Triazole derivative

Abstract

An object of the present invention is to provide a compound having an action of inhibiting binding between S1P and its receptor, Edg-1 (S1P 1 ), and is useful as a pharmaceutical compound. A compound or a pharmaceutically acceptable salt thereof, which compound is represented by the formula below (where A represents an oxygen atom, a sulfur atom, a group represented by Formula —SO—, a group represented by Formula —SO 2 —, or the like, R 1 represents a hydrogen atom, an alkyl group having 1-6 carbon atoms, or the like, R 1A represents a hydrogen atom or the like, R 2 represents an alkyl group having 1-6 carbon atoms, a cycloalkyl group having 3-6 carbon atoms, or the like, R 3 represents an aryl group, R 4 represents a hydrogen atom or an alkyl group having 1-6 carbon atoms and optionally substituted with a carboxyl group, and R 5 represents an alkyl group having 1-10 carbon atoms, a cycloalkyl group having 3-8 carbon atoms, an aryl group which is optionally substituted, or the like).

1 . A compound represented by Formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 A represents:
 an oxygen atom, 
 
 R 1  represents:
 a hydrogen atom, 
 an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:
 a hydroxyl group, 
 a halogen atom, 
 an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a phenyl group, and 
 a phenyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms, 
 
 a cycloalkyl group having from 3 to 8 carbon atoms, 
 an alkenyl group having from 2 to 8 carbon atoms, 
 an alkynyl group having from 2 to 8 carbon atoms, or 
 a phenyl group; 
 
 R 1A  represents:
 a hydrogen atom or 
 an alkyl group having from 1 to 6 carbon atoms; 
 
 R 1  and R 1A  optionally form, together with a carbon atom to which said R 1  and 
 R 1A  are attached, a cycloalkyl group having from 3 to 6 carbon atoms; 
 R 2  represents:
 a hydrogen atom, 
 an alkyl group having from 1 to 6 carbon atoms, 
 an alkenyl group having from 2 to 8 carbon atoms, 
 an alkynyl group having from 2 to 8 carbon atoms, or 
 a cycloalkyl group having from 3 to 6 carbon atoms; 
 
 R 3  represents:
 a 2-naphthyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms, 
 a 3-pyrazolyl group, optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, and a halogen atom, or 
 a 5-benzothiazolyl group, a 5-benzothiadiazolyl group, a 7-dihydroquinolinonyl group, a 7-isoquinolinyl group, a 7-quinolinyl group, a 3-pyridyl group, or an indolyl group, each optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms, 
 an unsubstituted phenyl group, or 
 a substituted phenyl group (A) or (B) below: 
 (A) a phenyl group substituted at 4 position with a substituent selected from the group consisting of:
 an alkyl group having from 1 to 6 carbon atoms, 
 a cycloalkyl group having from 3 to 8 carbon atoms, 
 an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, a morpholino group, and a phenyl group, 
 a halogen atom, 
 a trifluoromethoxy group, 
 a phenoxy group, 
 a phenyl group, 
 a 1-pyrrolyl group, and 
 —NR A R B , wherein each of R A  and R 3  is an alkyl group having from 1 to 6 carbon atoms, or R A  and R B  optionally form, together with the nitrogen atom to which said R A  and R B  are attached, a 3- to 5-membered saturated hydrocarbon ring, 
 
 wherein said phenyl group substituted at 4 position is further optionally substituted at 3 position with a substituent selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a halogen atom, and an alkoxy group having from 1 to 6 carbon atoms; and 
 (B) a phenyl group substituted at 3 position with a substituent selected from the group consisting of:
 a hydroxyl group, 
 an alkyl group having from 1 to 6 carbon atoms, and 
 an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, a morpholino group, and a phenyl group, 
 
 wherein said phenyl group substituted at 3 position is further optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or is further optionally substituted at 4 position with a halogen atom; 
 
 R 4  represents:
 a hydrogen atom or 
 an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a carboxyl group; 
 
 R 5  represents:
 (i) an alkyl group having from 1 to 10 carbon atoms, 
 (ii) an alkyl group having from 1 to 10 carbon atoms and substituted with 1 to 2 substituents selected from the group consisting of:
 a cycloalkyl group having from 3 to 8 carbon atoms, 
 a pyridyl group, and 
 a phenyl group, a phenoxy group, and a naphthyl group, each optionally substituted with 1 to 2 substituents selected from the group consisting of a halogen atom and an alkoxy group having from 1 to 6 carbon atoms, 
 
 (iii) a cycloalkyl group having from 3 to 8 carbon atoms, 
 (iv) an alkenyl group having from 2 to 8 carbon atoms, 
 (v) an alkenyl group having from 2 to 8 carbon atoms and substituted with a phenyl group, 
 (vi) an alkynyl group having from 2 to 8 carbon atoms, 
 (vii) an alkynyl group having from 2 to 8 carbon atoms and substituted with a phenyl group, or 
 (viii) an optionally substituted aryl group. 
 
 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein, in Formula (I):
 R 1  represents:
 a hydrogen atom, 
 an alkyl group having from 1 to 6 carbon atoms, 
 an alkyl group having from 1 to 6 carbon atoms and substituted with a phenyl group, 
 a cycloalkyl group having from 3 to 8 carbon atoms, 
 an alkenyl group having from 2 to 8 carbon atoms, 
 an alkynyl group having from 2 to 8 carbon atoms, or 
 a phenyl group; 
   R 1A  represents a hydrogen atom;   R 2  represents:
 an alkyl group having from 1 to 6 carbon atoms, 
 an alkenyl group having from 2 to 8 carbon atoms, 
 an alkynyl group having from 2 to 8 carbon atoms, or 
 a cycloalkyl group having from 3 to 6 carbon atoms; 
   R 4  represents:
 a hydrogen atom, or 
 an alkyl group having from 1 to 6 carbon atoms; 
   R 5  represents:
 (i) an alkyl group having from 1 to 10 carbon atoms, 
 (ii) an alkyl group having from 1 to 10 carbon atoms and substituted with 1 to 2 substituents selected from the group consisting of:
 a cycloalkyl group having from 3 to 8 carbon atoms, 
 a phenyl group, 
 a naphthyl group, 
 a pyridyl group, and 
 a phenyl group substituted with 1 to 2 substituents selected from the group consisting of a halogen atom and an alkoxy group having from 1 to 6 carbon atoms, 
 
 (iii) a cycloalkyl group having from 3 to 8 carbon atoms, 
 (iv) an alkenyl group having from 2 to 8 carbon atoms, 
 (v) an alkenyl group having from 2 to 8 carbon atoms and substituted with a phenyl group, 
 (vi) an alkynyl group having from 2 to 8 carbon atoms, 
 (vii) an alkynyl group having from 2 to 8 carbon atoms and substituted with a phenyl group, or 
 (viii) an optionally substituted aryl group. 
   
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 R 1  represents an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:
 a hydroxyl group, 
 a halogen atom, 
 an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a phenyl group; and 
 a phenyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms; 
   R 1A  represents:
 a hydrogen atom; or 
 an alkyl group having from 1 to 6 carbon atoms; and 
   R 1  and R 1A  optionally form, together with a carbon atom to which said R 1  and R 1A  are attached, a cycloalkyl group having from 3 to 6 carbon atoms.   
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is:
 an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a halogen atom(s), or 
 a benzyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms; and 
   R 1A  is a hydrogen atom.   
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is a methyl group or an ethyl group, and R 1A  is a hydrogen atom. 
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4  is a hydrogen atom. 
     
     
         7 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is an alkyl group having from 1 to 6 carbon atoms, or a cycloalkyl group having from 3 to 6 carbon atoms. 
     
     
         8 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is an ethyl group or a cyclopropyl group. 
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is:
 (i) an alkyl group having from 1 to 10 carbon atoms,   (ii) an alkyl group having from 1 to 10 carbon atoms and substituted with 1 to 2 substituents selected from the group consisting of:
 a cycloalkyl group having from 3 to 8 carbon atoms, 
 a pyridyl group, and 
 a phenyl group, a phenoxy group, and a naphthyl group, each optionally substituted with 1 to 2 substituents selected from the group consisting of a halogen atom and an alkoxy group having from 1 to 6 carbon atoms; 
   (iii) an alkenyl group having from 2 to 8 carbon atoms and optionally substituted with a phenyl group, or   (iv) a phenyl group, a naphthyl group, a thienyl group, a pyrrolyl group, a pyrazolyl group, a pyridyl group, a furanyl group, a benzothienyl group, an isoquinolinyl, an isoxazolyl group, a thiazolyl group, a benzothiadiazolyl group, a benzoxadiazolyl group, a dihydrobenzodioxepinyl group, a dihydrobenzodioxynyl group, a benzodioxolyl group, a dihydrobenzofuranyl group, an indanyl group, an uracil group, a coumaryl group, a chromanyl group, a dihydroindolyl group, a tetrahydronaphthyl group, or a tetrahydroisoquinolinyl group, each optionally substituted with 1 to 5 substituents selected from the group consisting of:
 an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a fluorine atom(s), 
 an alkenyl group having from 2 to 8 carbon atoms, 
 a halogen atom, 
 an alkoxy group having from 1 to 6 carbon atoms and optionally substituted with a fluorine atom(s), 
 a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiadiazolyl group, 
 and a pyrimidinyl group, each optionally substituted with a substituent(s) selected from Group X consisting of a methyl group, a trifluoromethyl group, a halogen atom, and a methylsulfanyl group, 
 an alkylthio group having from 1 to 6 carbon atoms, 
 an alkylsulfonyl group having from 1 to 6 carbon atoms, 
 a benzenesulfonyl group, 
 a morpholinosulfonyl group, 
 a morpholinocarbonylamino group, 
 an aminosulfonyl group, 
 an alkoxycarbonyl group having from 2 to 10 carbon atoms, 
 a morpholino group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms 
 a phenyl group optionally substituted with an alkoxy group(s) having from 1 to 6 carbon atoms, 
 a phenoxy group, 
 a pyridinecarbonyl group, 
 a pyridineoxy group, 
 a cyano group, 
 an alkanoyl group having from 2 to 7 carbon atoms and optionally substituted with a fluorine atom(s), and 
 an alkanoylamino group having from 2 to 7 carbon atoms. 
   
     
     
         10 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is:
 an alkyl group having from 1 to 10 carbon atoms and substituted with a cycloalkyl group having from 3 to 8 carbon atoms,   an alkyl group having from 1 to 10 carbon atoms and substituted with a naphthyl group,   an alkenyl group having from 2 to 8 carbon atoms and substituted with a phenyl group,   a phenyl group or a naphthyl group, each optionally substituted with 1 to 5 substituents selected from the group consisting of:
 an alkyl group having from 1 to 6 carbon atoms; 
 a halogen atom, 
 an alkoxy group having from 1 to 6 carbon atoms; 
 a trifluoromethoxy group, 
 a difluoromethoxy group, 
 a trifluoromethyl group, 
 an alkenyl group having from 1 to 6 carbon atoms, 
 an alkylsulfonyl group having from 1 to 6 carbon atoms, 
 an alkanoyl group having from 2 to 7 carbon atoms, 
 an alkoxycarbonyl group having from 2 to 7 carbon atoms, and 
 a cyano group, 
   a pyrrolyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a methoxycarbonyl group;   a furanyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, and a halogen atom;   a thienyl group optionally substituted with a substituent (s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, a thiadiazolyl group, an oxazolyl group, and a halogen atom; or   a benzothienyl group, a dihydrobenzodioxepinyl group, a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, a tetrahydronaphthyl group, an indanyl group, a thiadiazolyl group, a benzoxadiazolyl group, or a benzothiadiazolyl group, each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a halogen atom.   
     
     
         11 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is:
 an alkyl group having from 1 to 6 carbon atoms and substituted with a naphthyl group,   an alkenyl group having from 2 to 6 carbon atoms and substituted with a phenyl group;   an unsubstituted phenyl group,   a phenyl group substituted with 1 to 5 substituents selected from the group consisting of a methyl group, a methoxy group, and a halogen atom,   a phenyl group substituted with 1 to 3 substituents selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms,
 a halogen atom, 
 a methoxy group, 
 a trifluoromethoxy group, 
 a difluoromethoxy group, 
 a trifluoromethyl group, 
 an alkenyl group having from 1 to 6 carbon atoms, 
 a methylsulfonyl group, 
 an acetyl group, 
 a methoxycarbonyl group, and 
 a cyano group, 
 said phenyl group substituted at either 3 or 4 position or both; 
   a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of:
 a halogen atom, 
 an alkyl group having from 1 to 6 carbon atoms, 
 a cyano group, and 
 an alkylsulfonyl group having from 1 to 6 carbon atoms, or 
   a benzothienyl group, a benzoxadiazolyl group, a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, an indanyl group, or a benzothiadiazolyl group, each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a halogen atom.   
     
     
         12 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is:
 a phenyl group substituted at 3 and 4 positions each with a halogen atom, or   a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having from 1 to 6 carbon atoms, and a cyano group.   
     
     
         13 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is a phenyl group substituted at 4 position with a fluorine atom or a chlorine atom. 
     
     
         14 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is a 6-indolyl group. 
     
     
         15 . A pharmaceutical preparation, comprising the compound of  claim 1  or a pharmaceutically acceptable salt thereof.