The invention is directed to compounds that are P2X 7 antagonist and have the formula (I) or (II) or a pharmaceutically acceptable salt, prodrug, salt of a prodrug or a combination thereof, wherein R 1 , R 2 , and R 3 are defined in the specification. The invention is also directed to a method of selectively inhibiting P2X 7 activity comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (III), (IV) or (V) wherein R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are defined in the specification.
1. A compound having formula (I) or (II)
or a pharmaceutically acceptable salt, prodrug, salt of a prodrug or a combination thereof, wherein
R 1 is hydrogen, alkyl, haloalkyl or —CN;
R 2 is —N(H)—(CR u R v )—R 2a , —N(H)—R 2b or R 2b ; and R 3 is
wherein
R 2a is a group of formula (a) or (b);
R 2b is a group of formula (c), (d) or (e)
or
R 2 is
and R 3 is R 2b ;
wherein
R 2b is a group of formula (c), (d) or (e)
Z 1 at each occurrence is independently C, C(H), C(H) 2 , O, S, S(O), S(O) 2 , N(H), N(alkyl) or N(acyl);
Z 2 at each occurrence is independently C, C(H), or N;
Z 3 at each occurrence is independently O, S, S(O), S(O) 2 , N(H), N(alkyl) or N(acyl);
R 4 at each occurrence is independently halo, alkyl, —CN, —OR A , —SR A , —N(R A )(R B ) or haloalkyl;
R 5 at each occurrence is independently alkyl, halo or haloalkyl;
m at each occurrence is independently 0, 1, 2 or 3;
n at each occurrence is independently 0, 1, 2 or 3;
R a and R b at each occurrence are each independently halo, —CN, haloalkyl, haloalkoxy or alkyl;
R c at each occurrence is independently hydrogen, halo, haloalkyl, alkoxy, haloalkoxy or alkyl;
each of R u and R v at each occurrence is independently hydrogen, alkyl or haloalkyl;
A 1 , A 2 , A 3 and A 4 are —C(R w ); or
one or two of A 1 , A 2 , A 3 and A 4 are N, and the others are —C(R w ); or one of A 1 , A 2 , A 3 and A 4 is N + —O − and the others are —C(R w ); wherein R w at each occurrence is independently hydrogen, halo, alkyl, alkenyl, —OR A , —SR A , —N(R A )(R B ) or haloalkyl;
A 5 is N, A 6 is O or S and A 7 is C(H) or C(alkyl), or
A 5 is N, A 6 is C(H) or C(alkyl), and A 7 is O or S, or
one of A 5 , A 6 and A 7 is S and the others are independently C(H) or C(alkyl);
G is -W 2 or -L 2 -W 2 ; or
G is hydrogen, alkyl, —Oalkyl, —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , —S(O)alkyl, —S(O) 2 alkyl, —S(O) 2 NH 2 , —S(O) 2 N(H)(alkyl), —S(O) 2 N(alkyl) 2 , —C(O)NH 2 , —C(O)N(H)(alkyl), —C(O)N(alkyl) 2 , -W 2 or -L 2 -W 2 , when one of A 1 , A 2 , A 3 and A 4 is N;
L 2 is N(H), N(alkyl), O, S, S(O), S(O) 2 , S(O) 2 N(H), SO 2 N(alkyl), N(H)S(O) 2 , N(alkyl)S(O) 2 , CON(H), CON(alkyl), N(H)CO, N(alkyl)CO); and W 2 at each occurrence is independently aryl, heteroaryl or heterocycle; and each W 2 is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of ═O, halo, —CN, —NO 2 , alkyl, alkenyl, —OR A , —SR A , —S(O) 2 R A , —S(O) 2 N(R A )(R B ), —N(R A )(R B ), —C(O)R A , —C(O)N(R A )(R B ), —C(O)OR A , haloalkyl, -alkyl-OR A , -alkyl-SR A , -alkyl-S(O) 2 R A , -alkyl-S(O) 2 N(R A )(R B ), -alkyl-N(R A )(R B ), -alkyl-C(O)R A , -alkyl-C(O)N(R A )(R B ), and -alkyl-C(O)OR A ;
R A at each occurrence is independently hydrogen, alkyl, alkenyl or haloalkyl; and
R B at each occurrence is independently hydrogen, alkyl, or haloalkyl.
2. The compound of claim 1 having formula (I)
wherein R 1 is hydrogen, alkyl, haloalkyl or —CN;
R 3 is
and
R 2 is —N(H)—(CR u R v )—R 2a .
3. The compound of claim 2 wherein R 2a is
and G is -W 2 , wherein W 2 is independently aryl, heteroaryl or heterocycle, and is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of ═O, halo, —CN, —NO 2 , alkyl, alkenyl, —OR A , —SR A , —S(O) 2 R A , —S(O) 2 N(R A )(R B ), —N(R A )(R B ), —C(O)R A , —C(O)N(R A )(R B ), —C(O)OR A , haloalkyl, -alkyl-OR A , -alkyl-SR A , -alkyl-S(O) 2 R A , -alkyl-S(O) 2 N(R A )(R B ), -alkyl-N(R A )(R B ), -alkyl-C(O)R A , -alkyl-C(O)N(R A )(R B ), and -alkyl-C(O)OR A .
4. The compound of claim 3 that is selected from the group consisting of
[4-(2,3-Dichloro-phenyl)-4H-[1,2,4]triazol-3-yl]-(2-pyrrolidin-1-yl-pyridin-3-ylmethyl)-amine,
tert-butyl 4-[3-({[4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl]amino}methyl)pyridin-2-yl]-1,4-diazepane-1-carboxylate;
2-[4-(3-{[4-(2,3-Dichloro-phenyl)-4H-[1,2,4]triazol-3-ylamino]-methyl}-pyridin-2-yl)-[1,4]diazepan-1-yl]-acetamide;
4-(2,3-dichlorophenyl)-N-{[2-(4-isopropyl-1,4-diazepan-1-yl)pyridin-3-yl]methyl}-4H-1,2,4-triazol-3-amine;
[4-(2,3-Dichloro-phenyl)-4H-[1,2,4]triazol-3-yl]-(2-thiophen-3-yl-pyridin-3-ylmethyl)-amine, and
[4-(2,3-Dichloro-phenyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-(2-thiophen-3-yl-pyridin-3-ylmethyl)-amine.
5. The compound of claim 2 wherein R 2a is
and G is G is hydrogen, alkyl, —Oalkyl, —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , —S(O)alkyl, —S(O) 2 alkyl, —S(O) 2 NH 2 , —S(O) 2 N(H)(alkyl), —S(O) 2 N(alkyl) 2 , —C(O)NH 2 , —C(O)N(H)(alkyl), —C(O)N(alkyl) 2 , -W 2 or -L 2 -W 2 , when one of A 1 , A 2 , A 3 and A 4 is N.
6. The compound of claim 5 that is selected from the group consisting of
[4-(2,3-Dichloro-phenyl)-4H-[1,2,4]triazol-3-yl]-pyridin-3-ylmethyl-amine, and
[4-(2,3-Dichloro-phenyl)-4H-[1,2,4]triazol-3-yl]-(2-methyl-pyridin-3-ylmethyl)-amine.
7. The compound of claim 2 wherein R 2a is
and G is -L 2 -W 2 .
8. The compound of claim 7 wherein L 2 is O and W 2 is selected from unsubstituted or substituted aryl, heteroaryl or heterocycle.
9. The compound of claim 8 that is selected from the group consisting of
[4-(2,3-Dichloro-phenyl)-4H-[1,2,4]triazol-3-yl]-[2-(5-fluoro-pyridin-3-yloxy)-pyridin-3-ylmethyl]-amine,
[4-(2,3-Dichloro-phenyl)-4H-[1,2,4]triazol-3-yl]-[2-(pyridin-2-yloxy)-benzyl]-amine,
[4-(2,3-Dichloro-phenyl)-4H-[1,2,4]triazol-3-yl]-[2-(pyridin-3-yloxy)-benzyl]-amine,
[4-(2,3-Dichloro-phenyl)-4H-[1,2,4]triazol-3-yl]-[2-(pyridin-3-yloxy)-pyridin-3-ylmethyl]-amine, and
[4-(2,3-Dichloro-phenyl)-4H-[1,2,4]triazol-3-yl]-[2-(1-methyl-pyrrolidin-3-yloxy)-pyridin-3-ylmethyl]-amine.
10. The compound of claim 2 wherein R 2a is
and G is -W 2 or -L 2 -W 2 ; or
G is hydrogen, alkyl, —Oalkyl, —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , —S(O)alkyl, —S(O) 2 alkyl, —S(O) 2 NH 2 , —S(O) 2 N(H)(alkyl), —S(O) 2 N(alkyl) 2 , —C(O)NH 2 , —C(O)N(H)(alkyl), —C(O)N(alkyl) 2 , -W 2 or -L 2 -W 2 , when one of A 1 , A 2 , A 3 and A 4 is N.
11. The compound of claim 1 having formula (I)
wherein R 1 is hydrogen, alkyl, haloalkyl or —CN;
R 3 is
and
R 2 is —N(H)—R 2b .
12. The compound of claim 1 wherein
R 2b is
13. The compound of claim 11 wherein
R 2b is
14. The compound of claim 11 wherein
R 2b is
15. The compound of claim 1 having formula (I)
wherein R 1 is hydrogen, alkyl, haloalkyl or —CN;
R 3 is
and
R 2 is R 2b .
16. The compound of claim 15 wherein
R 2b is
17. The compound of claim 15 wherein
R 2b is
18. The compound of claim 15 wherein
R 2b is
19. The compound of claim 1 having formula (I)
wherein R 1 is hydrogen, alkyl, haloalkyl or —CN;
R 2 is
and
R 3 is R 2b .
20. The compound of claim 19 wherein
R 3 is R 2b , and
R 2b is a group of formula (c)
21. The compound of claim 18 that is selected from the group consisting of
3-(2,3-dichlorophenyl)-4-(2,3-dihydro-1H-inden-1-yl)-4H-1,2,4-triazol,
3-(2,3-dichlorophenyl)-4-[2,3-dihydro-1-benzofuran-3-yl]-4H-1,2,4-triazole,
3-(2,3-dichlorophenyl)-4-[(1R)-2,3-dihydro-1H-inden-1-yl]-4H-1,2,4-triazole,
3-(2,3-dichlorophenyl)-4-[(1S)-2,3-dihydro-1H-inden-1-yl]-4H-1,2,4-triazole,
3-(2,3-dichlorophenyl)-4-(3-methyl-2,3-dihydro-1H-inden-1-yl)-4H-1,2,4-triazole,
3-[2-chloro-3-(trifluoromethyl)phenyl]-4-[(1R)-2,3-dihydro-1H-inden-1-yl]-4H-1,2,4-triazole,-(2,3-dichlorophenyl)-4-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-4H-1,2,4-triazole, and
3-(2,3-dichlorophenyl)-4-[5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-4H-1,2,4- triazole.
22. The compound of claim 19 wherein
R 2b is a group of formula (d)
23. The compound of claim 22 that is selected from the group consisting of
3-(2,3-dichlorophenyl)-4-(1,2,3,4-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazole,
3-(2,3-dichlorophenyl)-4-(4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazole, and
3-(2,3-dichlorophenyl)-4-(3,4-dihydro-2H-chromen-4-yl)-4H-1,2,4-triazole.
24. The compound of claim 19 wherein
R 2b is a group of formula (e)
25. The compound of claim 1 having formula (II)
wherein
R 1 is hydrogen, alkyl, haloalkyl or —CN;
R 2 is —N(H)—(CR u R v )—R 2a ; and
R 3 is
26. The compound of claim 25 wherein R 2a is
and G is -W 2 , wherein W 2 is independently aryl, heteroaryl or heterocycle, and is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of ═O, halo, —CN, —NO 2 , alkyl, alkenyl, —OR A , —SR A , —S(O) 2 R A , —S(O) 2 N(R A )(R B ), —N(R A )(R B ), —C(O)R A , —C(O)N(R A )(R B ), —C(O)OR A , haloalkyl, -alkyl-OR A , -alkyl-SR A , -alkyl-S(O) 2 R A , -alkyl-S(O) 2 N(R A )(R B ), -alkyl-N(R A )(R B ), -alkyl-C(O)R A , -alkyl-C(O)N(R A )(R B ), and -alkyl-C(O)OR A .
27. The compound of claim 26 selected from the group consisting of:
1-(2,3-dichlorophenyl)-N-[(2-pyrrolidin-1-ylpyridin-3-yl)methyl]-1H-[1,2,4]triazole-5-amine,
1-(2,3-dichlorophenyl)-N-[(2-morpholin-4-ylpyridin-3-yl)methyl]-1H-[1,2,4]-triazol-5-amine,
[2-(2,3-Dichloro-phenyl)-2H-[1,2,4]triazol-3-yl]-(2-thiophen-3-yl-pyridin-3-ylmethyl)-amine, and
(2-Azetidin-1-yl-pyridin-3-ylmethyl)-[2-(2,3-dichloro-phenyl)-2H-[1,2,4]triazol-3-yl]-amine.
28. The compound of claim 25 wherein R 2a is
and G is hydrogen, alkyl, —Oalkyl, —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , —S(O)alkyl, —S(O) 2 alkyl, —S(O) 2 NH 2 , —S(O) 2 N(H)(alkyl), —S(O) 2 N(alkyl) 2 , —C(O)NH 2 , —C(O)N(H)(alkyl), or —C(O)N(alkyl) 2 .
29. The compound of claim 28 selected from the group consisting of:
[2-(2,3-Dichloro-phenyl)-2H-[1,2,4]triazol-3-yl]-pyridin-3-ylmethyl-amine, and
[2-(2,3-Dichloro-phenyl)-2H-[1,2,4]triazol-3-yl]-(2-methyl-pyridin-3-ylmethyl)-amine.
30. The compound of claim 25 wherein R 2a is
and G is -L 2 -W 2 .
31. The compound of claim 30 wherein L 2 is O and W 2 is aryl or heteroaryl.
32. The compound of claim 31 selected from the group consisting of:
[2-(2,3-Dichloro-phenyl)-2H-[1,2,4]triazol-3-yl]-[2-(pyridin-3-yloxy)-benzyl]-amine, and
[2-(2,3-Dichloro-phenyl)-2H-[1,2,4]triazol-3-yl]-[2-(pyridin-3-yloxy)-pyridin-3-ylmethyl]-amine.
33. The compound of claim 25 wherein R 2a is
34. The compound of claim 1 having formula (II)
wherein
R 1 is hydrogen, alkyl, haloalkyl or —CN;
R 2 is —N(H)—R 2b ; and
R 3 is
35. The compound of claim 34 wherein
R 2b is a group of formula (c)
36. The compound of claim 34 wherein
R 2b is a group of formula (d)
37. The compound of claim 34 wherein
R 2b is a group of formula (e)
38. The compound of claim 1 having formula (II)
wherein
R 1 is hydrogen, alkyl, haloalkyl or —CN;
R 2 is —R 2b ; and
R 3 is
39. The compound of claim 38 wherein
R 2b is a group of formula (c)
40. The compound of claim 39 that is
1-[2-chloro-3-(trifluoromethyl)phenyl]-5-(2,3-dihydro-1H-inden-1-yl)-1H-1,2,4-triazole.
41. The compound of claim 38 wherein
R 2b is a group of formula (d)
42. The compound of claim 38 wherein
R 2b is a group of formula (e)
43. The compound of claim 1 having formula (II)
wherein
R 1 is hydrogen, alkyl, haloalkyl or —CN;
R 2 is
and
R 3 is R 2b .
44. The compound of claim 43 wherein
R 2b is a group of formula (c)
45. The compound of claim 44 that is
5-[2-chloro-3-(trifluoromethyl)phenyl]-1-[2,3-dihydro-1H-inden-1-yl]-1H-1,2,4-triazole.
46. The compound of claim 43 wherein
R 2b is a group of formula (d)
47. The compound of claim 43 wherein
R 2b is a group of formula (e)
48. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or formula (II) as described in claim 1 , or a therapeutically acceptable salt, solvate, prodrug, salt of a prodrug, or combination thereof, and a pharmaceutically acceptable carrier.