US2012157458A1PendingUtilityA1
Imidazotriazinone compounds
Est. expirySep 20, 2030(~4.2 yrs left)· nominal 20-yr term from priority
A61P 31/18A61P 43/00A61P 25/00A61P 25/14A61P 25/28A61P 25/20A61P 25/18A61P 25/16A61P 27/06A61P 25/22C07D 487/04C07D 519/00A61P 21/00
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Claims
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.
Claims
exact text as granted — not AI-modified1 . 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.Cited by (0)
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