Isoxazole-pyridine derivatives

Abstract

The present invention is concerned with isoxazole-pyridine derivatives of formula I wherein X, R 1 to R 6 are as described herein. The compounds are active on the GABA A α5 receptor binding site and useful for the treatment of cognitive disorders, such as Alzheimer's disease.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         X is O or NH; 
         R 1  is phenyl, pyridinyl, or pyrimidinyl, each optionally substituted with 1, 2 or 3 halo, 
         R 2  is H or CH 3  or CF 3 ; 
         R 3 , R 4 , R 5 , and R 6  each are independently
 H, 
 C 1-7 alkyl, optionally substituted with one or more halo, cyano, or hydroxy, 
 C 1-7 alkoxy, optionally substituted with one or more halo, 
 CN, 
 halo, 
 NO 2 , 
 S—C 1-7 alkyl, 
 S(O)—C 1-7 alkyl 
 benzyloxy, optionally substituted with one or more E, 
 —C(O)—R 3 , wherein R a  is hydroxy, C 1-7 alkoxy, C 1-7 alkyl, phenoxy or phenyl, 
 3- to 7-membered heterocyclyl, optionally substituted with one or more A, 
 —C(O)—NR b R c , wherein R b  and R c  are each independently
 H, p 3  C 1-7 alkyl, optionally substituted with one or more halo, methyl, —(CH 2 ) t -hydroxy, or cyano, 
 —(CH 2 ) t —C 3-7 cycloalkyl, optionally substituted by one or more B, and t is 0, 1, 2, 3, 4, 5 or 6, 
 —(CH 2 ) u —O—C 1-7 alkyl, wherein u is 2, 3, 4, 5 or 6, 
 —CHR i —C(O)OR ii , wherein R i  is H, benzyl or C 1-4 alkyl, and R is H or C 1-7 alkyl, 
 —S(O) 2 —C 1-7 alkyl, 
 —S(O) 2 —C 3-7 cycloalkyl, 
 —(CH 2 CH 2 O) v R iii , wherein v is from 1 to 3, and R iii  is H or C 1-7 alkyl, 
 —(CH 2 )w-heteroaryl or —(CH 2 ) w -aryl, each optionally substituted by one or more E, and wherein w is 0, 1, 2, 3, or 4, 
 —(CH 2 ) x -heterocyclyl, wherein x is 0, 1, 2, 3 or 4, and wherein heterocyclyl is optionally substituted by one or more
 oxo, 
 C 1-7 alkyl, 
 C 3-7 cycloalkyl, optionally substituted with one or more B, 
 CN, 
 benzyl, optionally substituted with one or more E, 
 —(CH 2 ) y —C(O)R iv , wherein y is 0, 1, 2, 3 or 4, and R iv  is hydroxy, C 1-7 alkyl, or C 1-7 alkoxy, 
 —(CH 2 ) z —C(O)NR v R vi , —(CH 2 ) z  NR v R vi —C(O)—C 1-7 alkyl or —(CH 2 ) z  NR v R vi —C(O)—O—C 1-7 alkyl, wherein z is 0, 1, 2, 3 or 4, 
 and R v  and R vi  are independently 
  hydrogen, 
  C 1-7 alkyl, optionally substituted by one or more halo, OH or CN, 
  C 3-7 cycloalkyl, optionally substitutued by one or more B, 
  5- or 6-membered heterocyclyl, optionally substituted by one or more A, or 
  R v  and R vi  together with the nitrogen to which they are bound form a 5- or 6-membered heterocycloalkyl, optionally substituted by one or more A, or 
 
 R b  and R c  together with the nitrogen to which they are bound form a heterocyclyl or heteroaryl moiety, optionally substituted with one or more A, or 
 R b  and R c  together with the nitrogen to which they are bound form a 7- to 12-membered spirocyclic heterocycle, optionally substituted with one or more A; 
 with the proviso that R b  and R c  are not simultaneously H, 
 
 
         A is hydroxy, oxo, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, halo, or CN; 
         B is halo, hydroxy, CN, C 1-4 alkyl, benzyloxy, or C 1-4 haloalkyl; and 
         E is halo, CN, NO 2 , hydroxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 cyanoalkyl, C 1-7 haloalkoxy, or C 3-7 cycloalkyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein R 3  and R 6  are H, halo, CN or C 1-7 alkyl. 
     
     
         3 . The compound of  claim 1 , wherein R 4 is
 H,   C 1-7 alkyl, optionally substituted with one or more halo, cyano, or hydroxy,   C 1-7 alkoxy, optionally substituted with one or more halo,   CN,   halo,   NO 2 ,   S—C 1-7 alkyl,   S(O)—C 1-7 alkyl   benzyloxy, optionally substituted with one or more E,   —C(O)—R 3 , wherein R a  is hydroxy, C 1-7 alkoxy, C 1-7 alkyl, phenoxy or phenyl,   3- to 7-membered heterocyclyl, optionally substituted with one or more A,   —C(O)—NR b R c , wherein R b  and R c  are each independently
 H, 
 C 1-7 alkyl, optionally substituted with one or more halo, methyl, —(CH 2 ) t -hydroxy, or cyano, 
 —(CH 2 ) t —C 3-7 cycloalkyl, optionally substituted by one or more B, and t is 0, 1, 2, 3, 4, 5 or 6, 
 —(CH 2 ) u —O—C 1-7 alkyl, wherein u is 2, 3, 4, 5 or 6, 
 —CHR i —C(O)OR ii , wherein R i  is H, benzyl or C 1-4 alkyl, and R ii  is H or C 1-7 alkyl, 
 —S(O) 2 —C 1-7 alkyl 
 —S(O) 2 —C 3-7 cycloalkyl 
 —(CH 2 CH 2 O) v R iii , wherein v is from 1 to 3, and R iii  is H or C 1-7 alkyl, 
 —(CH 2 ) w -heteroaryl or —(CH 2 ) w -aryl, each optionally substituted by one or more E, and wherein w is 0, 1, 2, 3, or 4, 
 —(CH 2 ) x -heterocyclyl, wherein x is 0, 1, 2, 3 or 4, and wherein heterocyclyl is
 optionally substituted by one or more 
 oxo, 
 C 1-7 alkyl, 
 C 3-7 cycloalkyl, optionally substituted with one or more B, 
 CN, 
 benzyl, optionally substituted with one or more E, 
 —(CH 2 ) y —C(O)R iv , wherein y is 0, 1, 2, 3 or 4, and R iv  is hydroxy, C 1-7 alkyl, or C 1-7 alkoxy, 
 (CH 2 ) z —C(O)NR v R vi , —(CH 2 ) z  NR v R vi —C(O)—C 1-7 alkyl or —(CH 2 ) z  NR v R vi —C(O)—O—C 1-7 alkyl, wherein z is 0, 1, 2, 3 or 4, 
 and R v  and R vi  are independently
 hydrogen, 
 C 1-7 alkyl, optionally substituted by one or more halo, OH or CN, 
 C 3-7 cycloalkyl, optionally substitutued by one or more B, 
 5- or 6-membered heterocyclyl, optionally substituted by one or more A, or 
 R v  and R vi  together with the nitrogen to which they are bound form a 5- or 6-membered heterocycloalkyl, optionally substituted by one or more A, or 
 
 
 R b  and R c  together with the nitrogen to which they are bound form a heterocyclyl or heteroaryl moiety, optionally substituted with one or more A, or 
 R b  and R c  together with the nitrogen to which they are bound form a 7- to 12-membered spirocyclic heterocycle, optionally substituted with one or more A; 
 with the proviso that R b  and R c  are not simultaneously H, 
   A is hydroxy, oxo, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 17 hydroxyalkyl, halo, or CN;   B is halo, hydroxy, CN, C 1-4 alkyl, benzyloxy, or C 1-4 haloalkyl; and   E is halo, CN, NO 2 , hydroxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 cyanoalkyl, C 1-7 haloalkoxy, or C 3-7 cycloalkyl;   or a pharmaceutically acceptable salt thereof.   
     
     
         4 . The compound of  claim 1 , wherein R 4 is
 —C(O)—NR b R c , wherein R b  and R c  are each independently
 H, 
 C 1-7 alkyl, optionally substituted with one or more halo, methyl, —(CH 2 ) t -hydroxy, or cyano, 
 —(CH 2 ) t —C 3-7 cycloalkyl, optionally substituted by one or more B, and t is 0, 1, 2, 3, 4, 5 or 6, 
 —(CH 2 ) u —O—C 1-7 alkyl, wherein u is 2, 3, 4, 5 or 6, 
 —CHR i —C(O)OR ii , wherein R i  is H, benzyl or C 1-4 alkyl, and R ii  is H or C 1-7 alkyl, 
 —S(O) 2 —C 1-7 alkyl, 
 —S(O) 2 —C 3-7 cycloalkyl, 
 —(CH 2 CH 2 O) v R iii , wherein v is from 1 to 3, and R iii  is H or C 1-7 alkyl, 
 —(CH 2 ) w -heteroaryl or —(CH 2 ) w -aryl, each optionally substituted by one or more E, and wherein w is 0, 1, 2, 3, or 4, 
 —(CH 2 ) x -heterocyclyl, wherein x is 0, 1, 2, 3 or 4, and wherein heterocyclyl is
 optionally substituted by one or more 
 oxo, 
 C 1-7 alkyl, 
 C 3-7 cycloalkyl, optionally substituted with one or more B, 
 CN, 
 benzyl, optionally substituted with one or more E, 
 —(CH 2 ) y —C(O)R iv , wherein y is 0, 1, 2, 3 or 4, and R iv  is hydroxy, C 1-7 alkyl, or C 1-7 alkoxy, 
 —(CH 2 ) z —C(O)NR v R vi , —(CH 2 ) z  NR v R vi —C(O)—C 1-7 alkyl or —(CH 2 ) z  NR v R vi —C(O)—O—C 1-7 alkyl, wherein z is 0, 1, 2, 3 or 4, 
 and R v  and R vi  are independently
 hydrogen, 
 C 1-7 alkyl, optionally substituted by one or more halo, OH or CN, 
 C 3-7 cycloalkyl, optionally substitutued by one or more B, 
 5- or 6-membered heterocyclyl, optionally substituted by one or more A, or 
 R v  and R vi  together with the nitrogen to which they are bound form a 5- or 6-membered heterocycloalkyl, optionally substituted by one or more A, or 
 
 
 R b  and R c  together with the nitrogen to which they are bound form a heterocyclyl or heteroaryl moiety, optionally substituted with one or more A, or 
 R b  and R c  together with the nitrogen to which they are bound form a 7- to 12-membered spirocyclic heterocycle, optionally substituted with one or 
 with the proviso that R b  and R c  are not simultaneously H, 
   A is hydroxy, oxo, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, halo, or CN;   B is halo, hydroxy, CN, C 1-4 alkyl, benzyloxy, or C 1-4 haloalkyl; and   E is halo, CN, NO 2 , hydroxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 cyanoalkyl, C 1-7 haloalkoxy, or C 3-7 cycloalkyl;   or a pharmaceutically acceptable salt thereof.   
     
     
         5 . The compound of  claim 1 , wherein R 4  is
 H,   C 1-7 alkyl, optionally substituted with one or more halo, cyano, or hydroxy,   C 1-7 alkoxy, optionally substituted with one or more halo,   CN,   halo,   NO 2 ,   S—C 1-7 alkyl,   S(O)—C 1-7 alkyl, or   benzyloxy, optionally substituted with one or more E, and   
       E is halo, CN, NO 2 , hydroxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 cyanoalkyl, C 1-7 haloalkoxy, or C 3-7 cycloalkyl;
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         6 . The compound of  claim 1 , wherein R 4 is
 —C(O)—R a , wherein R a  is hydroxy, C 1-7 alkoxy, C 1-7 alkyl, phenoxy or phenyl.   
     
     
         7 . The compound of  claim 1 , wherein R 4  is benzyloxy optionally substituted with one or more E and E is halo, CN, NO 2 , hydroxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 cyanoalkyl, C 1-7 haloalkoxy, or C 3-7 cycloalkyl. 
     
     
         8 . The compound of  claim 1 , wherein R 4 is
 3- to 7-membered heterocyclyl, optionally substituted with one or more A, wherein   A is hydroxy, oxo, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, halo, or CN;   or a pharmaceutically acceptable salt thereof.   
     
     
         9 . The compound of  claim 1 , wherein R 4  is oxethenanyl substituted with one OH. 
     
     
         10 . The compound of  claim 1 , wherein R 5  is
 H,   C 1-7 alkyl, optionally substituted by one or more halo, hydroxy or CN,   benzyloxy, optionally substituted with one or more E,   3- to 7-membered heterocyclyl, optionally substituted with one or more A,   —C(O)—NR b R c , wherein R b  and R c  are each independently
 H, 
 3-7-membered heterocycloalkyl, optionally substituted with one or more A, and 
   
       A is hydroxy, oxo, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, halo, or CN; 
       E is halo, CN, NO 2 , hydroxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 cyanoalkyl, C 1-7 haloalkoxy, or C 3-7 cycloalkyl. 
     
     
         11 . The compound of  claim 10 , wherein R5 is H or trifluoromethyl. 
     
     
         12 . The compound of  claim 1 , wherein R 4  is H. 
     
     
         13 . The compound of  claim 1 , wherein R 4  is CN. 
     
     
         14 . The compound of  claim 1 , wherein R 4  is halo. 
     
     
         15 . The compound of  claim 1 , wherein R 4  is NO 2 . 
     
     
         16 . The compound of  claim 1 , wherein R 1  is phenyl optionally substituted with one or two halo. 
     
     
         17 . The compound of  claim 1 , wherein R 2  is methyl or trifluoromethyl. 
     
     
         18 . The compound of  claim 1 , whereinR 3  is H, halo, CN, or C 1-7 alkyl. 
     
     
         19 . The compound of  claim 18 , wherein R 3  is H, CN, or C1-4alkyl. 
     
     
         20 . The compound of  claim 19 , wherein R 3  is H, CN, or methyl. 
     
     
         21 . The compound of  claim 1 , wherein R 6  is H, halo, CN, or C1-7alkyl. 
     
     
         22 . The compound of  claim 21 , wherein R 6  is H, halo, or C1-4alkyl. 
     
     
         23 . The compound of  claim 22 , wherein R 6  is H, Br, or C1-4alkyl. 
     
     
         24 . The compound of  claim 23 , wherein R 6  is H, Br or methyl. 
     
     
         25 . The compound of  claim 1 , wherein R 4  is C(O)NR b R c , wherein R b  and R c  together with the N to which they are bound form a heterocyclyl moiety optionally substituted with one or more A. 
     
     
         26 . The compound of  claim 1 , wherein R 4  is C(O)NR b R c , wherein R b  and R c  together with the N to which they are bound form a 7- to 12-membered spirocyclic heterocycle optionally substituted with one or more A. 
     
     
         27 . The compound of  claim 1 , wherein R 3 , R 4 , R 5 , and R 6  are not simultaneously H. 
     
     
         28 . The compound of  claim 1 , selected from the group consisting of
 2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine,   N-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-ethyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(2-fluoro-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(2,2-difluoro-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-nicotinamide,   N-(2-hydroxy-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   (R,S)—N-(2-hydroxy-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(3-methoxy-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide, and   N-cyclopropylmethyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide.   
     
     
         29 . The compound of  claim 1 , selected from the group consisting of
 N-(2-ethyl-butyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(4-cyano-thiazol-2-ylmethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-pyridin-2-ylmethyl-nicotinamide,   N-(6-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylmethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-isopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-cyclopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-cyclobutyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-cyclopentyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide, and   (R,S)—N-(2,2-dimethyl-tetrahydro-pyran-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide.   
     
     
         30 . The compound of  claim 1 , selected from the group consisting of
 N-(1,1-dioxo-hexahydro-1,6-thiopyran-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(1-methyl-piperidin-4-yl)-nicotinamide,   N-(1-ethyl-piperidin-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(1-isopropyl-piperidin-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(1-benzyl-piperidin-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(1-ethyl-piperidin-3-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-acetic acid,   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-{1-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-piperidin-3-yl}-nicotinamide,   N-{1-[(2-hydroxy-ethylcarbamoyl)-methyl]-piperidin-3-yl}-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide, and   N-(4-fluoro-phenyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide.   
     
     
         31 . The compound of  claim 1 , selected from the group consisting of
 4-benzyloxy-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine,   1-methyl-2′-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-1,2,3,6-tetrahydro-[4,4′]bipyridinyl,   2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-isonicotinamide,   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-4-trifluoromethyl-nicotinamide,   5-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide,   N-isopropyl-5-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-furan-3-ylmethyl)-nicotinamide,   [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone,   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid isopropyl ester, and   6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide.   
     
     
         32 . The compound of  claim 1 , selected from the group consisting of
 6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,3,3,3-pentafluoro-propyl)-nicotinamide,   6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,   6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,   6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide,   N-cyclopropylmethyl-6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide,   6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,   6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,   6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide,   6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-cyclopropylmethyl-nicotinamide, and   6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-cyclopropyl-nicotinamide.   
     
     
         33 . The compound of  claim 1 , selected from the group consisting of
 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,   6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide,   N-cyclopropylmethyl-6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide,   6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,   N-cyclopropyl-6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide,   6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,   (1,1-dioxo-1λ 6 -thiomorpholin-4-yl)-{6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone,   3-{6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-oxetan-3-ol,   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, and   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide.   
     
     
         34 . The compound of  claim 1 , selected from the group consisting of
 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-cyclopropylmethyl-nicotinamide,   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-cyclopropyl-nicotinamide,   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,   {6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)-methanone,   {6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-morpholin-4-yl-methanone,   {6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-thiomorpholin-4-yl-methanone,   6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide,   6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide, and   6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide.   
     
     
         35 . The compound of  claim 1 , selected from the group consisting of
 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,   6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-nicotinamide,   N-cyclopropylmethyl-6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,   N-cyclopropyl-6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,   N-isopropyl-6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,   6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide,   N-isopropyl-6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinamide,   6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-N-(tetrahydro-pyran-4-yl)-nicotinamide,   6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-N-(2,2,2-trifluoro-ethyl)-nicotinamide, and   N-cyclopropylmethyl-6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinamide.   
     
     
         36 . The compound of  claim 1 , selected from the group consisting of
 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-N-isopropyl-nicotinamide,   N-cyclopropyl-6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino }-nicotinamide,   6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-N-(tetrahydro-pyran-4-yl)nicotinamide,   N-(2-hydroxy-1,1-dimethyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(2-methoxy-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(1,1-dioxo-tetrahydro-thiophen-3-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(3,3,3-trifluoro-2-hydroxy-propyl)-nicotinamide,   (4-hydroxy-piperidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone,   N-(3-hydroxy-2,2-dimethyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide, and   N-(2-isopropoxy-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide.   
     
     
         37 . The compound of  claim 1 , selected from the group consisting of
 N-(2-hydroxy-1-methyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   (3-hydroxy-azetidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone,   N-(2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(2-hydroxy-2-methyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(1-hydroxy-cyclopropylmethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N—((R)-2-hydroxy-1-methyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N—((S)-2-hydroxy-1-methyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-((1S,2S)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide, and   N-((1S,2R) and (1R,2S)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide.   
     
     
         38 . The compound of  claim 1 , selected from the group consisting of
 N-(2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(2-hydroxy-1-hydroxymethyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N—(S)-tetrahydro-furan-3-yl-nicotinamide,   N-((1R,2S)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-((1S,2R)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-((1S,2R)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-((1R,2S)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(2-acetylamino-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N—((S)-1-hydroxymethyl-2-methyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide, and   N—((S)-1-hydroxymethyl-3-methyl-butyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide.   
     
     
         39 . The compound of  claim 1 , selected from the group consisting of
 N—((S)-1-hydroxymethyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N—((R)-1-hydroxymethyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-((1R,2S)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-((1S,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-((1S,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-((1R,2S)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-((1S,2S)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-((1R,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-((1R,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-((1S,2S)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide.   
     
     
         40 . The compound of  claim 1 , selected from the group consisting of
 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-[2-(2-oxo-imidazolidin-1-yl)-ethyl]-nicotinamide,   N-(3-hydroxy-butyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-azetidine-1-carboxylic acid tert-butyl ester,   (2-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-ethyl)-carbamic acid tert-butyl ester,   N-(2,3-dihydroxy-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(3-hydroxy-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(4-hydroxy-butyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(5-hydroxy-pentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(6-hydroxy-hexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide, and   (3-hydroxy-pyrrolidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone.   
     
     
         41 . The compound of  claim 1 , selected from the group consisting of
 ((S)-2-hydroxymethyl-pyrrolidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone,   ((R)-2-hydroxymethyl-pyrrolidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone,   N-(3-benzyloxy-cyclobutyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-(2-methyl-pyrrolidin-1-yl)-methanone,   [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-pyrrolidin-1-yl-methanone,   (S)-2-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-3-phenyl-propionic acid methyl ester,   (cis or trans)-N-(3-benzyloxy-cyclobutyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   (S)-2-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-3-phenyl-propionic acid,   N-(3-methyl-oxetan-3-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide, and butane-1-sulfonic acid [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amide.   
     
     
         42 . The compound of  claim 1 , selected from the group consisting of
 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-1-methyl-ethyl)-nicotinamide,   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N—((S)-2,2,2-trifluoro-1-methyl-ethyl)-nicotinamide,   cyclopropanesulfonic acid methyl-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amide,   6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(1-methyl-1H-pyrazol-4-yl)-nicotinamide,   1-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-1,2-dihydro-pyrazol-3-one,   N-(1-methyl-cyclopropyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide,   azetidin-1-yl-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone,   (3-methoxy-azetidin-1-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone,   [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-thiazolidin-3-yl-methanone, and   N-(1-cyano-cyclopropyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide.   
     
     
         43 . The compound of  claim 1 , selected from the group consisting of
 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-nicotinamide,   5-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine,   2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,   2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-5-methylsulfanyl-pyridine,   5-methanesulfinyl-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine,   6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide   N-isopropyl-6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinamide,   6-(5-methyl-3-p-tolyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide   N-Isopropyl-6-(5-methyl-3-p-tolyl-isoxazol-4-ylmethoxy)-nicotinamide, and   6-[3-(2-fluoro-4-methyl-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide.   
     
     
         44 . The compound of  claim 1 , selected from the group consisting of
 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide,   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(1-methyl-1H-pyrazol-4-yl)-nicotinamide,   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N—((R)-2-hydroxy-1-methyl-ethyl)-nicotinamide,   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N—((S)-2-hydroxy-1-methyl-ethyl)-nicotinamide,   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N—((S)-2,2,2-trifluoro-1-methyl-ethyl)-nicotinamide,   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((1R,2R)-2-hydroxy-cyclopentyl)-nicotinamide,   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide,   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide,   6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((1R,2R)-2-hydroxy-cyclopentyl)-nicotinamide, and   6-[3-(2,3-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide.   
     
     
         45 . The compound of  claim 1 , selected from the group consisting of
 6-[3-(2,3-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,   6-[3-(2,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,   6-[3-(2,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,   6-[3-(2,5-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,   6-[3-(2,5-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,   6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide,   6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(3-hydroxy-2,2-dimethyl-propyl) -nicotinamide,   6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2-hydroxy-2-methyl-propyl)-nicotinamide,   6-[3-(4-chloro-2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide, and   6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester.   
     
     
         46 . The compound of  claim 1 , selected from the group consisting of
 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide,   N-isopropyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,   [6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-morpholin-4-yl-methanone,   6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-nicotinamide,   (1,1-dioxo-1,6-thiomorpholin-4-yl)-[6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-methanone,   N-cyclopropylmethyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,   N-cyclopropyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,   methyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,   ethyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide, and   (2-hydroxy-1,1-dimethyl-ethyl)-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide.   
     
     
         47 . The compound of  claim 1 , selected from the group consisting of
 [6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-thiomorpholin-4-yl-methanone,   6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid,   (2-hydroxy-ethyl)-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,   (2-methoxy-ethyl)-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester,   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid,   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(tetrahydro-pyran-4-yl)-nicotinamide,   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isopropyl-nicotinamide,   cyclopropyl-6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide, and   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy](2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide.   
     
     
         48 . The compound of  claim 1 , selected from the group consisting of
 cyclopropylmethyl-6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide,   (1,1-dioxo-1,6-thiomorpholin-4-yl)-{6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone,   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2,2,2-trifluoro-ethyl)-nicotinamide,   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(2-hydroxy-ethyl)-nicotinamide,   {6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-morpholin-4-yl-methanone,   ethyl-6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamide,   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-methyl-nicotinamide,   6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-N—((S)-2,2,2-trifluoro-1-methyl-ethyl)-nicotinamide,   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, and   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(tetrahydro-pyran-4-yl)-nicotinamide.   
     
     
         49 . The compound of  claim 1 , selected from the group consisting of
 6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isopropyl-nicotinamide,   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-cyclopropyl-nicotinamide,   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid,   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide,   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-cyclopropylmethyl-nicotinamide,   {6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-(1,1-dioxo-1,6-thiomorpholin-4-yl)-methanone,   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(2,2,2-trifluoro-ethyl)-nicotinamide,   {6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-morpholin-4-yl-methanone,   {6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-thiomorpholin-4-yl-methanone,   6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(2-hydroxy-ethyl)-nicotinamide, and   6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester.   
     
     
         50 . The compound of  claim 1 , selected from the group consisting of
 N-isopropyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,   N-cyclopropyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,   N-(2-hydroxy-1,1-dimethyl-ethyl)-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,   [6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-morpholin-4-yl-methanone,   N-ethyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,   N-methyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,   [6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-thiomorpholin-4-yl-methanone,   N-(2-hydroxy-ethyl)-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamide,   N-isopropyl-6-(3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide, and   6-(3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide,   
     
     
         51 . The compound of  claim 1 , selected from the group consisting of
 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1-methyl-ethyl)-nicotinamide,   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N—((R)-2-hydroxy-1-methyl-ethyl)-nicotinamide,   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N—((S)-2-hydroxy-1-methyl-ethyl)-nicotinamide,   N-cyclopropylmethyl-6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinamide,   N-cyclopropyl-6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinamide,   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide,   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide.   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1R,2R)-2-hydroxy-cyclopentyl)-nicotinamide, and   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide.   
     
     
         52 . The compound of  claim 1 , selected from the group consisting of
 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-nicotinamide,   N-(2-acetylamino-ethyl)-6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinamide,   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-methoxy-ethyl)-nicotinamide,   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N—((R)-2-hydroxy-propyl)-nicotinamide,   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-ethyl)-nicotinamide,   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-(1-hydroxy-cyclopropylmethyl)-nicotinamide,   N-(1,1-dioxo-tetrahydro-1,6-thiophen-3-yl)-6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinamide,   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1R,2R)-2-hydroxy-cyclopentyl)-nicotinamide,   6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide, and   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluoro-ethyl)-nicotinamide.   
     
     
         53 . The compound of  claim 1 , selected from the group consisting of
 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-cyclopropyl-nicotinamide,   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamide,   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamide,   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-ethyl)-nicotinamide,   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-propyl)-nicotinamide,   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(3-hydroxy-propyl)-nicotinamide,   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide,   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(3-hydroxy-2,2-dimethyl-propyl)-nicotinamide, and   3-({6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyridine-3-carbonyl}-amino)-azetidine-1-carboxylic acid tert-butyl ester.   
     
     
         54 . The compound of  claim 1 , selected from the group consisting of
 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-((1S,2S)-2-hydroxy-cyclopentyl)-nicotinamide,   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-((1R,2R)-2-hydroxy-cyclopentyl)-nicotinamide,   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-nicotinamide,   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N—((R)-2-hydroxy-1-methyl-ethyl)-nicotinamide,   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N—((S)-2-hydroxy-1-methyl-ethyl)-nicotinamide,   N-(2-acetylamino-ethyl)-6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinamide,   6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-N—((S)-2,2,2-trifluoro-1-methyl-ethyl)-nicotinamide,   6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide,   N-isopropyl-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,   N-cyclopropyl-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,   N-cyclopropylmethyl-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide, and   6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluoro-ethyl)-nicotinamide.   
     
     
         55 . The compound of  claim 1 , selected from the group consisting of
 N-(2-hydroxy-ethyl)-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,   N-ethyl-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamide,   6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(tetrahydro-pyran-4-yl)-nicotinamide,   6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-isopropyl-nicotinamide,   cyclopropyl-6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinamide,   6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide,   6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(2,2,2-trifluoro-ethyl)-nicotinamide.   6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(2-hydroxy-ethyl)-nicotinamide,   ethyl-6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinamide, and   6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-methyl-nicotinamide.   
     
     
         56 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         X is O or NH; 
         R 1  is phenyl, pyridinyl, or pyrimidinyl, each optionally substituted with 1, 2 or 3 halo, 
         R 2  is H or CH 3  or CF 3 ; 
         R 3 , R 4 , R 5 , and R 6  each are independently
 H, 
 C 1-7 alkyl, optionally substituted with one or more halo, cyano, or hydroxy, 
 C 1-7 alkoxy, optionally substituted with one or more halo, 
 CN, 
 halo, 
 NO 2 , 
 S—C 1-7 alkyl, 
 S(O)—C 1-7 alkyl 
 benzyloxy, optionally substituted with one or more E, 
 —C(O)—R a , wherein R a  is hydroxy, C 1-7 alkoxy, C 1-7 alkyl, phenoxy or phenyl, 
 3- to 7-membered heterocyclyl, optionally substituted with one or more A, 
 —C(O)—NR b R c , wherein R b  and R c  are each independently
 H, 
 C 1-7 alkyl, optionally substituted with one or more halo, methyl, —(CH 2 ) t -hydroxy, or cyano, 
 —(CH 2 ) t —C 3-7 cycloalkyl, optionally substituted by one or more B, and t is 0, 1, 2, 3, 4, 5 or 6, 
 —(CH 2 ) u —O—C 1-7 alkyl, wherein u is 2, 3, 4, 5 or 6, 
 —CHR i —C(O)OR ii , wherein R i  is H, benzyl or C 1-4 alkyl, and R ii  is H or C 1-7 alkyl, 
 —S(O) 2 —C 1-7 alkyl, 
 —S(O) 2 —C 3-7 cycloalkyl, 
 —(CH 2 CH 2 O) v R iii , wherein v is from 1 to 3, and R iii  is H or C 1-7 alkyl, 
 —(CH 2 ) w -heteroaryl or —(CH 2 ) w -aryl, each optionally substituted by one or more E, and wherein w is 0, 1, 2, 3, or 4, 
 —(CH 2 ) x -heterocyclyl, wherein x is 0, 1, 2, 3 or 4, and wherein heterocyclyl is
 optionally substituted by one or more 
 oxo, 
 C 1-7 alkyl, 
 C 3-7 cycloalkyl, optionally substituted with one or more B, 
 CN, 
 benzyl, optionally substituted with one or more E, 
 —(CH 2 ) y —C(O)R iv , wherein y is 0, 1, 2, 3 or 4, and R iv  is hydroxy, C 1-7 alkyl, or C 1-7 alkoxy, 
 —(CH 2 ) z —C(O)NR v R vi , —(CH 2 ) z  NR v R vi —C(O)—C 1-7 alkyl or —(CH 2 ) z  NR v R vi —C(O)—O—C 1-7 alkyl, wherein z is 0, 1, 2, 3 or 4, 
 and R v  and R vi  are independently 
  hydrogen, 
  C 1-7 alkyl, optionally substituted by one or more halo, OH or CN, 
  C 3-7 cycloalkyl, optionally substitutued by one or more B, 
  5- or 6-membered heterocyclyl, optionally substituted by one or more A, or 
  R v  and R vi  together with the nitrogen to which they are bound form a 5- or 6-membered heterocycloalkyl, optionally substituted by one or more A, or 
 
 R b  and R c  together with the nitrogen to which they are bound form a heterocyclyl or heteroaryl moiety, optionally substituted with one or more A, or 
 R b  and R c  together with the nitrogen to which they are bound form a 7- to 12-membered spirocyclic heterocycle, optionally substituted with one or more A; 
 with the proviso that R b  and R c  are not simultaneously H, 
 
 
         A is hydroxy, oxo, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, halo, or CN; 
         B is halo, hydroxy, CN, C 1-4 alkyl, benzyloxy, or C 1-4 haloalkyl; and 
         E is halo, CN, NO 2 , hydroxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 cyanoalkyl, C 1-7 haloalkoxy, or C 3-7 cycloalkyl; 
         or a pharmaceutically acceptable salt thereof 
         and a pharmaceutically acceptable carrier.