Imidazotriazinone compounds

Abstract

The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including humans.

1 . (canceled) 
     
     
         2 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         X is selected from a bond, C(O) or S(O) 2 ; 
         R 1  is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, (C 3 -C 7 ) cycloalkyloxy, heterocycloalkyl, heterocycloalkyl(C 1 -C 4 )alkyl and heterocycloalkyloxy, each of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, —S(O) 2 (C 1 -C 4 ) alkyl, OH, —C(O)—(C 1 -C 4 ) alkyl, oxo, CN, (C 1 -C 6 ) alkyl, (C 1 -C 4 )alkoxy, (C 3 -C 7 )cycloalkyl, —C(O)NH(C 1 -C 4 )alkyl, —C(O)N[(C 1 -C 4 )alkyl(C 1 -C 4 )alkyl], (C 1 -C 4 alkyl)-C(O)—, (C 1 -C 4 )alkylsulfonyl-, —S(O) 2 NH(C 1 -C 4 )alkyl, and —S(O) 2 N[(C 1 -C 4 )alkyl(C 1 -C 4 )alkyl]; 
         R 2  is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, heterocycloalkyl, heterocycloalkyl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 )alkyl, restricted phenyl and restricted phenyl(C 1 -C 4 )alkyl, each of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, —S(O) 2 (C 1 -C 4 )alkyl, OH, —C(O(C 1 -C 4 )alkyl, oxo, CN, (C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy, (C 3 -C 7 )cycloalkyl, —C(O)NH(C 1 -C 4 )alkyl, —C(O)N[(C 1 -C 4 )alkyl(C 1 -C 4 )alkyl], (C 1 -C 4 alkyl)-C(O)—, (C 1 -C 4 )alkylsulfonyl-, —S(O) 2 NH(C 1 -C 4 )alkyl, and —S(O) 2 N[(C 1 -C 4 )alkyl(C 1 -C 4 )alkyl]; and 
         R 3  is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, heterocycloalkyl, heterocycloalkyl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 )alkyl, restricted phenyl and restricted phenyl(C 1 -C 4 )alkyl, each of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, —S(O) 2 (C 1 -C 4 )alkyl, OH, —C(O(C 1 -C 4 )alkyl, oxo, CN, (C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy, (C 3 -C 7 )cycloalkyl, —C(O)NH(C 1 -C 4 )alkyl, —C(O)N[(C 1 -C 4 )alkyl(C 1 -C 4 )alkyl], (C 1 -C 4 alkyl)-C(O)—, (C 1 -C 4 )alkylsulfonyl-, —S(O) 2 NH(C 1 -C 4 )alkyl, and —S(O) 2 N[(C 1 -C 4 )alkyl(C 1 -C 4 )alkyl]. 
       
     
     
         3 . The compound of  claim 2 , wherein
 X is a bond;   R 1  is independently selected from the group consisting of (C 1 -C 6 )alkyl and (C 1 -C 6 ) alkoxy;   R 2  is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, heterocycloalkyl, heteroaryl, and restricted phenyl, each of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, —S(O) 2 (C 1 -C 4 )alkyl, OH, (C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy, and (C 1 -C 4 alkyl)-C(O)—; and   R 3  is independently selected from the group consisting of (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, heterocycloalkyl, heteroaryl(C 1 -C 4 )alkyl, and restricted phenyl(C 1 -C 4 )alkyl, each of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, CN, (C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy, and (C 1 -C 4 alkyl)-C(O)—.   
     
     
         4 . The compound of  claim 2 , wherein
 X is a bond;   R 1  is (C 1 -C 6 ) alkyl;   R 2  is selected from the group consisting of heterocycloalkyl, (C 3 -C 10 )cycloalkyl, and restricted phenyl, each of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, —S(0) 2 (C 1 -C 4 )alkyl, OH, —C(O)—(C 1 -C 4 )alkyl, CN, (C 1 -C 6 )alkyl, and (C 1 -C 4 )alkoxy; and   R 3  is selected from the group consisting of a mono or bicyclic heteroaryl(C 1 -C 4 )alkyl and restricted phenyl(C 1 -C 4 )alkyl, each of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, —S(O) 2 (C 1 -C 4 )alkyl, OH, —C(O)—(C 1 -C 4 )alkyl, CN, (C 1 -C 4 )alkyl, and (C 1 -C 4 )alkoxy.   
     
     
         5 . The compound of  claim 2 , wherein R 2  is tetrahydropyranyl. 
     
     
         6 . The compound of  claim 2 , wherein R 1  is methyl. 
     
     
         7 . The compound of  claim 2 , wherein R 3  is pyrimidinylmethyl-, which may be optionally substituted with one or more substituents selected from the group consisting of halogen, —S(O) 2 (C 1 -C 4 )alkyl, OH, —C(O)—(C 1 -C 4 )alkyl, CN, (C 1 -C 6 )alkyl, and (C 1 -C 4 )alkoxy; or
 R 3  is (restricted phenyl)methyl-, which may be optionally substituted with one or more substituents selected from the group consisting of halogen, —S(O) 2 (C 1 -C 4 )alkyl, OH, —C(O)—(C 1 -C 4 )alkyl, CN, (C 1 -C 6 )alkyl, and (C 1 -C 4 )alkoxy. 
 
     
     
         8 . The compound of  claim 2 , wherein the compound is selected from one of the following:
 (−)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one;   (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one;   (+)-2-((3,4-trans)-1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-2-((3,4-trans)-1-(imidazo[1,2-b]pyridazin-6-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-2-((3,4-trans)-1-(3-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-2-((3,4-trans)-1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-3-(((3,4-trans)-3-methyl-4-(4-oxo-7-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl)methyl)benzonitrile;   (−)-4-(((3,4-trans)-3-methyl-4-(4-oxo-7-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl)methyl)benzonitrile;   (+)-2-((3,4-trans)-1-(2-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-2-(((3,4-trans)-3-methyl-4-(4-oxo-7-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl)methyl)benzonitrile;   (+)-2-((3,4-trans)-4-methyl-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-2-((3,4-trans)-4-methyl-1-(quinolin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-2-((3,4-trans)-4-methyl-1-(quinazolin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-2-((3,4-trans)-4-methyl-1-(quinolin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-7-((1s,3R)-adamantan-1-yl)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-7-((1s,3R)-adamantan-1-yl)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(5-chloro-2-methylphenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(5-chloro-2-methylphenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(4-fluoro-2-methylphenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(4-fluoro-2-methylphenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(4,4-difluorocyclohexyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(4,4-difluorocyclohexyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-2-((3,4-trans)-4-methyl-1-(quinazolin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-2-((3,4-trans)-1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-2-((3,4-trans)-1-(imidazo[1,2-b]pyridazin-6-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-2-((3,4-trans)-4-methyl-1-(pyrazin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-2-((3,4-trans)-4-methyl-1-(pyrazin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-7-((1s,3R)-adamantan-1-yl)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one fraction 1;   2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one fraction 2;   2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one fraction 3;   (+)-2-((3,4-trans)-1-((6-methoxypyridin-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-7-(o-tolyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-7-(4-fluoro-2-methylphenyl)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-7-(4,4-difluorocyclohexyl)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-2-((3,4-trans)-4-methyl-1-((R)-1-phenylethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-2-((3,4-trans)-4-methyl-1-((S)-1-phenylethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-7-(5-chloro-2-methylphenyl)-2-((3,4-trans)-4-methylpyrrolidin-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(furan-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(furan-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-7-(1-acetylpiperidin-4-yl)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-7-(1-acetylpiperidin-4-yl)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(2-hydroxypropan-2-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(2-hydroxypropan-2-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(1-(ethylsulfonyl)piperidin-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-2-((3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(1-(ethylsulfonyl)piperidin-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-7-(1-acetylpiperidin-4-yl)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-7-(1-acetylpiperidin-4-yl)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (+)-7-(1-(ethylsulfonyl)piperidin-4-yl)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   (−)-7-(1-(ethylsulfonyl)piperidin-4-yl)-2-((3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one;   or a pharmaceutically acceptable salt thereof.   
     
     
         9 . A pharmaceutical composition comprising the compound of  claim 2 , and a pharmaceutically acceptable carrier or excipient. 
     
     
         10 . A method for treating a PDE9 associated disease or disorder comprising administering to a subject an effective amount of a compound of  claim 2 , such that the PDE9 associated disease or disorder is treated. 
     
     
         11 . The method of  claim 10 , wherein the PDE9 associated disease or disorder is a CNS or neurodegeneration disorder. 
     
     
         12 . The method of  claim 11 , wherein the disorder is Alzheimer's disease. 
     
     
         13 . A method of inhibiting PDE9 in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of  claim 2 , such that PDE9 is inhibited in the subject.