Patent
أعرض في EDS

Oxadiazole substituted indazole derivatives for use as sphingosine 1-phosphate (S1P) agonists

التفاصيل البيبلوغرافية
العنوان: Oxadiazole substituted indazole derivatives for use as sphingosine 1-phosphate (S1P) agonists
Patent Number: 8,324,254
تاريخ النشر: December 04, 2012
Appl. No: 12/596488
Application Filed: April 17, 2008
مستخلص: The present invention provides compounds of formula (I) or salts thereof: [chemical expression included] having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders mediated by S1P1 receptors.
Inventors: Ahmed, Mahmood (Singapore, SG); Giblin, Gerard Martin Paul (Harlow, GB); Myatt, James (Harlow, GB); Norton, David (Harlow, GB); Rivers, Dean Andrew (Singapore, SG)
Assignees: Glaxo Group Limited (Greenford, Middlesex, GB)
Claim: 1. A compound of formula (I) or salts thereof: [chemical expression included] wherein one of R 5 and R 6 is hydrogen and the other is (a): [chemical expression included] one of R 3 and R 4 is (b): [chemical expression included] A is a phenyl or a 5 or 6-membered heteroaryl ring; R 1 is hydrogen or up to three substituents independently selected from halogen, C (1-4) alkyl, C (1-4) alkoxy, C (5-7) cycloalkyl, C (5-7) cycloalkoxy, trifluoromethoxy, difluoromethoxy, trifluoromethyl, cyano, phenyl, 5 or 6 membered heteroaryl rings, piperidinyl and pyrrolidinyl; R 2 is hydrogen or up to three substituents independently selected from halogen, C (1-4) alkyl, C (1-4) alkoxy, trifluoromethoxy, difluoromethoxy, trifluoromethyl and cyano; R 7 is hydrogen or halogen; Z is C (1-4) alkyl may be optionally interrupted once by N or O and may be optionally substituted on carbon by up to four substituents independently selected from halogen, methyl and hydroxyl, with the proviso that no carbon atom is substituted by two hydroxyl groups.
Claim: 2. A compound of claim 1 of formula (IA) or salts thereof, [chemical expression included] wherein R 1 , R 2 , R 5 , R 6 , R 7 and Z are defined according to claim 1 .
Claim: 3. A compound of claim 1 of formula (IB) or salts thereof, [chemical expression included] wherein R 1 , R 2 , R 5 , R 6 , R 7 and Z are defined according to claim 1 .
Claim: 4. A compound according to claim 1 wherein: A is optionally substituted thiophene, pyridyl or phenyl; R 1 is two substituents independently selected from hydrogen, chloro, bromo, isopropoxy, propoxy, methoxy, 1-methylpropoxy, cyano, trifluoromethyl, trifluoromethoxy, cyclohexyl, piperidine, pyrrolidinyl, ethyl, 2-methylpropyl, phenyl and cyclopentoxy; R 2 is hydrogen; R 7 is hydrogen; and Z is ethylene or propylene optionally substituted by gem-dimethyl.
Claim: 5. A compound selected from: 3-[5-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]propanoic acid; 3-(5-{5-[3-Chloro-4-(ethyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)propanoic acid; 3-[5-(5-{3-Cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]propanoic acid; 4-[5-(5-{3-Cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]butanoic acid; 3-(5-{5-[4-[(1-Methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)propanoic acid; 4-[4-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]butanoic acid; 3-[4-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]propanoic acid; 3-(5-{5-[3-Chloro-4-(propyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)propanoic acid; 3-[5-(5-{3-Chloro-4-[(trifluoromethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]propanoic acid; 3-(5-{5-[4-Cyclohexyl-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)propanoic acid; 3-(5-{5-[4-(Methyloxy)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)propanoic acid; [5-(5-{3-Cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]acetic acid; 3-(5-{5-[3-Chloro-4-(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)propanoic acid; 3-(5-{5-[3-Ethyl-4-(1-piperidinyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)propanoic acid; 3-{5-[5-(4-Cyclohexyl-3-ethylphenyl)-1,2,4-oxadiazol-3-yl]-1H-indazol-1-yl}propanoic acid; 3-(5-{5-[3-Cyano-4-(2-methylpropyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)propanoic acid; 3-[5-(5-{3-Bromo-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]propanoic acid; 3-(5-{5-[3-Chloro-4-(2-methylpropyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)propanoic acid; 4-(5-{5-[4-[(1-Methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)butanoic acid; 3-{5-[5-(2-Cyano-4-biphenylyl)-1,2,4-oxadiazol-3-yl]-1H-indazol-1-yl}propanoic acid; 3-(5-{5-[3-Chloro-4-(1-pyrrolidinyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)propanoic acid; 4-[5-(5-{5-Chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]butanoic acid hydrochloride; 4-[5-(5-{5-Chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-2H-indazol-2-yl]butanoic acid hydrochloride; 4-(5-{5-[2-(Trifluoromethyl)-4-biphenylyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)butanoic acid; 4-(5-{5-[2-(Trifluoromethyl)-4-biphenylyl]-1,2,4-oxadiazol-3-yl}-2H-indazol-2-yl)butanoic acid; 3-[4-(5-{3-Cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]propanoic acid; 3-[4-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2H-indazol-2-yl]propanoic acid; 4-[4-(5-{3-Cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]butanoic acid; 4-(4-{5-[3-Ethyl-4-(1-piperidinyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)butanoic acid; 4-(4-{5-[2-(Trifluoromethyl)-4-biphenylyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)butanoic acid; 4-[4-(5-{3-Chloro-4-[(trifluoromethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]butanoic acid; 3-(4-{5-[4-[(1-Methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)propanoic acid; 4-[4-(5-{5-Chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]butanoic acid; 4-(4-{5-[4-Phenyl-5-(trifluoromethyl)-2-thienyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)butanoic acid; 4-[4-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2H-indazol-2-yl]butanoic acid; 3-{5-[5-(3-Cyano-4-{[(1S)-1-methylpropyl]oxy}phenyl)-1,2,4-oxadiazol-3-yl]-1H-indazol-1-yl}propanoic acid sodium salt; 3-{5-[5-(3-Cyano-4-{[(1R)-1-methylpropyl]oxy}phenyl)-1,2,4-oxadiazol-3-yl]-1H-indazol-1-yl}propanoic acid sodium salt; 3-(5-{5-[3-Cyano-4-(cyclopentyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)propanoic acid; 4-[5-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]butanoic acid; 4-(5-{5-[4-Phenyl-5-(trifluoromethyl)-2-thienyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)butanoic acid; 4-[5-(5-{3-|Cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2H-indazol-2-yl]butanoic acid; 3-[5-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]-2,2-dimethylpropanoic acid; 3-[5-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2H-indazol-2-yl]-2,2-dimethylpropanoic acid; 3-[4-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]-2,2-dimethylpropanoic acid; 3-[4-(5-{5-Chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]-2,2-dimethylpropanoic acid; 3-[5-(5-{3-Cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]-2,2-dimethylpropanoic acid; 4-[5-(5-{3-Cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]-2,2-dimethylbutanoic acid; 3-[4-(5-{3-Cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]-2,2-dimethylpropanoic acid; 3-[5-(5-{5-Chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]-2,2-dimethylpropanoic acid; 4-[4-(5-{3-Cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]-2,2-dimethylbutanoic acid; and 4-[4-(5-{5-Chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]-2,2-dimethylbutanoic acid; or salts thereof.
Claim: 6. A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically-acceptable excipients.
Claim: 7. A method of treating multiple sclerosis, comprising administering a safe and effective amount of a compound or salt according to claim 1 to a patient in need thereof.
Current U.S. Class: 514/338
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Primary Examiner: Jean-Louis, Samira
Attorney, Agent or Firm: Hall, Linda E.
Lemanowicz, John L.
رقم الانضمام: edspgr.08324254
قاعدة البيانات: USPTO Patent Grants
الوصف
الوصف غير متاح.