IMIDAZOTRIAZINONE COMPOUNDS

1 . 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].

2 . The compound of claim 1 , wherein the substituents are selected from 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.

3 . The compound of claim 1 , wherein R 1 is selected from (C 1 -C 6 ) alkyl.

4 . The compound of claim 1 , wherein R 2 is selected from the group consisting of heterocycloalkyl, (C 3 -C 10 )cycloalkyl, and restricted phenyl, 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.

5 . The compound of claim 1 , wherein 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, 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.

6 . The compound of claim 1 , wherein X is a bond.

7 . A compound of Formula (I)

or a pharmaceutically acceptable salt thereof,

wherein:

X is selected from a bond, C(O) and S(O) 2 ;

R 1 is (C 1 -C 6 ) alkyl;

R 2 is selected from the group consisting of heterocycloalkyl, (C 3 -C 10 )cycloalkyl, e.g., adamantyl, 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(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 6 )alkyl, and (C 1 -C 4 )alkoxy.

8 . The compound of claim 7 , where X is a bond.

9 . The compound of claim 1 , wherein R 1 is methyl.

10 . The compound of claim 1 , wherein said heterocycloalkyl is tetrahydropyranyl or piperidinyl, 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.

11 . The compound of claim 1 , wherein said halogen is F or Cl.

12 . A compound of Formula (I)

or a pharmaceutically acceptable salt thereof,

wherein:

Y is H or (C 1 -C 3 ) alkyl;

R 1 is (C 1 -C 6 ) alkyl;

R 2 is selected from the group consisting of heterocycloalkyl, (C 3 -C 10 )cycloalkyl, e.g., adamantyl, 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(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 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(O)—(C 1 -C 4 )alkyl, CN, (C 1 -C 6 )alkyl, and (C 1 -C 4 )alkoxy.

13 . The compound of claim 12 , where Y is H.

14 . The compound of claim 12 , wherein R 1 is methyl.

15 . The compound of claim 12 , wherein said heterocycloalkyl is tetrahydropyranyl or piperidinyl, 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.

16 . The compound of claim 12 , wherein said halogen is F or Cl.

17 . The compound of claim 12 , wherein R 3 is pyrimidinyl, 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.

18 . The compound of claim 12 , wherein R 3 is restricted phenyl, 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.

19 . The compound of claim 12 , 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.

20 . The compound of claim 12 , wherein 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.

21 . A compound selected from 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-(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[5,1,4][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.

22 . A pharmaceutical composition comprising the compound of claim 1 or 12 , and a pharmaceutically acceptable carrier or excipient.

23 . A method for treating a PDE9 associated disease or disorder comprising administering to a subject an effective amount of a compound of claim 1 or 12 , such that the PDE9 associated disease or disorder is treated.

24 . The method of claim 23 , wherein the PDE9 associated disease or disorder is a CNS or neurodegeneration disorder.

25 . The method of claim 24 wherein the disorder is Alzheimer's disease.

26 . 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 1 or 12 , such that PDE9 is inhibited in the subject.