (I) can be produced by reacting a compound having a reactive amino group (—NH—) in the ring with the halogen of the compound represented by the formula (III). The substituent on R 4 may be introduced prior to step 2 or after step 2.
As the reaction solvent, acetonitrile, tetrahydrofuran, toluene, benzene, 2-propanol, etc.) can be used.
The reaction can also be performed at room temperature. Moreover, you may heat suitably, seeing the progress of reaction. For example, it can be performed by heating to 100 to 120 ° C. in acetonitrile.
It can be performed under microwave irradiation.
The compound represented by the formula (III) is useful as a synthetic intermediate for the compound represented by the formula (I).
 上記工程1で使用する式(II)で示される化合物は、以下のように製造することができる。
Figure JPOXMLDOC01-appb-C000063

(式中、Xは-SO-であり、その他の各記号の意義は前記と同意義である。Proはアミノ保護基を意味する。)
The compound represented by the formula (II) used in the above step 1 can be produced as follows.
Figure JPOXMLDOC01-appb-C000063

(In the formula, X is —SO 2 —, and other symbols are as defined above. Pro represents an amino-protecting group.)
工程3
 式(IV)で示される化合物の-S-基を酸化して、式(V)で示される化合物を製造する工程である。
 酸化剤としては、mCPBA(メタクロロ過安息香酸)、KMnO(過マンガン酸カリウム)、Oxone、NaIO(過ヨウ素酸ナトリウム)、NaBO(過ホウ素酸ナトリウム)、過酸化水素などを用いることができる。
 反応溶媒として、ジクロロメタン、クロロホルム、アセトニトリル、アセトン、水などを用いることができる。
 反応は室温で行うこともできるし、また、反応の進行を見て、適宜加温してもよい。
Process 3
In this step, the —S— group of the compound represented by the formula (IV) is oxidized to produce the compound represented by the formula (V).
As the oxidizing agent, mCPBA (metachloroperbenzoic acid), KMnO 4 (potassium permanganate), Oxone, NaIO 4 (sodium periodate), NaBO 3 (sodium perborate), hydrogen peroxide, etc. may be used. it can.
As the reaction solvent, dichloromethane, chloroform, acetonitrile, acetone, water and the like can be used.
The reaction can be performed at room temperature, or may be appropriately heated while watching the progress of the reaction.
工程4
 式(IV)で示される化合物のアミノ保護基をはずして、式(II)で示される化合物を製造する工程である。
 アミノ保護基として、メトキシカルボニル基、tert-ブトキシカルボニル基、9-フルオレニルメトキシカルボニル、トリクロロエトキシカルボニルなどを用いることができる。
 脱保護条件は、保護基に応じて、適宜選択すればよい。たとえば、アルカリ性条件下で保護基を脱離すればよい。
Process 4
In this step, the amino protecting group of the compound represented by formula (IV) is removed to produce the compound represented by formula (II).
As the amino protecting group, a methoxycarbonyl group, tert-butoxycarbonyl group, 9-fluorenylmethoxycarbonyl, trichloroethoxycarbonyl and the like can be used.
What is necessary is just to select deprotection conditions suitably according to a protecting group. For example, the protecting group may be eliminated under alkaline conditions.
 式(I)で示される化合物は、以下のようにしても製造することができる。
Figure JPOXMLDOC01-appb-C000064

(式中、Zは-N=であり、その他の各記号の意義は前記と同意義である。)
The compound represented by the formula (I) can also be produced as follows.
Figure JPOXMLDOC01-appb-C000064

(In the formula, Z is -N =, and the other symbols are as defined above.)
工程5
 式(VI)で示される化合物に式:
Figure JPOXMLDOC01-appb-C000065

で示される化合物を塩基存在下で反応させ、アミド化を行い、式(VII)で示される化合物を製造する工程である。
 反応溶媒としては、ジクロロメタン、ジメチルホルムアミド、テトラヒドロフラン、1-メチルピロリジン-2-オン、N,N-ジメチルアセトアミド、アセトニトリルなど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、ジメチルアミノピリジン、N,N-ジイソプロピルエチルアミンなどを用いることができる。
 本工程において、HATU(2-(1H-7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチル ウロニウム ヘキサフルオロリン酸 メタンアミニウム)を縮合剤として用いることができる。
Process 5
The compound of formula (VI) is represented by the formula:
Figure JPOXMLDOC01-appb-C000065

In this step, the compound represented by formula (VII) is produced by reacting the compound represented by formula (II) in the presence of a base and performing amidation.
As the reaction solvent, dichloromethane, dimethylformamide, tetrahydrofuran, 1-methylpyrrolidin-2-one, N, N-dimethylacetamide, acetonitrile and the like can be used.
As the base, triethylamine, pyridine, dimethylaminopyridine, N, N-diisopropylethylamine and the like can be used.
In this step, HATU (2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium) can be used as a condensing agent.
工程6
 式(VII)で示される化合物を閉環させて、式(I)で示される化合物を製造する工程である。
 反応溶媒として酢酸、塩酸、硫酸、パラトルエンスルホン酸、10-カンファースルホン酸などを用い、100~150℃で行うことができる。
 なお、工程5及び工程6は、式:-X-Rで示される基を有する化合物で示しているが、-S-Rで示される基を有する化合物を用いて工程5及び6と同様に反応を行い、その後に-S-を酸化してもよい。
 また、R上の置換基は、工程5または6の後に導入してもよいし、工程5に先立ち導入しておいてもよい。
 式(VII)で示される化合物は、式(I)で示される化合物の合成中間体として有用である。
Step 6
In this step, the compound represented by the formula (VII) is cyclized to produce the compound represented by the formula (I).
The reaction can be carried out at 100 to 150 ° C. using acetic acid, hydrochloric acid, sulfuric acid, paratoluenesulfonic acid, 10-camphorsulfonic acid and the like as the reaction solvent.
Steps 5 and 6 are shown as compounds having a group represented by the formula: —X—R 2 , but are similar to steps 5 and 6 using a compound having a group represented by —S—R 2. The reaction may be carried out, followed by oxidation of -S-.
The substituent on R 4 may be introduced after Step 5 or 6 or may be introduced prior to Step 5.
The compound represented by the formula (VII) is useful as a synthetic intermediate for the compound represented by the formula (I).
 式(I)で示される化合物は、以下の工程でも、製造することができる。
Figure JPOXMLDOC01-appb-C000066

(式中、Xは-SO-であり、その他の各記号の意義は前記と同意義であり、Halはハロゲンを意味する。)
The compound represented by the formula (I) can also be produced by the following steps.
Figure JPOXMLDOC01-appb-C000066

(In the formula, X is —SO 2 —, and other symbols have the same meanings as described above, and Hal means halogen.)
工程7
 式(VIII)で示される化合物に、反応性のアミノ基(-NH-)を環内に有する化合物を反応させ、式(IX)で示される化合物を製造する工程である。
 本工程は、工程2に準じて行うことができる。
 DIEA(N,N-ジイソプロピルエチルアミン)、トリエチルアミンなどの存在下で行うことができる。室温でも行うことができるし、150~200℃に加温しておこなってもよい。
 反応溶媒としては、IPA(イソプロピルアルコール)、ジオキサン、トルエン、テトラヒドロフラン、エタノール、1-メチルピロリジン-2-オン、N,N-ジメチルホルムアミドなどを用いることができる。
Step 7
In this step, the compound represented by the formula (VIII) is reacted with a compound having a reactive amino group (—NH—) in the ring to produce a compound represented by the formula (IX).
This step can be performed according to step 2.
The reaction can be carried out in the presence of DIEA (N, N-diisopropylethylamine), triethylamine or the like. The reaction can be performed at room temperature or by heating to 150 to 200 ° C.
As the reaction solvent, IPA (isopropyl alcohol), dioxane, toluene, tetrahydrofuran, ethanol, 1-methylpyrrolidin-2-one, N, N-dimethylformamide and the like can be used.
工程8
 式(IX)で示される化合物に、式:RSH(式中、Rは前記と同意義)で示される化合物を反応させ、式(X)で示される化合物を製造する工程である。
 Pd(dba)(トリス(ジベンジリデンアセトン)ジパラジウム(0))、Pd(OAc)(酢酸パラジウム)、ヨウ化銅、Pd(PPh(テトラキストリフェニルホスフィンパラジウムなどの存在下で行うことができる。塩基としては、DIEA(N,N-ジイソプロピルエチルアミン)を用いることができる。Xantphos(キサントホス)の存在下で行うことができる。溶媒としては、DOX(ジオキサン)を用いることができる。室温でも行うことができるし、100~120℃に加温しておこなってもよい。
 本工程は、マイクロウェーブの照射下で行うことができる。
 なお、塩基存在下で式:RSH(式中、Rは前記と同意義)で示される化合物の代わりに、式:RSSR(式中、Rは前記と同意義)で示される化合物を用いることができる。
 また、塩基存在下で式:RSH(式中、Rは前記と同意義)で示される化合物の代わりに、式:RS(=O)O-R(たとえば、Rは2-ナフチルメチル)で示される化合物を用いて、-S(=O)-を有する化合物を製造し、その後に酸化して、式(I)で示される化合物を製造することもできる。
 塩基としてはn-ブチルリチウム、sec-ブチルリチウム、tert-ブチルリチウムを用いることができる。
 これらの場合、反応に先立って、式(IX)の縮合環の-NH-をSEM基(2-(トリメチルシリル)エトキシメチル基)で保護しておいてもよい。SEM基は、TBAF(テトラブチルアンモニウムフルオライド)の存在下で加熱することにより、脱離することができる。
Process 8
In this step, a compound represented by the formula (IX) is reacted with a compound represented by the formula: R 2 SH (wherein R 2 is as defined above) to produce a compound represented by the formula (X).
In the presence of Pd 2 (dba) 3 (tris (dibenzylideneacetone) dipalladium (0)), Pd (OAc) 2 (palladium acetate), copper iodide, Pd (PPh 3 ) 4 (tetrakistriphenylphosphine palladium, etc. As the base, DIEA (N, N-diisopropylethylamine) can be used, and in the presence of Xantphos (xantphos), DOX (dioxane) can be used as the solvent. The reaction can be performed at room temperature or by heating to 100 to 120 ° C.
This step can be performed under microwave irradiation.
In the presence of a base, instead of the compound represented by the formula: R 2 SH (wherein R 2 is as defined above), the formula: R 2 SSR 2 (wherein R 2 is as defined above) The compounds shown can be used.
Further, in the presence of a base, instead of the compound represented by the formula: R 2 SH (wherein R 2 is as defined above), the formula: R 2 S (═O) O—R (for example, R is 2- A compound having —S (═O) — can be produced using a compound represented by (naphthylmethyl), and then oxidized to produce a compound represented by formula (I).
As the base, n-butyllithium, sec-butyllithium, or tert-butyllithium can be used.
In these cases, prior to the reaction, —NH— of the condensed ring of the formula (IX) may be protected with an SEM group (2- (trimethylsilyl) ethoxymethyl group). The SEM group can be removed by heating in the presence of TBAF (tetrabutylammonium fluoride).
工程9
 式(X)で示される化合物の-S-基を酸化して、式(I)で示される化合物を製造する工程である。
 本工程は、工程3に準じて行うことができる。
 なお、R上の置換基は、工程7~9のそれぞれの工程の後に導入してもよいし、工程7に先立ち導入しておいてもよい。
 式(X)で示される化合物は、式(I)で示される化合物の合成中間体として有用である。
Step 9
In this step, the —S— group of the compound represented by the formula (X) is oxidized to produce the compound represented by the formula (I).
This step can be performed according to step 3.
The substituent on R 4 may be introduced after each of steps 7 to 9, or may be introduced prior to step 7.
The compound represented by the formula (X) is useful as a synthetic intermediate for the compound represented by the formula (I).
 Rの環内にある炭素原子を介して縮合環と結合する化合物について、以下のように製造することができる。
Figure JPOXMLDOC01-appb-C000067

(式中、各記号の意義は前記と同意義であり、Halはハロゲンを意味する。)
For compounds that bind to fused ring via a carbon atom within the R 4 ring, it can be prepared as follows.
Figure JPOXMLDOC01-appb-C000067

(In the formula, each symbol has the same meaning as described above, and Hal means halogen.)
工程10
 式(III)で示される化合物に、RB(OH)の存在下、Pd(PPh(テトラキス(トリフェニルホスフィン)パラジウム)、CSCO(炭酸セシウム)を用いて鈴木反応を行い、式(I)で示される化合物を製造する工程である。
Step 10
Suzuki reaction is performed on the compound represented by the formula (III) using Pd (PPh 3 ) 4 (tetrakis (triphenylphosphine) palladium) and CS 2 CO 3 (cesium carbonate) in the presence of RB (OH) 2. And a step for producing a compound represented by the formula (I).
 式(III)で示される化合物は、以下のように製造することができる。
Figure JPOXMLDOC01-appb-C000068

(式中、Zは-N=であり、その他の各記号の意義は前記と同意義であり、Halはハロゲンを意味する。)
The compound represented by the formula (III) can be produced as follows.
Figure JPOXMLDOC01-appb-C000068

(In the formula, Z is -N =, the meanings of the other symbols are the same as those described above, and Hal means halogen.)
工程11
 式(VI)で示される化合物に、CDI(N,N’-カルボジイミダゾール)を反応させ、式(XI)で示される化合物を製造する工程である。
 反応溶媒としては、ジメチルホルムアミド、1-メチルピロリジン-2-オン、N,N-ジメチルアセトアミド、ジクロロメタン、トルエンなどを用いることができる。反応は室温で行うことができ、また、適宜加温してもよい。
Step 11
In this step, the compound represented by the formula (VI) is reacted with CDI (N, N′-carbodiimidazole) to produce the compound represented by the formula (XI).
As the reaction solvent, dimethylformamide, 1-methylpyrrolidin-2-one, N, N-dimethylacetamide, dichloromethane, toluene and the like can be used. The reaction can be performed at room temperature, and may be appropriately heated.
工程12
 式(XI)で示される化合物に、ハロゲン化剤を反応させ、式(III)で示される化合物を製造する工程である。
 ハロゲン化剤としては、オキシ塩化リンなどを用いることができる。
Step 12
In this step, the compound represented by the formula (XI) is reacted with a halogenating agent to produce the compound represented by the formula (III).
As the halogenating agent, phosphorus oxychloride or the like can be used.
 Zが-C(R)=である化合物については、以下のように製造することができる。
Figure JPOXMLDOC01-appb-C000069

(式中、Zは-C(R)=であり、その他の各記号の意義は前記と同意義であり、Halはハロゲンを意味し、Rはアルキルを意味する。)
A compound in which Z is —C (R 9 ) ═ can be produced as follows.
Figure JPOXMLDOC01-appb-C000069

(In the formula, Z is —C (R 9 ) =, and other symbols are as defined above, Hal means halogen, and R means alkyl.)
工程13
 式(XII)で示される化合物に、式(XIII)で示される化合物を反応させ、式(XIV)で示される化合物を製造する工程である。
 本工程は、塩基の存在下で行うことができる。
 塩基としては、NaHMDS(ナトリウムビス(トリメチルシリル)アミド)などを用いることができる。
 塩基の量としては、(XIII)で示される化合物に対して、1.0~1.5当量用いることができる。
 反応溶媒としては、テトラヒドロフランなどを用いることができる。
Step 13
In this step, the compound represented by the formula (XII) is reacted with the compound represented by the formula (XIII) to produce the compound represented by the formula (XIV).
This step can be performed in the presence of a base.
As the base, NaHMDS (sodium bis (trimethylsilyl) amide) or the like can be used.
As the amount of the base, 1.0 to 1.5 equivalents can be used with respect to the compound represented by (XIII).
As the reaction solvent, tetrahydrofuran or the like can be used.
工程14
 式(XIV)で示される化合物のニトロ基を還元して、式(XV)で示される化合物を製造する工程である。
 本工程は、有機化学で知られるニトロ基の還元反応を用いて行うことができる。たとえば、Na(ナトリウムハイドロサルファイト)を還元剤として用いて、本工程を行うことができる。
 溶媒としては、メタノール、エタノール、テトラヒドロフラン、これらと水の混合溶媒を用いることできる。
 反応は、室温で行うことができるし、50~80℃に加温してもよい。
Step 14
In this step, the nitro group of the compound represented by the formula (XIV) is reduced to produce the compound represented by the formula (XV).
This step can be performed using a nitro group reduction reaction known in organic chemistry. For example, this step can be performed using Na 2 S 2 O 4 (sodium hydrosulfite) as a reducing agent.
As the solvent, methanol, ethanol, tetrahydrofuran, or a mixed solvent of these and water can be used.
The reaction can be carried out at room temperature or may be heated to 50-80 ° C.
工程15
 式(XV)で示される化合物のアミノ基に式:-C(=O)-OR(式中、Rはアルキル)で示される基を導入し、式(XVI)で示される化合物を製造する工程である。
 反応試薬として、Hal-C(=O)-ORで示される化合物を用いることができる。たとえば、クロロ炭酸エチル、クロロ炭酸エチルなどを用いることができる。
 本工程は塩基の存在下で行うことができる。塩基としては、ピリジン、ジメチルアミノピリジン、トリエチルアミンなどを用いることができる。
 反応溶媒としては、テトラヒドロフラン、N,N-ジメチルホルムアミドなどを用いることができる。
 本工程は、室温で行うことができるし、50~80℃に加温してもよい。
Step 15
A step of producing a compound represented by the formula (XVI) by introducing a group represented by the formula: —C (═O) —OR (wherein R is alkyl) into the amino group of the compound represented by the formula (XV). It is.
As the reaction reagent, a compound represented by Hal—C (═O) —OR can be used. For example, ethyl chlorocarbonate and ethyl chlorocarbonate can be used.
This step can be performed in the presence of a base. As the base, pyridine, dimethylaminopyridine, triethylamine and the like can be used.
As the reaction solvent, tetrahydrofuran, N, N-dimethylformamide and the like can be used.
This step can be performed at room temperature or may be heated to 50 to 80 ° C.
工程16
 式(XVI)で示される化合物から、式(IX)で示される化合物を製造する工程である。
 本工程は、TBAF(テトラブチルアンモニウムフルオライド)の存在下で行うことができる。
 TBAFは、式(XVI)で示される化合物に対して、2~3当量用いることができる。
 反応溶媒としては、テトラヒドロフラン、N,N-ジメチルホルムアミドなどを用いることができる。
 本工程は、室温で行うことができるし、50~80℃に加温してもよい。
 このようにして得られた式(IX)で示される化合物は、工程8、9を経て、式(I)で示される化合物に導くことができる。
 したがって、式(IX)で示される化合物は、式(I)で示される化合物の合成中間体として有用である。
Step 16
In this step, the compound represented by the formula (IX) is produced from the compound represented by the formula (XVI).
This step can be performed in the presence of TBAF (tetrabutylammonium fluoride).
TBAF can be used in an amount of 2 to 3 equivalents based on the compound represented by the formula (XVI).
As the reaction solvent, tetrahydrofuran, N, N-dimethylformamide and the like can be used.
This step can be performed at room temperature or may be heated to 50 to 80 ° C.
The compound represented by the formula (IX) thus obtained can be led to the compound represented by the formula (I) through steps 8 and 9.
Therefore, the compound represented by the formula (IX) is useful as a synthetic intermediate for the compound represented by the formula (I).
 このようにして得られた式(I)で示される化合物は、各種の溶媒で結晶化させて精製することができる。用いられる溶媒としては、アルコール(メタノール、エタノール、イソプロピルアルコール、n-ブタノールなど)、エーテル(ジエチルエーテル、ジイソプロピルエーテルなど)、酢酸メチルエステル、酢酸エチルエステル、クロロホルム、塩化メチレン、テトラヒドロフラン、N,N-ジメチルホルムアミド、トルエン、ベンゼン、キシレン、アセトニトリル、ヘキサン、ジオキサン、ジメトキシエタン、水またはそれらの混合溶媒などが挙げられる。これらの溶媒に加温下で溶解し、不純物を除去した後、徐々に温度を下げて、析出した固形物または結晶を濾取すればよい。 The compound represented by the formula (I) thus obtained can be purified by crystallization in various solvents. Solvents used include alcohol (methanol, ethanol, isopropyl alcohol, n-butanol, etc.), ether (diethyl ether, diisopropyl ether, etc.), acetic acid methyl ester, acetic acid ethyl ester, chloroform, methylene chloride, tetrahydrofuran, N, N— Examples thereof include dimethylformamide, toluene, benzene, xylene, acetonitrile, hexane, dioxane, dimethoxyethane, water or a mixed solvent thereof. After dissolving in these solvents under heating to remove impurities, the temperature may be gradually lowered and the precipitated solid or crystals may be collected by filtration.
 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、鬱血心不全又は睡眠障害の予防及び/又は治療に有効に作用する。特に肥満症の予防及び/又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、脂質異常症、動脈硬化、急性冠症候群等の予防及び/又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)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。
c)貧血誘発作用等の毒性が低い。
d)代謝安定性が高い。
e)水溶性が高い。
f)脳移行性が高い。
g)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。
 本発明化合物は、上記の中でも、特に、b)の点で優れている。
The compounds of the present invention prevent NPY Y5 related diseases in general, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension, cerebral hyperemia, congestive heart failure or sleep disorders And / or effective treatment. 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, dyslipidemia, 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) Good pharmacokinetics such as high bioavailability and moderate clearance.
c) Low toxicity such as anemia-inducing action.
d) High metabolic stability.
e) High water solubility.
f) High brain transferability.
g) Does not cause gastrointestinal disorders (eg, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).
Among the above, the compound of the present invention is particularly excellent in the point b).
 さらに、本発明化合物はNPY Y1及び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と考えられる。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、高いY5受容体選択性を有していると考えられる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。 Furthermore, it is considered that the compound of the present invention has low affinity for NPY Y1 and Y2 receptors and has 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, it is unlikely to induce side effects based on peripheral vasoconstriction, and the compound of the present invention considered to have high Y5 receptor selectivity is used as an active ingredient. The pharmaceutical composition to be used can be suitably used as a safe medicine.
 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、バッカル剤又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、炭酸カルシウム又は結晶セルロ-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、ゼラチン又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、カンテン末又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又はマクロゴ-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-ル又はメチルセルロ-ス等を用いることができる。また、液剤又は乳濁性、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。 Examples of excipients include lactose, sucrose, glucose, starch, calcium carbonate, and crystalline cellulose. 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。たとえば、抗肥満作用を有する化合物を含有する医薬組成物を、本発明化合物と併用することにより、肥満症の予防及び/又は治療や肥満症における体重管理等に用いることができる。また、本発明化合物を含有する医薬組成物を、抗肥満作用を有する化合物を含有する医薬組成物と併用することにより、肥満症の予防及び/又は治療や肥満症における体重管理等に用いることができる。また、本発明の医薬組成物の投与療法は、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。
 抗肥満作用を有する化合物を含有する医薬組成物としては、以下のものが挙げられる。
膵リパーゼ阻害剤:オルリスタット、セチリスタット。
 消化器官機能調節剤:6-クロロ-2-フェニル-8,8a-ジヒドロ-インデノール [1,2-d]チアゾーール-3a-オール。
 セロトニン2Cアゴニスト:ロルカセリン塩酸塩。
 カルボキシペプチダーゼ阻害剤:式:
Figure JPOXMLDOC01-appb-C000070

で示される化合物。
 GPR119アゴニスト:式:
Figure JPOXMLDOC01-appb-C000071

で示される化合物。
 カンナビノイドCB1受容体拮抗剤:リモナバン塩酸塩。
 ニューロキニンNK3受容体拮抗薬:リモナバン塩酸塩。
 モノアミン取り込み阻害剤:シブトラミン塩酸塩。
 メラニン凝集ホルモンMCH受容体(SLC-1)の選択的アンタゴニスト:式:
Figure JPOXMLDOC01-appb-C000072

で示される化合物。
 ステアロイル・コエンザイムA・デサチュラーゼ-1阻害剤:式:
Figure JPOXMLDOC01-appb-C000073

で示される化合物。
 ノルアドレナリンおよびドパミン再取り込み阻害薬:テソフェンシン。
また、ノルアドレナリンおよびドパミン再取り込み阻害薬であるブプロピオンとオピオイド受容体アンタゴニストであるナルトレキソンの配合剤、NE分泌促進作用を有するフェンタミンとGABAアゴニストであるトピラマートの配合剤なども抗肥満作用を有する化合物を含有する医薬組成物として例示される。
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). For example, by using a pharmaceutical composition containing a compound having an anti-obesity action in combination with the compound of the present invention, it can be used for prevention and / or treatment of obesity, weight management in obesity, and the like. The pharmaceutical composition containing the compound of the present invention can be used in combination with a pharmaceutical composition containing a compound having an anti-obesity action for the prevention and / or treatment of obesity or weight management in obesity. it can. Moreover, the administration therapy of the pharmaceutical composition of the present invention can be used in combination with diet therapy, drug therapy, exercise and the like.
The following are mentioned as a pharmaceutical composition containing the compound which has an anti-obesity action.
Pancreatic lipase inhibitor: Orlistat, cetiristat.
Gastrointestinal function regulator: 6-chloro-2-phenyl-8,8a-dihydro-indenol [1,2-d] thiazol-3a-ol.
Serotonin 2C agonist: lorcaserine hydrochloride.
Carboxypeptidase inhibitor: Formula:
Figure JPOXMLDOC01-appb-C000070

A compound represented by
GPR119 agonist: Formula:
Figure JPOXMLDOC01-appb-C000071

A compound represented by
Cannabinoid CB1 receptor antagonist: rimonabant hydrochloride.
Neurokinin NK3 receptor antagonist: rimonabant hydrochloride.
Monoamine uptake inhibitor: sibutramine hydrochloride.
Selective antagonist of melanin-concentrating hormone MCH receptor (SLC-1): Formula:
Figure JPOXMLDOC01-appb-C000072

A compound represented by
Stearoyl coenzyme A desaturase-1 inhibitor: Formula:
Figure JPOXMLDOC01-appb-C000073

A compound represented by
Noradrenaline and dopamine reuptake inhibitors: Tesofensin.
In addition, a combination of bupropion, a noradrenaline and dopamine reuptake inhibitor, and naltrexone, an opioid receptor antagonist, a combination of fentamine, which has an NE secretion-promoting action, and topiramate, a GABA agonist, also contain compounds having an anti-obesity effect Exemplified as a pharmaceutical composition.
 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
Bu:ブチル
Ph:フェニル
Boc:tert-ブトキシカルボニル
PhP:トリフェニルホスフィン
DME:ジメトキシエタン
DMF:N,N-ジメチルホルムアミド
TMSOTf:トリメチルシリルトリフラート
DIAD:アゾジカルボン酸ジイソプロピルエステル
TFA:トリフルオロ酢酸
DMSO:ジメチルスルホキシド
IBX:2-ヨードキシ安息香酸
THF:テトラヒドロフラン
HATU:2-(1H-7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチル ウロニウム ヘキサフルオロリン酸 メタンアミニウム
DIEA:N,N-ジイソプロピルエチルアミン
IPA:イソプロピルアルコール
TBAF:テトラブチルアンモニウムフルオライド
CDI:N,N’-カルボジイミダゾール
NaHMDS:ナトリウムビス(トリメチルシリル)アミド
SEM:2-(トリメチルシリル)エトキシメチル
SEMCl:2-(トリメチルシリル)エトキシメチル クロリド
MOM:メトキシメチル
Pd(PPh:テトラキス(トリフェニルホスフィン)パラジウム
POCl:塩化ホスホリル
xantphos:キサントホス
Hunig‘s Base:ジイソプロピルエチルアミン
NMP:1-メチルピロリジン-2-オン
Selectflour:N-フルオロ-N’-クロロメチルトリエチレンジアミン ビス (テトラフルオロボラート)
Ru-phos:ジシクロへキシル(2’,6’-ジイソプロポキシビフェニル-2-イル)ホスフィン
TBAF:フッ化テトラ-n-ブチルアンモニウム
 なお、各実施例で得られたNMR分析は300MHzで行い、d6-DMSO、CDClを用いて測定した。なお、DClは重水素化塩酸である。
 NMRデータ欄中にRTとあるのは、LC/MS:液体クロマトグラフィー/質量分析でのリテンションタイムを表し、測定には Shim-pack XR-ODS 50Lx3.0(Shimazu社製)を使用し、流速1.6ml/分でアセト二トリル/水(ギ酸0.1%)  10:90~100:0/3分 の直線勾配をかけて測定した。
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 Bu: butyl Ph: phenyl Boc: tert-butoxycarbonyl Ph 3 P: triphenylphosphine DME: dimethoxyethane DMF: N, N-dimethylformamide TMSOTf: trimethylsilyl triflate DIAD: azodicarboxylic acid diisopropyl ester TFA: Trifluoroacetic acid DMSO: Dimethyl sulfoxide IBX: 2-iodoxybenzoic acid THF: Tetrahydrofuran HATU: 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphoric acid Methanaminium DIEA: N, N-diisopropylethylamine IPA: isopropyl alcohol TBAF: tetrabutylammonium fluoride CDI: N, N′-carbodiimidazole NaHMDS: sodium bis (trimethylsilyl) amide SEM: 2-(trimethylsilyl) ethoxymethyl SEMCl: 2-(trimethylsilyl) ethoxymethyl chloride MOM: methoxymethyl Pd (PPh 3) 4: tetrakis (triphenylphosphine) palladium POCl 3: phosphoryl chloride xantphos: xanthophos Hunig's Base: diisopropylethylamine NMP: 1-methylpyrrolidin-2-one Selectflour: N-fluoro-N′-chloromethyltriethylenediamine bis (tetrafluoroborate)
Ru-phos: dicyclohexyl (2 ′, 6′-diisopropoxybiphenyl-2-yl) phosphine TBAF: tetra-n-butylammonium fluoride The NMR analysis obtained in each example was performed at 300 MHz. Measurement was performed using d6-DMSO and CDCl 3 . DCl is deuterated hydrochloric acid.
“RT” in the NMR data column represents the retention time in LC / MS: liquid chromatography / mass spectrometry. For the measurement, Shim-pack XR-ODS 50Lx3.0 (manufactured by Shimazu) was used, and the flow rate was Measurements were made at 1.6 ml / min with a linear gradient of 10:90 to 100: 0/3 min of acetonitryl / water (0.1% formic acid).
実施例1 化合物(I-3)の合成
第1工程
Figure JPOXMLDOC01-appb-C000074

 カルボン酸2(56 mg, 0.250 mmol)をN,N-ジメチルホルムアミド (3 ml)に溶解させ、HATU (95 mg, 0.250 mmol)を加えた後、トリエチルアミン (52 μl, 0.375 mmol) を滴下し、2分間、室温で攪拌した。これをジアミン1(50 mg, 0.833 mmol)のN,N-ジメチルホルムアミド (2 mL)溶液に滴下し、室温で2時間攪拌した。反応液に水を加え、目的物をろ取することで化合物3(77 mg, 収率76%)を得た。
1H-NMR (DMSO-d6) δ: 1.10 (3H, t, J = 7.4 Hz), 3.12 (2H, q, J = 7.3 Hz), 6.07 (2H, s), 6.87 (1H, d, J = 8.6 Hz), 7.44 (1H, dd, J = 8.6, 2.0 Hz), 7.59 (1H, d, J = 2.0 Hz), 7.68-7.71 (1H, m), 8.14-8.16 (2H, m), 9.91 (1H, s).
 第2工程
Figure JPOXMLDOC01-appb-C000075

 第1工程で得られたアミド体3(75 mg, 0.185 mmol)を酢酸(3 ml)に溶解させた後、2時間、加熱還流下で攪拌した。溶媒を減圧留去した後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィーにより精製した。酢酸エチルとジイソプロピルエーテルから固化することで化合物4(50 mg, 収率70%)を得た。
1H-NMR (DMSO-d6) δ: 1.12 (3H, t, J = 7.4 Hz), 7.75-7.85 (3H, m), 8.12-8.13 (1H, m), 8.29-8.37 (2H, m), 13.63-13.66 (1H, m).
 I-4~7,41も、同様の方法で合成した。
Example 1 First Step of Synthesis of Compound (I-3)
Figure JPOXMLDOC01-appb-C000074

Carboxylic acid 2 (56 mg, 0.250 mmol) was dissolved in N, N-dimethylformamide (3 ml), HATU (95 mg, 0.250 mmol) was added, and then triethylamine (52 μl, 0.375 mmol) was added dropwise. Stir for 2 minutes at room temperature. This was added dropwise to a solution of diamine 1 (50 mg, 0.833 mmol) in N, N-dimethylformamide (2 mL) and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the target product was collected by filtration to give compound 3 (77 mg, yield 76%).
1 H-NMR (DMSO-d 6 ) δ: 1.10 (3H, t, J = 7.4 Hz), 3.12 (2H, q, J = 7.3 Hz), 6.07 (2H, s), 6.87 (1H, d, J = 8.6 Hz), 7.44 (1H, dd, J = 8.6, 2.0 Hz), 7.59 (1H, d, J = 2.0 Hz), 7.68-7.71 (1H, m), 8.14-8.16 (2H, m), 9.91 (1H, s).
Second step
Figure JPOXMLDOC01-appb-C000075

The amide 3 (75 mg, 0.185 mmol) obtained in the first step was dissolved in acetic acid (3 ml), and then stirred for 2 hours under heating and reflux. After evaporating the solvent under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography. Compound 4 (50 mg, yield 70%) was obtained by solidifying from ethyl acetate and diisopropyl ether.
1 H-NMR (DMSO-d 6 ) δ: 1.12 (3H, t, J = 7.4 Hz), 7.75-7.85 (3H, m), 8.12-8.13 (1H, m), 8.29-8.37 (2H, m) , 13.63-13.66 (1H, m).
I-4 to 7, 41 were also synthesized by the same method.
実施例2 化合物(I-2)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000076

 カルボン酸6(172 mg, 0.833 mmol)をN,N-ジメチルホルムアミド (20 ml)に溶解させ、HATU (380 mg, 0.999 mmol)を加えた後、トリエチルアミン (173 μl, 1.249 mmol) を滴下し、2分間、室温で攪拌した。これをジアミン5(172 mg, 0.833 mmol)のN,N-ジメチルホルムアミド (10 mL)溶液に滴下し、室温で一晩攪拌した。反応液に水を加え、析出した固体をろ取し、ジイソプロピルエーテルで洗浄することで、化合物7(307 mg, 収率86%)を得た。
1H-NMR (DMSO-d6) δ: 6.91-6.95 (3H, m), 7.61-7.70 (3H, m), 7.77 (1H, d, J = 1.5 Hz), 7.97 (1H, s), 8.06 (1H, d, J = 7.6 Hz), 9.95 (1H, s).
 第2工程
Figure JPOXMLDOC01-appb-C000077

 第1工程で得られたアミド体7(300 mg, 0.7 mmol)を酢酸 (5 ml)に溶解させた後、1時間、加熱還流下で攪拌した。溶媒を減圧留去した後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製した。ヘキサンとジイソプロピルエーテルからトリチュレートすることで化合物8(220 mg, 収率77%)を得た。
1H-NMR (DMSO-d6) δ: 7.61-7.64 (1H, m), 7.79 (1H, t, J = 8.1 Hz), 7.92-7.94 (1H, m), 8.03 (1H, d, J = 8.6 Hz), 8.20 (1H, s), 8.28 (1H, d, J = 8.1 Hz), 8.39 (1H, s).
Example 2 Synthesis of Compound (I-2) First Step
Figure JPOXMLDOC01-appb-C000076

Carboxylic acid 6 (172 mg, 0.833 mmol) was dissolved in N, N-dimethylformamide (20 ml), HATU (380 mg, 0.999 mmol) was added, and then triethylamine (173 μl, 1.249 mmol) was added dropwise. Stir for 2 minutes at room temperature. This was added dropwise to a solution of diamine 5 (172 mg, 0.833 mmol) in N, N-dimethylformamide (10 mL) and stirred overnight at room temperature. Water was added to the reaction solution, and the precipitated solid was collected by filtration and washed with diisopropyl ether to obtain Compound 7 (307 mg, yield 86%).
1 H-NMR (DMSO-d 6 ) δ: 6.91-6.95 (3H, m), 7.61-7.70 (3H, m), 7.77 (1H, d, J = 1.5 Hz), 7.97 (1H, s), 8.06 (1H, d, J = 7.6 Hz), 9.95 (1H, s).
Second step
Figure JPOXMLDOC01-appb-C000077

The amide 7 (300 mg, 0.7 mmol) obtained in the first step was dissolved in acetic acid (5 ml), and then stirred for 1 hour under heating and refluxing. After evaporating the solvent under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography. Trituration from hexane and diisopropyl ether gave Compound 8 (220 mg, yield 77%).
1 H-NMR (DMSO-d 6 ) δ: 7.61-7.64 (1H, m), 7.79 (1H, t, J = 8.1 Hz), 7.92-7.94 (1H, m), 8.03 (1H, d, J = 8.6 Hz), 8.20 (1H, s), 8.28 (1H, d, J = 8.1 Hz), 8.39 (1H, s).
実施例3 化合物(I-8)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000078

 ブロモピリジン9(1g, 5.16mmol)をN,N-ジメチルホルムアミド(5ml)に溶解させ、トリエチルアミン(0.894ml, 6.45mmol)、ビフェニルカルボン酸(852mg, 4.3mmol)とHATU(1960mg, 5.16mmol)を加え、室温で15分攪拌後、60℃で4時間反応させた。酢酸エチルを加えた後、2molo/L 炭酸カリウムと水で洗浄し、有機層を無水硫酸マグネシウムで乾燥後、留去した。残渣をメタノールで洗浄し、目的物10(1086mg, 収率69%)を得た。
LCMS;369.80(M+H)
 第2工程
Figure JPOXMLDOC01-appb-C000079

 第1工程で得られたアミド体10(1080mg, 2.95mmol)に酢酸(10ml)を加えマイクロウェーブ照射下150℃で90分間反応させた。溶媒を留去し残渣をメタノールで洗浄し、目的物11(766mg, 収率74%)を得た。
LCMS:351.6, (M+H)
 第3工程
Figure JPOXMLDOC01-appb-C000080

 第2工程で得られた化合物11(100mg, 0.286mmol)をジオキサンに溶解させ、ジイソプロピルアミン(0.125ml, 0.714mmol)、xantphos(17mg, 0.029mmol)、Pd2(dba)3(13mg, 0.014mmol)とPrSH(0.039ml, 0.428mmol)を加え、マイクロウェーブ照射下130℃で1時間反応させた。溶媒を留去後、酢酸エチルで洗浄し、目的物12(98mg, 収率99%)を得た。
LCMS;346.85(M+H)
 第4工程
Figure JPOXMLDOC01-appb-C000081

 第3工程で得られた化合物12(98mg, 0.284mmol)を塩化メチレンに懸濁させ、mCPBA(156mg, 0.624mmol)の塩化メチレン溶液をゆっくり加えた。室温で1時間攪拌しNa2S2O3(45mg, 0.284mmol)と2mol/L 炭酸カリウム水溶液を加えた。室温で5分攪拌後、酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥後、留去した。逆相クロマトグラフィーで精製し、目的物13(18mg, 収率16.7%)を得た。
1H-NMR (DMSO-d6) δ: 0.93 (3H, t, J = 7.35 Hz), 1.59-1.63 (2H, m), 3.36-3.40 (2H, m), 7.44 (1H, t, J = 7.10 Hz), 7.55 (2H, t, J = 7.60 Hz), 7.68 (1H, t, J = 7.60 Hz), 7.81 (2H, d, J = 7.10 Hz), 7.87 (1H, d, J = 7.60 Hz), 8.29 (1H, d, J = 7.60 Hz), 8.39 (1H, d, J = 2.03 Hz), 8.60 (1H, s), 8.75 (1H, d, J = 2.03 Hz).
 I-47も、同様の方法で合成を行った。
Example 3 Synthesis of Compound (I-8) First Step
Figure JPOXMLDOC01-appb-C000078

Bromopyridine 9 (1 g, 5.16 mmol) was dissolved in N, N-dimethylformamide (5 ml), triethylamine (0.894 ml, 6.45 mmol), biphenylcarboxylic acid (852 mg, 4.3 mmol) and HATU (1960 mg, 5.16 mmol) were added. The mixture was further stirred at room temperature for 15 minutes and then reacted at 60 ° C. for 4 hours. After adding ethyl acetate, the mixture was washed with 2molo / L potassium carbonate and water, and the organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was washed with methanol to obtain the desired product 10 (1086 mg, yield 69%).
LCMS; 369.80 (M + H)
Second step
Figure JPOXMLDOC01-appb-C000079

Acetic acid (10 ml) was added to the amide compound 10 (1080 mg, 2.95 mmol) obtained in the first step and reacted at 150 ° C. for 90 minutes under microwave irradiation. The solvent was distilled off, and the residue was washed with methanol to obtain the desired product 11 (766 mg, yield 74%).
LCMS: 351.6, (M + H)
Third step
Figure JPOXMLDOC01-appb-C000080

Compound 11 (100 mg, 0.286 mmol) obtained in the second step was dissolved in dioxane, diisopropylamine (0.125 ml, 0.714 mmol), xantphos (17 mg, 0.029 mmol), Pd 2 (dba) 3 (13 mg, 0.014 mmol). ) And PrSH (0.039 ml, 0.428 mmol) were added and reacted at 130 ° C. for 1 hour under microwave irradiation. After the solvent was distilled off, the residue was washed with ethyl acetate to obtain the desired product 12 (98 mg, yield 99%).
LCMS; 346.85 (M + H)
4th process
Figure JPOXMLDOC01-appb-C000081

Compound 12 (98 mg, 0.284 mmol) obtained in the third step was suspended in methylene chloride, and mCPBA (156 mg, 0.624 mmol) in methylene chloride was slowly added. The mixture was stirred at room temperature for 1 hour, and Na 2 S 2 O 3 (45 mg, 0.284 mmol) and a 2 mol / L potassium carbonate aqueous solution were added. The mixture was stirred at room temperature for 5 minutes, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. Purification by reverse phase chromatography gave the target product 13 (18 mg, yield 16.7%).
1 H-NMR (DMSO-d 6 ) δ: 0.93 (3H, t, J = 7.35 Hz), 1.59-1.63 (2H, m), 3.36-3.40 (2H, m), 7.44 (1H, t, J = 7.10 Hz), 7.55 (2H, t, J = 7.60 Hz), 7.68 (1H, t, J = 7.60 Hz), 7.81 (2H, d, J = 7.10 Hz), 7.87 (1H, d, J = 7.60 Hz ), 8.29 (1H, d, J = 7.60 Hz), 8.39 (1H, d, J = 2.03 Hz), 8.60 (1H, s), 8.75 (1H, d, J = 2.03 Hz).
I-47 was synthesized in the same manner.
実施例4 化合物(I-9)の合成
第1工程
Figure JPOXMLDOC01-appb-C000082

 3-エチニルビフェニル(39mg, 2.01mmol)をテトラヒドロフラン(3.59ml)に加え、氷冷下でNaHMDSの1.9mol/Lテトラヒドロフラン溶液(1.59ml, 3.02mmol)を加え、氷冷下のまま5分攪拌した。氷冷下で4-ブロモ-2-フルオロ-1-ニトロベンゼン(513mg, 2.21mmol)のテトラヒドロフラン溶液(3.59ml)を加え、氷冷下のまま5時間弱攪拌した。酢酸エチルを加え、塩化アンモニウムの飽和水溶液で洗浄して、有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。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14 (310.9mg, 収率40.8%)を得た。
LCMS:379.60(M+H)
 第2工程
Figure JPOXMLDOC01-appb-C000083

 化合物14(300.0mg, 0.793mmol)にテトラヒドロフラン(3.0ml)、エタノール(3.0ml)、水(0.6ml)及び85%亜ジチオン酸ナトリウム(650mg, 3.17mmol)を加えた。反応液を60℃で4時間弱攪拌した。不溶物を濾過により除いた後、酢酸エチルで抽出した。有機層を水洗し、無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。得られた残渣にテトラヒドロフラン(4.0ml)、ピリジン(320μl, 3.95mmol)及びクロロギ酸エチル(151μl, 1.58mmol)を加え、2時間弱室温で攪拌を行なった。反応液に酢酸エチルを加え、1mol/Lの塩酸水溶液で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。得られた残渣にテトラヒドロフラン(1.5ml)及びテトラブチルアンモニウムフルオライドの1mol/Lテトラヒドロフラン溶液(2.25ml, 2.25mmol)を加え、60℃で4時間弱攪拌した。溶媒を減圧下留去し、酢酸エチルを加え、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15(106.7mg, 収率40.8%)を得た。
LCMS:349.80(M+H)
 第3工程
Figure JPOXMLDOC01-appb-C000084

 化合物15(90.0mg, 0.258mmol)に窒素気流下で1,4-ジオキサン(0.9ml)、N,N-ジイソプロピルエチルアミン(113μl, 0.646mmol)、Xantphos(14.9mg, 0.026mmol)、Pd2(dba)3(11.8mg, 0.013mmol)及びn-プロパンチオール(29.5mg, 0.388mmol)の1,4-ジオキサン溶液(0.9ml)を加え、マイクロウェーブ反応装置(130℃, 1時間)により反応を行なった。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16 (46.0mg, 収率51.8%)を得た。
LCMS:343.75(M+H)
 第4工程
Figure JPOXMLDOC01-appb-C000085

 化合物16(46.0mg, 0.134mmol)に窒素気流下で、テトラヒドロフラン(1.0ml)を加え溶解し、氷冷下でNaH(60% in oil, 8.0mg, 0.201 mmol)を加え、氷冷下のまま3分攪拌した。氷冷下でクロロギ酸エチル(26μl, 268mmol)を加え、氷冷下のまま3時間弱攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を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し、化合物17 (17.8mg, 収率32.0%)を得た。
LCMS:416.20(M+H)
 第5工程
Figure JPOXMLDOC01-appb-C000086

 化合物17(17.8mg, 0.043mmol)に塩化メチレン(0.5ml)を加えた後、氷冷下でmCPBA(23.5mg, 0.094 mmol)の塩化メチレン溶液(1.0m)を加え、氷冷下のまま1時間弱攪拌した。反応液に2mol/L 炭酸カリウムを加え、塩化メチレンで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。
 得られた残渣にテトラヒドロフラン(0.5ml)及びn-ブチルアミン(0.5ml)を加え、60℃で1時間攪拌した。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、目的物18 (11.1mg, 収率69.0%)を得た。
1H-NMR (DMSO-d6) δ: 0.90 (t, J = 7.35 Hz, 3H), 1.52-1.61 (m, 2H), 3.22 (t, J = 7.60 Hz, 2H), 7.25 (s, 1H), 7.43 (t, J = 7.35 Hz, 1H), 7.51-7.64 (m, 5H), 7.68 (d, J = 7.60 Hz, 1H), 7.80 (d, J = 7.60 Hz, 2H), 7.91 (d, J = 7.60 Hz, 1H), 8.11 (s, 1H), 8.21 (s, 1H), 12.21 (s, 1H).
Example 4 First Step of Synthesis of Compound (I-9)
Figure JPOXMLDOC01-appb-C000082

3-Ethynylbiphenyl (39 mg, 2.01 mmol) was added to tetrahydrofuran (3.59 ml), 1.9 mol / L tetrahydrofuran solution (1.59 ml, 3.02 mmol) of NaHMDS was added under ice cooling, and the mixture was stirred for 5 minutes with ice cooling. . A tetrahydrofuran solution (3.59 ml) of 4-bromo-2-fluoro-1-nitrobenzene (513 mg, 2.21 mmol) was added under ice-cooling, and the mixture was stirred slightly with ice-cooling for 5 hours. Ethyl acetate was added, and the mixture was washed with a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give compound 14 (310.9 mg, yield 40.8%).
LCMS: 379.60 (M + H)
Second step
Figure JPOXMLDOC01-appb-C000083

To compound 14 (300.0 mg, 0.793 mmol) was added tetrahydrofuran (3.0 ml), ethanol (3.0 ml), water (0.6 ml) and 85% sodium dithionite (650 mg, 3.17 mmol). The reaction solution was slightly stirred at 60 ° C. for 4 hours. Insoluble materials were removed by filtration, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Tetrahydrofuran (4.0 ml), pyridine (320 μl, 3.95 mmol) and ethyl chloroformate (151 μl, 1.58 mmol) were added to the resulting residue, and the mixture was stirred for 2 hours at room temperature. Ethyl acetate was added to the reaction solution, washed with 1 mol / L hydrochloric acid aqueous solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Tetrahydrofuran (1.5 ml) and a 1 mol / L tetrahydrofuran solution (2.25 ml, 2.25 mmol) of tetrabutylammonium fluoride were added to the resulting residue, and the mixture was slightly stirred at 60 ° C. for 4 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added, washed with water 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 15 (106.7 mg, yield 40.8%).
LCMS: 349.80 (M + H)
Third step
Figure JPOXMLDOC01-appb-C000084

Compound 15 (90.0 mg, 0.258 mmol) was mixed with 1,4-dioxane (0.9 ml), N, N-diisopropylethylamine (113 μl, 0.646 mmol), Xantphos (14.9 mg, 0.026 mmol), Pd 2 (dba ) 3 (11.8 mg, 0.013 mmol) and n-propanethiol (29.5 mg, 0.388 mmol) in 1,4-dioxane (0.9 ml) were added, and the reaction was carried out using a microwave reactor (130 ° C., 1 hour). It was. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give compound 16 (46.0 mg, yield 51.8%).
LCMS: 343.75 (M + H)
Fourth step
Figure JPOXMLDOC01-appb-C000085

To compound 16 (46.0 mg, 0.134 mmol) was dissolved by adding tetrahydrofuran (1.0 ml) under a nitrogen stream, and NaH (60% in oil, 8.0 mg, 0.201 mmol) was added under ice cooling. Stir for 3 minutes. Ethyl chloroformate (26 μl, 268 mmol) was added under ice-cooling, and the mixture was slightly stirred for 3 hours with ice-cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was 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 17 (17.8 mg, yield 32.0%).
LCMS: 416.20 (M + H)
5th process
Figure JPOXMLDOC01-appb-C000086

After adding methylene chloride (0.5 ml) to compound 17 (17.8 mg, 0.043 mmol), mCPBA (23.5 mg, 0.094 mmol) in methylene chloride (1.0 m) was added under ice cooling, and the mixture was kept under ice cooling. Stirred slightly for hours. To the reaction solution was added 2 mol / L potassium carbonate, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
Tetrahydrofuran (0.5 ml) and n-butylamine (0.5 ml) were added to the resulting residue, and the mixture was stirred at 60 ° C. for 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the target product 18 (11.1 mg, yield 69.0%).
1 H-NMR (DMSO-d 6 ) δ: 0.90 (t, J = 7.35 Hz, 3H), 1.52-1.61 (m, 2H), 3.22 (t, J = 7.60 Hz, 2H), 7.25 (s, 1H ), 7.43 (t, J = 7.35 Hz, 1H), 7.51-7.64 (m, 5H), 7.68 (d, J = 7.60 Hz, 1H), 7.80 (d, J = 7.60 Hz, 2H), 7.91 (d , J = 7.60 Hz, 1H), 8.11 (s, 1H), 8.21 (s, 1H), 12.21 (s, 1H).
実施例5 化合物(I-10,11)の合成
第1工程
Figure JPOXMLDOC01-appb-C000087

 2-ニトロ-5-(プロピルチオ)アニリン(1.000g, 4.71mmol)にエタノール(10.0ml)、水(2.0ml)及び85%亜ジチオン酸ナトリウム(3.860g, 18.84mmol)を加えた。反応液を60℃で4時間弱攪拌した。不溶物を濾過により除いた後、酢酸エチルで抽出した。有機層を水洗し無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去し、化合物19(859mg, 収率100%)を得た。
LCMS:182.70(M+H)
 第2工程
Figure JPOXMLDOC01-appb-C000088

 化合物19(859mg, 4.71mmol)に窒素気流下でN,N-ジメチルホルムアミド(10.0ml)、トリエチルアミン(979μl, 7.07mmol) 及び4-(t-ブトキシカルボニル)モルホリン-2-カルボン酸(1.089g, 4.71mmolを加えた。氷冷下でHATU(2.149g, 5.65mmol)を加え、氷冷下のまま1時間弱攪拌した。反応液に酢酸エチルを加え、水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。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20 (1.7451g, 収率93.7%)を得た。
LCMS:396.00(M+H)
 第3工程
Figure JPOXMLDOC01-appb-C000089

 化合物20(1.585g, 4.01mmol)を酢酸(10.0ml)に溶解し、マイクロウェーブ反応装置(150℃, 1時間)により反応を行なった。溶媒を減圧下留去し、残渣にNaOMeの28%メタノール溶液(15.0ml)を加え、90℃で13時間弱攪拌した。反応液に酢酸エチルを加え、水で洗浄して無水硫酸マグネシウムで乾燥した。得られた残渣に塩化メチレン(10.0ml)及びBoc2O(963mg, 4.41mmol)の塩化メチレン溶液(6.0ml)を加え、室温で1時間弱攪拌した。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21 (872.7mg, 収率57.7%)を得た。
LCMS:377.95(M+H)
 第4工程
Figure JPOXMLDOC01-appb-C000090

 化合物21 (745mg, 1.974mmol)に塩化メチレン(10.0ml)を加えた後、氷冷下でmCPBA(1.086g, 4.34mmol)の塩化メチレン溶液(10.0m)を加え、氷冷下のまま1時間弱攪拌した。反応液に2mol/L 炭酸カリウムを加え、塩化メチレンで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去し、粗生成物として目的物22 (912.3mg、88.5% Wt quant)を得た。
1H-NMR (DMSO-d6) δ: 0.89 (t, J = 7.07 Hz, 3H), 1.51-1.56 (m, 2H), 3.06 (br s, 1H), 3.26 (t, J = 7.33 Hz, 3H), 3.71 (t, J = 11.12 Hz, 1H), 3.83 (d, J = 13.14 Hz, 1H), 4.03 (d, J = 11.62 Hz, 1H), 4.20-4.33 (m, 1H), 4.83 (d, J = 10.11 Hz, 1H), 7.68-7.77 (m, 2H), 8.05 (s, 1H), 13.12 (br s, 1H).
 第5工程
Figure JPOXMLDOC01-appb-C000091

 第4工程で得られた化合物22(862.3mg, 88.5% Wt, 1.864mmol)に塩化メチレン(10.0ml)及びTFA(5.0ml)を加え、室温で3時間弱攪拌を行なった。溶媒を減圧下留去し、2mol/L 炭酸カリウムを加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。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23 (502.2mg, 収率87.1%)を得た。
LCMS:310.00(M+H)
 第6工程
Figure JPOXMLDOC01-appb-C000092

 化合物23(50.0mg, 0.162mmol), t-ブトキシナトリウム(35.2mg, 0.356mmol)及びブロモベンゼン(30.4mg, 0.194mmol)の1,4-ジオキサン溶液(1.0ml)に、窒素気流下で予めPd2(dba)3(5.92mg, 6.46μmol)及びRuPhos(12.7mg, 0.026mmol)を1,4-ジオキサン(1.0ml)中室温で5分間攪拌したものを加えた。
 反応液を90℃で1時間弱攪拌後、t-ブトキシナトリウム(17.6mg, 0.178mmol)を追加し、さらに90℃で2時間弱攪拌した。その後、100℃で2時間弱攪拌を行った。反応液を室温まで冷却後、酢酸エチルを加え、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、目的物24(6.6mg, 収率10.6%)を得た。
1H-NMR (DMSO-d6) δ: 0.89 (t, J = 7.33 Hz, 3H), 1.51-1.57 (m, 2H), 2.88-2.93 (m, 1H), 3.00-3.06 (m, 1H), 3.24-3.28 (m, 2H), 3.59-3.62 (m, 1H), 3.92-4.00 (m, 2H), 4.14-4.17 (m, 1H), 5.06 (d, J = 9.09 Hz, 1H), 6.83-6.87 (m, 1H), 7.04 (d, J = 8.08 Hz, 2H), 7.25-7.29 (m, 2H), 7.69-7.71 (m, 1H), 7.76-7.78 (m, 1H), 8.06 (s, 1H).
 I-12は化合物23のベンゾイル化により、またI-13はシクロヘキサノンを用いる還元的アミノ化により得た。
Example 5 First Step of Synthesis of Compound (I-10,11)
Figure JPOXMLDOC01-appb-C000087

Ethanol (10.0 ml), water (2.0 ml) and 85% sodium dithionite (3.860 g, 18.84 mmol) were added to 2-nitro-5- (propylthio) aniline (1.000 g, 4.71 mmol). The reaction solution was slightly stirred at 60 ° C. for 4 hours. Insoluble materials were removed by filtration, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain Compound 19 (859 mg, yield 100%).
LCMS: 182.70 (M + H)
Second step
Figure JPOXMLDOC01-appb-C000088

N, N-dimethylformamide (10.0 ml), triethylamine (979 μl, 7.07 mmol) and 4- (t-butoxycarbonyl) morpholine-2-carboxylic acid (1.089 g, 1.09 g) were added to compound 19 (859 mg, 4.71 mmol) under a nitrogen stream. 4.71 mmol was added, HATU (2.149 g, 5.65 mmol) was added under ice cooling, and the mixture was stirred slightly for 1 hour with ice cooling, ethyl acetate was added to the reaction mixture, washed with water, and dried over anhydrous magnesium sulfate. After that, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 20 (1.7451 g, yield 93.7%).
LCMS: 396.00 (M + H)
Third step
Figure JPOXMLDOC01-appb-C000089

Compound 20 (1.585 g, 4.01 mmol) was dissolved in acetic acid (10.0 ml), and the reaction was performed with a microwave reactor (150 ° C., 1 hour). The solvent was evaporated under reduced pressure, and 28% methanol solution (15.0 ml) of NaOMe was added to the residue, followed by slight stirring at 90 ° C. for 13 hours. Ethyl acetate was added to the reaction solution, washed with water and dried over anhydrous magnesium sulfate. To the obtained residue were added methylene chloride (10.0 ml) and Boc 2 O (963 mg, 4.41 mmol) in methylene chloride (6.0 ml), and the mixture was stirred slightly at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give compound 21 (872.7 mg, yield 57.7%).
LCMS: 377.95 (M + H)
Fourth step
Figure JPOXMLDOC01-appb-C000090

After adding methylene chloride (10.0 ml) to compound 21 (745 mg, 1.974 mmol), mCPBA (1.086 g, 4.34 mmol) in methylene chloride (10.0 m) was added under ice cooling, and the mixture was kept under ice cooling for 1 hour. Weakly stirred. To the reaction solution was added 2 mol / L potassium carbonate, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain the target product 22 (912.3 mg, 88.5% Wt quant) as a crude product.
1 H-NMR (DMSO-d 6 ) δ: 0.89 (t, J = 7.07 Hz, 3H), 1.51-1.56 (m, 2H), 3.06 (br s, 1H), 3.26 (t, J = 7.33 Hz, 3H), 3.71 (t, J = 11.12 Hz, 1H), 3.83 (d, J = 13.14 Hz, 1H), 4.03 (d, J = 11.62 Hz, 1H), 4.20-4.33 (m, 1H), 4.83 ( d, J = 10.11 Hz, 1H), 7.68-7.77 (m, 2H), 8.05 (s, 1H), 13.12 (br s, 1H).
5th process
Figure JPOXMLDOC01-appb-C000091

Methylene chloride (10.0 ml) and TFA (5.0 ml) were added to compound 22 (862.3 mg, 88.5% Wt, 1.864 mmol) obtained in the fourth step, and the mixture was slightly stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, 2 mol / L potassium carbonate was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 23 (502.2 mg, yield 87.1%).
LCMS: 310.00 (M + H)
6th process
Figure JPOXMLDOC01-appb-C000092

Compound 23 (50.0 mg, 0.162 mmol), t-butoxy sodium (35.2 mg, 0.356 mmol) and bromobenzene (30.4 mg, 0.194 mmol) in 1,4-dioxane solution (1.0 ml) were mixed with Pd2 in advance under a nitrogen stream. (dba) 3 (5.92 mg, 6.46 μmol) and RuPhos (12.7 mg, 0.026 mmol) in 1,4-dioxane (1.0 ml) stirred at room temperature for 5 minutes were added.
After the reaction solution was slightly stirred at 90 ° C. for 1 hour, sodium t-butoxy (17.6 mg, 0.178 mmol) was added, and the mixture was further stirred at 90 ° C. for 2 hours. Thereafter, the mixture was slightly stirred at 100 ° C. for 2 hours. After cooling the reaction solution to room temperature, ethyl acetate was added, washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the desired product 24 (6.6 mg, yield: 10.6%).
1 H-NMR (DMSO-d 6 ) δ: 0.89 (t, J = 7.33 Hz, 3H), 1.51-1.57 (m, 2H), 2.88-2.93 (m, 1H), 3.00-3.06 (m, 1H) , 3.24-3.28 (m, 2H), 3.59-3.62 (m, 1H), 3.92-4.00 (m, 2H), 4.14-4.17 (m, 1H), 5.06 (d, J = 9.09 Hz, 1H), 6.83 -6.87 (m, 1H), 7.04 (d, J = 8.08 Hz, 2H), 7.25-7.29 (m, 2H), 7.69-7.71 (m, 1H), 7.76-7.78 (m, 1H), 8.06 (s , 1H).
I-12 was obtained by benzoylation of compound 23 and I-13 by reductive amination with cyclohexanone.
実施例6 化合物(I-18,30,31)の合成
第1工程
Figure JPOXMLDOC01-appb-C000093

 3-ブテン-1-オール(2g, 27.7mmol)にベンズアルデヒド(1.14ml, 14.1mmol)を加え0℃に冷却した。これに濃硫酸(1.4ml, 26.3mmol)を滴下し、室温で一晩反応させた。水を加え、酢酸エチルで抽出し、有機層を水で洗浄した。無水硫酸マグネシウムで乾燥後、溶媒を留去した。残渣をカラムクロマトグラフィーで生成し目的物25(945mg, 収率38%)を得た。
1H-NMR (CDCl3) δ: 1.51-1.69 (3 H, m), 1.97 (1H, m), 2.16-2.22 (1H, m), 3.59 (1H, td, J = 12.17, 2.37 Hz), 3.91-3.98 (1H, m), 4.18 (1H, dq, J = 11.9, 2.20 Hz), 4.32 (1H, dd, J = 11.9, 2.03 Hz), 7.25-7.35 (5H, m).
 第2工程
Figure JPOXMLDOC01-appb-C000094

 第1工程で得られた化合物25(969mg, 5.44mmol)をTHF(5ml)に溶解させ0℃に冷却後、トリエチルアミン(0.904ml, 6.52mmol)とメシルクロリド(0.508ml, 6.52mmol)を加え0℃で1時間反応させた。反応液に水を加え、酢酸エチルで抽出した。無水硫酸マグネシウムで乾燥後、溶媒を留去した。得られた残渣に対し、N,N-ジメチルホルムアミド(5ml)を加えた後、シアン化ナトリウム(400mg, 8.16mmol)とテトラブチルアンモニウムヨード(201mg, 0.554mmol)を加えた。100℃で8時間反応させ、室温まで冷却した。水を加え酢酸エチルで抽出し、有機層を水で洗浄した。硫酸マグネシウムで乾燥後、溶媒を留去しカラムクロマトグラフィーで精製し、目的物26(346mg, 収率34%)で得た。
1H-NMR (CDCl3) δ: 1.84-1.92 (2H, m), 1.94-2.05 (1H, m), 2.04-2.15 (1H, m), 3.23 (1H, d, J = 1.01 Hz), 3.99 (1H, td, J = 12.4, 2.37 Hz), 4.15 (1H, dd, J = 12.4, 4.82 Hz), 4.71 (1H, dd, J = 11.15, 2.03 Hz), 7.28-7.38 (5H, m).
 第3工程
Figure JPOXMLDOC01-appb-C000095

 第2工程で得られた化合物26(465mg, 2.48mmol)に対し、28%NaOMeのメタノール溶液を加え100℃で2時間攪拌した。水(89μl)を加えた後、2時間100℃で反応させた。さらに28%NaOMeを1ml加え、100℃で4時間反応を行い、水(1.5ml)を加えた。0℃まで冷却し、濃塩酸を加えた。クロロホルムで抽出し、硫酸マグネシウムで乾燥後、残渣を留去し、目的物27(515mg, quant)を得た。
1H-NMR (CDCl3) δ: 1.70-1.96 (3H, m), 2.17 (1H, m), 2.77 (1H, m), 3.64 (1H, td, J = 12.17, 2.53 Hz), 4.24 (1H, dq, J = 11.66, 2.03 Hz), 4.35 (1H, dd, J = 11.66, 2.03 Hz), 7.25-7.35 (5H, m).
 第4工程
Figure JPOXMLDOC01-appb-C000096

 第3工程で得られた27(517mg, 2.48mmol)をN,N-ジメチルホルムアミド(5ml)に溶解させ、ジアミン(479mg, 2.48mmol)、トリエチルアミン(0.52ml, 3.72mmol)を加えた。0℃に冷却しHATU(1133mg, 2.98mmol)を加え0℃で40分反応させた。酢酸エチルを加えた後、2mol/L 炭酸カリウムと水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、留去し、粗生成物として目的物28(932mg)を得た。
LCMS;376.6(M+H)
 第5工程
Figure JPOXMLDOC01-appb-C000097

 第4工程で得られた化合物28(932mg)に対し、酢酸(10ml)を加えマイクロウェーブ照射下150℃で1時間反応させた。クロロホルムと2mol/L 炭酸カリウムを加えて室温で5分攪拌した後クロロホルムで抽出を行った。無水硫酸マグネシウムで乾燥後、溶媒を留去した。カラムクロマトグラフィーで精製し、目的物29(688mg, 2段階収率78%)を得た。
LCMS;358.65(M+H)
 第6工程 
Figure JPOXMLDOC01-appb-C000098

 第5工程で得られた化合物29(100mg, 0.28mmol)をジオキサン(1ml)に溶解させ、ジイソプロピルエチルアミン(0.122ml, 0.7mmol)、Xantphos(16mg, 0.028mmol)、Pd2(dba)3(13mg, 0.014mmol)とEtSH(26.1mg, 0.42mmol)を加え、マイクロウェーブ照射下130℃で1時間反応させた。酢酸エチルを加え、有機層を水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を留去しカラムクロマトグラフィーで精製し目的物30(45.5mg, 0.134mmol)を得た。
LCMS;338.95(M)
 第7工程
Figure JPOXMLDOC01-appb-C000099

 第6工程で得られた化合物30(40mg, 0.118mmol)を塩化メチレン(2ml)に溶解させ0℃まで冷却した。mCPBA(65mg, 0.26mmol)を加え0℃で1時間反応させた。2mol/L 炭酸カリウム(2ml)を加え塩化メチレンで抽出し、無水硫酸マグネシウムで乾燥後、留去した。カラムクロマトグラフィーで精製し、ジアステレオ混合物である化合物31(41.5mg, 収率95%)を得た。
1H-NMR (DMSO-d6) δ: 1.05-1.09 (m, 3H), 1.76-1.94 (m, 2H), 2.05-2.09 (m, 1H), 2.26-2.30 (m, 1H), 3.22-3.28 (m, 2H), 3.38-3.49 (m, 1H), 3.75 (t, J = 11.15 Hz, 1H), 4.20 (dd, J = 10.90, 3.80 Hz, 1H), 4.55 (d, J = 10.65 Hz, 1H), 7.28 (tt, J = 7.10, 1.94 Hz, 1H), 7.34-7.41 (m, 4H), 7.61-8.03 (m, 3H), 12.81 (s, 1H). 
また逆相クロマトグラフィーによる精製でシス体 (I-30, 21.8mg) と、トランス体(I-31, 1.4mg)を得た。
Example 6 First Step of Synthesis of Compound (I-18, 30, 31)
Figure JPOXMLDOC01-appb-C000093

Benzaldehyde (1.14 ml, 14.1 mmol) was added to 3-buten-1-ol (2 g, 27.7 mmol) and cooled to 0 ° C. Concentrated sulfuric acid (1.4 ml, 26.3 mmol) was added dropwise thereto and reacted at room temperature overnight. Water was added, extracted with ethyl acetate, and the organic layer was washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was produced by column chromatography to obtain the intended product 25 (945 mg, 38% yield).
1 H-NMR (CDCl 3 ) δ: 1.51-1.69 (3 H, m), 1.97 (1H, m), 2.16-2.22 (1H, m), 3.59 (1H, td, J = 12.17, 2.37 Hz), 3.91-3.98 (1H, m), 4.18 (1H, dq, J = 11.9, 2.20 Hz), 4.32 (1H, dd, J = 11.9, 2.03 Hz), 7.25-7.35 (5H, m).
Second step
Figure JPOXMLDOC01-appb-C000094

Compound 25 (969 mg, 5.44 mmol) obtained in the first step was dissolved in THF (5 ml), cooled to 0 ° C., triethylamine (0.904 ml, 6.52 mmol) and mesyl chloride (0.508 ml, 6.52 mmol) were added. The reaction was carried out at 0 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off. N, N-dimethylformamide (5 ml) was added to the resulting residue, and then sodium cyanide (400 mg, 8.16 mmol) and tetrabutylammonium iodide (201 mg, 0.554 mmol) were added. The mixture was reacted at 100 ° C. for 8 hours and cooled to room temperature. Water was added and extracted with ethyl acetate, and the organic layer was washed with water. After drying over magnesium sulfate, the solvent was distilled off and the residue was purified by column chromatography to obtain the title compound 26 (346 mg, yield 34%).
1 H-NMR (CDCl 3 ) δ: 1.84-1.92 (2H, m), 1.94-2.05 (1H, m), 2.04-2.15 (1H, m), 3.23 (1H, d, J = 1.01 Hz), 3.99 (1H, td, J = 12.4, 2.37 Hz), 4.15 (1H, dd, J = 12.4, 4.82 Hz), 4.71 (1H, dd, J = 11.15, 2.03 Hz), 7.28-7.38 (5H, m).
Third step
Figure JPOXMLDOC01-appb-C000095

To a compound 26 (465 mg, 2.48 mmol) obtained in the second step, a 28% NaOMe methanol solution was added and stirred at 100 ° C. for 2 hours. After adding water (89 μl), the mixture was reacted at 100 ° C. for 2 hours. Further, 1 ml of 28% NaOMe was added, the reaction was performed at 100 ° C. for 4 hours, and water (1.5 ml) was added. Cool to 0 ° C. and add concentrated hydrochloric acid. After extraction with chloroform and drying over magnesium sulfate, the residue was distilled off to obtain the desired product 27 (515 mg, quant).
1 H-NMR (CDCl 3 ) δ: 1.70-1.96 (3H, m), 2.17 (1H, m), 2.77 (1H, m), 3.64 (1H, td, J = 12.17, 2.53 Hz), 4.24 (1H , dq, J = 11.66, 2.03 Hz), 4.35 (1H, dd, J = 11.66, 2.03 Hz), 7.25-7.35 (5H, m).
Fourth step
Figure JPOXMLDOC01-appb-C000096

27 (517 mg, 2.48 mmol) obtained in the third step was dissolved in N, N-dimethylformamide (5 ml), and diamine (479 mg, 2.48 mmol) and triethylamine (0.52 ml, 3.72 mmol) were added. After cooling to 0 ° C., HATU (1133 mg, 2.98 mmol) was added and reacted at 0 ° C. for 40 minutes. After adding ethyl acetate, it was washed with 2 mol / L potassium carbonate and water. The organic layer was dried over anhydrous magnesium sulfate and evaporated to give the target product 28 (932 mg) as a crude product.
LCMS; 376.6 (M + H)
5th process
Figure JPOXMLDOC01-appb-C000097

Acetic acid (10 ml) was added to compound 28 (932 mg) obtained in the fourth step, and the mixture was reacted at 150 ° C. for 1 hour under microwave irradiation. Chloroform and 2 mol / L potassium carbonate were added and stirred at room temperature for 5 minutes, followed by extraction with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off. Purification by column chromatography gave the target product 29 (688 mg, 2-step yield 78%).
LCMS; 358.65 (M + H)
6th process
Figure JPOXMLDOC01-appb-C000098

Compound 29 (100 mg, 0.28 mmol) obtained in the fifth step was dissolved in dioxane (1 ml), diisopropylethylamine (0.122 ml, 0.7 mmol), Xantphos (16 mg, 0.028 mmol), Pd2 (dba) 3 (13 mg, 0.014 mmol) and EtSH (26.1 mg, 0.42 mmol) were added and reacted at 130 ° C. for 1 hour under microwave irradiation. Ethyl acetate was added and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography to obtain the intended product 30 (45.5 mg, 0.134 mmol).
LCMS; 338.95 (M)
7th process
Figure JPOXMLDOC01-appb-C000099

Compound 30 (40 mg, 0.118 mmol) obtained in the sixth step was dissolved in methylene chloride (2 ml) and cooled to 0 ° C. mCPBA (65 mg, 0.26 mmol) was added and reacted at 0 ° C. for 1 hour. 2 mol / L potassium carbonate (2 ml) was added, extracted with methylene chloride, dried over anhydrous magnesium sulfate and evaporated. Purification by column chromatography gave Compound 31 (41.5 mg, 95% yield) as a diastereo mixture.
1 H-NMR (DMSO-d 6 ) δ: 1.05-1.09 (m, 3H), 1.76-1.94 (m, 2H), 2.05-2.09 (m, 1H), 2.26-2.30 (m, 1H), 3.22- 3.28 (m, 2H), 3.38-3.49 (m, 1H), 3.75 (t, J = 11.15 Hz, 1H), 4.20 (dd, J = 10.90, 3.80 Hz, 1H), 4.55 (d, J = 10.65 Hz , 1H), 7.28 (tt, J = 7.10, 1.94 Hz, 1H), 7.34-7.41 (m, 4H), 7.61-8.03 (m, 3H), 12.81 (s, 1H).
Further, purification by reverse phase chromatography gave a cis form (I-30, 21.8 mg) and a trans form (I-31, 1.4 mg).
実施例7 化合物(I-20,21)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000100

 ジアミン体32(5g, 25.9mmol)をN,N-ジメチルホルムアミド(50ml)に溶解させ、トリエチルアミン(5.39ml, 38.9mmol)、カルボン酸(4.08g, 25.9mmol)を加え、0℃に冷却しHATU(12.2g, 32.1mmol)を加えた。室温で1時間攪拌し酢酸エチルを加えた。2mol/L 炭酸カリウム(50ml)と水(50mlx3)で洗浄し無水硫酸マグネシウムで乾燥させた。溶媒を留去し残渣を酢酸エチルで洗浄し、目的物33(5.91g, 収率69.8%)を得た。
LCMS;325.70(M+H)
 第2工程
Figure JPOXMLDOC01-appb-C000101

 工程1で得られた化合物33(3g, 9.19mmol)に対し酢酸(15ml)を加えマイクロウェーブ照射下150℃で1時間反応させた。溶媒を留去し、残渣にオキシ塩化リン(15ml)を加え100℃で1時間攪拌した。溶媒を留去後、残渣にクロロホルムと2mol/L 炭酸カリウムを加え攪拌し有機層を減圧下濃縮した。得られた固体を濾過し、水で洗浄することで目的物34(3.48g, 収率91%)を得た。
LCMS;309.65(M+H)
 第3工程
Figure JPOXMLDOC01-appb-C000102

 第2工程で得られた化合物34(3.48g, 11.27mmol)に対しN,N-ジメチルホルムアミド(35ml)を加え0℃まで冷却した。NaH(60% in oil, 0.676g, 16.9mmol)を加え0℃で5分間攪拌した。これに対しメトキシメチルクロライド(1.29ml, 16.9mmol)を滴下し、0℃で45分反応させた。さらにNaH(60% in oil, 220mg, 5.6mmol)を加え0℃で3分反応後、メトキシメチルクロライド(0.43ml, 5.6mmol)を加え30分反応させた。水を加え、酢酸エチルで抽出後、有機層を水で洗浄した。無水硫酸マグネシウムで乾燥後、留去することで目的物35(3.61g, 収率91%)を得た。
LCMS;353.60(M+H)
 第4工程
Figure JPOXMLDOC01-appb-C000103

 ベンジルアルコール(3.52ml, 33.8mmol)にNMP(15ml)を加え、これに対しNaH(60% in oil, 0.81g, 33.8mmol)を加えた。室温で5分攪拌後、工程3で得られた化合物35(3.6g, 10.25mmol)のNMP(30ml)溶液を滴下した。100℃で15分攪拌し室温まで冷却した。ジエチルエーテルを加え有機層を水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を留去し、残渣をカラムクロマトグラフィーで精製することで、目的物36(2.31g, 収率53%)を得た。
LCMS;425.65(M+H)
 第5工程
Figure JPOXMLDOC01-appb-C000104

 第4工程で得られた化合物36(1.63g, 3.84mmol)に、ジイソプロピルエチルアミン(1.7ml, 9.6mmol)、Xantphos(0.22g, 0.384mmol)、Pd2(dba)3(0.176g, 0.192mmol)、tBuSH(0.52g, 5.76mmol)を加えマイクロウェーブ照射下110℃で5時間反応させた。室温まで冷却後、溶媒を留去し、残渣に酢酸エチルを加え不溶物を濾別した。ろ液を水と飽和食塩水で洗浄し無水硫酸マグネシウムで乾燥後、留去した。残渣をカラムクロマトグラフィーで精製し目的物37(1.51g, 収率91%)を得た。
LCMS;434.00(M+H)
 第6工程
Figure JPOXMLDOC01-appb-C000105

 第5工程で得られた化合物37(1.51g, 3.49mmol)に、ジクロロメタンを加え0℃に冷却した。mCPBA(1.92g, 7.67mmol)を加え0℃で30分攪拌した。2mol/L 炭酸カリウムを加えジクロロメタンで抽出した。無水硫酸マグネシウムで乾燥後、溶媒を留去した。残渣をメタノール(10ml)とTHF(10ml)に溶解させ、10%Pd/C(324mg)を加え水素雰囲気下で一晩反応させた。溶媒を留去し、残渣にクロロホルムとメタノール(9:1)の混合溶媒を加え、不溶物を濾別した。ろ液を留去し、残渣をジエチルエーテルで洗浄することで目的物38(1.23g, 収率95%)を得た。
LCMS;375.95(M+H)
 第7工程
Figure JPOXMLDOC01-appb-C000106

 フェニルブロマイド(0.042ml, 0.4mmol)にDMA(1ml)、工程6で得られた化合物38(100mg, 0.26mmol)、炭酸カリウム(81mg, 0.586mmol)、よう化銅(10.2mg, 0.053mmol)及びジメチルグリシン(11mg, 0,107mmol)を加えた。マイクロウェーブ照射下170℃で1時間反応させた。水と酢酸エチルを加え不溶物を濾過し、固体を塩化メチレン/メタノールの混合溶媒で洗浄した。ろ液を分配後、有機層を無水硫酸マグネシウムで乾燥させ、留去した。残渣をカラムクロマトグラフィーで精製し、目的物である化合物39(93.2mg, 収率76%)を得た。
LCMS;451.95(M+H)
 第8工程
Figure JPOXMLDOC01-appb-C000107

 工程7で得られた化合物39(90mg, 0.199mmol)に対し2mol/L HClのメタノール溶液(2ml)を加えた。60℃で6時間攪拌後、室温まで冷却した。生成した固体をろ取し、目的物である化合物40(53mg, 収率59%)を得た。
1H-NMR (DMSO-d6) δ: 1.26 (s, 9H), 6.73 (d, J = 9.63 Hz, 1H), 7.52-7.66 (m, 6H), 7.79 (d, J = 8.11 Hz, 1H), 7.96 (d, J = 1.52 Hz, 1H), 8.30 (dd, J = 9.63, 3.04 Hz, 1H), 8.63 (d, J = 2.53 Hz, 1H).
 第9工程
Figure JPOXMLDOC01-appb-C000108

 工程8で得られた化合物40(16mg)に対し、塩化メチレン(15ml)と2mol/L 炭酸カリウム水溶液(2m)を加えた。硫酸マグネシウムで乾燥させ溶媒を留去した。カラムクロマトグラフィーで精製することで目的物である化合物41(12.3mg)を得た。
1H-NMR (DMSO-d6) δ: 1.25 (s, 9H), 6.72 (d, J = 9.63 Hz, 1H), 7.51-7.63 (m, 6H), 7.73-7.79 (m, 1H), 7.90-7.99 (m, 1H), 8.29 (dd, J = 9.63, 2.53 Hz, 1H), 8.57 (d, J = 2.53 Hz, 1H), 13.22 (br s, 1H).
 I-22~29,32~38,40も、同様の方法で合成を行った。
Example 7 Synthesis of Compound (I-20, 21) First Step
Figure JPOXMLDOC01-appb-C000100

Diamine compound 32 (5 g, 25.9 mmol) was dissolved in N, N-dimethylformamide (50 ml), triethylamine (5.39 ml, 38.9 mmol) and carboxylic acid (4.08 g, 25.9 mmol) were added, and the mixture was cooled to 0 ° C. and HATU (12.2 g, 32.1 mmol) was added. The mixture was stirred at room temperature for 1 hour, and ethyl acetate was added. It was washed with 2 mol / L potassium carbonate (50 ml) and water (50 ml × 3) and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was washed with ethyl acetate to obtain the desired product 33 (5.91 g, yield 69.8%).
LCMS; 325.70 (M + H)
Second step
Figure JPOXMLDOC01-appb-C000101

Acetic acid (15 ml) was added to Compound 33 (3 g, 9.19 mmol) obtained in Step 1, and reacted at 150 ° C. for 1 hour under microwave irradiation. The solvent was distilled off, phosphorus oxychloride (15 ml) was added to the residue, and the mixture was stirred at 100 ° C. for 1 hr. After the solvent was distilled off, chloroform and 2 mol / L potassium carbonate were added to the residue and stirred, and the organic layer was concentrated under reduced pressure. The obtained solid was filtered and washed with water to obtain the target product 34 (3.48 g, yield: 91%).
LCMS; 309.65 (M + H)
Third step
Figure JPOXMLDOC01-appb-C000102

N, N-dimethylformamide (35 ml) was added to compound 34 (3.48 g, 11.27 mmol) obtained in the second step and cooled to 0 ° C. NaH (60% in oil, 0.676 g, 16.9 mmol) was added, and the mixture was stirred at 0 ° C. for 5 minutes. To this, methoxymethyl chloride (1.29 ml, 16.9 mmol) was added dropwise and reacted at 0 ° C. for 45 minutes. Further, NaH (60% in oil, 220 mg, 5.6 mmol) was added and reacted at 0 ° C. for 3 minutes, and then methoxymethyl chloride (0.43 ml, 5.6 mmol) was added and reacted for 30 minutes. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with water. After drying over anhydrous magnesium sulfate, the target product 35 (3.61 g, yield 91%) was obtained by distilling off.
LCMS; 353.60 (M + H)
Fourth step
Figure JPOXMLDOC01-appb-C000103

NMP (15 ml) was added to benzyl alcohol (3.52 ml, 33.8 mmol), and NaH (60% in oil, 0.81 g, 33.8 mmol) was added thereto. After stirring at room temperature for 5 minutes, a solution of compound 35 (3.6 g, 10.25 mmol) obtained in Step 3 in NMP (30 ml) was added dropwise. The mixture was stirred at 100 ° C. for 15 minutes and cooled to room temperature. Diethyl ether was added and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography to give the intended product 36 (2.31 g, yield 53%).
LCMS; 425.65 (M + H)
5th process
Figure JPOXMLDOC01-appb-C000104

Compound 36 (1.63 g, 3.84 mmol) obtained in the fourth step was added to diisopropylethylamine (1.7 ml, 9.6 mmol), Xantphos (0.22 g, 0.384 mmol), Pd 2 (dba) 3 (0.176 g, 0.192 mmol). , TBuSH (0.52 g, 5.76 mmol) was added and reacted at 110 ° C. for 5 hours under microwave irradiation. After cooling to room temperature, the solvent was distilled off, ethyl acetate was added to the residue, and the insoluble material was filtered off. The filtrate was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography to obtain the target compound 37 (1.51 g, yield: 91%).
LCMS; 434.00 (M + H)
6th process
Figure JPOXMLDOC01-appb-C000105

Dichloromethane was added to compound 37 (1.51 g, 3.49 mmol) obtained in the fifth step and cooled to 0 ° C. mCPBA (1.92 g, 7.67 mmol) was added and stirred at 0 ° C. for 30 minutes. 2 mol / L potassium carbonate was added and extracted with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was dissolved in methanol (10 ml) and THF (10 ml), 10% Pd / C (324 mg) was added, and the mixture was reacted overnight under a hydrogen atmosphere. The solvent was distilled off, a mixed solvent of chloroform and methanol (9: 1) was added to the residue, and the insoluble material was filtered off. The filtrate was distilled off, and the residue was washed with diethyl ether to obtain the desired product 38 (1.23 g, yield: 95%).
LCMS; 375.95 (M + H)
7th process
Figure JPOXMLDOC01-appb-C000106

Phenyl bromide (0.042 ml, 0.4 mmol) in DMA (1 ml), compound 38 (100 mg, 0.26 mmol) obtained in step 6, potassium carbonate (81 mg, 0.586 mmol), copper iodide (10.2 mg, 0.053 mmol) and Dimethylglycine (11 mg, 0,107 mmol) was added. The reaction was performed at 170 ° C. for 1 hour under microwave irradiation. Water and ethyl acetate were added, the insoluble material was filtered, and the solid was washed with a mixed solvent of methylene chloride / methanol. After partitioning the filtrate, the organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography to obtain the target compound 39 (93.2 mg, yield 76%).
LCMS; 451.95 (M + H)
8th step
Figure JPOXMLDOC01-appb-C000107

To a compound 39 (90 mg, 0.199 mmol) obtained in Step 7, 2 mol / L HCl in methanol (2 ml) was added. After stirring at 60 ° C. for 6 hours, the mixture was cooled to room temperature. The resulting solid was collected by filtration to obtain the target compound 40 (53 mg, yield 59%).
1 H-NMR (DMSO-d 6 ) δ: 1.26 (s, 9H), 6.73 (d, J = 9.63 Hz, 1H), 7.52-7.66 (m, 6H), 7.79 (d, J = 8.11 Hz, 1H ), 7.96 (d, J = 1.52 Hz, 1H), 8.30 (dd, J = 9.63, 3.04 Hz, 1H), 8.63 (d, J = 2.53 Hz, 1H).
9th step
Figure JPOXMLDOC01-appb-C000108

To compound 40 (16 mg) obtained in step 8, methylene chloride (15 ml) and 2 mol / L aqueous potassium carbonate solution (2 m) were added. The solvent was distilled off after drying with magnesium sulfate. Purification by column chromatography gave Compound 41 (12.3 mg) which was the target product.
1 H-NMR (DMSO-d 6 ) δ: 1.25 (s, 9H), 6.72 (d, J = 9.63 Hz, 1H), 7.51-7.63 (m, 6H), 7.73-7.79 (m, 1H), 7.90 -7.99 (m, 1H), 8.29 (dd, J = 9.63, 2.53 Hz, 1H), 8.57 (d, J = 2.53 Hz, 1H), 13.22 (br s, 1H).
I-22 to 29, 32 to 38, and 40 were synthesized in the same manner.
実施例8 化合物(I-15)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000109

 4-(プロピルチオ)ベンゼン-1,2-ジアミン19(500mg, 2.74mmol)に窒素気流下でN,N-ジメチルホルムアミド(5.0ml)、トリエチルアミン(0.570ml, 4.11mmol) 及び6-クロロニコチン酸(432mg, 2.74mmol)を加えた。氷冷下でHATU(1252mg, 3.29mmol)を加え、氷冷下のまま1時間強攪拌した。反応液に酢酸エチルを加え、2mol/L 炭酸カリウム水溶液及び水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。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42 (679.3mg, 収率77.0%)を得た。
LCMS:322.85(M+H)
 第2工程
Figure JPOXMLDOC01-appb-C000110

 化合物42(390mg, 1.212mmol)を酢酸(3.9ml)に溶解し、マイクロウェーブ反応装置(150℃, 1時間)により反応を行なった。溶媒を減圧下留去し、酢酸エチルを加えて不溶物を濾去し、2mol/L 炭酸カリウム水溶液で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。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43 (184.3mg, 収率50.1%)を得た。
LCMS:304.00(M+H)
 第3工程
Figure JPOXMLDOC01-appb-C000111

 化合物43(150mg, 0.494mmol)に窒素気流下でN,N-ジメチルホルムアミド(3.0ml)を加え、氷冷下でNaH(60% in oil, 29.6mg, 0.741mmol)を加え、氷冷下のまま5分攪拌した。氷冷下でクロロメチルメチルエーテル(56μl, 0.741mmol)を加え、氷冷下のまま4時間弱攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣(208.2mg, 82.5Wt%)のうち一部(172mg) に窒素気流下でN -メチル-2-ピロリドン(1.0ml)を加え溶解したものを、予めベンジルアルコール(176mg, 1.63mmol)と60%水素化ナトリウム(39.1mg, 1.63mmol)をN -メチル-2-ピロリドン(1.0ml)中、室温で5分攪拌したものへ加えた。反応液を100℃で4時間弱攪拌した後、室温まで冷却し、ジエチルエーテルを加え、水で洗浄した。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44(191.1mg, 収率92.2%)を得た。
LCMS:420.00(M+H)
 以下、実施例7と同様に反応を行い目的物であるI-15を得た。
 I-14,16,17は同様の方法で合成を行った。
Example 8 Synthesis of Compound (I-15) First Step
Figure JPOXMLDOC01-appb-C000109

N, N-dimethylformamide (5.0 ml), triethylamine (0.570 ml, 4.11 mmol) and 6-chloronicotinic acid (5.0 ml) were added to 4- (propylthio) benzene-1,2-diamine 19 (500 mg, 2.74 mmol) under a nitrogen stream. 432 mg, 2.74 mmol) was added. HATU (1252 mg, 3.29 mmol) was added under ice cooling, and the mixture was vigorously stirred for 1 hour with ice cooling. Ethyl acetate was added to the reaction solution, washed with a 2 mol / L potassium carbonate aqueous solution and water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give compound 42 (679.3 mg, yield 77.0%).
LCMS: 322.85 (M + H)
Second step
Figure JPOXMLDOC01-appb-C000110

Compound 42 (390 mg, 1.212 mmol) was dissolved in acetic acid (3.9 ml), and the reaction was carried out using a microwave reactor (150 ° C., 1 hour). The solvent was distilled off under reduced pressure, ethyl acetate was added and the insoluble material was filtered off, washed with a 2 mol / L aqueous potassium carbonate solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give compound 43 (184.3 mg, yield 50.1%).
LCMS: 304.00 (M + H)
Third step
Figure JPOXMLDOC01-appb-C000111

N, N-dimethylformamide (3.0 ml) was added to Compound 43 (150 mg, 0.494 mmol) under a nitrogen stream, and NaH (60% in oil, 29.6 mg, 0.741 mmol) was added under ice cooling. The mixture was stirred for 5 minutes. Chloromethyl methyl ether (56 μl, 0.741 mmol) was added under ice-cooling, and the mixture was stirred slightly for 4 hours with ice-cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. A part (172 mg) of the obtained residue (208.2 mg, 82.5 Wt%) was dissolved in N-methyl-2-pyrrolidone (1.0 ml) under a nitrogen stream in advance, and benzyl alcohol (176 mg, 1.63 mmol) was dissolved in advance. ) And 60% sodium hydride (39.1 mg, 1.63 mmol) were added to N-methyl-2-pyrrolidone (1.0 ml) stirred at room temperature for 5 minutes. The reaction mixture was stirred slightly at 100 ° C. for 4 hours, cooled to room temperature, diethyl ether was added, and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 44 (191.1 mg, yield 92.2%).
LCMS: 420.00 (M + H)
Thereafter, the reaction was carried out in the same manner as in Example 7 to obtain the target product I-15.
I-14, 16, and 17 were synthesized by the same method.
実施例9 化合物(I-19)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000112

 t-ブトキシカリウム(648mg, 5.78mmol)に窒素気流下で、テトラヒドロフラン(5.0ml)を加え、氷冷下でギ酸エチル(4.279g, 57.8mmol)を加えた。氷冷下のまま3分攪拌し、ケトエステル(535mg, 2.89mmol)のTHF溶液(5.0ml)を加え、室温で4時間弱攪拌した。氷冷下で反応液に2mol/Lの塩酸水溶液を加え、酢酸エチル及びクロロホルムで抽出した後、溶媒を減圧下留去した。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45 (135.1mg, 収率27.8%)を得た。
LCMS:168.95(M+H)
 第2工程
Figure JPOXMLDOC01-appb-C000113

 化合物45(127.2mg, 0.756mmol)及びアニリン(77mg, 0.832mmol)を酢酸(1.0ml)に溶解し、60℃で1時間弱攪拌した。反応液に酢酸エチルを加え、2mol/L 炭酸カリウムで中和した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。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46 (171.5mg, 収率93.2%)を得た。
LCMS:243.90(M+H)
 第3工程
Figure JPOXMLDOC01-appb-C000114

 化合物46(165mg, 0.678mmol)をメタノール(1.0ml)に溶解し、2mol/Lの水酸化ナトリウム水溶液(0.373ml, 0.746mmol)を加え、室温で1時間弱攪拌した。反応液に2mol/Lの塩酸水溶液(0.406ml, 0.813mmol)を加え、生じた固体を濾取することで化合物47(128.9mg, 0.599mmol)を得た。
LCMS:215.90(M+H)
 以下、実施例1と同様に反応を行い、目的物であるI-19を得た。
Example 9 Synthesis of Compound (I-19) First Step
Figure JPOXMLDOC01-appb-C000112

Tetrahydrofuran (5.0 ml) was added to t-butoxypotassium (648 mg, 5.78 mmol) under a nitrogen stream, and ethyl formate (4.279 g, 57.8 mmol) was added under ice cooling. The mixture was stirred for 3 minutes under ice-cooling, a keto ester (535 mg, 2.89 mmol) in THF (5.0 ml) was added, and the mixture was stirred slightly at room temperature for 4 hours. Under ice-cooling, 2 mol / L hydrochloric acid aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate and chloroform, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 45 (135.1 mg, yield 27.8%).
LCMS: 168.95 (M + H)
Second step
Figure JPOXMLDOC01-appb-C000113

Compound 45 (127.2 mg, 0.756 mmol) and aniline (77 mg, 0.832 mmol) were dissolved in acetic acid (1.0 ml) and stirred slightly at 60 ° C. for 1 hour. Ethyl acetate was added to the reaction solution and neutralized with 2 mol / L potassium carbonate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 46 (171.5 mg, yield 93.2%).
LCMS: 243.90 (M + H)
Third step
Figure JPOXMLDOC01-appb-C000114

Compound 46 (165 mg, 0.678 mmol) was dissolved in methanol (1.0 ml), 2 mol / L aqueous sodium hydroxide solution (0.373 ml, 0.746 mmol) was added, and the mixture was slightly stirred at room temperature for 1 hour. A 2 mol / L hydrochloric acid aqueous solution (0.406 ml, 0.813 mmol) was added to the reaction solution, and the resulting solid was collected by filtration to obtain Compound 47 (128.9 mg, 0.599 mmol).
LCMS: 215.90 (M + H)
Thereafter, the reaction was carried out in the same manner as in Example 1 to obtain the target product, I-19.
実施例10 化合物(I-43)の合成
Figure JPOXMLDOC01-appb-C000115

 化合物I-9(8.8mg, 0.023mmol)に窒素気流下で、ジメチルスルホキシド(0.4ml)及びアセトニトリル(0.4ml)を加えた。氷冷下でSelectflour (9.51mg, 0.026mmol)を加え、氷冷下のままで1時間弱攪拌した。その後、室温で1時間弱攪拌し、さらに50℃で1時間弱攪拌した。Selectflour(9.51mg, 0.026mmolさらに19.02mg, 0.052mmol)を追加し、50℃で反応を行なった。反応液を逆相クロマトグラフィーにより精製し、48(1.7mg, 収率18.4% )を得た。
LCMS:393.95(M+H)
1H-NMR (DMSO-d6) δ: 0.91 (t, J = 7.35 Hz, 3H), 1.57 (dd, J = 15.21, 7.60 Hz, 2H), 7.41-7.45 (m, 1H), 7.52-7.56 (m, 2H), 7.59-7.70 (m, 4H), 7.77 (d, J = 7.10 Hz, 2H), 7.91 (d, J = 7.60 Hz, 1H), 8.07 (s, 1H), 8.17 (s, 1H).
Example 10 Synthesis of Compound (I-43)
Figure JPOXMLDOC01-appb-C000115

Dimethyl sulfoxide (0.4 ml) and acetonitrile (0.4 ml) were added to compound I-9 (8.8 mg, 0.023 mmol) under a nitrogen stream. Selectflour (9.51 mg, 0.026 mmol) was added under ice-cooling, and the mixture was slightly stirred for 1 hour with ice-cooling. Thereafter, the mixture was slightly stirred at room temperature for 1 hour and further stirred at 50 ° C. for 1 hour. Selectflour (9.51 mg, 0.026 mmol, further 19.02 mg, 0.052 mmol) was added, and the reaction was performed at 50 ° C. The reaction solution was purified by reverse phase chromatography to obtain 48 (1.7 mg, yield 18.4%).
LCMS: 393.95 (M + H)
1 H-NMR (DMSO-d 6 ) δ: 0.91 (t, J = 7.35 Hz, 3H), 1.57 (dd, J = 15.21, 7.60 Hz, 2H), 7.41-7.45 (m, 1H), 7.52-7.56 (m, 2H), 7.59-7.70 (m, 4H), 7.77 (d, J = 7.10 Hz, 2H), 7.91 (d, J = 7.60 Hz, 1H), 8.07 (s, 1H), 8.17 (s, 1H).
実施例11 化合物(I-45)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000116

 4-(トリフロオロメチルスルホニル)ベンゼン-1,2-ジアミン(1.00g, 4.16mmol)に窒素気流下で、N,N-ジメチルホルムアミド(5.0ml)、トリエチルアミン(0.866ml, 6.24mmol) 及び6-ベンジロキシ-ニコチン酸(1.089g, 4.71mmol)を加えた。氷冷下でHATU(1900mg, 5.00mmol)を加え、氷冷下のまま1時間弱攪拌した。反応液に酢酸エチルを加え、2mol/L 炭酸カリウム及び水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。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49 (757.6mg, 収率40.3%)を得た。
LCMS:451.90(M+H)
 第2工程
Figure JPOXMLDOC01-appb-C000117

 化合物49(350mg, 0.775mmol)を酢酸(7.0ml)に溶解し、100℃で10時間弱攪拌を行なった。溶媒を減圧下留去し、酢酸エチルを加え、2mol/L 炭酸カリウム及び水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。得られた残渣に窒素気流下でN,N-ジメチルホルムアミド(3.5ml)を加え溶解し、氷冷下で60% NaH(60% in oil, 46.5mg, 1.163 mmol)を加え、氷冷下のまま3分攪拌した。氷冷下でクロロメチル メチルエーテル(88μl, 1.163mmol)を加え、氷冷下のまま2時間弱攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。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50 (311.5mg, 収率84.1%)を得た。
LCMS:477.90(M+H)
 以下、実施例7と同様に反応を行い、目的物であるI-45を得た。
Example 11 Synthesis of Compound (I-45) First Step
Figure JPOXMLDOC01-appb-C000116

N, N-dimethylformamide (5.0 ml), triethylamine (0.866 ml, 6.24 mmol) and 6- (trifluoromethylsulfonyl) benzene-1,2-diamine (1.00 g, 4.16 mmol) under nitrogen flow -Benzyloxy-nicotinic acid (1.089 g, 4.71 mmol) was added. HATU (1900 mg, 5.00 mmol) was added under ice-cooling, and the mixture was slightly stirred for 1 hour with ice-cooling. Ethyl acetate was added to the reaction solution, washed with 2 mol / L potassium carbonate and water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give compound 49 (757.6 mg, yield 40.3%).
LCMS: 451.90 (M + H)
Second step
Figure JPOXMLDOC01-appb-C000117

Compound 49 (350 mg, 0.775 mmol) was dissolved in acetic acid (7.0 ml), and the mixture was slightly stirred at 100 ° C. for 10 hours. The solvent was evaporated under reduced pressure, ethyl acetate was added, washed with 2 mol / L potassium carbonate and water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue, N, N-dimethylformamide (3.5 ml) was added and dissolved under a nitrogen stream, and 60% NaH (60% in oil, 46.5 mg, 1.163 mmol) was added under ice cooling. The mixture was stirred for 3 minutes. Chloromethyl methyl ether (88 μl, 1.163 mmol) was added under ice-cooling, and the mixture was slightly stirred for 2 hours with ice-cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 50 (311.5 mg, yield 84.1%).
LCMS: 477.90 (M + H)
Thereafter, the reaction was carried out in the same manner as in Example 7 to obtain the target product, I-45.
実施例12 化合物(I-49)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000118

 ジアミン19(336 mg, 1.84 mmol)にN,N-ジメチルホルムアミド(2 ml)を加えた後、カルボン酸(200 mg, 1.54 mmol)、トリエチルアミン(639 μl, 4.61 mmol)及びHATU(876 mg, 2.31 mmol)を加え1.5時間攪拌した。水に反応液を注ぎ、酢酸エチルで抽出した。有機層を水洗し、更に飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した。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アミドを得た。
 得られたアミド(452 mg, 1.54 mmol)に酢酸(5 ml)を加えた後、150℃の条件下、マイクロウェーブを1時間照射した。その後、反応液を飽和炭酸水素ナトリウム水溶液に注ぎ、中和し、酢酸エチルで抽出した。有機層を更に飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、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51(218 mg, 収率51%)を得た。
LCMS: 308.85(M+H)
 第2工程
Figure JPOXMLDOC01-appb-C000119

 化合物51(217 mg, 0.787 mmol)に塩化メチレン(2 ml)を加えた後、0℃の条件下mCPBA(599 mg, 2.36 mmol)を加え、室温にて1時間攪拌した。その後、飽和炭酸水素ナトリウム水溶液に反応液を注ぎ、酢酸エチルで抽出した。有機層を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52(120 mg, 収率50%)を得た。
1H-NMR (DMSO-d6) δ: 0.89 (3H, t, J = 7.60 Hz), 1.53 (2H,m), 1.99-1.81 (4H, m), 3.23 (3H, m), 3.49 (2H, m), 3.95 (2H, m), 7.84 (3H, m).
 I-1,48も、同様の方法で合成した。
Example 12 Synthesis of Compound (I-49) First Step
Figure JPOXMLDOC01-appb-C000118

N, N-dimethylformamide (2 ml) was added to diamine 19 (336 mg, 1.84 mmol), followed by carboxylic acid (200 mg, 1.54 mmol), triethylamine (639 μl, 4.61 mmol) and HATU (876 mg, 2.31 mmol) was added and stirred for 1.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, and further washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain an amide.
Acetic acid (5 ml) was added to the obtained amide (452 mg, 1.54 mmol), followed by irradiation with microwaves at 150 ° C. for 1 hour. Thereafter, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution, neutralized, and extracted with ethyl acetate. The organic layer was further washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 51 (218 mg, yield 51%).
LCMS: 308.85 (M + H)
Second step
Figure JPOXMLDOC01-appb-C000119

Methylene chloride (2 ml) was added to compound 51 (217 mg, 0.787 mmol), then mCPBA (599 mg, 2.36 mmol) was added under the condition of 0 ° C., and the mixture was stirred at room temperature for 1 hour. Thereafter, the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give compound 52 (120 mg, yield 50%).
1 H-NMR (DMSO-d 6 ) δ: 0.89 (3H, t, J = 7.60 Hz), 1.53 (2H, m), 1.99-1.81 (4H, m), 3.23 (3H, m), 3.49 (2H , m), 3.95 (2H, m), 7.84 (3H, m).
I-1 and 48 were also synthesized by the same method.
実施例13 化合物(I-58)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000120

 アルベンダゾール53 (5 g, 18.8 mmol)にジクロロメタン(50 ml)を加えた後、氷冷下でmCPBA(10.4 ml, 96.0 mmol)を加え、氷冷下のまま30分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて中和した。その際に析出した固体を濾取し、乾燥することによりスルホン体を得た。
 スルホン体(5.6g, 18.8 mmol)に2mol/Lの水酸化ナトリウム水溶液(65.9 ml, 132 mmol)を加え6.5時間85℃で攪拌した。0℃で希塩酸水を加えて中和を行い、クロロホルムとエタノールの比率が5対1の混合溶媒で抽出した。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54(4.08g, 収率90%)を得た。
1H-NMR (DMSO-d6) δ: 0.89 (3H, t, J = 7.35 Hz), 1.58-1.48 (2H, m), 3.16-3.13 (2H, m), 6.63 (2H, br-s), 7.53-7.24 (3H, m).
 第2工程
Figure JPOXMLDOC01-appb-C000121

 第1工程で得られたアミン54(1.9 g, 7.94 mmol)を水(100 ml)に溶解させた後、濃塩酸水(2.76ml, 31.8 mmol)及び臭化銅(3.42 g, 23.8 mmol)を加え、その後水に溶解させた亜硝酸ナトリウム(2.74 g, 39.7 mmol)を60℃の条件下滴下し、1.5時間60℃で攪拌した。その後、2mol/Lの水酸化ナトリウム水溶液(65.9 ml, 132 mmol)を加え中和した後、クロロホルムとエタノールの比率が5対1の混合溶媒で抽出した。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55(800 mg, 収率33%)を得た。
1H-NMR (DMSO-d6) δ: 7.58 (3H, m), 3.20 (1H,m), 1.53 (2H, m), 0.90 (3H, t, J = 7.35 Hz).
 第3工程
Figure JPOXMLDOC01-appb-C000122

 ブロマイド55 (50.0 mg, 0.165 mmol)にイソプロパノール(2 ml)を加えた後、モルホリン(22 μl, 0.247 mmol)及びジイソプロピルエチルアミン (86 μl, 0.495 mmol)を加えた。150℃の条件下、マイクロウェーブを30分間照射した。その後、減圧下溶媒を留去し、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56(30.3mg, 収率59%)を得た。
1H-NMR (DMSO-d6) δ: 0.90-0.84 (3H, m), 1.52 (2H, m), 3.20-3.16 (2H, m), 3.53 (4H, m), 3.73 (4H, m), 7.51 (3H, m), 11.92 (1H, m).
 I-46,51,53,55,56~57,60,64,83~85,89,90,91も、同様の方法で合成を行った。
Example 13 Synthesis of Compound (I-58) First Step
Figure JPOXMLDOC01-appb-C000120

Dichloromethane (50 ml) was added to albendazole 53 (5 g, 18.8 mmol), then mCPBA (10.4 ml, 96.0 mmol) was added under ice cooling, and the mixture was stirred for 30 minutes with ice cooling. The reaction solution was neutralized by adding a saturated aqueous sodium hydrogen carbonate solution. The solid precipitated at this time was collected by filtration and dried to obtain a sulfone compound.
A 2 mol / L aqueous sodium hydroxide solution (65.9 ml, 132 mmol) was added to the sulfone compound (5.6 g, 18.8 mmol), and the mixture was stirred for 6.5 hours at 85 ° C. The mixture was neutralized by adding dilute hydrochloric acid at 0 ° C., and extracted with a mixed solvent having a ratio of chloroform to ethanol of 5: 1. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain Compound 54 (4.08 g, yield 90%).
1 H-NMR (DMSO-d 6 ) δ: 0.89 (3H, t, J = 7.35 Hz), 1.58-1.48 (2H, m), 3.16-3.13 (2H, m), 6.63 (2H, br-s) , 7.53-7.24 (3H, m).
Second step
Figure JPOXMLDOC01-appb-C000121

The amine 54 (1.9 g, 7.94 mmol) obtained in the first step was dissolved in water (100 ml), and then concentrated hydrochloric acid (2.76 ml, 31.8 mmol) and copper bromide (3.42 g, 23.8 mmol) were added. Thereafter, sodium nitrite (2.74 g, 39.7 mmol) dissolved in water was added dropwise under the condition of 60 ° C., and the mixture was stirred at 60 ° C. for 1.5 hours. Thereafter, a 2 mol / L sodium hydroxide aqueous solution (65.9 ml, 132 mmol) was added to neutralize, and the mixture was extracted with a mixed solvent having a ratio of chloroform to ethanol of 5: 1. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain Compound 55 (800 mg, yield 33%).
1 H-NMR (DMSO-d 6 ) δ: 7.58 (3H, m), 3.20 (1H, m), 1.53 (2H, m), 0.90 (3H, t, J = 7.35 Hz).
Third step
Figure JPOXMLDOC01-appb-C000122

Isopropanol (2 ml) was added to bromide 55 (50.0 mg, 0.165 mmol), followed by morpholine (22 μl, 0.247 mmol) and diisopropylethylamine (86 μl, 0.495 mmol). Microwave was irradiated for 30 minutes at 150 ° C. Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 56 (30.3 mg, yield 59%).
1 H-NMR (DMSO-d 6 ) δ: 0.90-0.84 (3H, m), 1.52 (2H, m), 3.20-3.16 (2H, m), 3.53 (4H, m), 3.73 (4H, m) , 7.51 (3H, m), 11.92 (1H, m).
I-46, 51, 53, 55, 56 to 57, 60, 64, 83 to 85, 89, 90, 91 were synthesized in the same manner.
実施例14 化合物(I-59,75)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000123

 クロライド57 (3.0 g, 13.0 mmol)に2-プロパノール(15 ml)を加えた後、氷冷下で2-フェニルモルホリン塩酸塩(2.59 g, 13.0 mmol)及びジイソプロピルエチルアミン (4.50 ml, 26.0 mmol)を加えた。180℃の条件下、マイクロウェーブを30分間照射した。その後、減圧下溶媒を留去し、残渣をカラムクロマトグラフィーにより精製し、化合物58を定量的に得た。
1H-NMR (CDCl3) δ: 3.05 (1H, m), 3.29 (1H, dd, J = 11.91, 8.36 Hz), 3.91-3.79 (2H, m), 4.00 (1H, d, J = 12.17 Hz), 4.11 (1H, m), 4.52 (1H, m), 7.42-7.12 (8H, m).
 第2工程
Figure JPOXMLDOC01-appb-C000124

 第1工程で得られた化合物58 (1.0 g, 2.79 mmol)に1,4-ジオキサン(10ml)を加えた後、ジイソプロピルエチルアミン(1.46 ml, 8.37 mmol)、Pd2(dba)3 (256 mg, 0.279 mmol)、Xantphos (323 mg, 0.558 mmol)及びエタンチオール(0.204 ml,2.79 mmol)を加えた。150℃で、マイクロウェーブを1時間照射した。その後、飽和炭酸水素ナトリウム水溶液に反応液を注ぎ、酢酸エチルで抽出した。有機層を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59(692mg, 収率73%)を得た。
1H-NMR (CDCl3) δ: 1.24 (3H, t, J = 7.35 Hz), 2.87 (2H, m), 3.10 (1H, dd, J = 12.17, 10.65 Hz), 3.35-3.29 (1H, m), 4.00-3.87 (3H, m), 4.17 (1H, dd, J = 10.90, 3.30 Hz), 4.61 (1H, dd, J = 10.65, 3.04 Hz), 7.91 (8H, m).
 第3工程
Figure JPOXMLDOC01-appb-C000125

 化合物59(692 mg, 2.04 mmol)に塩化メチレン(2 ml)を加えた後、0℃の条件下mCPBA(1.09 g, 4.28 mmol)を加え、室温にて3時間攪拌した。その後、飽和炭酸水素ナトリウム水溶液に反応液を注ぎ、クロロホルムで抽出した。有機層を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60 (587 mg, 収率78%)を得た。
 I-54,62,65,69,70は同様の方法で合成を行った。
Example 14 Synthesis of Compound (I-59,75) First Step
Figure JPOXMLDOC01-appb-C000123

After 2-propanol (15 ml) was added to chloride 57 (3.0 g, 13.0 mmol), 2-phenylmorpholine hydrochloride (2.59 g, 13.0 mmol) and diisopropylethylamine (4.50 ml, 26.0 mmol) were added under ice cooling. added. Microwave was irradiated for 30 minutes under the condition of 180 ° C. Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain Compound 58 quantitatively.
1 H-NMR (CDCl 3 ) δ: 3.05 (1H, m), 3.29 (1H, dd, J = 11.91, 8.36 Hz), 3.91-3.79 (2H, m), 4.00 (1H, d, J = 12.17 Hz ), 4.11 (1H, m), 4.52 (1H, m), 7.42-7.12 (8H, m).
Second step
Figure JPOXMLDOC01-appb-C000124

After adding 1,4-dioxane (10 ml) to compound 58 (1.0 g, 2.79 mmol) obtained in the first step, diisopropylethylamine (1.46 ml, 8.37 mmol), Pd2 (dba) 3 (256 mg, 0.279 mmol), Xantphos (323 mg, 0.558 mmol) and ethanethiol (0.204 ml, 2.79 mmol) were added. Microwave was irradiated for 1 hour at 150 ° C. Thereafter, the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give compound 59 (692 mg, yield 73%).
1 H-NMR (CDCl 3 ) δ: 1.24 (3H, t, J = 7.35 Hz), 2.87 (2H, m), 3.10 (1H, dd, J = 12.17, 10.65 Hz), 3.35-3.29 (1H, m ), 4.00-3.87 (3H, m), 4.17 (1H, dd, J = 10.90, 3.30 Hz), 4.61 (1H, dd, J = 10.65, 3.04 Hz), 7.91 (8H, m).
Third step
Figure JPOXMLDOC01-appb-C000125

After adding methylene chloride (2 ml) to compound 59 (692 mg, 2.04 mmol), mCPBA (1.09 g, 4.28 mmol) was added under the condition of 0 ° C., and the mixture was stirred at room temperature for 3 hours. Thereafter, the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give compound 60 (587 mg, yield 78%).
I-54, 62, 65, 69 and 70 were synthesized in the same manner.
実施例15 化合物(I-61)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000126

 化合物58 (600 mg, 1.68 mmol)にN,N-ジメチルホルムアミド(6 ml)を加えた後、水素化ナトリウム(87.0 mg, 2.18 mmol)加えた。その後、SEMCl(356 μl, 2.01 mmol)を加え、室温で3時間攪拌した。その後、水に反応液を注ぎ、酢酸エチルで抽出した。有機層を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61(710 mg, 収率87%)を得た。
LCMS: 489.80(M+H)
 第2工程
Figure JPOXMLDOC01-appb-C000127

 化合物61(230 mg, 0.47 mmol)をテトラヒドロフラン(2.0 ml)に溶解させた後、-78℃下、n-ブチルリチウム2.6mol/Lヘキサン溶液(181 μl, 0.47 mmol)を加え、同温度下で30分攪拌した。その後、テトラヒドロフラン(1.0 ml)に溶解させたジメチルジスルフィド(54 μl, 0.611 mmol)を加え、-78℃にて1時間攪拌した。その後、水に反応液を注ぎ、クロロホルムで抽出した。有機層を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でメチルスルフィド付加物を得た。
 得られたメチルスルフィド体(264 mg, 0.58 mmol)に塩化メチレン(2 ml)を加えた後、0℃下、mCPBA(441 mg, 1.74 mmol)を加え、室温にて1.5時間攪拌した。その後、飽和炭酸水素ナトリウム水溶液に反応液を注ぎ、クロロホルムで抽出した。有機層を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62(25.8 mg, 収率9%)を得た。
LCMS: 488.05(M+H)
 第3工程
Figure JPOXMLDOC01-appb-C000128

 化合物62 (24.5 mg, 0.05 mmol)にテトラヒドロフラン(1.5 ml)を加えた後、TBAF 1水和物 (70.2 mg, 0.251 mmol)を加え、80℃にて4時間攪拌した。その後、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63 (15.0 mg, 収率84%)を得た。
1H-NMR (CDCl3) δ: 3.07 (3H, s), 3.17 (1H, dd, J = 12.67, 10.65 Hz), 3.42-3.36 (1H, m), 3.95 (2H, m), 4.24-4.13 (2H, m), 4.64 (1H, dd, J = 10.65, 2.53 Hz), 7.50 (7H, m), 7.85 (1H, s).
Example 15 Synthesis of Compound (I-61) First Step
Figure JPOXMLDOC01-appb-C000126

N, N-dimethylformamide (6 ml) was added to compound 58 (600 mg, 1.68 mmol), and then sodium hydride (87.0 mg, 2.18 mmol) was added. Then, SEMCl (356 μl, 2.01 mmol) was added and stirred at room temperature for 3 hours. Thereafter, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 61 (710 mg, yield 87%).
LCMS: 489.80 (M + H)
Second step
Figure JPOXMLDOC01-appb-C000127

Compound 61 (230 mg, 0.47 mmol) was dissolved in tetrahydrofuran (2.0 ml), and n-butyllithium 2.6 mol / L hexane solution (181 μl, 0.47 mmol) was added at -78 ° C. Stir for 30 minutes. Thereafter, dimethyl disulfide (54 μl, 0.611 mmol) dissolved in tetrahydrofuran (1.0 ml) was added, and the mixture was stirred at −78 ° C. for 1 hour. Thereafter, the reaction solution was poured into water and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain a methyl sulfide adduct.
After adding methylene chloride (2 ml) to the obtained methyl sulfide (264 mg, 0.58 mmol), mCPBA (441 mg, 1.74 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. Thereafter, the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was 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 62 (25.8 mg, yield 9%).
LCMS: 488.05 (M + H)
Third step
Figure JPOXMLDOC01-appb-C000128

After adding tetrahydrofuran (1.5 ml) to compound 62 (24.5 mg, 0.05 mmol), TBAF monohydrate (70.2 mg, 0.251 mmol) was added and stirred at 80 ° C. for 4 hours. Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 63 (15.0 mg, yield 84%).
1 H-NMR (CDCl 3 ) δ: 3.07 (3H, s), 3.17 (1H, dd, J = 12.67, 10.65 Hz), 3.42-3.36 (1H, m), 3.95 (2H, m), 4.24-4.13 (2H, m), 4.64 (1H, dd, J = 10.65, 2.53 Hz), 7.50 (7H, m), 7.85 (1H, s).
実施例16 化合物(I-63)の合成
Figure JPOXMLDOC01-appb-C000129

 化合物55 (70 mg, 0.231 mmol)に1,4-ジオキサン(2 ml)及び水(0.2 ml)を加えた後、ボロン酸(17.6 mg, 0.231 mmol)、炭酸セシウム(113 mg, 8.37 mmol)及びPd(PPh3)4 (256 mg, 0.279 mmol)を加えた。180℃の条件下、マイクロウェーブを20分間照射した。その後、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64(60mg, 収率68%)を得た。
1H-NMR (DMSO-d6, DCl) δ: 0.92 (3H, m), 1.59 (2H, m), 3.41 (2H, t, J = 7.86 Hz), 7.51 (2H, t, J = 8.87 Hz), 7.91 (2H, m), 8.05 (2H, m), 8.23 (1H, s), 8.97 (1H, s), 9.87 (1H, s).
 I-50,81,82,86,87,88も、同様の方法で合成を行った。
Example 16 Synthesis of Compound (I-63)
Figure JPOXMLDOC01-appb-C000129

After adding 1,4-dioxane (2 ml) and water (0.2 ml) to compound 55 (70 mg, 0.231 mmol), boronic acid (17.6 mg, 0.231 mmol), cesium carbonate (113 mg, 8.37 mmol) and Pd (PPh3) 4 (256 mg, 0.279 mmol) was added. Microwave was irradiated for 20 minutes at 180 ° C. Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 64 (60 mg, yield 68%).
1 H-NMR (DMSO-d 6 , DCl) δ: 0.92 (3H, m), 1.59 (2H, m), 3.41 (2H, t, J = 7.86 Hz), 7.51 (2H, t, J = 8.87 Hz ), 7.91 (2H, m), 8.05 (2H, m), 8.23 (1H, s), 8.97 (1H, s), 9.87 (1H, s).
I-50, 81, 82, 86, 87, and 88 were synthesized in the same manner.
実施例17 化合物(I-67)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000130

 化合物61(200 mg, 0.409 mmol)をテトラヒドロフラン(2.0 ml)に溶解させた後、-78℃下、n-ブチルリチウム2.6mol/Lヘキサン溶液(173 μl, 0.450 mmol)を加え、同温度下で30分攪拌した。その後、テトラヒドロフラン(1.0 ml)に溶解させたスルフィン酸エステル (215 ml, 0.819 mmol)を加え、-78℃にて1時間攪拌した。水に反応液を注ぎ、クロロホルムで抽出し、有機層を飽和食塩水で洗浄した。その後、無水硫酸マグネシウムで乾燥した後、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化合物65(141mg, 収率67%)を得た。
LCMS: 514.10(M+H)
 第2工程
Figure JPOXMLDOC01-appb-C000131

 化合物65(141 mg, 0.274 mmol)に塩化メチレン(4 ml)を加えた後、0℃下、mCPBA(83 mg, 0.328 mmol)を加え、室温にて3時間攪拌した。その後、飽和炭酸水素ナトリウム水溶液に反応液を注ぎ、酢酸エチルで抽出した。有機層を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66(127 mg, 収率88%)を得た。
LCMS: 530.10(M+H)
 第3工程
Figure JPOXMLDOC01-appb-C000132

 化合物66(127 mg, 0.240 mmol)にテトラヒドロフラン(3.0 ml)を加えた後、TBAF 1水和物(335 mg, 1.20 mmol)を加え、80℃にて7時間攪拌した。その後、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67(77.5 mg, 収率81%)を得た。
1H-NMR (CDCl3) δ: 1.31 (9H, s), 3.15 (1H, t, J = 11.91 Hz), 3.37 (1H, m), 3.90 (1H, m), 4.13 (3H, m), 4.64 (1H, d, J = 10.14 Hz), 7.57-7.31 (7H, m), 7.75 (1H, s), 9.98 (1H, s).
Example 17 Synthesis of Compound (I-67) First Step
Figure JPOXMLDOC01-appb-C000130

Compound 61 (200 mg, 0.409 mmol) was dissolved in tetrahydrofuran (2.0 ml), and n-butyllithium 2.6 mol / L hexane solution (173 μl, 0.450 mmol) was added at −78 ° C. Stir for 30 minutes. Thereafter, sulfinic acid ester (215 ml, 0.819 mmol) dissolved in tetrahydrofuran (1.0 ml) was added, and the mixture was stirred at -78 ° C for 1 hour. The reaction mixture was poured into water, extracted with chloroform, and the organic layer was washed with saturated brine. Then, after drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 65 (141 mg, 67% yield).
LCMS: 514.10 (M + H)
Second step
Figure JPOXMLDOC01-appb-C000131

Methylene chloride (4 ml) was added to compound 65 (141 mg, 0.274 mmol), then mCPBA (83 mg, 0.328 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 3 hr. Thereafter, the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 66 (127 mg, yield 88%).
LCMS: 530.10 (M + H)
Third step
Figure JPOXMLDOC01-appb-C000132

Tetrahydrofuran (3.0 ml) was added to compound 66 (127 mg, 0.240 mmol), TBAF monohydrate (335 mg, 1.20 mmol) was added, and the mixture was stirred at 80 ° C. for 7 hr. Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 67 (77.5 mg, yield 81%).
1 H-NMR (CDCl 3 ) δ: 1.31 (9H, s), 3.15 (1H, t, J = 11.91 Hz), 3.37 (1H, m), 3.90 (1H, m), 4.13 (3H, m), 4.64 (1H, d, J = 10.14 Hz), 7.57-7.31 (7H, m), 7.75 (1H, s), 9.98 (1H, s).
実施例18 化合物(I-68)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000133

 化合物55(75mg, 0.247mmol)にNMP(0.25ml)、2-プロパノール(0.5ml)及びアミン68(65mg, 0.,247mmol)を加えて、マイクロウェーブ照射下180℃で1時間反応させた。10%クエン酸水溶液に反応液を注ぎ、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。残渣をカラムクロマトグラフィーで精製し、アミン付加物(79mg)を得た。
 得られたアミン付加物(79mg)をメタノールに溶解させ、Pd(OH)2(116mg, 0.165mmol)を加え水素雰囲気下で反応させた。不溶物をセライト濾過し、ろ液を留去した。残渣をカラムクロマトグラフィーで精製することで目的物69(2.0mg, 収率4%, 2steps)を得た。
LCMS;357.95(M+H)
Example 18 Synthesis of Compound (I-68) First Step
Figure JPOXMLDOC01-appb-C000133

NMP (0.25 ml), 2-propanol (0.5 ml) and amine 68 (65 mg, 0, 247 mmol) were added to compound 55 (75 mg, 0.247 mmol) and reacted at 180 ° C. for 1 hour under microwave irradiation. The reaction solution was poured into a 10% aqueous citric acid solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by column chromatography to obtain an amine adduct (79 mg).
The obtained amine adduct (79 mg) was dissolved in methanol, Pd (OH) 2 (116 mg, 0.165 mmol) was added, and the reaction was performed in a hydrogen atmosphere. The insoluble material was filtered through Celite, and the filtrate was distilled off. The residue was purified by column chromatography to give the intended product 69 (2.0 mg, 4% yield, 2steps).
LCMS; 357.95 (M + H)
実施例19 化合物72(I-71)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000134

 ジアミン5(1g, 4.16mmol)をN,N-ジメチルホルムアミド(10ml)に溶解させ、カルボニルジイミダゾール(743mg, 4.58mmol)を加えた。室温で一晩反応させた後、反応液を2mol/L 塩酸水溶液に注いだ。酢酸エチルで抽出した後、飽和炭酸水素ナトリウム、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させた。溶媒を留去し目的物である化合物70(897mg, 収率81%)を得た。
LCMS: 265.05 (M-1)
 第2工程
Figure JPOXMLDOC01-appb-C000135

 工程1で得た化合物70(200mg,0.751mmol)にPOCl3(3.5ml)を加え、120℃で4時間反応させた。一晩静置後、飽和炭酸水素ナトリウム水溶液に反応液を注ぎ、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、留去した。残渣をカラムクロマトグラフィーで精製することで目的物71(91.2mg, 収率43%)を得た。
LCMS: 284.80 (M+H)
 第3工程
Figure JPOXMLDOC01-appb-C000136

 工程2で得られた化合物71(91mg, 0.32mmol)を2-プロパノールに溶解させ、アミン塩酸塩(64mg, 0.32mmol)及びジイソプロピルエチルアミン(0.12ml, 0.71mmol)を加えた。マイクロウェーブ照射下180℃で30分反応させた。溶媒を留去後、残渣をカラムクロマトグラフィーで精製することで目的物である化合物72(127mg, 収率96%)を得た。
LCMS: 411.95 (M+H)
Example 19 Synthesis of Compound 72 (I-71) First Step
Figure JPOXMLDOC01-appb-C000134

Diamine 5 (1 g, 4.16 mmol) was dissolved in N, N-dimethylformamide (10 ml) and carbonyldiimidazole (743 mg, 4.58 mmol) was added. After reacting overnight at room temperature, the reaction solution was poured into a 2 mol / L aqueous hydrochloric acid solution. After extraction with ethyl acetate, the extract was washed with saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain the target compound 70 (897 mg, 81% yield).
LCMS: 265.05 (M-1)
Second step
Figure JPOXMLDOC01-appb-C000135

POCl3 (3.5 ml) was added to compound 70 (200 mg, 0.751 mmol) obtained in step 1 and reacted at 120 ° C. for 4 hours. After allowing to stand overnight, the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography to give the intended product 71 (91.2 mg, 43% yield).
LCMS: 284.80 (M + H)
Third step
Figure JPOXMLDOC01-appb-C000136

Compound 71 (91 mg, 0.32 mmol) obtained in Step 2 was dissolved in 2-propanol, and amine hydrochloride (64 mg, 0.32 mmol) and diisopropylethylamine (0.12 ml, 0.71 mmol) were added. The mixture was reacted at 180 ° C. for 30 minutes under microwave irradiation. After the solvent was distilled off, the residue was purified by column chromatography to obtain the intended compound 72 (127 mg, yield: 96%).
LCMS: 411.95 (M + H)
実施例20 化合物(I-72)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000137

 実施例化合物I-2の第1工程と同様の方法で反応を行い、化合物73を得た。
LCMS;322.80(M+H)
 第2工程
Figure JPOXMLDOC01-appb-C000138

 実施例化合物I-2の第2工程と同様の方法で反応を行い化合物74を得た。
1H-NMR (CDCl3) δ: 1.02 (3H, t, J = 7.1 Hz), 1.64-1.69 (2H, m), 2.91 (2H, t, J = 7.1 Hz), 7.27 (1H, s), 7.33 (1H, dd, J = 8.62, 1.27 Hz), 7.57 (1H, d, J = 8.62 Hz), 7.61 (1H, s), 7.82 (1H, dd, J = 5.07, 1.27 Hz), 7.94 (1H, t, J = 2.28 Hz), 8.46 (1H, d, J = 5.07 Hz).
 第3工程
Figure JPOXMLDOC01-appb-C000139

 工程2で得られた化合物74(620mg, 2.04mmol)をジクロロメタンに溶解させ、0℃に冷却しmCPBAを加えた。室温まで昇温し1時間反応させた。反応液を飽和炭酸水素ナトリウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。残渣をカラムクロマトグラフィーで精製し、目的物75(581mg, 収率53%)を得た。
LCMS;335.80 (M+H)
 第4工程
Figure JPOXMLDOC01-appb-C000140

 工程3で得られた化合物75(80mg, 0.24mmol)を2-プロパノールに溶解させ、ジメチルモルホリン(0.32ml, 0.262mmol)及びジイソプロピルアミン(0.083ml, 0.476mmol)を加えてマイクロウェーブ照射下150℃で1時間、さらに180℃で2時間反応させた。溶媒を留去し、残渣をカラムクロマトグラフィーで精製することで目的物76(70mg, 収率71%)を得た。
LCMS;415.00(M+H)
Example 20 Synthesis of Compound (I-72) First Step
Figure JPOXMLDOC01-appb-C000137

Reaction was carried out in the same manner as in Step 1 of Example Compound I-2 to give compound 73.
LCMS; 322.80 (M + H)
Second step
Figure JPOXMLDOC01-appb-C000138

Compound 74 was obtained by reacting in the same manner as in Step 2 of Example Compound I-2.
1 H-NMR (CDCl 3 ) δ: 1.02 (3H, t, J = 7.1 Hz), 1.64-1.69 (2H, m), 2.91 (2H, t, J = 7.1 Hz), 7.27 (1H, s), 7.33 (1H, dd, J = 8.62, 1.27 Hz), 7.57 (1H, d, J = 8.62 Hz), 7.61 (1H, s), 7.82 (1H, dd, J = 5.07, 1.27 Hz), 7.94 (1H , t, J = 2.28 Hz), 8.46 (1H, d, J = 5.07 Hz).
Third step
Figure JPOXMLDOC01-appb-C000139

Compound 74 (620 mg, 2.04 mmol) obtained in step 2 was dissolved in dichloromethane, cooled to 0 ° C., and mCPBA was added. The temperature was raised to room temperature and reacted for 1 hour. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by column chromatography to obtain the intended product 75 (581 mg, yield: 53%).
LCMS; 335.80 (M + H)
Fourth step
Figure JPOXMLDOC01-appb-C000140

Compound 75 (80 mg, 0.24 mmol) obtained in Step 3 was dissolved in 2-propanol, dimethylmorpholine (0.32 ml, 0.262 mmol) and diisopropylamine (0.083 ml, 0.476 mmol) were added, and the mixture was heated at 150 ° C. under microwave irradiation. For 1 hour and at 180 ° C. for 2 hours. The solvent was distilled off, and the residue was purified by column chromatography to obtain the desired product 76 (70 mg, 71% yield).
LCMS; 415.00 (M + H)
実施例21 化合物(I-73)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000141

 化合物75(250mg, 0.744mmol)をN,N-ジメチルホルムアミド(3ml)に溶解させ、0℃に冷却し、NaH(60% in oil, 38.7mg, 0.968mmol)を加え、メトキシメチルクロライド(0.074ml, 0.968mmol)を滴下した。0℃で4時間反応させ、水に反応液を注いだ。酢酸エチルで抽出し、有機層を水で洗浄した。無水硫酸マグネシウムで乾燥した後、溶媒を留去した。残渣をカラムクロマトグラフィーで精製し目的物77(175mg, 収率62%)を得た。
LCMS;379.85(M+H)
 第2工程
Figure JPOXMLDOC01-appb-C000142

 工程1で得られた化合物77(42mg, 0.11mmol)をジオキサンに溶解させ、フェニルボロン酸(13.6mg, 0.11mmol)、炭酸セシウム(54mg, 0.167mmol)及びPd(PPh3)4(12.9mg, 0.011mmol)を加え、マイクロウェーブ照射下150℃で30分反応させた。溶媒を留去し残渣をカラムクロマトグラフィーで精製することで目的物78(46.2mg, 収率98%)を得た。
LCMS;422.20(M+H)
 第3工程
Figure JPOXMLDOC01-appb-C000143

 工程2で得られた化合物78(46mg, 0.11mmol)に、2mol/L HClのメタノール溶液を加え60℃で7時間反応させた。2mol/L 水酸化ナトリウム水溶液で中和し、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をカラムクロマトグラフィーで精製し目的物79(11.1mg, 収率27%)を得た。
LCMS;377.95(M+H)
Example 21 Synthesis of Compound (I-73) First Step
Figure JPOXMLDOC01-appb-C000141

Compound 75 (250 mg, 0.744 mmol) was dissolved in N, N-dimethylformamide (3 ml), cooled to 0 ° C., NaH (60% in oil, 38.7 mg, 0.968 mmol) was added, and methoxymethyl chloride (0.074 ml) was added. , 0.968 mmol) was added dropwise. The mixture was reacted at 0 ° C. for 4 hours, and the reaction solution was poured into water. Extraction with ethyl acetate was performed, and the organic layer was washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by column chromatography to obtain the desired product 77 (175 mg, yield: 62%).
LCMS; 379.85 (M + H)
Second step
Figure JPOXMLDOC01-appb-C000142

Compound 77 (42 mg, 0.11 mmol) obtained in Step 1 was dissolved in dioxane, phenylboronic acid (13.6 mg, 0.11 mmol), cesium carbonate (54 mg, 0.167 mmol) and Pd (PPh3) 4 (12.9 mg, 0.011 mmol) was added and reacted at 150 ° C. for 30 minutes under microwave irradiation. The target product 78 (46.2 mg, 98% yield) was obtained by evaporating the solvent and purifying the residue by column chromatography.
LCMS; 422.20 (M + H)
Third step
Figure JPOXMLDOC01-appb-C000143

2 mol / L HCl in methanol was added to compound 78 (46 mg, 0.11 mmol) obtained in step 2 and reacted at 60 ° C. for 7 hours. The mixture was neutralized with 2 mol / L sodium hydroxide aqueous solution and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography to obtain the desired product 79 (11.1 mg, 27% yield).
LCMS; 377.95 (M + H)
実施例22 化合物(I-74)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000144

 トリフルオロエタノール(0.034ml, 0.446mmol)をNMPに溶解させ、NaH(60% in oil, 18.6mg, 0.446mmol)を加えた。これに対し、化合物77(59mg, 0.155mmol)のNMP(1ml)溶液を滴下し100℃で1日反応させた。反応液を水に注ぎ、ジエチルエーテルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、溶媒を留去した。残渣をカラムクロマトグラフィーで精製することで目的物80(25.7mg, 収率37%)を得た。
LCMS;443.95(M+H)
 第2工程
Figure JPOXMLDOC01-appb-C000145

 実施例化合物(I-73)の第3工程と同様に反応で化合物81(収率17%)を得た。
LCMS;399.90(M+H)
 I-77は同様の方法で合成を行った。
Example 22 Synthesis of Compound (I-74) First Step
Figure JPOXMLDOC01-appb-C000144

Trifluoroethanol (0.034 ml, 0.446 mmol) was dissolved in NMP, and NaH (60% in oil, 18.6 mg, 0.446 mmol) was added. On the other hand, an NMP (1 ml) solution of compound 77 (59 mg, 0.155 mmol) was added dropwise and reacted at 100 ° C. for 1 day. The reaction mixture was poured into water, extracted with diethyl ether, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by column chromatography to give the intended product 80 (25.7 mg, yield: 37%).
LCMS; 443.95 (M + H)
Second step
Figure JPOXMLDOC01-appb-C000145

Compound 81 (yield 17%) was obtained by reaction in the same manner as in Step 3 of Example compound (I-73).
LCMS; 399.90 (M + H)
I-77 was synthesized in the same manner.
実施例23 化合物86(I-78)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000146

 実施例化合物(I-1)の第1工程と同様の反応で、目的物82(収率93.3%)を得た。
LCMS;339.85(M+H)
 第2工程
Figure JPOXMLDOC01-appb-C000147

実施例化合物(I-1)の第2工程と同様の反応で目的物83(収率93%)を得た。
LCMS;321.85(M+H)
 第3工程
Figure JPOXMLDOC01-appb-C000148

実施例化合物(I-73)の第1工程と同様の反応で、目的物84(79%)を得た。
LCMS;365.85(M+H)
 第4工程
Figure JPOXMLDOC01-appb-C000149

 工程3で得られた化合物84(50mg, 0.137mmol)をN,N-ジメチルホルムアミド(2ml)に溶解させ、フェニルボロン酸(25mg, 0.205mmol)、Pd触媒(13.4mg, 0.021mmol)、炭酸カリウム(57mg, 0.41mmol)及び少量(1滴)の水を加え、マイクロウェーブ照射下120℃で30分反応させた。10%クエン酸に反応液を注ぎ、酢酸エチルで抽出した。飽和炭酸水素ナトリウム水溶液、続いて飽和食塩水で洗浄し無水硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をカラムクロマトグラフィーで精製し目的物85(43.2mg, 78%)を得た。
LCMS;407.95(M+H)
 第4工程
Figure JPOXMLDOC01-appb-C000150

 実施例化合物(I-73)の第4工程と同様の反応で、化合物86(収率87%)を得た。
LCMS;363.90(M+H)
Example 23 Synthesis of Compound 86 (I-78) First Step
Figure JPOXMLDOC01-appb-C000146

The target product 82 (yield 93.3%) was obtained by the same reaction as in the first step of Example compound (I-1).
LCMS; 339.85 (M + H)
Second step
Figure JPOXMLDOC01-appb-C000147

The target product 83 (yield 93%) was obtained by the same reaction as in the second step of Example compound (I-1).
LCMS; 321.85 (M + H)
Third step
Figure JPOXMLDOC01-appb-C000148

The target compound 84 (79%) was obtained by the same reaction as in the first step of Example compound (I-73).
LCMS; 365.85 (M + H)
4th process
Figure JPOXMLDOC01-appb-C000149

Compound 84 (50 mg, 0.137 mmol) obtained in Step 3 was dissolved in N, N-dimethylformamide (2 ml), phenylboronic acid (25 mg, 0.205 mmol), Pd catalyst (13.4 mg, 0.021 mmol), potassium carbonate (57 mg, 0.41 mmol) and a small amount (1 drop) of water were added and reacted at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was poured into 10% citric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution and then with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography to obtain the desired product 85 (43.2 mg, 78%).
LCMS; 407.95 (M + H)
Fourth step
Figure JPOXMLDOC01-appb-C000150

Compound 86 (yield 87%) was obtained by the same reaction as in the fourth step of Example compound (I-73).
LCMS; 363.90 (M + H)
実施例24 化合物(I-76)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000151

 実施例化合物(I-78)の第3工程で得られた化合物84(22mg, 0.06mmol)に、Pd2(dba)3(22mg, 0.06mmol)、Ru-phos(1.8mg, 0.0006mmol)、t-ブトキシナトリウム(17.3mg, 0.18mmol)をジオキサン及びアミン塩酸塩(10mg, 0.066mmol)を加え、マイクロウェーブ照射下100℃で30分、120℃で30分、さらに140℃で30分反応させた。溶媒を留去しカラムクロマトグラフィーで精製することで目的物87(12.1mg, 収率45%)を得た。
LCMS;451.00(M+H)
 第2工程
Figure JPOXMLDOC01-appb-C000152

 第1工程で得られた化合物を用い、実施例化合物(I-74)の第2工程と同様に反応で、目的物88(29%)を得た。
LCMS;406.95(M+H)
Example 24 Synthesis of Compound (I-76) First Step
Figure JPOXMLDOC01-appb-C000151

Compound 84 (22 mg, 0.06 mmol) obtained in the third step of Example compound (I-78) was added to Pd2 (dba) 3 (22 mg, 0.06 mmol), Ru-phos (1.8 mg, 0.0006 mmol), t -Butoxy sodium (17.3 mg, 0.18 mmol) was added with dioxane and amine hydrochloride (10 mg, 0.066 mmol) and reacted under microwave irradiation at 100 ° C. for 30 minutes, 120 ° C. for 30 minutes, and further at 140 ° C. for 30 minutes. . The target product 87 (12.1 mg, 45% yield) was obtained by distilling off the solvent and purifying by column chromatography.
LCMS; 451.00 (M + H)
Second step
Figure JPOXMLDOC01-appb-C000152

Using the compound obtained in the first step, the target product 88 (29%) was obtained in the same manner as in the second step of Example compound (I-74).
LCMS; 406.95 (M + H)
実施例25 化合物(I-79)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000153

 実施例化合物(I-74)の第1、2工程と同様の反応で、目的化合物89(収率44%)を得た。
LCMS;479.90(M+H)
Example 25 Synthesis of Compound (I-79) First Step
Figure JPOXMLDOC01-appb-C000153

The target compound 89 (44% yield) was obtained by the same reaction as in the 1st and 2nd steps of Example compound (I-74).
LCMS; 479.90 (M + H)
実施例26 化合物(I-80)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000154

 スルホニルクロライド90 (7g, 27.3mmol)をTHF(70ml)に溶解させた後、モルホリン(7.14ml, 82mmol)を加え、室温で20分間攪拌した。反応液に水と2mol/L 塩酸を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥後、溶媒を留去し、残渣をカラムクロマトグラフィーで精製し化合物91 (3.72g、収率44%)を得た。
1H-NMR (CDCl3) δ: 3.08 (4H, dd, J = 5.57, 3.89 Hz), 3.78 (4H, t, J = 4.73 Hz), 7.77 (1H, d, J = 8.39 Hz), 7.88 (1H, dd, J = 8.39, 1.98 Hz), 8.24 (1H, d, J = 1.98 Hz).
 第2工程
Figure JPOXMLDOC01-appb-C000155

 第1工程で得られた化合物91 (3.6g, 11.8mmol)をアセトニトリル(36ml)に溶解させ、トリエチルアミン(1.96ml, 14.1mmol)及びベンジルアミン(2.13ml, 14.12mmol)を加え、65℃で3時間攪拌した。さらにトリエチルアミン(0.98ml, 7.06mmol)及びベンジルアミン(1.07ml, 7.06mmol)を加え3時間攪拌した。反応液に水を加え、生じた固体を濾取し水で洗い、化合物92 (4.86g、収率94%)を得た。
1H-NMR (CDCl3) δ: 3.07 (4H, dd, J = 5.54, 3.94 Hz), 3.79 (4H, dd, J = 10.41, 5.54 Hz), 3.95 (6H, s), 4.57 (2H, d, J = 5.37 Hz), 6.89-6.96 (3H, m), 7.01 (1H, d, J = 9.40 Hz), 7.76 (1H, dd, J = 9.40, 2.18 Hz), 8.65 (1H, d, J = 2.18 Hz), 8.72 (1H, dd, J = 7.39, 3.53 Hz).
 第3工程
Figure JPOXMLDOC01-appb-C000156

 第2工程で得られた化合物92 (3.26g, 7.45mmol)をテトラヒドロフラン(150ml)及びエタノール(45ml)に溶解させ、パラジウムカーボン(0.3g)を加え水素雰囲気下で3.5時間反応を行った。不溶物を濾過し、ろ液を濃縮することで目的物93(560mg, 収率18%)を得た。
1H-NMR (CDCl3) δ: 2.97-2.98 (4H, m), 3.73-3.75 (4H, m), 3.9 (6H, s), 4.22 (1H, br s), 4.32 (2H, d, J = 5.19 Hz), 6.70 (1H, d, J = 8.39 Hz), 6.88-6.93 (3H, m), 7.10 (1H, d, J = 2.53 Hz), 7.23 (1H, dd, J = 8.39, 2.53 Hz).
 第4工程
Figure JPOXMLDOC01-appb-C000157

 第3工程で得られたアニリン体93(560mg, 1.37mmol)を塩化メチレンに溶解させ、トリエチルアミン(0.46ml, 3.3mmol)及びトリホスゲン(163mg, 0,55mmol)を0℃で加えた。3日間攪拌し、反応液に水と飽和炭酸水素ナトリウム水溶液を加えた。酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥後、溶媒を留去した。残渣をカラムクロマトグラフィーで精製し目的物94(169mg, 収率28%)を得た。
LCMS;434.00(M+H)
 第5工程
Figure JPOXMLDOC01-appb-C000158

 第4工程で得られた化合物94(1.3g, 3.0mmol)にオキシ塩化リン(13ml)を室温で滴下し、混合物を120℃で5時間反応させた。水(0.108ml, 6mmol)を加え、120℃で2時間攪拌した後、反応液に氷水を加え、クロロホルムで抽出した。有機層は無水硫酸マグネシウムで乾燥した後、減圧下留去した。残渣を塩化メチレンとヘキサンの混合溶媒で洗い目的物95(275mg, 収率30%)を得た。 
LCMS;301.85(M)
 第6工程
Figure JPOXMLDOC01-appb-C000159

 第5工程で得られた化合物95(60mg, 0.2mmol)にジオキサン(2ml)を加えた後、ボロン酸(47mg, 0.239mmol)、炭酸セシウム(97mg)及びPd(PPh3)4(12mg, 0.239mmol)を加え、マイクロウェーブ照射下200℃で30分反応させた。溶媒を留去し、カラムクロマトグラフィーで精製することで、目的物96(66mg, 収率79%)を得た。
1H-NMR (DMSO-d6) δ: 2.90 (4H, t, J = 4.31 Hz), 3.64 (4H, t, J = 4.31 Hz), 7.43 (1H, t, J = 7.35 Hz), 7.52 (2H, t, J = 7.35 Hz), 7.59 (1H, dd, J = 8.36, 1.27 Hz), 7.80 (2H, t, J = 4.31 Hz), 7.85 (1H, bs), 7.93 (2H, d, J = 8.11 Hz), 7.95(bs, 1H), 8.32 (2H, d, J = 8.11 Hz).
Example 26 Synthesis of Compound (I-80) First Step
Figure JPOXMLDOC01-appb-C000154

After sulfonyl chloride 90 (7 g, 27.3 mmol) was dissolved in THF (70 ml), morpholine (7.14 ml, 82 mmol) was added and stirred at room temperature for 20 minutes. Water and 2 mol / L hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated, and the residue was purified by column chromatography to give compound 91 (3.72 g, yield 44%).
1 H-NMR (CDCl 3 ) δ: 3.08 (4H, dd, J = 5.57, 3.89 Hz), 3.78 (4H, t, J = 4.73 Hz), 7.77 (1H, d, J = 8.39 Hz), 7.88 ( 1H, dd, J = 8.39, 1.98 Hz), 8.24 (1H, d, J = 1.98 Hz).
Second step
Figure JPOXMLDOC01-appb-C000155

Compound 91 (3.6 g, 11.8 mmol) obtained in the first step was dissolved in acetonitrile (36 ml), and triethylamine (1.96 ml, 14.1 mmol) and benzylamine (2.13 ml, 14.12 mmol) were added. Stir for hours. Further, triethylamine (0.98 ml, 7.06 mmol) and benzylamine (1.07 ml, 7.06 mmol) were added and stirred for 3 hours. Water was added to the reaction mixture, and the resulting solid was collected by filtration and washed with water to obtain Compound 92 (4.86 g, yield 94%).
1 H-NMR (CDCl 3 ) δ: 3.07 (4H, dd, J = 5.54, 3.94 Hz), 3.79 (4H, dd, J = 10.41, 5.54 Hz), 3.95 (6H, s), 4.57 (2H, d , J = 5.37 Hz), 6.89-6.96 (3H, m), 7.01 (1H, d, J = 9.40 Hz), 7.76 (1H, dd, J = 9.40, 2.18 Hz), 8.65 (1H, d, J = 2.18 Hz), 8.72 (1H, dd, J = 7.39, 3.53 Hz).
Third step
Figure JPOXMLDOC01-appb-C000156

Compound 92 (3.26 g, 7.45 mmol) obtained in the second step was dissolved in tetrahydrofuran (150 ml) and ethanol (45 ml), palladium carbon (0.3 g) was added, and the reaction was performed in a hydrogen atmosphere for 3.5 hours. The insoluble material was filtered off, and the filtrate was concentrated to give the intended product 93 (560 mg, yield 18%).
1 H-NMR (CDCl 3 ) δ: 2.97-2.98 (4H, m), 3.73-3.75 (4H, m), 3.9 (6H, s), 4.22 (1H, br s), 4.32 (2H, d, J = 5.19 Hz), 6.70 (1H, d, J = 8.39 Hz), 6.88-6.93 (3H, m), 7.10 (1H, d, J = 2.53 Hz), 7.23 (1H, dd, J = 8.39, 2.53 Hz ).
Fourth step
Figure JPOXMLDOC01-appb-C000157

The aniline compound 93 (560 mg, 1.37 mmol) obtained in the third step was dissolved in methylene chloride, and triethylamine (0.46 ml, 3.3 mmol) and triphosgene (163 mg, 0,55 mmol) were added at 0 ° C. The mixture was stirred for 3 days, and water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution. After extraction with ethyl acetate and drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by column chromatography to obtain the desired product 94 (169 mg, 28% yield).
LCMS; 434.00 (M + H)
5th process
Figure JPOXMLDOC01-appb-C000158

Phosphorous oxychloride (13 ml) was added dropwise at room temperature to compound 94 (1.3 g, 3.0 mmol) obtained in the fourth step, and the mixture was reacted at 120 ° C. for 5 hours. Water (0.108 ml, 6 mmol) was added, and the mixture was stirred at 120 ° C. for 2 hr. Ice water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. The residue was washed with a mixed solvent of methylene chloride and hexane to obtain the desired product 95 (275 mg, yield 30%).
LCMS; 301.85 (M)
6th process
Figure JPOXMLDOC01-appb-C000159

After adding dioxane (2 ml) to compound 95 (60 mg, 0.2 mmol) obtained in the fifth step, boronic acid (47 mg, 0.239 mmol), cesium carbonate (97 mg) and Pd (PPh3) 4 (12 mg, 0.239 mmol) ) Was added and reacted at 200 ° C. for 30 minutes under microwave irradiation. The solvent was distilled off and the residue was purified by column chromatography to obtain the desired product 96 (66 mg, yield 79%).
1 H-NMR (DMSO-d 6 ) δ: 2.90 (4H, t, J = 4.31 Hz), 3.64 (4H, t, J = 4.31 Hz), 7.43 (1H, t, J = 7.35 Hz), 7.52 ( 2H, t, J = 7.35 Hz), 7.59 (1H, dd, J = 8.36, 1.27 Hz), 7.80 (2H, t, J = 4.31 Hz), 7.85 (1H, bs), 7.93 (2H, d, J = 8.11 Hz), 7.95 (bs, 1H), 8.32 (2H, d, J = 8.11 Hz).
実施例27 化合物(I-93)の合成
 第1工程
Figure JPOXMLDOC01-appb-C000160

 ブロマイド58(1g, 2.79mmol)にジオキサン(10ml)を加えた後、Pd2(dba)3(256mg, 0.279mmol)、ジイソプロピルエチルアミン(1.46ml, 8.37mmol)、Xantphos(323mg, 0.558 mmol)及び4―メトキシベンジルチオール(0.389mmol, 2.79mmol)を加え、マイクロウェーブ照射下、120℃で1時間反応を行った。反応液をセライト濾過し、ろ液を留去した。残渣をシリカゲルクロマトグラフィにより精製しチオール付加物を得た。これをTFA(2ml)に溶解させマイクロウェーブ照射下100℃で30分反応させた。TFAを減圧下留去し、残渣をカラムクロマトグラフィーで精製し化合物97(310mg, 収率35%)を得た。
LCMS;312.05(M+H)
 第2工程
Figure JPOXMLDOC01-appb-C000161

 第1工程で得られたチオール体97(50mg, 0.161mmol)をN,N-ジメチルホルムアミド(2ml)に溶解させた後、炭酸セシウム(52.3mg, 0.161mmol)とヨウ素体(0.019ml, 0.161mmol)を加え室温で1時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を2回水洗し、無水硫酸マグネシウムで乾燥後、溶媒を留去し、残渣をカラムクロマトグラフィーで精製することで化合物98 (38.4mg、収率58%)を得た。
LCMS;407.95(M)
 第3工程
Figure JPOXMLDOC01-appb-C000162

 第2工程で得られたスルフィド体98 (38mg, 0.093mmol)を塩化メチレン(2ml)に溶解させた後、mCPBA(52mg, 0.205mmol)を0℃で加え、室温で1時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで2回抽出した。有機層を2回水洗し、無水硫酸マグネシウムで乾燥後、溶媒を留去した。残渣をカラムクロマトグラフィーで精製し化合物99 (27mg、収率66%)を得た。
LCMS;440.95(M+H)
Example 27 Synthesis of Compound (I-93) First Step
Figure JPOXMLDOC01-appb-C000160

Dioxane (10 ml) was added to bromide 58 (1 g, 2.79 mmol) followed by Pd2 (dba) 3 (256 mg, 0.279 mmol), diisopropylethylamine (1.46 ml, 8.37 mmol), Xantphos (323 mg, 0.558 mmol) and 4- Methoxybenzylthiol (0.389 mmol, 2.79 mmol) was added, and the reaction was performed at 120 ° C. for 1 hour under microwave irradiation. The reaction solution was filtered through Celite, and the filtrate was distilled off. The residue was purified by silica gel chromatography to obtain a thiol adduct. This was dissolved in TFA (2 ml) and reacted at 100 ° C. for 30 minutes under microwave irradiation. TFA was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain Compound 97 (310 mg, yield 35%).
LCMS; 312.05 (M + H)
Second step
Figure JPOXMLDOC01-appb-C000161

The thiol compound 97 (50 mg, 0.161 mmol) obtained in the first step was dissolved in N, N-dimethylformamide (2 ml), then cesium carbonate (52.3 mg, 0.161 mmol) and iodine compound (0.019 ml, 0.161 mmol). ) Was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by column chromatography to give compound 98 (38.4 mg, yield 58%).
LCMS; 407.95 (M)
Third step
Figure JPOXMLDOC01-appb-C000162

The sulfide compound 98 (38 mg, 0.093 mmol) obtained in the second step was dissolved in methylene chloride (2 ml), mCPBA (52 mg, 0.205 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic layer was washed twice with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography to obtain compound 99 (27 mg, 66% yield).
LCMS; 440.95 (M + H)
 上記実施例に従い、以下の化合物を合成した。なお、表中のRacはラセミ体を意味し、Absは光学活性体を意味する。構造式中のCyは、シクロヘキシルである。 The following compounds were synthesized according to the above examples. In the table, Rac means a racemate, and Abs means an optically active substance. Cy in the structural formula is cyclohexyl.
Figure JPOXMLDOC01-appb-T000163
Figure JPOXMLDOC01-appb-T000163
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000165
Figure JPOXMLDOC01-appb-T000165
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000173
Figure JPOXMLDOC01-appb-T000173
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000183
 本発明化合物である、式(I):
Figure JPOXMLDOC01-appb-C000184

で示される化合物における各置換基について、以下に例示する。
The compound of the present invention, formula (I):
Figure JPOXMLDOC01-appb-C000184

Examples of each substituent in the compound represented by the formula:
 本発明化合物におけるY、Y、Y、Zの組合せの例としては、以下の表22及び23に記載の組合せを挙げることができる。 Examples of combinations of Y 1 , Y 2 , Y 3 , and Z in the compounds of the present invention include the combinations described in Tables 22 and 23 below.
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000186
 本発明化合物におけるR、Xの組合せの例としては、以下の表24及び25に記載の組合せを挙げることができる。 Examples of combinations of R 2 and X in the compounds of the present invention include the combinations described in Tables 24 and 25 below.
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000188
Figure JPOXMLDOC01-appb-T000188
 本発明化合物におけるRの例としては、以下の表26に記載の例を挙げることができる。なお、表中の(VI)~(XVIII)は、式(VI)~(XVIII)で示される化合物のRに該当する基と同じ基を意味する。 Examples of R 4 in the compound of the present invention include the examples described in Table 26 below. In the table, (VI) to (XVIII) mean the same groups as those corresponding to R 4 of the compounds represented by formulas (VI) to (XVIII).
Figure JPOXMLDOC01-appb-T000189
Figure JPOXMLDOC01-appb-T000189
 本発明化合物におけるRの例としては、以下の表27に記載の組合せを挙げることができる。 Examples of R 5 in the compound of the present invention include combinations described in Table 27 below.
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000190
本発明化合物におけるR11の例としては、以下の表28に記載の組合せを挙げることができる。 Examples of R 11 in the compound of the present invention include combinations described in Table 28 below.
Figure JPOXMLDOC01-appb-T000191
Figure JPOXMLDOC01-appb-T000191
本発明化合物におけるR12の例としては、以下の表29に記載の組合せを挙げることができる。 Examples of R 12 in the compound of the present invention include the combinations described in Table 29 below.
Figure JPOXMLDOC01-appb-T000192
Figure JPOXMLDOC01-appb-T000192
 上記A群、B群、C群、D群、E群、F群から任意に選択した組み合わせによりできる個々の化合物もすべて本発明に含まれる。 All the individual compounds formed by combinations arbitrarily selected from the above-mentioned groups A, B, C, D, E, and F are also included in the present invention.
以下に、本発明化合物の生物試験例を記載する。
試験例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30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-T000193
Hereinafter, biological test examples of the compound of the present invention will be described.
Test Example 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 30.
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-T000193
試験例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 2 Affinity for human NPY Y5 receptor A cDNA sequence encoding human NPY Y5 receptor (see WO96 / 16542) was expressed in expression vector pME18S (Takebe et al. Mol. Cell. Biol. 8, 466-472). Cloning into 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3 ラット脳移行性評価
 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)への静脈内投与(0.5mg/mL/kg)30分後の血漿及び脳内濃度から、脳移行性(脳/血漿分配係数;Kp)を評価した。
 その結果、本発明化合物は、良好な脳移行性を示した。例えば、化合物I-82は脳Kp:0.49であった。
Test Example 3 Rat Brain Migration Evaluation Intravenous to rats (Crl; CD (SD), ♂, 8weeks) using the cassette dosing method (Drug. Metab. Dispos. (2001); see 29, 957-966) From the plasma and brain concentration 30 minutes after administration (0.5 mg / mL / kg), brain transferability (brain / plasma partition coefficient; Kp) was evaluated.
As a result, the compound of the present invention showed good brain migration. For example, Compound I-82 had a brain Kp: 0.49.
試験例4 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、マウス(Jcl;C57BL/6J, ♂, 8weeks)への経口投与(2mg/10mL/kg)3時間又は5時間後の血漿及び脳内濃度から、脳移行性(脳/血漿分配係数;Kp)を評価することができる。
Test Example 4 Evaluation of transferability to mouse brain Oral administration to mice (Jcl; C57BL / 6J, ♂, 8weeks) using a cassette dosing method (Drug. Metab. Dispos. (2001); see 29, 957-966) 2 mg / 10 mL / kg) From the plasma and brain concentrations after 3 or 5 hours, the brain transferability (brain / plasma partition coefficient; Kp) can be evaluated.
試験例5 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)及び全身クリアランス(CLtot)を評価した。その結果、本発明化合物は、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した。
Test Example 5 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. As a result, the compound of the present invention showed good pharmacokinetics such as high bioavailability and appropriate clearance.
試験例6 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及び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-T000194
Test Example 6 Inhibition of cAMP production in CHO cells CHO cells expressing human NPY Y5 receptor were incubated at 37 ° C. for 20 minutes in the presence of 2.5 mM isobutylmethylxanthine (SIGMA), and then the compound 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-T000194
試験例7 NPY Y5受容体選択性
 Y1発現細胞(human neuroblastoma, SK-N-MC)膜標品及び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受容体及び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 7 NPY Y5 Receptor Selectivity Test Examples 1-2 and Y1-expressing cells (human neuroblastoma, SK-N-MC) membrane preparation and Y2-expressing cells (human neuroblastoma, SMS-KAN) membrane preparation 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 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8 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時間後及び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25mg/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I-50 25mg/kgの用量で投与した群(A群)の注入2時間後及び4時間後の摂食量はそれぞれ0.28±0.04g、0.45±0.09g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時間後及び4時間後の摂食量はそれぞれ0.63±0.06g、1.22±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±0.07g、0.17±0.06g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時間後及び4時間後のB群に対する摂食抑制率はそれぞれ65.9%、74.2%になる。
Test Example 8 Feeding Inhibitory Action Under ether anesthesia, skin was incised along the midline from the outer 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 the mice was measured 2 hours and 4 hours after the injection, and the difference in food intake between the 0.5% hydroxypropylmethylcellulose solution administration group and the test substance administration group was investigated.
As a result, when the compound of the present invention was administered at a dose of 25 mg / kg, the amount of food intake was significantly suppressed as compared with the case where 0.5% hydroxypropylmethylcellulose was administered.
For example, in the group administered with Compound I-50 at a dose of 25 mg / kg (Group A), the food intake after 2 hours and 4 hours after injection was 0.28 ± 0.04 g and 0.45 ± 0.09 g, respectively. . On the other hand, the amount of food intake 2 hours and 4 hours after injection in the 0.5% hydroxypropylmethylcellulose solution administration group (Group B) was 0.63 ± 0.06 g and 1.22 ± 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 ± 0.07 g, 0.17 ± 0.06 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 2 hours and 4 hours after the injection in the A group are 65.9% and 74.2%, respectively.
試験例9 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 9 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of major human 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I-18:5種 >20μM
化合物I-20:5種 >20μM
化合物I-59:5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 I-18: 5 species> 20 μM
Compound I-20: 5 species> 20 μM
Compound I-59: 5 species> 20 μM
試験例10 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)及び各化合物(終濃度2μM)を添加し、37℃で0分及び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分及び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I-5:98.6%
化合物I-12:96.6%
化合物I-22:92.7%
化合物I-49:96.0%
化合物I-78:88.8%
Test Example 10 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 I-5: 98.6%
Compound I-12: 96.6%
Compound I-22: 92.7%
Compound I-49: 96.0%
Compound I-78: 88.8%
試験例11 粉末溶解度試験
 適当な容器に検体を適量入れ、JP-1液(塩化ナトリウム2.0g、塩酸7.0mLに水を加えて1000mLとした)、JP-2液(pH6.8のリン酸塩緩衝液500mLに水500mLを加えた)、20mmol/L TCA(タウロコール酸ナトリウム)/JP-2液(TCA 1.08gに水を加え100mLとした)を200μLずつ添加した。試験液添加後に溶解した場合には、適宜原末を追加した。密閉し37℃で1時間振とうした。濾過し、各濾液100μLにメタノール100μLを添加して2倍希釈を行った。希釈倍率は、必要に応じて変更した。気泡及び析出物がないかを確認し、密閉して振とうした。絶対検量線法によりHPLCを用いて定量を行った。
 例えば、化合物I-15の結果は以下のとおりである。
JP-1液;555μg/mL,
JP-2液:60.9μg/mL 
TCA/JP-2液:60.0μg/mL
Test Example 11 Powder Solubility Test An appropriate amount of a specimen is placed in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid is added to make 1000 mL), JP-2 solution (pH 6.8 of phosphorus) 200 mL of water was added to 500 mL of an acid buffer, and 20 mmol / L TCA (sodium taurocholate) / JP-2 solution (1.08 g of TCA was added with water to make 100 mL). When dissolved after adding the test solution, a bulk powder was added as appropriate. Sealed and shaken at 37 ° C. for 1 hour. After filtration, 100 μL of methanol was added to 100 μL of each filtrate to perform 2-fold dilution. The dilution factor was changed as necessary. After confirming that there were no bubbles and precipitates, the mixture was sealed and shaken. Quantification was performed using HPLC by the absolute calibration curve method.
For example, the results of Compound I-15 are as follows.
JP-1 solution; 555 μg / mL,
JP-2 solution: 60.9 μg / mL
TCA / JP-2 solution: 60.0 μg / mL
 試験例12 CYP3A4蛍光MBI試験
 CYP3A4蛍光MBI試験は、代謝反応による化合物のCYP3A4阻害の増強を調べる試験であり、酵素に大腸菌発現CYP3A4を用いて、7-ベンジルオキシトリフルオロメチルクマリン(7-BFC)がCYP3A4酵素により脱ベンジル化し、蛍光を発する代謝物7-ハイドロキシトリフルオロメチルクマリン(HFC)を生成する反応を指標として行った。
Test Example 12 CYP3A4 Fluorescence MBI Test The CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of a compound by metabolic reaction, using 7-benzyloxytrifluoromethylcoumarin (7-BFC) using E. coli-expressed CYP3A4 as an enzyme. Was subjected to debenzylation with CYP3A4 enzyme to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (HFC) as an indicator.
 反応条件は以下のとおり:基質、5.6μmol/L 7-BFC;プレ反応時間、0または30分;反応時間、15分;反応温度、25℃(室温);CYP3A4含量(大腸菌発現酵素)、プレ反応時62.5pmol/mL,反応時6.25pmol/mL(10倍希釈時);被検薬物濃度、0.625、1.25、2.5、5、10、20μmol/L(6点)。 The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); test drug concentration, 0.625, 1.25, 2.5, 5, 10, 20 μmol / L (6 points) ).
 96穴プレートにプレ反応液としてK-Pi緩衝液(pH7.4)中に酵素、被検薬物溶液を上記のプレ反応の組成で加え、別の96穴プレートに基質とK-Pi緩衝液で1/10希釈されるようにその一部を移行し、補酵素であるNADPHを添加して指標とする反応を開始し(プレ反応無)、所定の時間反応後、アセトニトリル/0.5mol/L Tris(トリスヒドロキシアミノメタン)=4/1を加えることによって反応を停止させた。また残りのプレ反応液にもNADPHを添加しプレ反応を開始し(プレ反応有)、所定時間プレ反応後、別のプレートに基質とK-Pi緩衝液で1/10希釈されるように一部を移行し指標とする反応を開始させた。所定の時間反応後、アセトニトリル/0.5mol/L Tris(トリスヒドロキシアミノメタン)=4/1を加えることによって反応を停止させた。それぞれの指標反応を行ったプレートを蛍光プレートリーダーで代謝物である7-HFCの蛍光値を測定した。(Ex=420nm、Em=535nm) Enzyme and test drug solution are added to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) with the above pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate. A part of the solution was transferred so that it was diluted to 1/10, and the reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction). After reaction for a predetermined time, acetonitrile / 0.5 mol / L The reaction was stopped by adding Tris (trishydroxyaminomethane) = 4/1. In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction exists). The reaction was started by moving the part. After the reaction for a predetermined time, the reaction was stopped by adding acetonitrile / 0.5 mol / L Tris (trishydroxyaminomethane) = 4/1. The fluorescence value of 7-HFC, which is a metabolite, was measured using a fluorescent plate reader on the plate on which each index reaction was performed. (Ex = 420nm, Em = 535nm)
 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。IC50値の差が5μM以上の場合を(+)とし、3μM以下の場合を(-)とした。
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 case where the difference in IC 50 values was 5 μM or more was designated as (+), and the case where it was 3 μM or less was designated as (−).
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又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 form a powder as a powder or fine particles. 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.

Claims (21)

  1. 式(I):
    Figure JPOXMLDOC01-appb-C000001

    (式中、
    Xは-SO-または-N(-R)-SO-であり、
    は=C(-R)-または=N-であり、
    は-C(-R)=または-N=であり、
    は=C(-R)-または=N-であり、
    Zは-C(-R)=または-N=であり、
    、R、R、R、R11及びR12はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
    10は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
    は置換もしくは非置換の炭素数2~10のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルであり、
    は置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基であり、
    は置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基であり、
    nは1であり、
    は水素または置換もしくは非置換のアルキルであり、またはRはRと共に隣接する窒素原子と一緒になって置換もしくは非置換の複素環を形成していてもよい。上記の置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換の非芳香族複素環式基は、1または2個のオキソ、チオキソまたは置換もしくは非置換のイミノで置換されていてもよい。ただし、Xが-SO-であり、Yが=C(-H)-であり、Yが-C(-H)=であり、Yが=C(-H)-であり、Zが-N=であり、Rがシクロプロピルであり、R11及びR12が水素であり、Rがフェニルであり、nが1であり、かつRが2-フルオロフェニルである場合、及び、Xが-N(-Et)-SO-であり、Yが=C(-H)-であり、Yが-C(-H)=であり、Yが=C(-H)-であり、Zが-N=であり、Rがエチルであり、R11がアミノであり、R12が水素であり、Rがピペリジン-4-イルであり、nが1であり、かつRが7H-ピロロ[2,3-d]-ピリミジン-4-イルである場合を除く。)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。
    Formula (I):
    Figure JPOXMLDOC01-appb-C000001

    (Where
    X is —SO 2 — or —N (—R 6 ) —SO 2 —,
    Y 1 is ═C (—R 8 ) — or ═N—,
    Y 2 is —C (—R 3 ) ═ or —N═,
    Y 3 is ═C (—R 1 ) — or ═N—,
    Z is —C (—R 9 ) ═ or —N═,
    R 1 , R 3 , R 8 , R 9 , R 11 and R 12 are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by the formula: —O—R 10 , formula: A group represented by —O—C (═O) —R 10 , represented by the formula: —C (═O) —R 10 A group represented by the formula: —C (═O) —O—R 10 , a group represented by the formula: —S—R 10 , a group represented by the formula: —SO 2 —R 10 or a formula: A group represented by O—SO 2 —R 10 ;
    R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
    R 2 is substituted or unsubstituted alkyl having 2 to 10 carbon atoms, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
    R 4 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group,
    R 5 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group,
    n is 1,
    R 6 is hydrogen or substituted or unsubstituted alkyl, or R 6 together with the adjacent nitrogen atom together with R 2 may form a substituted or unsubstituted heterocycle. The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group is substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino It may be. However, X is —SO 2 —, Y 1 is ═C (—H) —, Y 2 is —C (—H) =, and Y 3 is ═C (—H) —, When Z is —N═, R 2 is cyclopropyl, R 11 and R 12 are hydrogen, R 4 is phenyl, n is 1, and R 5 is 2-fluorophenyl , And X is —N (—Et) —SO 2 —, Y 1 is ═C (—H) —, Y 2 is —C (—H) =, and Y 3 is ═C ( -H)-, Z is -N =, R 2 is ethyl, R 11 is amino, R 12 is hydrogen, R 4 is piperidin-4-yl, and n is 1 And R 5 is 7H-pyrrolo [2,3-d] -pyrimidin-4-yl. ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
  2. 式(I):
    Figure JPOXMLDOC01-appb-C000002

    (式中、
    Xは-SO-または-N(-R)-SO-であり、
    は=C(-R)-または=N-であり、
    は-C(-R)=または-N=であり、
    は=C(-R)-または=N-であり、
    Zは-C(-R)=または-N=であり、
    、R、R、R、R11及びR12はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
    10は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
    は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルであり、
    は置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基であり、
    は置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基であり、
    nは1であり、
    ただし、Rが置換もしくは非置換のフェニルまたは置換もしくは非置換の6員単環ヘテロアリールである場合、Rは該フェニルまたは6員単環ヘテロアリールのメタ位に置換している、
    は水素または置換もしくは非置換のアルキルであり、またはRはRと共に隣接する窒素原子と一緒になって置換もしくは非置換の複素環を形成していてもよい。上記の置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換の非芳香族複素環式基は、1または2個のオキソ、チオキソまたは置換もしくは非置換のイミノで置換されていてもよい。ただし、Xが-N(-Et)-SO-であり、Yが=C(-H)-であり、Yが-C(-H)=であり、Yが=C(-H)-であり、Zが-N=であり、Rがエチルであり、R11がアミノであり、R12が水素であり、Rがピペリジン-4-イルであり、nが1であり、かつRが7H-ピロロ[2,3-d]-ピリミジン-4-イルである場合を除く。)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。
    Formula (I):
    Figure JPOXMLDOC01-appb-C000002

    (Where
    X is —SO 2 — or —N (—R 6 ) —SO 2 —,
    Y 1 is ═C (—R 8 ) — or ═N—,
    Y 2 is —C (—R 3 ) ═ or —N═,
    Y 3 is ═C (—R 1 ) — or ═N—,
    Z is —C (—R 9 ) ═ or —N═,
    R 1 , R 3 , R 8 , R 9 , R 11 and R 12 are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by the formula: —O—R 10 , formula: A group represented by —O—C (═O) —R 10 , represented by the formula: —C (═O) —R 10 A group represented by the formula: —C (═O) —O—R 10 , a group represented by the formula: —S—R 10 , a group represented by the formula: —SO 2 —R 10 or a formula: A group represented by O—SO 2 —R 10 ;
    R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
    R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
    R 4 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group,
    R 5 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or a substituted or unsubstituted non-aromatic heterocyclic group,
    n is 1,
    Provided that when R 4 is substituted or unsubstituted phenyl or substituted or unsubstituted 6-membered monocyclic heteroaryl, R 5 is substituted at the meta position of the phenyl or 6-membered monocyclic heteroaryl.
    R 6 is hydrogen or substituted or unsubstituted alkyl, or R 6 together with the adjacent nitrogen atom together with R 2 may form a substituted or unsubstituted heterocycle. The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group is substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino It may be. However, X is —N (—Et) —SO 2 —, Y 1 is ═C (—H) —, Y 2 is —C (—H) =, and Y 3 is ═C (— H) —, Z is —N═, R 2 is ethyl, R 11 is amino, R 12 is hydrogen, R 4 is piperidin-4-yl, and n is 1. Except when R 5 is 7H-pyrrolo [2,3-d] -pyrimidin-4-yl. ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
  3. が置換もしくは非置換の非芳香族複素環式基である、請求項1または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 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 4 is a substituted or unsubstituted non-aromatic heterocyclic group.
  4. が置換もしくは非置換のフェニルであり、かつRが該フェニルのメタ位に置換している、請求項1または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 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 4 is substituted or unsubstituted phenyl, and R 5 is substituted at the meta position of the phenyl. .
  5. が置換もしくは非置換の5員単環ヘテロアリールである、請求項1または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 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 4 is substituted or unsubstituted 5-membered monocyclic heteroaryl.
  6. が置換もしくは非置換の6員単環ヘテロアリールであり、かつRが該ヘテロアリールのメタ位に置換している、請求項1または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 1 or 2, a pharmaceutically acceptable salt thereof, wherein R 4 is a substituted or unsubstituted 6-membered monocyclic heteroaryl, and R 5 is substituted at the meta position of the heteroaryl. Or a solvate thereof.
  7. が置換もしくは非置換の非芳香族複素環式基である、請求項1または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 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 5 is a substituted or unsubstituted non-aromatic heterocyclic group.
  8. Xが-SO-である、請求項1~7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 1 to 7, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein X is -SO 2- .
  9. が置換もしくは非置換の炭素数2~10のアルキルである、請求項8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. The compound according to claim 8, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 2 is substituted or unsubstituted alkyl having 2 to 10 carbon atoms.
  10. Xが-N(-R)-SO-であり、RがRと共に隣接する窒素原子と一緒になって置換もしくは非置換の複素環を形成している、請求項1~7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。 X is -N (-R 6 ) -SO 2- , and R 6 together with the adjacent nitrogen atom together with R 2 forms a substituted or unsubstituted heterocycle. The compound according to any one of the above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  11. が=C(-R)-であり、Yが-C(-R)=であり、かつYが=C(-R)-である、請求項1~10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。 11. The method according to claim 1, wherein Y 1 is ═C (—R 8 ) —, Y 2 is —C (—R 3 ) =, and Y 3 is ═C (—R 1 ) —. Or a pharmaceutically acceptable salt or solvate thereof.
  12. Zが-N=である、請求項1~11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 1 to 11, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Z is -N =.
  13. 請求項1~12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含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  14. 請求項1~12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含有する、NPY Y5受容体拮抗作用を有する医薬組成物。 A pharmaceutical composition having an NPY Y5 receptor antagonistic action, comprising the compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  15. 式(I):
    Figure JPOXMLDOC01-appb-C000003

    (式中、
    Xは-SO-、-N(-R)-SO-または-SO-N(-R)-であり、
    は=C(-R)-または=N-であり、
    は-C(-R)=または-N=であり、
    は=C(-R)-または=N-であり、
    Zは-C(-R)=または-N=であり、
    、R、R、R、R11及びR12はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
    10は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミジノであり、
    は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルであり、
    は置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基であり、
    はハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換もしくは非置換のアミノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミジノ、式:-O-R10で示される基、式:-O-C(=O)-R10で示される基、式:-C(=O)-R10で示される基、式:-C(=O)-O-R10で示される基、式:-S-R10で示される基、式:-SO-R10で示される基または式:-O-SO-R10で示される基であり、
    nは0または1であり、
    及びRは水素または置換もしくは非置換のアルキルであり、またはRはRと共に隣接する窒素原子と一緒になって置換もしくは非置換の複素環を形成していてもよく、RはRと共に隣接する窒素原子及び-SO-と一緒になって置換もしくは非置換の複素環を形成していてもよい。
    上記の置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換の非芳香族複素環式基は、1または2個のオキソ、チオキソまたは置換もしくは非置換のイミノで置換されていてもよい。ただし、Rが置換もしくは非置換の非芳香族複素環式基である場合、nは1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NPY Y5受容体拮抗作用を有する医薬組成物。
    Formula (I):
    Figure JPOXMLDOC01-appb-C000003

    (Where
    X is —SO 2 —, —N (—R 6 ) —SO 2 — or —SO 2 —N (—R 7 ) —,
    Y 1 is ═C (—R 8 ) — or ═N—,
    Y 2 is —C (—R 3 ) ═ or —N═,
    Y 3 is ═C (—R 1 ) — or ═N—,
    Z is —C (—R 9 ) ═ or —N═,
    R 1 , R 3 , R 8 , R 9 , R 11 and R 12 are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by the formula: —O—R 10 , formula: A group represented by —O—C (═O) —R 10 , represented by the formula: —C (═O) —R 10 A group represented by the formula: —C (═O) —O—R 10 , a group represented by the formula: —S—R 10 , a group represented by the formula: —SO 2 —R 10 or a formula: A group represented by O—SO 2 —R 10 ;
    R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino;
    R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
    R 4 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group,
    R 5 is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R 10 , group represented by formula: —O—C (═O) —R 10 , formula: —C (= O) group represented by -R 10, wherein: -C (= O) groups represented by -O-R 10, wherein: -S-R Groups represented by 0, the formula: or a group represented by the formula represented by -SO 2 -R 10: is a group represented by -O-SO 2 -R 10,
    n is 0 or 1;
    R 6 and R 7 are hydrogen or substituted or unsubstituted alkyl, or R 6 together with the adjacent nitrogen atom together with R 2 may form a substituted or unsubstituted heterocycle, R 7 May combine with R 2 and the adjacent nitrogen atom and —SO 2 — to form a substituted or unsubstituted heterocycle.
    The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group is substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino It may be. However, when R 4 is a substituted or unsubstituted non-aromatic heterocyclic group, n is 1. ), A pharmaceutically acceptable salt thereof, or a solvate thereof, a pharmaceutical composition having an NPY Y5 receptor antagonistic action.
  16. nが1であり、Rが置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換の非芳香族複素環式基である、請求項15記載の医薬組成物。 n is 1, and R 5 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted non-aromatic heterocycle The pharmaceutical composition according to claim 15, which is a formula group.
  17. nが1であり、Rが置換もしくは非置換の非芳香族複素環式基である、請求項16記載の医薬組成物。 The pharmaceutical composition according to claim 16, wherein n is 1 and R 5 is a substituted or unsubstituted non-aromatic heterocyclic group.
  18. nが1であり、Rがシアノ、置換もしくは非置換のアルキルまたは式:-O-R10で示される基であり、R10が置換もしくは非置換のアルキルまたは置換もしくは非置換のアリールである、請求項15記載の医薬組成物。 n is 1, R 5 is cyano, substituted or unsubstituted alkyl or a group represented by the formula: —O—R 10 , and R 10 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl The pharmaceutical composition according to claim 15.
  19. が置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリールである、請求項15記載の医薬組成物。 R 4 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, claim 15 pharmaceutical composition.
  20. Xが-SO-または-N(-R)-SO-であり、Yが=C(-R)-であり、Yが-C(-R)=であり、Yが=C(-R)-であり、かつZが-N=である、請求項15~19のいずれかに記載の医薬組成物。 X is —SO 2 — or —N (—R 6 ) —SO 2 —, Y 1 is ═C (—R 8 ) —, Y 2 is —C (—R 3 ) ═, Y The pharmaceutical composition according to any one of claims 15 to 19, wherein 3 is = C (-R 1 )-and Z is -N =.
  21. 抗肥満作用を有する化合物を含有する、請求項13~20のいずれかに記載の医薬組成物と併用するための、肥満症の予防および/または治療用、または肥満症における体重管理用の医薬組成物。 A pharmaceutical composition for the prevention and / or treatment of obesity or for weight management in obesity for use in combination with the pharmaceutical composition according to any one of claims 13 to 20, comprising a compound having an anti-obesity effect object.
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