Isoxazolyl ether derivatives as gaba a alpha5 pam

Abstract

Compounds having the formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y and Z are as described herein, compositions including the compounds and methods of using the compounds.

1 . A method for treatment of prophylaxis of a disease mediated by GABA A  α5 receptor, the method comprising administering, to a subject in need thereof, an effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         X is selected from
 i) N, and 
 ii) CH; 
 
         Y is selected from
 i) N, and 
 ii) CR 10 ; 
 
         Z is selected from
 i) N, and 
 ii) CR 11 ; 
 
         R 1  is selected from
 i) C 1-6 -alkyl, 
 ii) halo-C 1-6 -alkyl, 
 iii) C 1-6 -alkoxy, 
 iv) halo-C 1-6 -alkoxy, 
 v) hydroxy-C 1-6 -alkyl, 
 vi) C 3-8 -cycloalkyl, 
 vii) halogen, and 
 viii) amino substituted on the nitrogen atom by one or two substituents independently selected from
 a. H, 
 b. C 1-6 -alkyl, and 
 c. C 3-8 -cycloalkyl; 
 
 
         R 2  is selected from
 i) H, and 
 ii) halogen; 
 
         R 3  is selected from
 i) H, 
 ii) C 1-6 -alkyl, 
 iii) C 3-8 -cycloalkyl, 
 iv) hydroxy-C 1-6 -alkyl, and 
 v) halo-C 1-6 -alkyl; 
 
         R 4  is selected from
 i) H, 
 ii) C 1-6 -alkyl, 
 iii) C 1-6 -alkoxy, 
 iv) C 3-8 -cycloalkyl, and 
 v) halogen; 
 
         R 5  is H; 
         R 6  is selected from
 i) H, 
 ii) C 1-6 -alkyl, 
 iii) C 3-8 -cycloalkyl substituted with R 7 , R 8  and R 9 , 
 iv) C 3-8 -cycloalkyl-C 1-6 -alkyl substituted with R 7 , R 8  and R 9 , 
 v) C 1-6 -alkylsulfonyl-C 1-6 -alkyl, 
 vi) cyano-C 1-6 -alkyl, 
 vii) hydroxy-C 1-6 -alkyl, 
 viii) dihydroxy-C 1-6 -alkyl, 
 ix) halo-C 1-6 -alkyl, 
 x) heterocycloalkyl substituted with R 7 , R 8  and R 9 , and 
 xi) heterocycloalkyl-C 1-6 -alkyl substituted with R 7 , R 8  and R 9 ; 
 
         R 7 , R 8  and R 9  are independently selected from
 i) H, 
 ii) C 1-6 -alkyl, 
 iii) C 1-6 -alkoxy, 
 iv) C 1-6 -alkoxyalkyl, 
 v) C 1-6 -alkoxycarbonyl, 
 vi) cyano, 
 vii) C 3-8 -cycloalkoxy, 
 viii) C 3-8 -cycloalkyl, 
 ix) halo-C 1-6 -alkoxy, 
 x) halo-C 1-6 -alkyl, 
 xi) halogen, 
 xii) hydroxy, 
 xiii) hydroxy-C 1-6 -alkyl, and 
 xiv) oxo; 
 
         R 10  is selected from
 i) H, 
 ii) C 1-6 -alkyl, 
 iii) C 1-6 -alkoxy, 
 iv) C 3-8 -cycloalkyl, and 
 v) halogen; 
 
         R 11  is selected from
 i) H, 
 ii) C 1-6 -alkyl, 
 iii) C 1-6 -alkoxy, 
 iv) C 3-8 -cycloalkyl, and 
 v) halogen; 
 
         or R 5  and R 10  together form —(CH 2 ) n —; 
         or R 5  and R 11  together form —(CH 2 ) n —; 
         or R 5  and R 6  together with the nitrogen atom to which they are attached form a heterocycloalkyl substituted with R 7 , R 8  and R 9 ; 
         n is selected from 1 and 2; 
         or pharmaceutically acceptable salts. 
       
     
     
         2 . The method of  claim 1 , wherein
 X is selected from
 i) N, and 
 ii) CH; 
   Y is selected from
 i) N, and 
 ii) CR 10 ; 
   Z is selected from
 i) N, and 
 ii) CR 11 ; 
   R 1  is selected from
 i) C 1-6 -alkyl, 
 ii) halo-C 1-6 -alkyl, 
 iii) C 1-6 -alkoxy, 
 iv) C 3-8 -cycloalkyl, 
 v) halogen, and 
 vi) amino substituted on the nitrogen atom by two independently selected C 1-6 -alkyl; 
   R 2  is selected from
 i) H, 
 ii) halogen; 
   R 3  is selected from
 i) H, 
 ii) C 1-6 -alkyl, 
 iii) C 3-8 -cycloalkyl, and 
 iv) halo-C 1-6 -alkyl; 
   R 4  is selected from
 i) H, and 
 ii) C 1-6 -alkyl; 
   R 5  is H;   R 6  is selected from
 i) H, 
 ii) C 1-6 -alkyl, 
 iii) C 3-8 -cycloalkyl substituted with R 7 , R 8  and R 9 , wherein R 7 , R 8  and R 9  are independently selected from
 a. H, 
 b. C 1-6 -alkyl, 
 c. C 1-6 -alkoxy, 
 d. C 1-6 -alkoxyalkyl, 
 e. C 1-6 -alkoxycarbonyl, 
 f. cyano, 
 g. C 3-8 -cycloalkoxy, 
 h. halo-C 1-6 -alkoxy, 
 i. halo-C 1-6 -alkyl, 
 j. halogen, 
 k. hydroxy, and 
 l. hydroxy-C 1-6 -alkyl; 
 
 iv) C 3-8 -cycloalkyl-C 1-6 -alkyl substituted with R 7 , R 8  and R 9 , wherein R 7 , R 8  and B 9  are independently selected from
 a. H, 
 b. C 1-6 -alkyl, 
 c. C 1-6 -alkoxy, 
 d. C 1-6 -alkoxyalkyl, 
 e. C 1-6 -alkoxycarbonyl, 
 f. cyano, 
 g. C 3-8 -cycloalkoxy, 
 h. halo-C 1-6 -alkoxy, 
 i. halo-C 1-6 -alkyl, 
 j. halogen, 
 k. hydroxy, and 
 l. hydroxy-C 1-6 -alkyl; 
 
 v) C 1-6 -alkylsulfonyl-C 1-6 -alkyl, 
 vi) cyano-C 1-6 -alkyl, 
 vii) dihydroxy-C 1-6 -alkyl, 
 viii) halo-C 1-6 -alkyl, 
 ix) heterocycloalkyl substituted with R 7 , R 8  and R 9 , wherein R 7 , R 8  and R 9  are independently selected from
 a. H, 
 b. C 1-6 -alkyl, 
 c. hydroxy, and 
 d. oxo; 
 
  and wherein the heterocycloalkyl is selected from
 a. oxetanyl, 
 b. tetrahydrofuranyl, 
 c. tetrahydropyranyl, 
 d. oxepanyl, 
 e. oxabicyclo[2.2.1]heptanyl, 
 f. oxaspiro[3.3]heptanyl, 
 g. azetidinyl, 
 h. tetrahydrothiophenyl, and 
 i. tetrahydrothiopyranyl; and 
 
 x) oxetanyl-C 1-6 -alkyl substituted with R 7 , R 8  and R 9 , wherein R 7 , R 8  and R 9  are independently selected from
 a. H, 
 b. hydroxy; 
 
   R 10  is selected from
 i) H, and 
 ii) halogen; 
   R 11  is selected from
 i) H, 
 ii) C 1-6 -alkyl, and 
 iii) C 1-6 -alkoxy; 
   or R 5  and R 10  together form —(CH 2 ) n —;   or R 5  and R 11  together form —(CH 2 ) n —;   or R 5  and R 6  together with the nitrogen atom to which they are attached form a heterocycloalkyl substituted with R 7 , R 8  and R 9 , wherein R 7 , R 8  and R 9  are independently selected from    a. H,    b. C 1-6 -alkyl,    c. C 1-6 -alkoxy,    d. cyano,    e. halogen,    f. hydroxy, and    g. oxo;   and wherein the heterocycloalkyl is selected from    a. azetidinyl,    b. pyrrolidinyl,    c. piperidinyl,    d. morpholinyl,    e. thiomorpholinyl,    f. oxaazabicyclo[3.1.1]heptanyl,    g. oxaazabicyclo[2.2.1]heptanyl,    h. azaspiro[3.3]heptanyl,    i. oxaazaspiro[3.3]heptanyl,    j. thiaazaspiro[3.3]heptanyl;   n is 1;   or pharmaceutically acceptable salts.   
     
     
         3 . The method of  claim 1 , wherein
 X is selected from
 i) N, and 
 ii) CH; 
   Y is selected from
 i) N, and 
 ii) CR 10 ; 
   Z is selected from
 i) N, and 
 ii) CR 11 ; 
   R 1  is selected from
 i) C 1-6 -alkyl, 
 ii) halo-C 1-6 -alkyl, 
 iii) C 1-6 -alkoxy, 
 iv) C 3-8 -cycloalkyl, 
 v) halogen, and 
 vi) amino substituted on the nitrogen atom by two independently selected C 1-6 -alkyl; 
   R 2  is selected from
 i) H, 
 ii) halogen; 
   R 3  is selected from
 i) H, 
 ii) C 1-6 -alkyl, 
 iii) C 3-8 -cycloalkyl, and 
 iv) halo-C 1-6 -alkyl; 
   R 4  is selected from
 i) H, and 
 ii) C 1-6 -alkyl; 
   R 5  is H;   R 6  is selected from
 i) H, 
 ii) C 1-6 -alkyl, 
 iii) C 3-8 -cycloalkyl substituted with R 7 , R 8  and R 9 , wherein R 7 , R 8  and R 9  are independently selected from
 a. H, 
 b. C 1-6 -alkyl, 
 c. C 1-6 -alkoxy, 
 d. C 1-6 -alkoxyalkyl, 
 e. C 1-6 -alkoxycarbonyl, 
 f. cyano, 
 g. C 3-8 -cycloalkoxy, 
 h. halo-C 1-6 -alkoxy, 
 i. halo-C 1-6 -alkyl, 
 j. halogen, 
 k. hydroxy, and 
 l. hydroxy-C 1-6 -alkyl; 
 
 iv) C 3-8 -cycloalkyl-C 1-6 -alkyl substituted with R 7 , R 8  and R 9 , wherein R 7 , R 8  and R 9  are independently selected from
 a. H, 
 b. C 1-6 -alkyl, 
 c. C 1-6 -alkoxy, 
 d. C 1-6 -alkoxyalkyl, 
 e. C 1-6 -alkoxycarbonyl, 
 f. cyano, 
 g. C 3-8 -cycloalkoxy, 
 h. halo-C 1-6 -alkoxy, 
 i. halo-C 1-6 -alkyl, 
 j. halogen, 
 k. hydroxy, and 
 l. hydroxy-C 1-6 -alkyl; 
 
 v) C 1-6 -alkylsulfonyl-C 1-6 -alkyl, 
 vi) cyano-C 1-6 -alkyl, 
 vii) dihydroxy-C 1-6 -alkyl, 
 viii) halo-C 1-6 -alkyl, 
 ix) heterocycloalkyl substituted with R 7 , R 8  and R 9 , wherein R 7 , R 8  and R 9  are independently selected from
 a. H, 
 b. C 1-6 -alkyl, 
 c. hydroxy, and 
 d. oxo; 
 
  and wherein the heterocycloalkyl is selected from
 a. oxetanyl, 
 b. tetrahydrofuranyl, 
 c. tetrahydropyranyl, 
 d. oxepanyl, 
 e. oxabicyclo[2.2.1]heptanyl, 
 f. oxaspiro[3.3]heptanyl, 
 g. azetidinyl, 
 h. tetrahydrothiophenyl, and 
 i. tetrahydrothiopyranyl; and 
 
 x) oxetanyl-C 1-6 -alkyl substituted with R 7 , R 8  and R 9 , wherein R 7 , R 8  and R 9  are independently selected from
 a. H, 
 b. hydroxy; 
 
   R 10  is selected from
 i) H, and 
 ii) halogen; 
   R 11  is selected from
 i) H, 
 ii) C 1-6 -alkyl, and 
 iii) C 1-6 -alkoxy; 
   or pharmaceutically acceptable salts.   
     
     
         4 . The method of  claim 1 , wherein
 X is selected from
 i) N, and 
 ii) CH; 
   Y is selected from
 i) N, and 
 ii) CR 10 ; 
   Z is CR 11 ;   R 1  is C 1-6 -alkyl;   R 2  is selected from
 i) H, 
 ii) halogen; 
   R 3  is selected from
 i) C 1-6 -alkyl, 
 ii) C 3-8 -cycloalkyl, and 
 iii) halo-C 1-6 -alkyl; 
   R 4  is selected from
 i) H, and 
 ii) C 1-6 -alkyl; 
   R 5  is H;   R 6  is selected from
 i) C 1-6 -alkyl, 
 ii) C 3-8 -cycloalkyl substituted with R 7 , R 8  and R 9 , wherein R 7 , R 8  and R 9  are independently selected from
 a. H, 
 b. C 1-6 -alkyl, 
 c. C 1-6 -alkoxyalkyl, and 
 d. halo-C 1-6 -alkyl; 
 
 iii) hydroxy-C 1-6 -alkyl, 
 iv) halo-C 1-6 -alkyl, 
 v) heterocycloalkyl substituted with R 7 , R 8  and R 9 , wherein R 7 , R 8  and R 9  are independently selected from
 a. H, and 
 b. C 1-6 -alkyl; 
 
  and wherein the heterocycloalkyl is selected from
 a. oxetanyl, 
 b. tetrahydrofuranyl, 
 c. tetrahydropyranyl, 
 d. oxepanyl, and 
 e. oxaspiro[3.3]heptanyl; 
 
   R 10  is H;   R 11  is H;   or pharmaceutically acceptable salts.   
     
     
         5 . The method of  claim 1 , wherein
 X is CH;   Y is N;   Z is CR 11 ;   R 1  is C 1-6 -alkyl;   R 2  is H;   R 3  is C 1-6 -alkyl;   R 4  is H;   RS is H;   R is heterocycloalkyl substituted with R 7 , R 8  and R 9 ;   R 7 , R 8  and R 9  are H;   R 11  is H;   or pharmaceutically acceptable salts.   
     
     
         6 . The method of  claim 1 , wherein
 X is CH;   Y is N;   Z is CR 11 ;   R 1  is C 1-6 -alkyl;   R 2  is H;   R 3  is C 1-6 -alkyl;   R 4  is H;   R 5  is H;   R 6  is tetrahydropyranyl substituted with R 7 , R 8  and R 9 ;   R 7 , R 8  and R 9  are H;   R 11  is H;   or pharmaceutically acceptable salts.   
     
     
         7 . The method of  claim 1 , wherein the compound is selected from
 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide;   N-(cyclopropylmethyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide;   N-ethyl-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide;   N-((1S)-1-(hydroxymethyl)butyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide;   6-((5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3-carboxamide;   6-((5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide;   (S)—N-(1-hydroxypentan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide;   2-isobutyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;   2-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;   N-isobutyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;   2-(2-hydroxyethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;   (S)-2-(1-hydroxypentan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;   (S)—N-(1-hydroxypentan-2-yl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;   5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide;   N-(1,1-dioxothiolan-3-yl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-((3S)-1,1-dioxothiolan-3-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyridine-3-carboxamide;   N-((3R)-1,1-dioxothiolan-3-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyridine-3-carboxamide;   N-(1,1-dioxothian-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyridine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;   N-((1S,2R)-2-Hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-((1S,2S)-2-Hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-((1R,2R)-2-Hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-cyclopropyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-((1R,2S)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-((3S,4R)-3-hydroxytetrahydropyran-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-(2-hydroxyethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-(1,1-dioxothian-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-(cyclopropylmethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-(cyclopropylmethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-(2-cyanoethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   (RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1,1,1-trifluoropropan-2-yl)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(oxetan-3-yl)pyridazine-3-carboxamide;   (RS)—N-(1,1-dioxothiolan-3-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-ethyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-isopropyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-isobutyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2,2,2-trifluoroethyl)pyridazine-3-carboxamide;   N-tert-butyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-(3,3-difluorocyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-(4,4-difluorocyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   6-((3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide;   (RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide;   N-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   (3,3-difluoroazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;   (3,3-difluoropyrrolidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-((3-methyloxetan-3-yl)methyl)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-(oxetan-3-ylmethyl)pyridazine-3-carboxamide;   N-((3-hydroxyoxetan-3-yl)methyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-((3R,4R)-3-methyltetrahydropyran-4-yl)pyridazine-3-carboxamide;   (4,4-difluoropiperidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;   N-(1-(methoxymethyl)cyclopropyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   (3-methoxyazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;   (3-hydroxy-3-methylazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;   azetidin-1-yl(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;   (RS)—N-(2,2-dimethyltetrahydropyran-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-(trifluoromethyl)cyclopropyl)pyridazine-3-carboxamide;   (6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)(morpholino)methanone;   (6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone;   4-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide;   (6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridazine-3-carboxamide;   (3-fluoroazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;   (3-hydroxyazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;   (3-fluoro-3-methylazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;   ethyl 1-(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamido)cyclopropanecarboxylate;   N-(1-cyanocyclopropyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   5-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   5-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide;   N-(1,1-dioxothian-4-yl)-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;   N-(2-hydroxy-1,1-dimethyl-ethyl)-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;   N-cyclopropyl-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;   (RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclopropyl)pyridazine-3-carboxamide;   5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-(oxetan-3-yl)pyrazine-2-carboxamide;   5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-(2,2,2-trifluoroethyl)pyrazine-2-carboxamide;   N-(4-hydroxy-2-methylbutan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-methyl-4-(methylsulfonyl)butan-2-yl)pyridazine-3-carboxamide;   (S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide;   (R)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide;   1-(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carbonyl)azetidine-3-carbonitrile;   N-(1-(hydroxymethyl)cyclopropyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-(4,4-difluorocyclohexyl)-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;   (S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide;   (S)—N-(1-cyanobutan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   (R)-5-((5-Methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyrazine-2-carboxamide;   N-(2-Hydroxyethyl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;   2-(1,1-Dioxothian-4-yl)-6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]-1#H!-pyrrolo[3,4-c]pyridin-3-one;   (S)-5-((5-Methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyrazine-2-carboxamide;   2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy]-6-tetrahydropyran-4-yl-7H-pyrrolo[3,4-b]pyridin-5-one;   N-(1,1-Dioxothiolan-3-yl)-5-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyrazine-2-carboxamide;   N-(Cyclopropylmethyl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;   2-(4,4-Difluorocyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;   6-((5-Methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4-methyltetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide;   (R)-5-((5-Methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-3-yl)pyrazine-2-carboxamide;   (R)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-3-yl)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide;   5-((5-Methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyrazine-2-carboxamide;   5-((5-Methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-((cis)-4-(trifluoromethyl)cyclohexyl)pyrazine-2-carboxamide;   (S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-3-yl)pyridazine-3-carboxamide;   N-((cis)-4-Hydroxy-4-methylcyclohexyl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;   N-((trans)-4-Hydroxy-4-methylcyclohexyl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4-methyltetrahydro-2H-pyran-4-yl)nicotinamide;   6-((5-Methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-2-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;   6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide;   N-((1S)-1-(hydroxymethyl)butyl)-6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4-methyltetrahydrothiopyran-4-yl)pyridazine-3-carboxamide;   N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   (2,2-dioxido-2-thia-6-azaspiro[3.3]heptan-6-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;   (2,2-Dioxido-2-thia-6-azaspiro[3.3]heptan-6-yl)(5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazin-2-yl)methanone;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclopentyl)pyridazine-3-carboxamide;   5-((5-Methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4,4,4-trifluorobutyl)pyrazine-2-carboxamide;   N-(1-isopropylazetidin-3-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   6-((5-Methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-2-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclobutyl)pyridazine-3-carboxamide;   6-((5-Ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide;   N-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;   6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide;   6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide;   N-cyclopropyl-6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   (R)—N-(1-hydroxypentan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;   6-((5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3-carboxamide;   6-((5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide;   N-((3R,4S)-3-hydroxytetrahydropyran-4-yl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide;   6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide;   6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3-carboxamide;   6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-(1,1-dioxothian-4-yl)pyridine-3-carboxamide;   N-((1R,2S)-3,3-difluoro-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;   N-((1R,2R)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;   N-((1S,2R)-3,3-difluoro-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;   N-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;   N-((1S,2S)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;   2-fluoro-N-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;   6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide;   N-isopropyl-6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)nicotinamide;   (S)—N-(1-hydroxypentan-2-yl)-6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)nicotinamide;   (1,1-dioxidothiomorpholino)(6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)pyridin-3-yl)methanone;   (S)-6-((3-(6-(dimethylamino)pyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(1-hydroxypentan-2-yl)nicotinamide;   4-methoxy-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide;   6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide;   6((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-isopropyl-pyridine-3-carboxamide;   6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3-carboxamide;   N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-(1,3-dihydroxy-2-methylpropan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-((1R,3S)-3-hydroxy-3-(trifluoromethyl)cyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-((1S,3R)-3-hydroxy-3-(trifluoromethyl)cyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;   N-((1RS,3RS)-3-hydroxycyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   trans-N-(4-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   trans-N-(4-methoxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   (6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;   N-(3-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   3-oxa-6-azabicyclo[3.1.1]heptan-6-yl(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;   cis-N-(4-methoxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   6-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide;   (S)-6-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide;   6-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide;   6-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide;   trans-N-(3-methoxycyclobutyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   cis-N-(3-methoxycyclobutyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   6-((5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide;   trans-N-((1RS,3RS)-3-methoxycyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-(6,6-difluorospiro[3.3]heptan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   6-((5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide;   cis-N-3-((2,2-difluoroethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   trans-N-3-((2,2-difluoroethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   cis-N-(3-ethoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   trans-N-(3-ethoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   cis-N-(3-(difluoromethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   trans-N-(3-(difluoromethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   trans-N-(3-cyclopropoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   cis-N-(3-cyclopropoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   6-((3-(6-chloropyridin-3-yl)-5-cyclopropylisoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide;   6-((3-(6-chloropyridin-3-yl)-5-cyclopropylisoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide;   (S)-6-((3-(6-chloropyridin-3-yl)-5-cyclopropylisoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide;   6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide;   6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide;   (S)-6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide;   6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide;   6-((5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-(trifluoromethyl)cyclopropyl)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide;   N-((2S)-7-oxabicyclo[2.2.1]heptan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   (RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(oxepan-4-yl)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1R,3S,4R)-7-oxabicyclo[2.2.1]heptan-3-yl)pyridazine-3-carboxamide;   N-((2R)-7-oxabicyclo[2.2.1]heptan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-((1R,3R)-3-ethoxycyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-((1R,3R)-3-(2,2-difluoroethoxy)cyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   6-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide;   N-[4-(2,2-difluoroethoxy)cyclohexyl]-6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]pyridazine-3-carboxamide;   N-(4-ethoxycyclohexyl)-6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]pyridazine-3-carboxamide;   or pharmaceutically acceptable salts.   
     
     
         8 . The method of  claim 1 , wherein the compound is selected from
 N-((1S)-1-(hydroxymethyl)butyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide;   N-cyclopropyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   (RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1,1,1-trifluoropropan-2-yl)pyridazine-3-carboxamide;   N-isopropyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-tert-butyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   N-(1-(methoxymethyl)cyclopropyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-(trifluoromethyl)cyclopropyl)pyridazine-3-carboxamide;   5-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclopropyl)pyridazine-3-carboxamide;   (S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide;   (R)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide;   (S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide;   6-((5-Methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4-methyltetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide;   (R)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-3-yl)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclobutyl)pyridazine-3-carboxamide;   6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3-carboxamide;   6-((5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide;   6-((5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide;   6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide;   (RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(oxepan-4-yl)pyridazine-3-carboxamide;   6-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide;   6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide;   or pharmaceutically acceptable salts.   
     
     
         9 . The method of  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         10 . The method of  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         11 . The method of  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         14 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         15 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         16 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         18 . The method of  claim 1 , wherein the disease is Alzheimer's disease, mild cognitive impairment, age-related cognitive decline, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism spectrum disorder, Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis, or fragile-X disorder.