Indane derivatives as modulators of ion channels
The present invention relates to indane derivatives useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.
1. A method of inhibiting one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in:
(a) a patient; or
(b) a biological sample;
comprising administering to said patient, or contacting said biological sample with a compound of formula I:
or a pharmaceutically acceptable salt thereof;
wherein:
ring Z is a 5-7 membered unsaturated or aromatic ring having at least one ring heteroatom selected from O, S, N, or NH, wherein and said ring Z is optionally substituted with z occurrence of R z ;
z is 0-4;
R z is selected from R 1 , R 2 , R 3 , R 4 , or R 5 ;
X is a bond, 0, NR 2 , or C(R 2 ) 2 ;
Q is a bond or a C1-C6 straight or branched alkylidine chain, wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR 2 —, —CONR 2 NR 2 —, —CO 2 —, —OCO—, —NR 2 CO 2 —, —O—, —NR 2 CONR 2 —, —OCONR 2 —, —NR 2 NR 2 , —NR 2 NR 2 CO—, —NR 2 CO—, —S—, —SO, —SO 2 —, —NR—, —SO 2 NR 2 —, NR 2 SO 2 —, —NR 2 SO 2 NR 2 —, or a spirocycloalkylene moeity;
R Q is a C 1-6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from O, S, N, or NH, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from O, S, N, or NH;
wherein R Q is optionally substituted with up to 4 substituents selected from R 1 , R 2 , R 3 , R 4 , or R 5 ;
R M and R N are independently R 2 ;
R 1 is oxo, ═NN(R 6 ) 2 , ═NN(R 7 ) 2 , ═NN(R 6 R 7 ), R 6 or (CH 2 ) n —Y;
n is 0, 1 or 2;
Y is halo, CN, NO 2 , CF 3 , OCF 3 , OH, SR 6 , S(O)R 6 , SO 2 R 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NR 6 R 8 , COOH, COOR 6 or OR 6 ; or
two R 1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy;
R 2 is hydrogen or C1-C6 aliphatic, wherein each R 2 is optionally substituted with up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
R 3 is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, optionally substituted with up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ;
R 4 is OR 5 , OR 6 , OC(O)R 6 , OC(O)R 5 , OC(O)OR 6 , OC(O)OR 5 , OC(O)N(R 6 ) 2 , OC(O)N(R 5 ) 2 , OC(O)N(R 6 R 5 ), OP(O)(OR 6 ) 2 , OP(O)(OR 5 ) 2 , OP(O)(OR 6 )(OR 5 ), SR 6 , SR 5 , S(O)R 6 , S(O)R 5 , SO 2 R 6 , SO 2 R 5 , SO 2 N(R 6 ) 2 , SO 2 N(R 5 ) 2 , SO 2 NR 5 R 6 , SO 3 R 6 , SO 3 R 5 , C(O)R 5 , C(O)OR 5 , C(O)R 6 , C(O)OR 6 , C(O)N(R 6 ) 2 , C(O)N(R 5 ) 2 , C(O)N(R 5 R 6 ), C(O)N(OR 6 )R 6 , C(O)N(OR 5 )R 6 , C(O)N(OR 6 )R 5 , C(O)N(OR 5 )R 5 , C(NOR 6 )R 6 , C(NOR 6 )R 5 , C(NOR 5 )R 6 , C(NOR 5 )R 5 , N(R 6 ) 2 , N(R 5 ) 2 , N(R 5 R 6 ), NR 5 C(O)R 5 , NR 6 C(O)R 6 , NR 6 C(O)R 5 , NR 6 C(O)OR 6 , NR 5 C(O)OR 6 , NR 6 C(O)OR 5 , NR 5 C(O)OR 5 , NR 6 C(O)N(R 6 ) 2 , NR 6 C(O)NR 5 R 6 , NR 6 C(O)N(R 5 ) 2 , NR 5 C(O)N(R 6 ) 2 , NR 5 C(O)NR 5 R 6 , NR 5 C(O)N(R 5 ) 2 , NR 6 SO 2 R 6 , NR 6 SO 2 R 5 , NR 5 SO 2 R 5 , NR 6 SO 2 N(R 6 ) 2 , NR 6 SO 2 NR 5 R 6 , NR 6 SO 2 N(R 5 ) 2 , NR 5 SO 2 NR 5 R 6 , NR 5 SO 2 N(R 5 ) 2 , N(OR 6 )R 6 , N(OR 6 )R 5 , N(OR 5 )R 5 , N(OR 5 )R 6 , P(O)(OR 6 )N(R 6 ) 2 , P(O)(OR 6 )N(R 5 R 6 ), P(O)(OR 6 )N(R 5 ) 2 , P(O)(OR 5 )N(R 5 R 6 ), P(O)(OR 5 )N(R 6 ) 2 , P(O)(OR 5 )N(R 5 ) 2 , P(O)(OR 6 ) 2 , P(O)(OR 5 ) 2 , or P(O)(OR 6 )(OR 5 );
R 5 is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, optionally substituted with up to 3 R 1 substituents;
R 6 is H or C1-C6 aliphatic, wherein R 6 is optionally substituted with a R 7 substituent;
R 7 is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, and each R 7 is optionally substituted with up to 2 substituents independently chosen from H, C1-C6 aliphatic, or (CH 2 ) m —Z′ wherein m is 0-2;
Z′ is selected from halo, CN, NO 2 , C(halo) 3 , CH(halo) 2 , CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , —OCH 2 (halo), OH, S—(C1-C6) aliphatic, S(O)—(C1-C6) aliphatic, SO 2 —(C1-C6)aliphatic, NH 2 , NH—(C1-C6)aliphatic, N((C1-C6)aliphatic) 2 , N((C1-C6)aliphatic)R 8 , COOH, C(O)O(—(C1-C6)aliphatic), or O—(C1-C6)aliphatic; and
R 8 is acetyl, C6-C10 aryl sulfonyl, or C1-C6 alkyl sulfonyl; provided that:
(i) when ring Z is an optionally substituted pyrimidin-2-yl, the sulfonyl group is attached at the 5-position and the N(R 2 )C(O) group is attached at the 2-position, R 2 is H, and X and Q each is a bond, then R Q is not an optionally substituted phenyl or 6-chloro-quinolin-8-yl, fluoren-9-ylethyl, fluoren-9-ylmethyl, indolin-1-yl, cyclohexyl, (phenylthio)methyl, 3-methoxy-thiophen-2-yl, furan-2-yl, (phenoxy)methyl, 3-chloro-thiophen-2-yl, (optionally substituted phenyl)ethyl, or butyl;
(ii) when ring Z is an optionally substituted pyrimidin-2-yl, the sulfonyl group is attached at the 5-position and the N(R 2 )C(O) group is attached at the 2-position, R 2 is H, and X and Q each is a bond, then R Q is not 2-methyl-5-chloro-2,3, -dihydro-benzofuran-7-yl;
(iii) when ring Z is an optionally substituted pyrimidin-2-yl, the sulfonyl group is attached at the 5-position and the N(R 2 )C(O) group is attached at the 2-position, R 2 is H, and X is —O—, Q is a bond, then R Q is not ethyl or benzyl; and
(iv) when ring Z is an optionally substituted pyrimidin-2-yl, the sulfonyl group is attached at the 5-position and the N(R 2 )C(O) group is attached at the 2-position, R 2 is H, and X is —N(Me)—, Q is a bond, then R Q is not 2-methylphenyl.
2. The method according to claim 1 , wherein said compound has formula I-A, or formula I-B:
3. A method of treating or lessening the severity of a disease, disorder, or condition selected from acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epileptic conditions, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, stroke, bipolar disorders, or cancer pain in a patient comprising the step of administering to said patient an effective amount of a compound according of formula I, formula I-A, or formula I-B:
or a pharmaceutically acceptable salt thereof;
wherein:
ring Z is a 5-7 membered unsaturated or aromatic ring having at least one ring heteroatom selected from O, S, N, or NH, wherein and said ring Z is optionally substituted with z occurrence of R z ;
z is 0-4;
R z is selected from R 1 , R 2 , R 3 , R 4 , or R 5 ;
X is a bond, 0, NR 2 , or C(R 2 ) 2 ;
Q is a bond or a C1-C6 straight or branched alkylidine chain, wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR 2 —, —CONR 2 NR 2 —, —CO 2 —, —OCO—, —NR 2 CO 2 —, —O—, —NR 2 CONR 2 —, —OCONR 2 —, —NR 2 NR 2 , —NR 2 NR 2 CO—, —NR 2 CO—, —S—, —SO, —SO 2 —, —NR 2 —, —SO 2 NR 2 —, NR 2 SO 2 —, —NR 2 SO 2 NR 2 —, or a spirocycloalkylene moeity;
R Q is a C 1-6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from O, S, N, or NH, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from O, S, N, or NH;
wherein R Q is optionally substituted with up to 4 substituents selected from R 1 , R 2 , R 3 , R 4 , or R 5 ;
R M and R N are independently R 2 ;
R 1 is oxo, ═NN(R 6 ) 2 , ═NN(R 7 ) 2 , ═NN(R 6 R 7 ), R 6 or (CH 2 ) n —Y;
n is 0, 1 or 2;
Y is halo, CN, NO 2 , CF 3 , OCF 3 , OH, SR 6 , S(O)R 6 , SO 2 R 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NR 6 R 8 , COOH, COOR 6 or OR 6 ; or
two R 1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy;
R 2 is hydrogen or C1-C6 aliphatic, wherein each R 2 is optionally substituted with up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
R 3 is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, optionally substituted with up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ;
R 4 is OR 5 , OR 6 , OC(O)R 6 , OC(O)R 5 , OC(O)OR 6 , OC(O)OR 5 , OC(O)N(R 6 ) 2 , OC(O)N(R 5 ) 2 , OC(O)N(R 6 R 5 ), OP(O)(OR 6 ) 2 , OP(P)OR 5 ) 2 , OP(O)(OR 6 )(OR 5 ), SR 6 , SR 5 , S(O)R 6 , S(O)R 5 , SO 2 R 6 , SO 2 R 5 , SO 2 N(R 6 ) 2 , SO 2 N(R 5 ) 2 , SO 2 NR 5 R 6 , SO 3 R 6 , SO 3 R 5 , C(O)R 5 , C(O)OR 5 , C(O)R 6 , C(O)OR 6 , C(O)N(R 6 ) 2 , C(O)N(R 5 ) 2 , C(O)N(R 5 R 6 ), C(O)N(OR 6 )R 6 , C(O)N(OR 5 )R 6 , C(O)N(OR 6 )R 5 , C(O)N(OR 5 )R 5 , C(NOR 6 )R 6 , C(NOR 6 )R 5 , C(NOR 5 )R 6 , C(NOR 5 )R 5 , N(R 6 ) 2 , N(R 5 ) 2 , N(R 5 R 6 ), NR 5 C(O)R 5 , NR 6 C(O)R 6 , NR 6 C(O)R 5 , NR 6 C(O)OR 6 , NR 5 C(O)OR 6 , NR 6 C(O)OR 5 , NR 5 C(O)OR 5 , NR 6 C(O)N(R 6 ) 2 , NR 6 C(O)NR 5 R 6 , NR 6 C(O)N(R 5 ) 2 , NR 5 C(O)N(R 6 ) 2 , NR 5 C(O)NR 5 R 6 , NR 5 C(O)N(R 5 ) 2 , NR 6 SO 2 R 6 , NR 6 SO 2 R 5 , NR 5 SO 2 R 5 , NR 6 SO 2 N(R 6 ) 2 , NR 6 SO 2 NR 5 R 6 , NR 6 SO 2 N(R 5 ) 2 , NR 5 SO 2 NR 5 R 6 , NR 5 SO 2 N(R 5 ) 2 , N(OR 6 )R 6 , N(OR 6 )R 5 , N(OR 5 )R 5 , N(OR 5 )R 6 , P(O)(OR 6 )N(R 6 ) 2 , P(O)(OR 6 )N(R 5 R 6 ) 2 , P(O)(OR 6 )N(R 5 ) 2 , P(O)(OR 5 )N(R 5 R 6 ), P(O)(OR 5 )N(R 6 ) 2 , P(O)(OR 5 )N(R 5 ) 2 , P(O)(OR 6 ) 2 , P(O)(OR 5 ) 2 , or P(O)(OR 6 )(OR 5 );
R 5 is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, optionally substituted with up to 3 R 1 substituents;
R 6 is H or C1-C6 aliphatic, wherein R 6 is optionally substituted with a R 7 substituent;
R 7 is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, and each R 7 is optionally substituted with up to 2 substituents independently chosen from H, C1-C6 aliphatic, or (CH 2 ) m —Z′ wherein m is 0-2;
Z′ is selected from halo, CN, NO 2 , C(halo) 3 , CH(halo) 2 , CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , —OCH 2 (halo), OH, S—(C1-C6) aliphatic, S(O)—(C1-C6) aliphatic, SO 2 —(C1-C6)aliphatic, NH 2 , NH—(C1-C6)aliphatic, N((C1-C6)aliphatic) 2 , N((C1-C6)aliphatic)R 8 , COOH, C(O)O(—(C1-C6)aliphatic), or O—(C1-C6)aliphatic; and
R 8 is acetyl, C6-C10 aryl sulfonyl, or C1-C6 alkyl sulfonyl; provided that:
(i) when ring Z is an optionally substituted pyrimidin-2-yl, the sulfonyl group is attached at the 5-position and the N(R 2 )C(O) group is attached at the 2-position, R 2 is H, and X and Q each is a bond, then R Q is not an optionally substituted phenyl or 6-chloro-quinolin-8-yl, fluoren-9-ylethyl, fluoren-9-ylmethyl, indolin-1-yl, cyclohexyl, (phenylthio)methyl, 3-methoxy-thiophen-2-yl, furan-2-yl, (phenoxy)methyl, 3-chloro-thiophen-2-yl, (optionally substituted phenyl)ethyl, or butyl;
(ii) when ring Z is an optionally substituted pyrimidin-2-yl, the sulfonyl group is attached at the 5-position and the N(R 2 )C(O) group is attached at the 2-position, R 2 is H, and X and Q each is a bond, then R Q is not 2-methyl-5-chloro-2,3, -dihydro-benzofuran-7-yl;
(iii) when ring Z is an optionally substituted pyrimidin-2-yl, the sulfonyl group is attached at the 5-position and the N(R 2 )C(O) group is attached at the 2-position, R 2 is H, and X is —O—, Q is a bond, then R Q is not ethyl or benzyl; and
(iv) when ring Z is an optionally substituted pyrimidin-2-yl, the sulfonyl group is attached at the 5-position and the N(R 2 )C(O) group is attached at the 2-position, R 2 is H, and X is —N(Me)—, Q is a bond, then R Q is not 2-methylphenyl.
4. The method according to claim 3 , wherein the disease, condition, or disorder is implicated in the activation or hyperactivity of voltage-gated sodium channels.
5. The method according to claim 4 , wherein the disease, condition, or disorder is radicular pain, sciatica, back pain, head pain, neck pain, or neuropathies.
6. The method according to claim 4 , wherein the disease, condition, or disorder is severe or intractable pain, acute pain, post-surgical pain, back pain, or cancer pain.
7. The method according to claim 3 , wherein the disease, condition, or disorder is implicated in the activation or hyperactivity of voltage-gated calcium channels.
8. The method according to claim 7 , wherein the disease, condition, or disorder is acute, chronic, neuropathic, inflammatory pain, or inflammatory breakthrough pain.
9. The method according to claim 3 , wherein Z is selected from:
10. The method according to claim 3 , wherein z is 0-2.
11. The method according to claim 9 , wherein Z is selected from:
12. The method according to claim 9 , wherein Z is selected from:
13. The method according to claim 9 , wherein Z is selected from:
14. The method according to claim 9 , wherein Z is selected from:
15. The method according to claim 9 , wherein Z is selected from:
16. The method according to claim 9 , wherein Z is selected from:
17. The method according to claim 9 , wherein Z is selected from:
18. The method according to claim 9 , wherein Z is selected from:
19. The method according to claim 9 , wherein Z is selected from:
20. The method according to claim 9 , wherein Z is selected from:
21. The method according to claim 9 , wherein Z is selected from:
22. The method according to claim 9 , wherein Z is selected from:
23. The method according to claim 9 , wherein Z is selected from:
24. The method according to claim 3 , wherein R z is selected from R 1 , R 2 , or R 5 .
25. The method according to claim 24 , wherein R z is selected from a hydrogen, halo, a C1-C6 aliphatic, or an optionally substituted group independently selected from C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring; wherein said cycloaliphatic, said aryl, said heterocyclic, or said heteroaryl is optionally substituted with up to 3 substituents selected from R 1 , R 2 , R 4 , or R 5 .
26. The method according to claim 25 , wherein R z is selected from hydrogen, C1, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl, or C2-C6 straight or branched alkynyl.
27. The method according to claim 3 , wherein R M is hydrogen.
28. The method according to claim 3 , wherein R N is hydrogen.
29. The method according to claim 3 , wherein X is selected from a bond, CH 2 , or O.
30. The method according to claim 3 , wherein Q is selected from a bond or a C1-C6 straight or branched alkylidene chain, wherein up to two methylene units of said alkylidene is independently replaced by O, S, OCO, NH, N(R 2 ), or a spirocycloalkylene group.
31. The method according to claim 30 , wherein Q is —X 2 —(X 1 ) p —,
wherein:
X 2 is a bond or C1-C6 aliphatic, optionally substituted with up to two substituents independently selected from R 1 , R 4 , or R 5 ;
p is 0 or 1; and
X 1 is 0, S, or NR 2 .
32. The method according to claim 31 , wherein X 2 is a bond, C1-C6 alkyl, or C2-C6 alkylidene, and said alkyl and alkylidene are independently and optionally substituted with R 1 or R 4 .
33. The method according to claim 32 , wherein X 2 is selected from a bond, —CH 2 —, —CH 2 —CH 2 —, —(CH 2 ) 3 —, —C(Me) 2 -, —CH(Me)—, —C(Me)═CH—, —CH═CH—, —CH(Ph)—, —CH 2 —CH(Me)—, —CH(Et)-, or —CH(i-Pr)—.
34. The method according to claim 31 , wherein X 1 is NH or —N(C1-C6 alkyl)-.
35. The method according to claim 3 , wherein R Q is optionally substituted with up to 4 substituents selected from halo, cyano, trifluoromethyl, OH, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, trifluoromethoxy, C(O)NH 2 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , NHC(O)C 1-4 alkyl, or C(O)C 1-4 alkyl.
36. The method according to claim 3 , wherein R Q is an optionally substituted C1-C6 aliphatic group.
37. The method according to claim 3 , wherein R Q is an optionally substituted 3-8 membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteratoms independently selected from O, S, N, or NH.
38. The method according to claim 37 , wherein R Q is an optionally substituted 3-8 membered cycloaliphatic ring.
39. The method according to claim 38 , wherein R Q is an optionally substituted ring selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
40. The method according to claim 37 , wherein R Q is an optionally substituted phenyl.
41. The method according to claim 40 , wherein said phenyl is optionally substituted with up to 3 substituents selected from halo, cyano, trifluoromethyl, OH, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, trifluoromethoxy, C(O)NH 2 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , NHC(O)C 1-4 alkyl, or C(O)C 1-4 alkyl.
42. The method according to claim 40 , wherein R Q is selected from:
43. The method according to claim 37 , wherein R Q is an optionally substituted 3-7 membered monocyclic heterocyclic ring.
44. The method according to claim 37 , wherein R Q is an optionally substituted 5-6 membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteratoms independently selected from O, S, N, or NH.
45. The method according to claim 44 , wherein R Q is an optionally substituted ring selected from pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.
46. The method according to claim 44 , wherein R Q is an optionally substituted ring selected from:
47. The method according to claim 46 , wherein R Q is optionally fused to an optionally substituted phenyl ring.
48. The method according to claim 3 , wherein R Q is an optionally substituted 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from O, S, N, or NH.
49. The method according to claim 48 , wherein R Q is an optionally substituted naphthyl.
50. The method according to claim 49 , wherein said naphthyl is optionally substituted with up to 5 substituents selected from halo, cyano, trifluoromethyl, OH, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, trifluoromethoxy, C(O)NH 2 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , NHC(O)C 1-4 alkyl, or C(O)C 1-4 alkyl.
51. The method according to claim 48 , wherein R Q is an optionally substituted 8-10 membered, bicyclic, heteroaromatic ring.
52. The method according to claim 48 , wherein R Q is an optionally substituted 8-10 membered, bicyclic, heterocyclic ring.
53. The method according to claim 48 , wherein R Q is an optionally substituted ring selected from:
54. The method according to claim 3 , wherein R Q is selected from pyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, piperidin-1-yl, 3-methyl-piperidin-1-yl, 4-methyl-piperidin-1-yl, 4,4-difluoropiperidin-1-yl, 4,5-dimethyl-4-morpholin-1-yl, 2,6-dimethyl-morpholin-4-yl, indol-1-yl, 4-fluoro-indol-1-yl, 5-chloro-indol-1-yl, 7-chloro-indol-1-yl, tetrahydroquinolin-1-yl, 7-trifluoromethyl-tetrahydroquinolin-1-yl, 6-methyl-tetrahydroquinolin-1-yl, 6-chloro-tetrahydroquinolin-1-yl, tetrahydro-isoquinolin-2-yl, 7-chloro-tetrahydroisoquinolin-2-yl, 7-trifluoromethyl-tetrahydro-isoquinolin-2-yl, 7-fluoro-tetrahydro-isoquinolin-2-yl, 6-methyl-tetrahydro-isoquinolin-2-yl, 8-trifluoromethyl-quinolin-4-yl, pyridine-3-yl, or pyridine-4-yl.
55. A method according to claim 3 , wherein the compound is selected from