Thienoisoxazole phenoxy unsubstituted ethyl and propyl derivatives useful as d
View Patent ↗The compounds are of the class of thienoisoxazole phenoxy unsubstituted ethyl and propyl derivatives, useful as D 4 antagonists. Said compounds are useful for the treatment of medical conditions mediated by inhibition of D 4 receptor. These conditions comprise, for example, Attention Deficit Hyperactivity Disorder, Obsessive-Compulsive Disorder, Psychoses, Substance Abuse, Substance Dependence, Parkinson's Disease, Parkinsonism, Tardive Diskinesia, Gilles de la Tourette Syndrome, Conduct Disorder, and Oppositional Defiant Disorder. A further aspect of the invention is to provide a pharmaceutical composition, intermediates, and a method of making said class of compounds.
1. A compound of Formula I:
a pharmaceutically acceptable salt or stereoisomer thereof,
wherein
A is C 2-3 alkylene-N(R 1 )(R 2 ) or 1-(phenylmethyl)-pyrrolidin-3-yl;
R 1 is (CH 2 ) n Q, CH 2 CH(OH)Q, CH(CH 3 )Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein
Q is thienyl, phenyl, furanyl, naphthyl, pyridyl, indolyl, indazolyl, cyclohexyl, 1,2-methylenedioxyphenyl, cyclohexenyl, 1H-pyrazolo[4,3-c]pyridyl; and
Q is optionally substituted with one or two moieties independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, S(O) 2 NH 2 , trifluoromethyl, or cyano, and
n is 1 or 2;
R 2 is H or C 1-6 alkyl; or
R 1 and R 2 , together with the nitrogen atom to which R 1 and R 2 are attached, form 4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl, 1,4-dioxa-8-azo-spiro[4.5]decanyl, piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azocanyl, azepanyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-1H-β-carbolinyl, or 8-aza-bicyclo[3.2.1]octanyl, each of which may be mono- or independently di-substituted with halo, C 1-6 alkyl, C 1-6 alkoxy, C(O)phenyl, OH, CN, O-phenyl or (CH 2 ) m Z,
Z is benzisoxazolyl, indazolyl, benzisothiazolyl, benzthienyl, pyrimidinyl, pyridyl, 1,2-methylenedioxyphenyl, or phenyl, and
Z, CH(OH)phenyl or O-phenyl are optionally substituted with one or two moieties independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, trifluoromethyl, S(O) 2 NH 2 , or cyano, and
m is 0 or 1.
2. A compound according to claim 1 wherein R 1 and R 2 , together with the nitrogen atom to which R 1 and R 2 are attached, form piperazinyl.
3. The compound according to claim 2 which is 3-{3-[3-(4-pyrimidin-2-yl-piperazin-1- yl)-propoxy]-phenyl}-thieno[2,3-d]isoxazole.
4. The compound according to claim 2 which is 3-{3-[3-(4-phenyl-piperazin-1-yl)-propoxy]-phenyl}-thieno[2,3-d]isoxazole.
5. The compound according to claim 2 which is 3-(3-{3-[4(4-fluoro-phenyl)-piperazin-1-yl]-propoxy}-phenyl)-thieno[2,3-d]isoxazole.
6. The compound according to claim 2 which is 3-(3-{3-[4-(2-fluoro-phenyl)-piperazin-1-yl]-propoxy}-phenyl)-thieno[2,3-d]isoxazole.
7. The compound according to claim 2 which is 3-{3-[2-(4-phenyl-piperazin-1-yl)-ethoxy]-phenyl}-thieno[2,3-d]isoxazole.
8. A compound according to claim 1 wherein R 1 is indanyl.
9. The compound according to claim 8 which is indan-2-yl-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
10. The compound according to claim 8 which is indan-1-yl-[2(3-thieno[2,3-d)isoxazol-3-yl-phenoxy)-ethyl]-amine.
11. The compound according to claim 8 which is indan-1-yl-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-amine.
12. The compound according to claim 8 which is indan-2-yl-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-amine.
13. A compound according to claim 1 , wherein R 1 and R 2 together with the nitrogen atom to which R 1 and R 2 are attached, form 1,2,3,4-tetrahydroisoquinolinyl.
14. The compound according to claim 13 which is 2-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-1,2,3,4-tetrahydro-isoquinoline.
15. The compound according to claim 13 which is 2-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-1,2,3,4-tetrahydro-isoquinoline.
16. A compound according to claim 1 wherein R 1 and R 2 , together with the nitrogen atom to which R 1 and R 2 are attached, form azepanyl.
17. The compound according to claim 16 which is 3-[3-(2-azepan-1-yl-ethoxy)-phenyl]-thieno[2,3-d]isoxazole.
18. A compound according to claim 1 wherein R 1 is adamantyl.
19. The compound according to claim 18 which is adamantan-1-yl-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-amine.
20. The compound according to claim 18 which is adamantan-1-yl-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
21. A compound according to claim 1 wherein
Q is thienyl, phenyl, or pyridyl, or
R 1 and R 2 , together with the nitrogen atom to which R 1 and R 2 are attached, form morpholinyl, piperidinyl, pyrrolidinyl, or azocanyl.
22. The compound according to claim 21 which is 1-phenyl-2-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propylamino]-ethanol.
23. The compound according to claim 21 which is 4-{2-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propylamino]-ethyl}-benzenesulfonamide.
24. A compound according to claim 1 wherein A is
C 2-3 alkylene-N(R 1 )(R 2 );
R 1 is (CH 2 )nQ;
n is 1;
R 2 is H;
Q is thienyl, phenyl, or pyridyl; or
R 1 and R 2 , together with the nitrogen atom to which R 1 and R 2 are attached, form morpholinyl, piperidinyl, pyrrolidinyl, or azocanyl.
25. The compound according to claim 24 wherein Q is thienyl.
26. The compound of claim 25 which is [3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-thiophen-2-ylmethyl-amine.
27. The compound of claim 25 which is [2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-thiophen-2-ylmethyl-amine.
28. The compound of claim 25 which is [2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-thiophen-3-ylmethyl-amine.
29. The compound of claim 25 which is [3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-thiophen-3-ylmethyl-amine.
30. A compound according to claim 24 wherein Q is phenyl.
31. The compound according to claim 30 which is benzyl-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-amine.
32. The compound of claim 30 which is benzyl-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
33. The compound of claim 30 which is (2-methoxy-benzyl)-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
34. The compound of claim 30 which is (3-fluoro-benzyl)-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
35. The compound of claim 30 which is (2,&difluoro-benzyl)-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
36. The compound of claim 30 which is (2,6-difluoro-benzyl)-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-amine.
37. The compound of claim 30 which is (2-fluoro-benzyl)-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-amine.
38. The compound of claim 30 which is (4-fluoro-benzyl)-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl)-amine.
39. The compound of claim 30 which is (4-chloro-benzyl)-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-amine.
40. The compound of claim 30 which is (4-methoxy-benzyl)-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-amine.
41. The compound of claim 30 which is 4-{[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propylamino]-methyl}-benzenesulfonamide.
42. The compound of claim 30 which is (4-chloro-benzyl)-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
43. The compound of claim 30 which is (4-methyl-benzyl)-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
44. The compound of claim 30 which is (3,4-dichloro-benzyl)-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
45. The compound of claim 30 which is (2,4-difluoro-benzyl)-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)ethyl]-amine.
46. The compound of claim 30 which is [2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-(4-trifluoromethyl-benzyl)-amine.
47. The compound of claim 30 which is (2-fluoro-benzyl)[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
48. The compound of claim 30 which is 2-chloro-benzyl)-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
49. The compound of claim 30 which is (3-methoxy-benzyl)-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
50. The compound of claim 30 which is (3,4-difluoro-benzyl)-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
51. The compound of claim 30 which is (4-methyl-benzyl)-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-amine.
52. The compound of claim 30 which is (2-chloro-benzyl)-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-amine.
53. The compound of claim 30 which is (3-methoxy-benzyl)-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy]propyl]-amine.
54. The compound of claim 30 which is (3,4-difluoro-benzyl)-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-amine.
55. The compound of claim 30 which is (2,4-difluoro-benzyl)-3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-amine.
56. The compound of claim 30 which is [3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-(2-trifluoromethyl-benzyl)-amine.
57. The compound of claim 30 which is [3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-(4-trifluoromethyl-benzyl)-amine.
58. The compound of claim 30 which is (4-fluoro-benzyl)-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
59. The compound of claim 30 which is [2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-(2-trifluoromethyl-benzyl)-amine.
60. The compound of claim 30 which is benzyl-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
61. A compound according to claim 24 wherein Q is pyridyl.
62. The compound of claim 61 which is pyridin-3-ylmethyl-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
63. The compound of claim 61 which is pyridin-3-ylmethyl-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-amine.
64. A compound according to claim 24 wherein R 1 and R 2 , together with the nitrogen atom to which R 1 and R 2 are attached, form piperidinyl.
65. The compound according to claim 64 which is 3-[3-(3-piperidin-1-yl-propoxy)-phenyl]-thieno[2,3-d]isoxazole.
66. The compound of claim 64 which is 3-{3-[2-(4-phenyl-piperidin-1-yl)-ethoxy]phenyl}-thieno[2,3-d]isoxazole.
67. The compound of claim 64 which is 3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-thieno[2,3-d]isoxazole.
68. The compound of claim 64 which is 3-{3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-thieno[2,3-d]isoxazole.
69. The compound of claim 64 which is 3-{3-[2-(4-propyl-piperidin-1-yl)-ethoxy]phenyl}-thieno[2,3-d]isoxazole.
70. A compound according to claim 24 wherein R 1 and R 2 , together with the nitrogen atom to which R 1 and R 2 are attached, form pyrrolidinyl.
71. The compound of claim 70 which is 3-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-thieno[2,3-d]isoxazole.
72. A compound according to claim 24 wherein R 1 and R 2 , together with the nitrogen atom to which R 1 and R 2 are attached, form azocanyl.
73. The compound of claim 72 which is 3-[3-(2-azocan-1-yl-ethoxy)-phenyl]-thieno[2,3-d]isoxazole.
74. A compound according to claim 24 wherein R 1 and R 2 , together with the nitrogen atom to which R 1 and R 2 are attached, form morpholinyl.
75. A compound according to claim 1 wherein A is 1-(phenylmethyl)-pyrrolidin-3-yl.
76. The compound of claim 75 which is (S)-(+)-3-[3-(1-benzyl-pyrrolidin-3-yloxy)-phenyl]-thieno[2,3-d]isoxazole.
77. The compound according to claim 75 which is (R)-(−)- 3-[3 -(1-benzyl-pyrrolidin-3-yloxy)-phenyl]-thieno[2,3-d]isoxazole.
78. A composition comprising a compound according to claim 1 in admixture with an inert carrier.
79. The composition according to claim 78 wherein said inert carrier is a pharmaceutical carrier.
80. A method of treating psychoses comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 .
81. The method as defined in claim 80 wherein the compound is (3-fluoro-benzyl)-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
82. A method of treating Parkinson's Disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 .
83. The method as defined in claim 82 wherein the compound is (3-fluoro-benzyl)-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
84. A method of treating Parkinsonism comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 .
85. The method as defined in claim 84 wherein the compound is (3-fluoro-benzyl)-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
86. A method of treating Tardive Dyskinesia comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 .
87. The method as defined in claim 86 wherein the compound is (3-fluoro-benzyl)-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine.
88. A method of making a compound of Formula I:
a pharmaceutically acceptable salt or stereoisomer thereof,
wherein
A is C 2-3 alkylene-N(R 1 )(R 2 );
R 1 is (CH 2 ) n Q, CH 2 CH(OH)Q, CH(CH 3 )Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein
Q is thienyl, phenyl, furanyl, naphthyl, pyridyl, indolyl, indazolyl, cyclohexyl, 1,2-methylenedioxyphenyl, cyclohexenyl, 1H-pyrazolo[4,3-c]pyridyl; and
Q is optionally substituted with one or two moieties independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, S(O) 2 NH 2 , trifluoromethyl, or cyano, and
n is 1 or 2;
R 2 is H or C 1-6 alkyl; or
R 1 and R 2 , together with the nitrogen atom to which R 1 and R 2 are attached, form 4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl, 1,4-dioxa-8-azo-spiro[4.5]decanyl, piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azocanyl, azepanyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-1H-β-carbolinyl, or 8-aza-bicyclo[3.2.1]octanyl, each of which may be mono- or independently di-substituted with halo, C 1-6 alkyl, C 1-6 alkoxy, C(O)phenyl, OH, CN, O-phenyl or (CH 2 ) m Z,
Z is benzisoxazolyl, indazolyl, benzisothiazolyl, benzthienyl, pyrimidinyl; pyridyl, 1,2-methylenedioxyphenyl, or phenyl, and
Z, CH(OH)phenyl or O-phenyl are optionally substituted with one or two moieties independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, trifluoromethyl, S(O) 2 NH 2 , or cyano, and
m is 0 or 1;
comprising the step coupling a reagent of formula II
wherein
X is Br, Cl or I; and
p is 2 or 3;
with a reagent of formula III
wherein R 1 and R 2 are defined as in formula I;
to provide a compound of formula I.
89. A method of making a compound of Formula I:
a pharmaceutically acceptable salt or stereoisomer thereof,
wherein
A is 1-(phenylmethyl)-pyrrolidin-3-yl;
comprising the step of coupling a reagent of formula II
with a reagent of formula III
to provide the compound of formula I.
90. A method of making a compound of Formula I:
a pharmaceutically acceptable salt or stereoisomer thereof,
wherein
A is C 2-3 alkylene-N(R 1 )(R 2 );
R 1 is (CH 2 ) n Q, CH 2 CH(OH)Q, CH(CH 3 )Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein
Q is thienyl, phenyl, furanyl, naphthyl, pyridyl, indolyl, indazolyl, cyclohexyl, 1,2-methylenedioxyphenyl, cyclohexenyl, 1H-pyrazolo[4,3-c]pyridyl; and
Q is optionally substituted with one or two moieties independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, S(O) 2 NH 2 , trifluoromethyl, or cyano, and
n is 1 or 2;
R 2 is H or C 1-6 alkyl; or
R 1 and R 2 , together with the nitrogen atom to which R 1 and R 2 are attached, form 4,5,6,7-tetrahydrothieno [3,2-c]pyridinyl, 1,4-dioxa-8-azo-spiro[4.5]decanyl, piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azocanyl, azepanyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-1H-β-carbolinyl, or 8-aza-bicyclo[3.2.1.]octanyl, each of which may be mono- or independently di-substituted with halo, C 1-6 alkyl, C 1-6 alkoxy, C(O)phenyl, OH, CN, O-phenyl or (CH 2 ) m Z,
Z is benzisoxazolyl, indazolyl, benzisothiazolyl, benzthienyl, pyrimidinyl, pyridyl, 1,2-methylenedioxyphenyl, or phenyl, and
Z, CH(OH)phenyl or O-phenyl are optionally substituted with one or two moieties, independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, trifluoromethyl, S(O) 2 NH 2 , or cyano, and
m is 0 or 1;
comprising the step of coupling a reagent of formula II
with a reagent of formula m
wherein
R 1 , and R 2 are defined as in formula I;
p is 2 or 3; and
Y is Br, Cl, I, aryl sulfonate or alkyl sulfonate;
to provide the compound of formula I.
91. A method of making a compound of Formula I:
a pharmaceutically acceptable salt or stereoisomer thereof,
wherein
A is C 2-3 alkylene-N(R 1 )(R 2 );
R 1 is (CH 2 ) n Q, CH 2 CH(OH)Q, CH(CH 3 )Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein
Q is thienyl, phenyl, furanyl, naphthyl, pyridyl, indolyl, indazolyl, cyclohexyl, 1,2-methylenedioxyphenyl, cyclohexenyl, 1H-pyrazolo[4,3-c]pyridyl; and
Q is optionally substituted with one or two moieties independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, S(O) 2 NH 2 , trifluoromethyl, or cyano, and
n is 1 or 2;
R 2 is H or C 1-6 alkyl; or
R 1 and R 2 , together with the nitrogen atom to which R 1 and R 2 are attached, form 4,5,6,7-tetrahydrothieno [3,2-c]pyridinyl, 1,4-dioxa-8-azo-spiro[4.5]decanyl, piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azocanyl, azepanyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-1H-β-carbolinyl, or 8-aza-bicyclo[3.2.1.]octanyl, each of which nay be mono- or independently di-substituted with halo, C 1-6 alkyl, C 1-6 alkoxy, C(O)phenyl, OH, CN, O-phenyl or (CH 2 ) m Z,
Z is benzisoxazolyl, indazolyl, benzisothiazolyl, benzthienyl, pyrimidinyl, pyridyl, 1,2-methylenedioxyphenyl, or phenyl, and
Z, CH(OH)phenyl or O-phenyl are optionally substituted with one or two moieties independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, trifluoromethyl, S(O) 2 NH 2 , or cyano, and
m is 0 or 1;
comprising the step of reducing a compound of the formula
wherein
p is 1 or 2; and
R 1 and R 2 are as defined in formula I;
to provide a compound of formula I.
92. A compound of formula
wherein
p is 1 or 2; and
R 1 is (CH 2 ) n Q, CH 2 CH(OH)Q, CH(CH 3 )Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein
Q is thienyl, phenyl, furanyl, naphthyl, pyridyl, indolyl, indazolyl, cyclohexyl, 1,2-methylenedioxyphenyl, cyclohexenyl, 1H-pyrazolo[4,3-c]pyridyl; and
Q is optionally substituted with one or two moieties independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, S(O) 2 NH 2 , trifluoromethyl, or cyano, and
n is 1 or 2;
R 2 is H or C 1-6 alkyl; or
R 1 and R 2 , together with the nitrogen atom to which R 1 and R 2 are attached, form 4,5,6,7-tetrahydrothieno [3-c] pyridinyl, 1,4-dioxa-8-azo-spiro[4.5]decanyl, piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azocanyl, azepanyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-1H-β-carbolinyl, or 8-aza-bicyclo[3.2.1.]octanyl, each of which may be mono- or independently di-substituted with halo, C 1-6 alkyl, C 1-6 alkoxy, C(O)phenyl, OH, CN, O-phenyl or (CH 2 ) m Z,
Z is benzisoxazolyl, indazolyl, benzisothiazolyl, benzthienyl, pyrimidinyl, pyridyl, 1,2-methylenedioxyphenyl, or phenyl, and
Z, CH(OH)phenyl or O-phenyl are optionally substituted with one or two moieties independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, trifluoromethyl, S(O) 2 NH 2 , or cyano, and
m is 0 or 1.
93. A compound of formula
wherein
X is Br, Cl or I; and
p is 2 or 3.