Patent EA-004177-B1 (EA)
Title: Thienoisoxazole phenoxy unsubstituted ethyl and propyl derivatives useful as d4 antagonists
Inventor: LEE GEORGE E
IPC: A61K31/4725
Filed: 2000-09-13
Abstract: 1. A compound of Formula I: a pharmaceutically acceptable salt or stereoisomer thereof, wherein A is C2-3 alkylene-N(R1)(R2) or 1-(phenylmethyl)-pyrrolidin-3-yl; R1 is (CH2)n Q, CH2CH(OH)Q, CH(CH3)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, C1-6 alkyl, C1-6 alkoxy, hydroxy, S(O)2NH2, trifluoromethyl, or cyano, and n is 1 or 2; R2 is H or C1-6 alkyl; or R1 and R2, together with the nitrogen atom to which R1 and R2 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-beta-carbolinyl, or 8-aza-bicyclo[3,2,1]octanyl, each of which may be mono- or independently di- substituted with halo, C1-6 alkyl, C1-6alkoxy, C(O)phenyl, OH, CN, O-phenyl or (CH2)mZ, 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, C1-6 alkyl, C1-6 alkoxy, hydroxy, trifluoromethyl, S(O)2NH2, or cyano, and m is 0 or 1. 2. A compound according to claim 1 wherein R1 and R2 together with the nitrogen atom to which R1 and R2 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. 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 R1 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 R1 and R2 together with the nitrogen atom to which R1 and R2 are attached, form 1,2,3,4 tetrahydroisoquinolinyl. 14. The compound according to claim 13 which is 2-[2-(3-thieno[2,3-djisoxazol-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 R1 and R2, together with the nitrogen atom to which R1 and R2are 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 R1 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 R1 and R2, together with the nitrogen atom to which R1 and R2are 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 C2-3alkylene-N(R1)(R2); R1 is (CH2)nQ; n is 1; R2 is H; Q is thienyl, phenyl, or pyridyl; or R1 and R2, together with the nitrogen atom to which R1 and R2 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-yl-methyl-amine. 27. The compound of claim 25 which is [2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-thiophen-2-yl-methyl-amine. 28. The compound of claim 25 which is [2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-thiophen-3-yl-methyl-amine. 29. The compound of claim 25 which is [3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl)-thiophen-3-yl-methyl-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 (2,6-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-yl-methyl-[2-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-ethyl]-amine. 63. The compound of claim 61 which is pyridin-3-yl-methyl-[3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl]-amine. 64. A compound according to claim 24 wherein R1 and R2, together with the nitrogen atom to which R1 and R2 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-f]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 R1 and R2, together with the nitrogen atom to which R1 and R2 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 R1 and R2, together with the nitrogen atom to which R1 and R2 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 R1 and R2, together with the nitrogen atom to which R1 and R2are attached, form morph