Substituted piperidine compound and use thereof

Abstract

Provided is a substituted piperidine compound having an orexin type 2 receptor agonist activity. A compound represented by the formula (I):wherein each symbol is as described in the DESCRIPTION, or a salt thereof has an orexin type 2 receptor agonist activity, and is useful as a prophylactic or therapeutic agent for narcolepsy.

21 . A compound represented by the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is an acyl group, or a hydrogen atom; 
 R 2  is an optionally substituted 3- to 6-membered saturated cyclic group; and 
 R 3  is an optionally substituted C 1-6  alkyl group, a mono- or di-C 1-6  alkylamino group or a C 3-6  cycloalkyl group, 
 
       or a salt thereof. 
     
     
         22 . The compound according to  claim 21 , wherein R 3  is an optionally substituted C 1-6  alkyl group or a mono- or di-C 1-6  alkylamino group, or a salt thereof. 
     
     
         23 . The compound according to  claim 21 , which is represented by the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are as defined in  claim 21 , or a salt thereof. 
     
     
         24 . The compound according to  claim 21 , wherein R 1  is an acyl group, or a salt thereof. 
     
     
         25 . The compound according to  claim 21 , wherein R 2  is a C 3-6  cycloalkyl group substituted by one optionally substituted phenyl group, or a salt thereof. 
     
     
         26 . The compound according to  claim 21 , wherein R 3  is an optionally substituted C 1-6  alkyl group, or a salt thereof. 
     
     
         27 . The compound according to  claim 21 , wherein R 1  is
 (1) a hydrogen atom,   (2) an optionally substituted C 1-6  alkyl-carbonyl group,   (3) an optionally substituted C 3-10  cycloalkyl-carbonyl group,   (4) an optionally substituted C 1-6  alkoxy-carbonyl group,   (5) an optionally substituted C 3-10  cycloalkyloxy-carbonyl group,   (6) an optionally substituted C 6-14  aryl-carbonyl group,   (7) an optionally substituted C 6-14  aryloxy-carbonyl group,   (8) an optionally substituted 5- to 14-membered aromatic heterocyclylcarbonyl group,   (9) an optionally substituted 3- to 14-membered non-aromatic heterocyclylcarbonyl group,   (10) an optionally substituted mono- or di-C 1-6  alkyl-carbamoyl group,   (11) an optionally substituted mono- or di-C 3-10  cycloalkyl-carbamoyl group,   (12) an optionally substituted mono- or di-C 6-14  aryl-carbamoyl group,   (13) an optionally substituted C 1-6  alkylsulfonyl group,   (14) an optionally substituted C 3-10  cycloalkylsulfonyl group,   (15) an optionally substituted C 6-14  arylsulfonyl group,   (16) an optionally substituted heterocyclyl-sulfonyl group,   (17) an optionally substituted mono- or di-C 1-6  alkyl-sulfamoyl group or   (18) an optionally substituted C 1-6  alkyl-carbonyl-carbonyl group;
 R 2  is a C 3-6  cycloalkyl group or a 3- to 6-membered saturated monocyclic non-aromatic heterocyclic group, each of which is optionally substituted by 1 to 3 substituents selected from 
   (1) deuterium,   (2) a halogen atom,   (3) a hydroxy group,   (4) an optionally substituted C 1-6  alkyl group,   (5) a C 3-10  cycloalkyl group,   (6) an optionally substituted C 1-6  alkoxy group,   (7) an optionally substituted C 6-14  aryl group,   (8) a C 6-14  aryloxy group,   (9) a tri-C 1-6  alkylsilyloxy group,   (10) an optionally substituted 5- to 14-membered aromatic heterocyclic group and   (11) an optionally substituted C 6-14  aryl-carbonyl group; and
 R 3  is a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a C 6-14  aryl group, or a mono- or di-C 1-6  alkylamino group, or a salt thereof. 
   
     
     
         28 . The compound according to  claim 21 , wherein R 1  is
 (1) a hydrogen atom,   (2) a C 1-6  alkyl-carbonyl group optionally substituted by 1 to 7 substituents selected from   (i) a halogen atom, (ii) a cyano group, (iii) a hydroxy group, (iv) a C 3-10  cycloalkyl group, (v) a C 1-6  alkoxy group, (vi) a C 6-14  aryl group, (vii) a C 6-14  aryloxy group, (viii) a pyrazolyl group, a thiazolyl group, a pyrimidinyl group or a pyridazinyl group, each of which is optionally substituted by an oxo group, (ix) a pyrazolyloxy group optionally substituted by 1 to 3 C 1-6  alkyl groups, (x) a C 1-6  alkyl-carbonyl group, (xi) a C 1-6  alkoxy-carbonyl group, (xii) a C 1-6  alkyl-carbonyloxy group, (xiii) a C 1-6  alkylsulfonyl group, (xiv) a mono- or di-C 1-6  alkylamino group, (xv) a C 1-6  alkyl-carbonylamino group and (xvi) a (C 1-6  alkyl) (C 1-6  alkyl-carbonyl)amino group,   (3) a C 3-10  cycloalkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a cyano group, a hydroxy group, an oxo group and a C 1-6  alkyl group,   (4) a C 1-6  alkoxy-carbonyl group optionally substituted by 1 to 6 substituents selected from deuterium, a halogen atom and a C 6-14  aryl group,   (5) a C 3-10  cycloalkyloxy-carbonyl group optionally substituted by 1 to 3 substituents selected from a C 1-6  alkyl group,   (6) a C 6-14  aryl-carbonyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a C 6-14  aryl group,   (7) a C 6-14  aryloxy-carbonyl group,   (8) a furylcarbonyl group, a thienylcarbonyl group, a pyrazolylcarbonyl group, an isoxazolylcarbonyl group or a pyridylcarbonyl group, each of which is optionally substituted by 1 to 3 substituents selected from a C 1-6  alkyl group,   (9) an azetidinylcarbonyl group, an oxetanylcarbonyl group, a pyrrolidinylcarbonyl group, a tetrahydrofuranylcarbonyl group, a tetrahydropyranylcarbonyl group or a morpholinylcarbonyl group, each of which is optionally substituted by 1 to 3 substituents selected from an oxo group, a C 1-6  alkyl-carbonyl group, a C 1-6  alkoxy-carbonyl group and a C 1-6  alkylsulfonyl group,   (10) a mono- or di-C 16  alkyl-carbamoyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a cyano group, a hydroxy group and a C 1-6  alkoxy group,   (11) a mono- or di-C 3-10  cycloalkyl-carbamoyl group,   (12) a mono- or di-C 6-14  aryl-carbamoyl group,   (13) a C 1-6  alkylsulfonyl group,   (14) a C 3-10  cycloalkylsulfonyl group,   (15) a C 6-14  arylsulfonyl group optionally substituted by 1 to 3 halogen atoms,   (16) a thienylsulfonyl group, a pyrazolylsulfonyl group, an imidazolylsulfonyl group, a pyridylsulfonyl group or a dihydrochromenylsulfonyl group, each of which is optionally substituted by 1 to 3 substituents selected from a C 1-6  alkyl group,   (17) a mono- or di-C 1-6  alkyl-sulfamoyl group or   (18) a C 1-6  alkyl-carbonyl-carbonyl group;
 R 2  is a C 3-6  cycloalkyl group, a pyrrolidinyl group, a piperidinyl group or a dioxanyl group, each of which is optionally substituted by 1 to 3 substituents selected from 
   (1) deuterium,   (2) a halogen atom,   (3) a hydroxy group,   (4) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a C 6-14  aryl group,   (5) a C 3-10  cycloalkyl group,   (6) a C 1-6  alkoxy group optionally substituted by a C 3-10  cycloalkyl group,   (7) a C 6-14  aryl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a cyano group, a C 1-6  alkyl group optionally substituted by 1 to 3 halogen atoms, a C 1-6  alkoxy group optionally substituted by 1 to 3 halogen atoms and a hydroxy group,   (8) a C 6-14  aryloxy group,   (9) a tri-C 1-6  alkylsilyloxy group,   (10) a pyrazolyl group, a thiazolyl group, a pyridyl group, a pyrimidinyl group, a quinazolinyl group, a benzothiazolyl group or an isoquinolinyl group, each of which is optionally substituted by 1 to 3 substituents selected from a halogen atom, a C 1-6  alkyl group and a C 1-6  alkoxy group, and   (11) a C 6-14  aryl-carbonyl group; and
 R 3  is a C 1-6  alkyl group, or a mono- or di-C 1-6  alkylamino group, or a salt thereof. 
   
     
     
         29 . The compound according to  claim 21 , wherein R 1  is
 (1) a hydrogen atom,   (2) a C 1-6  alkyl-carbonyl group optionally substituted by a hydroxy group,   (3) a cyclopropanecarbonyl group,   (4) a C 1-6  alkoxy-carbonyl group or   (5) a mono- or di-C 1-6  alkyl-carbamoyl group;
 R 2  is 
   (A) a cyclohexyl group optionally substituted by 1 to 3 substituents selected from
 (1) a C 1-6  alkyl group and 
 (2) a phenyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a C 1-6  alkyl group optionally substituted by 1 to 3 halogen atoms and a C 1-6  alkoxy group or 
   (B) a piperidinyl group optionally substituted by 1 to 3 pyrimidinyl groups; and
 R 3  is a C 1-6  alkyl group or a di-C 1-6  alkylamino group, or a salt thereof. 
   
     
     
         30 . The compound according to  claim 21 , wherein R 1  is
 (1) a C 1-6  alkyl-carbonyl group optionally substituted by a hydroxy group,   (2) a C 1-6  alkoxy-carbonyl group or   (3) a mono- or di-C 1-6  alkyl-carbamoyl group;
 R 2  is a cyclohexyl group optionally substituted by 1 to 3 substituents selected from 
   (1) a C 1-6  alkyl group and   (2) a phenyl group optionally substituted by 1 to 3 halogen atoms; and
 R 3  is a C 1-6  alkyl group, or a salt thereof. 
   
     
     
         31 . A medicament comprising N-((2R,3S)-1-glycoloyl-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide or a salt thereof.