US2018118749A1PendingUtilityA1
P2x7 modulators
Est. expirySep 12, 2034(~8.2 yrs left)· nominal 20-yr term from priority
Inventors:Jose Ignacio Andres GilChrista C. ChrovianMichael A. LetavicJason C. RechDale A. RudolphAkinola Soyode Johnson
A61P 25/24A61P 11/06A61P 25/28A61P 31/00A61P 9/12A61P 3/10A61P 25/08A61P 25/00A61P 25/16A61P 37/08A61P 17/00A61P 25/18A61P 11/00A61P 25/04A61P 31/04A61P 27/06A61P 13/10A61P 25/22A61P 35/00A61P 33/00A61P 17/06A61P 7/02A61P 1/00A61P 19/10A61P 19/02A61P 13/12A61P 17/10C07D 487/04
39
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Claims
Abstract
The present invention is directed to compounds of Formula (I), which includes enantiomer and diasteromers thereof: These compounds are suitable for use in the treatment of diseases associated with P2X7 receptor activity such as diseases of the autoimmune and inflammatory system, diseases of the nervous and neuro-immune system, diseases involved with neuroinflammation of the Central Nervous System (CNS) or diseases of the cardiovascular, metabolic, gastrointestinal and urogenital systems.
Claims
exact text as granted — not AI-modifiedWhat is claimed:
1 . A compound of Formula (I):
and enantiomers or diastereomers thereof;
and pharmaceutically acceptable salts thereof;
wherein:
R a is
R 1 is halo or C 1 -C 3 alkyl;
R 2 is independently selected from the group consisting of: H, halo, and C 1 -C 3 perhaloalkyl;
R 3 is H or halo;
R 4 is halo,
R 5 is halo or C 1 -C 3 perhaloalkyl;
R b is independently selected from the group consisting of:
Wherein:
R 6 , R 9 , R 10 , and R 12 are independently H or halo;
R 7 and R 13 are independently selected from the group consisting of: H, halo and OC 1 -C 3 alkyl;
R 8 is independently selected from the group consisting of: H, halo, OH and OC 1 -C 3 alkyl;
R 11 is independently selected from the group consisting of: H, halo and C 1 -C 3 perhaloalkyl;
R c is selected from the group consisting of:
R d and R e are independently H or C 1 -C 3 alkyl; and
provided that at least one of R c , R d and R e are not H.
2 . A compound as claimed in claim 1 wherein, R a is
3 . A compound as claimed in claim 1 wherein, R a is
4 . A compound as claimed in claim 1 wherein, R a is
and R 1 is halo.
5 . A compound as claimed in claim 1 wherein R a is
and R 1 is C 1 -C 3 alkyl.
6 . A compound as claimed in claim 1 wherein R a is
and R 2 is C 1 -C 3 perhaloalkyl.
7 . A compound as claimed in claim 1 wherein R a is
and R 2 is halo.
8 . A compound as claimed in claim 1 wherein R a is
and R 3 is H.
9 . A compound as claimed in claim 1 wherein R a is
R 1 is halo, R 2 is C 1 -C 3 perhaloalkyl, and R 3 is H.
10 . A compound as claimed in claim 1 wherein R a is
and R 1 , R 2 , and R 3 are halo.
11 . A compound as claimed in claim 1 wherein R a is
R 1 and R 3 are halo and R 2 is H.
12 . A compound as claimed in claim 1 wherein R a is
R 1 and R 2 are halo and R 3 is H.
13 . A compound as claimed in claim 1 wherein R a is
R 4 is halo and R 5 is C 1 -C 3 perhaloalkyl.
14 . A compound as claimed in claim 1 wherein R b is independently selected from the group consisting of:
15 . A compound as claimed in claim 1 wherein R b is independently selected from the group consisting of:
16 . A compound as claimed in claim 1 wherein R b is independently selected from the group consisting of: C 3 -C 6 cycloalkyl and C 1 -C 4 alkyl.
17 . A compound as claimed in claim 1 wherein R b is
18 . A compound as claimed in claim 1 wherein R b is
19 . A compound as claimed in claim 1 wherein R b is
20 . A compound as claimed in claim 1 wherein R b is
R 6 and R 7 are H and R 8 is OCH 3 .
21 . A compound as claimed in claim 1 wherein R b is
and R 6 , R 7 and R 8 are H.
22 . A compound as claimed in claim 1 wherein R b is
and R 8 is OH, and R 6 and R 7 are H.
23 . A compound as claimed in claim 1 wherein R b is
24 . A compound as claimed in claim 1 wherein R b is
25 . A compound as claimed in claim 1 wherein R b is
R 9 , R 10 and R 12 are H and R 11 is F.
26 . A compound as claimed in claim 1 wherein R b is
27 . A compound as claimed in claim 1 wherein R b is
28 . A compound as claimed in claim 1 wherein R c is H or CH 3 .
29 . A compound as claimed in claim 1 wherein R c is selected from the group consisting of:
30 . A compound as claimed in claim 1 wherein R c is
31 . A compound as claimed in claim 1 wherein R c is:
32 . A compound as claimed in claim 1 wherein R d is CH 3 .
33 . A compound as claimed in claim 1 wherein R e is CH 3 .
34 . A compound as claimed in claim 1 wherein R c is CH 3 and R d and R e are H.
35 . A compound as claimed in claim 1 wherein R d is CH 3 and R c and R e are H.
36 . A compound as claimed in claim 1 wherein R e is CH 3 and R c and R d are H.
37 . A compound as claimed in claim 1 wherein R a is
R 1 and R 2 are Cl, R c is CH 3 , R b is
and R d , R e , R 3 , R 6 , R 7 and R 8 are H.
38 . A compound as claimed in claim 1 wherein R a is
R 1 and R 2 are Cl, R d is CH 3 , R b
is R c , R e , R 3 , R 9 , R 19 and R 12 are H and R 11 is F.
39 . A compound as claimed in claim 1 wherein R a is
R 1 is Cl, and R 2 is CF 3 , R d is CH 3 , R b is
R c , R e , R 3 , R 9 , R 19 and R 12 are H and R 11 is F.
40 . A compound as claimed in claim 1 wherein R a is
R 1 and R 2 are Cl, R d is CH 3 , R b is
R 8 is OCH 3 , and R c , R e , R 3 , R 6 , and R 7 are H.
41 . A compound as claimed in claim 1 wherein R a is
R 1 is Cl, and R 2 is CF 3 , R d is CH 3 , R c is
R b is
and R d , R e , and R 3 are H.
42 . A compound as claimed in claim 1 wherein R a is
R 1 is Cl, and R 2 is CF 3 , R d is CH 3 , R c is
R b is
and R d , R e , and R 3 are H.
43 . A compound as claimed in claim 1 wherein R a is
R 1 is Cl, and R 2 is CF 3 , R d is CH 3 , R c is
R b is
and R d , R e , and R 3 are H.
44 . A compound selected from the group consisting of:
(2,3-dichlorophenyl)(8-methyl-3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2,3-dichlorophenyl)(8-methyl-3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(8-methyl-3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; 2-chloro-3-(trifluoromethyl)phenyl)(5-methyl-3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2,3-dichlorophenyl)(5-methyl-3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(3-(4-fluorophenyl)-5-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2,3-dichlorophenyl)(3-(4-fluorophenyl)-5-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(3-(4-fluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2,3-dichlorophenyl)(3-(4-fluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(6-methyl-3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2,3-dichlorophenyl)(6-methyl-3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2,3-dichlorophenyl)(6-methyl-3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(6-methyl-3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2-chloro-3-(trifluoromethyl)phenyl)(6-methyl-3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(6-methyl-3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (3-chloro-2-(trifluoromethyl)pyridin-4-yl)(8-methyl-3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(8-methyl-3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2,3-dichlorophenyl)(3-(4-fluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(4-fluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2-fluoro-3-(trifluoromethyl)phenyl)(8-methyl-3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-fluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(6-methyl-3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(6-methyl-3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(furan-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(3-(4-fluorophenyl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(6-methyl-3-(4-(trifluoromethyl)phenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(6-methyl-3-(4-(trifluoromethyl)phenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(3-fluoro-4-(trifluoromethyl)phenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(3-fluoro-4-(trifluoromethyl)phenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(6-methyl-3-(3,4,5-trifluorophenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(6-methyl-3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(4-fluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (2,3-dichlorophenyl)(5-methyl-3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(8-methyl-3-(4-(trifluoromethyl)phenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(8-methyl-3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(3-(4-chlorophenyl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(2-fluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(2-fluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichloro-4-fluorophenyl)(3-(2-fluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(3-fluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(3-fluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichloro-4-fluorophenyl)(3-(3-fluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(2,3-difluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(2,3-difluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichloro-4-fluorophenyl)(3-(2,3-difluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(3,4-difluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(3,4-difluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichloro-4-fluorophenyl)(3-(3,4-difluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(2,4-difluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(2,4-difluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichloro-4-fluorophenyl)(3-(2,4-difluorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(3-methyl-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(6-fluoropyridin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(4-methoxypyridin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2-chlorophenyl)(6-methyl-3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (3,4-difluoro-2-methylphenyl)(6-methyl-3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2-chloro-4-fluorophenyl)(6-methyl-3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (2,3-dichloropyridin-4-yl)(6-methyl-3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (3-cyclohexyl-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(2,3-dichlorophenyl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(3-cyclohexyl-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (3-cyclohexyl-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(2,3-dichloro-4-fluorophenyl)methanone; (3-cyclopropyl-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(2,3-dichlorophenyl)methanone; (3-cyclopropyl-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(2,3-dichloro-4-fluorophenyl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(3-cyclopropyl-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-methyl-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2-chloro-3-(trifluoromethyl)phenyl)(3-methyl-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(4-fluoropyridin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(5-fluoropyridin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(5-fluoropyridin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; ((S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(5-methoxypyridin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(5-methoxypyridin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(5-fluoropyrimidin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(5-fluoropyrimidin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (±)-(2-chloro-3-(trifluoromethyl)phenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-cyclopropyl-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2-chloro-3-(trifluoromethyl)phenyl)(3-cyclopropyl-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(5-methoxypyrimidin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (±)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(furan-2-yl)-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (±)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(1-hydroxyethyl)-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(3-(tert-butyl)-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone; (S)-(3-(tert-butyl)-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone; (R)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(furan-2-yl)-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(furan-2-yl)-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (±)-(2-chloro-3-(trifluoromethyl)phenyl)(3-methyl-8-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2-chloro-3-(trifluoromethyl)phenyl)(3-ethyl-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-ethyl-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2-chloro-3-(trifluoromethyl)phenyl)(3-isopropyl-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-isopropyl-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (±)-(2,3-dichlorophenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2-chloro-3-(trifluoromethyl)phenyl)(3-methyl-8-(pyridin-2-yl)-5,6-dihydro-[[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-methyl-8-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2-chloro-3-(trifluoromethyl)phenyl)(3-cyclobutyl-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-cyclobutyl-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R*)-(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S*)-(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2-chloro-3-(trifluoromethyl)phenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R*)-(3-chloro-2-(trifluoromethyl)pyridin-4-yl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S*)-(3-chloro-2-(trifluoromethyl)pyridin-4-yl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (±)-(2-chloro-3-(trifluoromethyl)phenyl)(8-(4-fluorophenyl)-3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2,3-dichlorophenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2,3-dichlorophenyl)(8-(4-fluorophenyl)-3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(8-(4-fluorophenyl)-3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2-chloro-3-(trifluoromethyl)phenyl)(3-cyclopropyl-8-(4-fluorophenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-cyclopropyl-8-(4-fluorophenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(difluoromethyl)-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(difluoromethyl)-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2,3-dichlorophenyl)(3-(difluoromethyl)-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(difluoromethyl)-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2,3-dichlorophenyl)(3-methyl-8-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-methyl-8-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2-chloro-3-(trifluoromethyl)phenyl)(8-(4-fluorophenyl)-3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(8-(4-fluorophenyl)-3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(8-(4-fluorophenyl)-3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone; (S)-(8-(4-fluorophenyl)-3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone; (R)-(2-chloro-4-fluorophenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-chloro-4-fluorophenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2,4-dichlorophenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,4-dichlorophenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2-methyl-3-(trifluoromethyl)phenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-methyl-3-(trifluoromethyl)phenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2,3-dichloro-4-fluorophenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichloro-4-fluorophenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (±)-(8-(1 H-pyrazol-5-yl)-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone; (±)-(2-chloro-3-(trifluoromethyl)phenyl)(8-(pyridin-3-yl)-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2-fluoro-3-(trifluoromethyl)phenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2-fluoro-3-(trifluoromethyl)phenyl)(8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (±)-(2-chloro-3-(trifluoromethyl)phenyl)(6-methyl-8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (±)-benzyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone; (S)-(2,3-dichlorophenyl)(3-(4-hydroxypyridin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(3-(4-[ 11 C]methoxypyridin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone and (S)-(2,3-dichlorophenyl)(3-(4-[ 18 F]fluoropyridin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone.
45 . A pharmaceutical composition, comprising:
(a) a therapeutically effective amount of at least one compound independently selected from compounds of Formula (I):
and enantiomers or diastereomers thereof;
and pharmaceutically acceptable salts thereof;
wherein:
R a is
R 1 is halo or C 1 -C 3 alkyl;
R 2 is independently selected from the group consisting of: H, halo, and C 1 -C 3 perhaloalkyl;
R 3 is H or halo;
R 4 is halo,
R 5 is halo or C 1 -C 3 perhaloalkyl;
R b is independently selected from the group consisting of:
Wherein:
R 6 , R 9 , R 10 , R 12 , R 14 are independently H or halo;
R 7 and R 13 are independently selected from the group consisting of: H, halo and OC 1 -C 3 alkyl;
R 8 is independently selected from the group consisting of: H, halo, OH and OC 1 -C 3 alkyl;
R 11 is independently selected from the group consisting of: H, halo and C 1 -C 3 perhaloalkyl;
R c is selected from the group consisting of:
R d and R e are independently H or C 1 -C 3 alkyl; and
provided that at least one of R c , R d and R e are not H; and
(b) at least one pharmaceutically acceptable excipient.
46 . A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 44 and at least one pharmaceutically acceptable excipient.
47 . A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by P2X7 receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound selected from compounds of Formula (I):
and enantiomers or diastereomers thereof;
and pharmaceutically acceptable salts thereof;
wherein:
R a is
R 1 is halo or C 1 -C 3 alkyl;
R 2 is independently selected from the group consisting of: H, halo, and C 1 -C 3 perhaloalkyl;
R 3 is H or halo;
R 4 is halo,
R 5 is halo or C 1 -C 3 perhaloalkyl;
R b is independently selected from the group consisting of:
Wherein:
R 6 , R 9 , R 10 , R 12 , R 14 are independently H or halo;
R 7 and R 13 are independently selected from the group consisting of: H, halo and OC 1 -C 3 alkyl;
R 8 is independently selected from the group consisting of: H, halo, OH and OC 1 -C 3 alkyl;
R 11 is independently selected from the group consisting of: H, halo and C 1 -C 3 perhaloalkyl;
R c is selected from the group consisting of:
R d and R e are independently H or C 1 -C 3 alkyl; and
provided that at least one of R c , R d and R e are not H.
48 . A method according to claim 47 , wherein the disease, disorder, or medical condition is selected from the group consisting of: diseases of the autoimmune and inflammatory system; diseases of the nervous and neuro-immune system;
diseases involved with, and without, neuroinflammation of the Central Nervous System (CNS); diseases of the cardiovascular, metabolic, gastrointestinal and urogenital systems; skeletal disorders, diseases involving the secretory function of exocrine glands and glaucoma, Glomerulonephritis, Chaga's Disease, chlamydia, neuroblastoma, Tuberculosis, Polycystic Kidney Disease, cancer, and acne.
49 . A method according to claim 47 wherein the disease, disorder, or medical condition is selected from the group consisting of: rheumatoid arthritis, osteoarthritis, interstitial cystitis, psoriasis, septic shock, sepsis, allergic dermatitis, asthma, allergic asthma, mild to severe asthma, and steroid resistant asthma, idiopathic pulmonary fibrosis, allergic rhinitis, chronic obstructive pulmonary disease and airway hyper-responsivenes; acute and chronic pain,neuropathic pain, inflammatory pain, migraine, spontaneous pain, opioid induced pain, diabetic neuropathy, postherpetic neuralgia, low back pain, chemotherapy-induced neuropathic pain, fibromyalgia; mood disorders, major depression, major depressive disorder, treatment resistant depression, bipolar disorder, anxious depression, anxiety, cognition, sleep disorders, multiple sclerosis, epileptic seizures, Parkinson's disease, schizophrenia, Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, autism, spinal cord injury and cerebral ischemia/traumatic brain injury, and stress-related disorders; diabetes, diabetes mellitus, thrombosis, irritable bowel disease, irritable bowel syndrome, Crohn's disease, cardiovascular diseases (examples of cardiovascular disease include hypertension, myocardial infarction, ischemic heart disease, ischemia, ureteric obstruction, lower urinary tract syndrome, lower urinary tract dysfunction such as incontinence, and disease after cardiac transplantation, osteoporosis/osteopetrosis, diseases involving the secretory function of exocrine glands, glaucoma, Glomerulonephritis, Chaga's Disease, chlamydia, neuroblastoma, Tuberculosis, Polycystic Kidney Disease, cancer, and acne.
50 . A method according to claim 48 , wherein the disease, disorder, or medical condition is diseases of the autoimmune and inflammatory system.
51 . A method according to claim 50 , wherein the diseases of the autoimmune and inflammatory system selected from the group consisting of rheumatoid arthritis, osteoarthritis, interstitial cystitis, psoriasis, septic shock, sepsis, allergic dermatitis, asthma, idiopathic pulmonary fibrosis, allergic rhinitis, chronic obstructive pulmonary disease and airway hyper-responsivenes
52 . The method of claim 48 , wherein the disease, disorder or medical condition is a disease involved with, and without, neuroinflammation of the Central Nervous System (CNS).
53 . A method according to claim 52 , wherein the diseases involved with, and without, neuroinflammation of the Central Nervous System (CNS) is selected from the group consisting of: mood disorders, cognition, sleep disorders, multiple sclerosis, epileptic seizures, Parkinson's disease, schizophrenia, Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, autism, spinal cord injury and cerebral ischemia/traumatic brain injury, and stress-related disorders
54 . The method of claim 53 , wherein wherein the mood disorder selected from the group consisting of: major depression, major depressive disorder, treatment resistant depression, bipolar disorder, anxious depression, and anxiety.
55 . The method of claim 54 , wherein wherein the mood disorder is treatment resistant depression.Cited by (0)
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