Compounds and compositions as lxr modulators

Abstract

The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of liver X receptors (LXRs).

We claim: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         in which
 n is selected from 0, 1, 2 and 3; 
 Z is selected from C and S(O); each 
 Y is independently selected from —CR 4 ═ and —N═; wherein R 4  is selected from hydrogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkyl and halo-substituted-C 1-6 alkoxy; 
 R 1  is selected from halo, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkyl, halo-substituted-C 1-6 alkoxy and —C(O)OR 4 ; wherein R 4  is as described above; 
 R 2  is selected from C 6-10 aryl, C 5-10 heteroaryl, C 3-12 cycloalkyl and C 3-8 heterocycloalkyl;
 wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 2  is optionally substituted with 1 to 5 radicals independently selected from halo, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkyl, halo-substituted-C 1-6 alkoxy, —C(O)NR 5 R 5 , —OR 5 , —OC(O)R 5 , —NR 5 R 6 , —C(O)R 5  and —NR 5 C(O)R 5 ;
 wherein R 5  and R 6  are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkyl, halo-substituted-C 1-6 alkoxy, C 6-10 aryl-C 0-4 alkyl, C 3-8 heteroaryl-C 0-4 alkyl, C 3-12 cycloalkyl-C 0-4 alkyl and C 3-8 heterocycloalkyl-C 0-4 alkyl; or R 5  and R 6  together with the nitrogen atom to which R 5  and R 6  are attached form C 5-10 heteroaryl or C 3-8 heterocycloalkyl; 
  wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 5  or the combination of R 5  and R 6  is optionally substituted with 1 to 4 radicals independently selected from halo, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkyl and halo-substituted-C 1-6 alkoxy; 
 
 
 R 3  is selected from C 6-10 aryl, C 5-10 heteroaryl, C 3-12 cycloalkyl and C 3-8 heterocycloalkyl;
 wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 3  is substituted with 1 to 5 radicals independently selected from halo, C 1-6 alkoxy, halo-substituted-C 1-6 alkyl, halo-substituted-C 1-6 alkoxy, —OXR 7 , —OXC(O)NR 7 R 8 , —OXC(O)NR 7 XC(O)OR 8 , —OXC(O)NR 7 XOR 8 , —OXC(O)NR 7 XNR 7 R 8 , —OXC(O)NR 7 XS(O) 0-2 R 8 , —OXC(O)NR 7 XNR 7 C(O)R 8 , —OXC(O)NR 7 XC(O)XC(O)OR 8 , —OXC(O)NR 7 R 9 , —OXC(O)OR 7 , —OXOR 7 , —OXR 9 , —XR 9 , —OXC(O)R 9 , —OXS(O) 0-2 R 9  and —OXC(O)NR 7 CR 7 [C(O)R 8 ] 2 ;
 wherein X is a selected from a bond and C 1-6 alkylene wherein any methylene of X can optionally be replaced with a divalent radical selected from C(O), NR 7 , S(O) 2  and O; R 7  and R 8  are independently selected from hydrogen, cyano, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, C 2-6 alkenyl and C 3-12 cycloalkyl-C 0-4 alkyl; R 9  is selected from C 6-10 aryl-C 0-4 alkyl, C 5-10 heteroaryl-C 0-4 alkyl, C 3-12 cycloalkyl-C 0-4 alkyl and C 3-8 heterocycloalkyl-C 0-4 alkyl; 
  wherein any alkyl of R 9  can have a hydrogen replaced with —C(O)OR 10 ; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 9  is optionally substituted with 1 to 4 radicals independently selected from halo, C 1-6 alkyl, C 3-12 cycloalkyl, halo-substituted-C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkoxy, —XC(O)OR 10 , —XC(O)R 10 , —XC(O)NR 10 R 10 , —XS(O) 0-2 NR 10 R 10  and —XS(O) 0-2 R 10 ; wherein 
  R 10  is independently selected from hydrogen and C 1-6 alkyl; and 
  the pharmaceutically acceptable salts, hydrates, solvates and isomers thereof. 
 
 
 
       
     
     
         2 . The compound of  claim 1  of Formula (Ia): 
       
         
           
           
               
               
           
         
         in which
 n is selected from 1, 2 and 3; 
 Y is selected from —CH═ and —N═; 
 R 1  is selected from halo, C 1-6 alkyl, and —C(O)OR 4 ; wherein R 4  is selected from hydrogen and C 1-6 alkyl; 
 R 2  is selected from C 6-10 aryl, C 5-10 heteroaryl, C 3-12 cycloalkyl and C 3-8 heterocycloalkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 2  is optionally substituted with 1 to 4 radicals independently selected from halo, hydroxy, C 1-6 alkyl, halo-substituted-C 1-6 alkyl and —OC(O)R 5 ; wherein R 5  is selected from hydrogen and C 1-6 alkyl; and 
 R 3  is selected from C 6-10 aryl, C 5-10 heteroaryl, C 3-12 cycloalkyl and C 3-8 heterocycloalkyl;
 wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 3  is substituted with 1 to 5 radicals independently selected from halo, hydroxyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkyl, halo-substituted-C 1-6 alkoxy, —OXR 7 , —OXC(O)NR 7 R 8 , —OXC(O)NR 7 XC(O)OR 8 , —OXC(O)NR 7 XOR 8 , —OXC(O)NR 7 XNR 7 R 8 , —OXC(O)NR 7 XS(O) 0-2 R 8 , —OXC(O)NR 7 XNR 7 C(O)R 8 , —OXC(O)NR 7 XC(O)XC(O)OR 8 , —OXC(O)NR 7 R 9 , —OXC(O)OR 7 , —OXOR 7 , —OXR 9 , —XR 9 , —OXC(O)R 9  and —OXC(O)NR 7 CR 7 [C(O)R 8 ] 2 ;
 wherein X is a selected from a bond and C 1-6 alkylene; R 7  and R 8  are independently selected from hydrogen, cyano, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, C 2-6 alkenyl and C 3-12 cycloalkyl-C 0-4 alkyl; R 9  is selected from C 6-10 aryl-C 0-4 alkyl, C 5-10 heteroaryl-C 0-4 alkyl, C 3-12 cycloalkyl-C 0-4 alkyl and C 3-8 heterocycloalkyl-C 0-4 alkyl; 
  wherein any alkyl of R 9  can have a hydrogen replaced with —C(O)OR 10 ; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 9  is optionally substituted with 1 to 4 radicals independently selected from halo, C 1-6 alkyl, C 3-12 cycloalkyl, halo-substituted-C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkoxy, —XC(O)OR 10 , —XC(O)R 10 , —CR 10 (NR 10 R 10 )═NOR 10 , —XC(O)NR 10 R 10 , —XS(O) 0-2 NR 10 R 10  and —XS(O) 0-2 R 10 ; wherein R 10  is independently selected from hydrogen and C 1-6 alkyl. 
 
 
 
       
     
     
         3 . The compound of  claim 2  in which
 R 1  is selected from fluoro, chloro, methyl and —C(O)OCH 3 ; and 
 R 2  is selected from phenyl, cyclohexyl, cyclopentyl, pyrrolyl, pyrazolyl, naphthyl, benzo[1,3]-dioxolyl, thienyl, furanyl and pyridinyl; wherein any aryl, heteroaryl or cycloalkyl of R 2  is optionally substituted with 1 to 4 radicals independently selected from fluoro, chloro, bromo, hydroxy, methyl, ethyl, propyl, t-butyl, amino, dimethyl-amino, methoxy, trifluoromethyl, trifluoromethoxy and —OC(O)CH 3 . 
 
     
     
         4 . The compound of  claim 3  in which R 3  is selected from phenyl, benzol[1,3]-dioxolyl, pyridinyl, 2,2-difluoro-benzol[1,3]dioxol-5-yl and benzooxazolyl; wherein any aryl or heteroaryl of R 3  is substituted with 1 to 5 radicals independently selected from fluoro, chloro, bromo, methoxy, hydroxyl, difluoromethoxy, —OCH 2 C(O)NH 2 , —OCH 2 C(O)OCH 3 , —OCH 2 C(O)NHCH 3 , —OCH 2 C(O)N(CH 3 ) 2 , —R 9 , —OR 9 , —OCH 2 R 9 , —OCH 2 C(O)R 9 , —OCH 2 C(O)NHR 9 , —OCH 2 C(O)N(CH 3 )R 9 , —OCH 2 C(O)NHCH 2 R 9 , —OCH 2 CN, —OCH 2 C 2 H 3 , —OCH 2 C 2 H 4 , —O(CH 2 ) 2 OH, —OCH 2 C(O)NH(CH 2 ) 2 C(O)OC 2 H 5 , —OCH 2 C(O)NH(CH 2 ) 2 CH 2 F, —OCH 2 C(O)NHCH 2 CH 2 F, —OCH 2 C(O)NH(CH 2 ) 2 C(O)OH, —OCH 2 C(O)NHCH(CH 2 R 9 )C(O)OC 2 H 5 , —OCH 2 C(O)NHC(O)(CH 2 ) 2 C(O)OCH 3 , —OCH 2 C(O)NH(CH 2 ) 2 NHC(O)CH 3 , —OCH 2 C(O)NHCH 2 C(O)C 2 H 5 , —OCH 2 C(O)NH(CH 2 ) 2 C(O)OC 4 H 9 , —OCH 2 C(O)NHCH 2 C(O)OC 2 H 5 , —OCH 2 C(O)NHCH[C(O)OC 2 H 5 ] 2 , —S(O) 2 CH 3 , —OCH 2 C(O)NHCH 2 CF 3 , —OCH 2 C(O)NHCH 2 C(O)(CH 2 ) 2 C(O)OCH 3 , —OCH 2 C(O)N(CH 3 )CH 2 C(O)OCH 3 , —OCH 2 C(O)NH(CH 2 ) 3 OC 2 H 5 , —OCH 2 C(O)NH(CH 2 ) 3 OCH(CH 3 ) 2 , —OCH 2 C(O)NH(CH 2 ) 2 SCH 3 , —OCH 2 C(O)NHCH 2 CH(CH 3 ) 2 , —OCH 2 C(O)NHCH(CH 3 )CH 2 OH, —OCH 2 C(O)NHCH 2 CH(CH 3 )C 2 H 5 , —OCH 2 C(O)NHCH(CH 3 )C(O)OC 2 H 5 , —OCH 2 C(O)NHCH 2 CH(CH 3 ) 2  and —OCH 2 C(O)(CH 2 ) 3 OCH(CH 3 ) 2 ;
 wherein R 9  is phenyl, cyclopropyl-methyl, isoxazolyl, benzthiazolyl, furanyl, furanyl-methyl, tetrahydro-furanyl, pyridinyl, 4-oxo-4,5-dihydro-thiazol-2-yl, pyrazolyl, isothiazolyl, 1,3,4-thiadiazolyl, thiazolyl, phenethyl, morpholino, morpholino-propyl, isoxazolyl-methyl, pyrimidinyl, tetrahydro-pyranyl, 2-oxo-2,3-dihydro-pyrimidin-4-yl, piperazinyl, pyrrolyl, piperidinyl, pyrazinyl, imidazolyl, imidazolyl-propyl, benzol[1,3]-dioxolyl, benzol[1,3]-dioxolyl-propyl, 2-oxo-pyrrolidin-1-yl and 2-oxo-pyrrolidin-1-yl-propyl; wherein any alkyl of R 9  can have a hydrogen replaced with —C(O)OC 2 H 5 ; wherein any aryl, heteroaryl or heterocycloalkyl of R 9  is optionally substituted with 1 to 4 radicals independently selected from methyl, ethyl, cyclopropyl, methoxy, trifluoromethyl, —OC(O)CH 3 , —COOH, —S(O) 2 NH 2 , —CH(NH 2 )═NOH, —C(O)OC 2 H 5 , —CH 2 C(O)OH, —CH 2 C(O)OC 2 H 5 , —CH 2 C(O)OCH 3 , —C(O)OCH 3 , —C(O)NH 2 , —C(O)NHCH 3  and —C(O)CH 3 . 
 
     
     
         5 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  in combination with a pharmaceutically acceptable excipient. 
     
     
         6 . A method for treating a disease or disorder in an animal in which modulation of LXR activity can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of a compound of  claim 1 . 
     
     
         7 . The method of  claim 6  wherein the diseases or disorder are selected from cardiovascular disease, diabetes, neurodegenerative diseases and inflammation. 
     
     
         8 . The use of a compound of  claim 1  in the manufacture of a medicament for treating a disease or disorder in an animal in which LXR activity contributes to the pathology and/or symptomatology of the disease, said disease being selected from cardiovascular disease, diabetes, neurodegenerative diseases and inflammation. 
     
     
         9 . A method for treating a disease or disorder in an animal in which modulation of LXR activity can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of a compound of  claim 1 . 
     
     
         10 . The method of  claim 9  further comprising administering a therapeutically effective amount of a compound of  claim 1  in combination with another therapeutically relevant agent.