(Dihydro)imidazoiso[5,1-A]quinolines
View Patent ↗The invention relates to imidazoiso[5,1-a]quinoline and 5,6-dihydro-imidazoiso[5,1-a]quinoline derivatives according to general Formula I or a pharmaceutically acceptable salt thereof. The compounds can be used for the treatment of infertility.
1. A compound according to formula I:
or a pharmaceutically acceptable salt thereof wherein
the C5-C6 bond can either be saturated or unsaturated;
R 1 is phenyl or (2-5C)heteroaryl, both optionally substituted with one or more substituents selected from R 13 or
R 1 is (1-6C)alkyl, halogen, cyano, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl, (5-6C)cycloalkenyl, (2-5C)heterocycloalkyl or (2-5C)-heterocycloalkenyl;
R 3 is (di)[(1-6C)alkyl]amino, optionally substituted with hydroxy or
R 3 is a group selected from
or
R 3 is (1-6C)alkyl, (3-6C)cycloalkyl, (di)[(1-4C)alkyl]amino(1-4C)alkyl or
R 3 is (2-6C)heterocycloalkyl; (2-6C)heterocycloalkyl(1-4C)alkyl, the (2-6C)heterocycloalkyl moiety of which optionally may be substituted with (1-4C)alkylcarbonyl or (3-6C)cycloalkylcarbonyl,
R 3 is pyrrolidin-1-yl, azepin-1-yl, 1,4-oxazepin-1-yl, all optionally substituted with one or more (1-4C)alkyl substituents
R 8 is H, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkoxy(1-4C)alkyl, hydroxy or (2-4C)alkenyl;
R 9 is H, halogen, hydroxy, amino, (2-6C)alkynyl, (2-5C)heterocycloalkyl, (3-6C)cycloalkoxy, (2-5C)heterocycloalkoxy, (di)[(1-4C)alkyl]aminocarbonyl, (2-5C)heterocycloalkylcarbonyl, (2-5C)heteroarylaminocarbonyl, (2-5C)heterocycloalkylcarbonylamino, (2-5C)heteroarylcarbonylamino, formyl, cyano, nitro, (di)[(1-4C)alkyl]aminocarboxy, (1-6C)alkylcarbonyl, (1-4C)alkoxycarbonyl, (di)[(1-4C)alkyl]amino, (di)[(1-4C)alkyl]aminocarbonylamino, (1-4C)alkoxycarbonylamino, (di)[(1-4C)alkyl]aminosulfonylamino, (1-6C)alkylthio or (1-4C)alkylsulfonylamino or
R 9 is (1-6C)alkyl, (1-6C)alkoxy or (2-6C)alkenyl, all optionally substituted with one or more substituents selected from halogen, hydroxy, amine, azide, (1-4C)alkoxy, (1-4C)alkoxycarbonylamino or (1-4C)alkylcarbonylamino or
R 9 is (1-5C)heteroaryl, phenyl, (2-5C)heteroaryloxy or phenoxy, all optionally substituted with one or more substituents selected from R 14 or
R 9 is (1-6C)alkylcarbonylamino, optionally substituted with hydroxy, amino, (2-5C)heterocycloalkyl or (di)[(1-4C)alkyl]amino or
R 9 is phenyl substituted at two adjacent positions together representing a fused O—(CH 2 ) m —O ring wherein m is 1 or 2;
R 10 is H, methoxy, halogen or methyl
R 11 is H, (1-4C)alkyl or (2-4C)alkenyl;
R 12 is (1-4C)alkylcarbonyl or (3-6C)cycloalkylcarbonyl, both optionally substituted with one or more substituents selected from R 15 ;
R 13 is hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylthio or (di)[(1-4C)alkyl]amino;
R 14 is hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylthio, (di)[(1-4C)alkyl]amino, (2-5C)heteroaryl, (di)[(1-4C)alkyl]aminocarbonyl, (1-4C)alkylcarbonylamino or (1-4C)alkylsulfonyl or
R 14 is (2-5C)heterocycloalkyl optionally substituted with (1-4C)alkyl or (1-4C)alkoxycarbonyl; and
R 15 is hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylthio or (di)[(1-4C)alkyl]amino.
2. The compound according to claim 1 wherein
R 1 is phenyl or (2-5C)heteroaryl, both optionally substituted with one or more substituents selected from R 13 or
R 1 is (1-6C)alkyl, halogen, cyano, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl, (5-6C)cycloalkenyl; and
R 3 is (di)[(1-6C)alkyl]amino, optionally substituted with hydroxy or
R 3 is a group selected from
or
R 3 is (1-6C)alkyl, (3-6C)cycloalkyl, (di)[(1-4C)alkyl]amino(1-4C)alkyl or
R 3 is (2-6C)heterocycloalkyl(1-4C)alkyl, the (2-6C)heterocycloalkyl moiety of which optionally may be substituted with (1-4C)alkylcarbonyl or (3-6C)cycloalkylcarbonyl, or
R 3 is pyrrolidin-1-yl, azepin-1-yl, 1,4-oxazepin-1-yl, all optionally substituted with one or more (1-4C)alkyl substituents
R 9 is H, halogen, hydroxy, amino, (2-6C)alkynyl, (2-5C)heterocycloalkyl, (3-6C)cycloalkoxy, (2-5C)heterocycloalkoxy, (di)[(1-4C)alkyl]aminocarbonyl, (2-5C)heterocycloalkylcarbonyl, (2-5C)heteroarylaminocarbonyl, (2-5C)heterocycloalkylcarbonylamino, (2-5C)heteroarylcarbonylamino, formyl, cyano, nitro, (di)[(1-4C)alkyl]aminocarboxy, (1-6C)alkylcarbonyl, (1-4C)alkoxycarbonyl, (di)[(1-4C)alkyl]amino, (di)[(1-4C)alkyl]aminocarbonylamino, (1-4C)alkoxycarbonylamino, (di)[(1-4C)alkyl]aminosulfonylamino, (1-6C)alkylthio or (1-4C)alkylsulfonylamino or
R 9 is (1-6C)alkyl, (1-6C)alkoxy or (2-6C)alkenyl, all optionally substituted with one or more substituents selected from halogen, hydroxy, amine, azide, (1-4C)alkoxy, (1-4C)alkoxycarbonylamino or (1-4C)alkylcarbonylamino or
R 9 is (1-5C)heteroaryl, phenyl, (2-5C)heteroaryloxy or phenoxy, all optionally substituted with one or more substituents selected from R 14 or
R 9 is (1-6C)alkylcarbonylamino, optionally substituted with hydroxy, amino, (2-5C)heterocycloalkyl or (di)[(1-4C)alkyl]amino.
3. The compound according to claim 1 wherein
R 1 is phenyl or (2-5C)heteroaryl, both optionally substituted with one or more substituents selected from R 13 or
R 1 is (1-6C)alkyl;
R 3 is (di)[(1-6C)alkyl]amino, optionally substituted with hydroxy or
R 3 is a group selected from
or
R 3 is pyrrolidin-1-yl, optionally substituted with one or more (1-4C)alkyl substituents
R 8 is H, (1-4C)alkyl, (1-4C)alkoxy or (2-4C)alkenyl;
R 9 is H, halogen, hydroxy, amino, (2-6C)alkynyl, (2-5C)heterocycloalkyl, (3-6C)cycloalkoxy, (2-5C)heterocycloalkoxy, (di)[(1-4C)alkyl]aminocarbonyl, (2-5C)heterocycloalkylcarbonyl, (2-5C)heteroarylaminocarbonyl, (2-5C)heterocycloalkylcarbonylamino, (2-5C)heteroarylcarbonylamino or (1-6C)alkylthio or
R 9 is (1-6C)alkyl, (1-6C)alkoxy or (2-6C)alkenyl, all optionally substituted with one or more substituents selected from halogen, hydroxy, amine, azide, (1-4C)alkoxy, (1-4C)alkoxycarbonylamino or (1-4C)alkylcarbonylamino or
R 9 is (1-5C)heteroaryl, phenyl, phenyloxy or (2-5C)heteroaryloxy, all optionally substituted with one or more substituents selected from R 14 or
R 9 is (1-6C)alkylcarbonylamino, optionally substituted with hydroxy, amino, (2-5C)heterocycloalkyl or (di)[(1-4C)alkyl]amino or
R 9 is phenyl substituted at two adjacent positions together representing dioxomethylene;
R 10 is H or halogen;
R 11 is (1-4C)alkyl or (2-4C)alkenyl;
R 12 is (1-4C)alkylcarbonyl or (3-6C)cycloalkylcarbonyl;
R 13 is halogen; and
R 14 is amino, halogen, trifluoromethyl, cyano, (1-4C)alkyl, (1-4C)alkoxy, (di)[(1-4C)alkyl]amino, (2-5C)heteroaryl, (di)[(1-4C)alkyl]aminocarbonyl, (1-4C)alkylcarbonylamino or (1-4C)alkylsulfonyl or
R 14 is (2-5C)heterocycloalkyl optionally substituted with (1-4C)alkoxycarbonyl.
4. The compounds according to claim 1 wherein
R 9 is H, halogen, hydroxy, amino, (2-6C)alkynyl, (2-5C)heterocycloalkyl, (3-6C)cycloalkoxy, (2-5C)heterocycloalkoxy, (di)[(1-4C)alkyl]aminocarbonyl, (2-5C)heterocycloalkylcarbonyl, (2-5C)heteroarylaminocarbonyl, (2-5C)heterocycloalkylcarbonylamino, (2-5C)heteroarylcarbonylamino or (1-6C)alkylthio or
R 9 is (1-6C)alkyl, (1-6C)alkoxy or (2-6C)alkenyl, all optionally substituted with one or more substituents selected from halogen, hydroxy, amine, azide, (1-4C)alkoxy, (1-4C)alkoxycarbonylamino or (1-4C)alkylcarbonylamino or
R 9 is (1-5C)heteroaryl or phenyl, both optionally substituted with one or more substituents selected from R 14 or
R 9 is (1-6C)alkylcarbonylamino, optionally substituted with hydroxy, amino, (2-5C)heterocycloalkyl or (di)[(1-4C)alkyl]amino.
5. The compound according to claim 1 wherein the C5-C6 bond is saturated.
6. The compound according to anyone of claim 1 wherein R 1 is (2-5C)heteroaryl.
7. The compound according to claim 6 wherein R 1 is thien-2-yl or thiazol-5-yl.
8. The compound according to claim 7 wherein R 1 is thien-2-yl.
9. The compound according to claim 1 wherein R 3 is (di)[(1-6C)alkyl]amino,
or pyrrolidin-1-yl, optionally substituted with one or more (1-4C)alkyl substituents.
10. The compound according to claim 9 wherein R 12 is (3-6C)cycloalkylcarbonyl.
11. The compound according to claim 1 wherein R 8 is (1-4C)alkoxy.
12. The compound according to claim 1 wherein R 9 is (1-6C)alkoxy, optionally substituted with hydroxyl; (1-6C)alkyl; (1-4C)alkenyl; (2-5C)heteroarylaminocarbonyl; (1-6C)alkylcarbonylamino, optionally substituted with (2-5C)heterocycloalkyl; or (1-5C)heteroaryl, or phenyl, both optionally substituted with one or more substituents selected from R 14 .
13. The compound according to claim 12 wherein R 14 is amino, halogen, cyano, (1-4C)alkyl, (di)[(1-4C)alkyl]amino, (2-5C)heteroaryl, (1-4C)alkylcarbonylamino or (2-5C)heterocycloalkyl.
14. The compound according to anyone of claim 1 wherein R 10 is H.
15. The compound according to claim 1 wherein R 14 is amino, halogen, cyano, (1-4C)alkyl, (di)[(1-4C)alkyl]amino, (2-5C)heteroaryl, (1-4C)alkylcarbonylamino or (2-5C)heterocycloalkyl.
16. The compound according to claim 1 wherein R 1 is thien-2-yl, R 3 is (di)[(1-6C)alkyl]amino and R 8 is (1-4C)alkoxy.
17. The compound according to claim 1 wherein R 8 is methoxy.
18. A pharmaceutical composition which comprises a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
19. A method of treating infertility in a patient in need of induced ovulation or controlled ovarian stimulation, the method comprising administering to the patient an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.