Tetrahydrobenzofurodiazepinone compound and pharmaceutical use thereof
The present invention provides a compound having a Pim-1 inhibitory activity. The present invention provides a compound of Formula [I] or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof, and the like. wherein each symbol is as defined in the description.
1. A compound of Formula [I], or a pharmaceutically acceptable salt thereof:
wherein
Cy 1 is
(1) C 3-7 cycloalkyl,
(2) 4 to 7-membered heterocycloalkyl containing one or two heteroatoms independently selected from the group consisting of oxygen and optionally oxidized sulfur, as a ring constituting atom besides carbon atom(s),
(3) C 5-8 bridged cycloalkyl,
(4) 7 to 9-membered bridged heterocycloalkyl containing one oxygen atom as a ring constituting atom besides carbon atom(s),
(5) C 7-11 spirocycloalkyl, or
(6) 7 to 11-membered spiroheterocycloalkyl containing one to three oxygen atoms as a ring constituting atom besides carbon atom(s);
R 1 in the number of m are each independently
(1) halogen,
(2) hydroxy,
(3) C 1-6 alkyl wherein the alkyl is optionally substituted by
(a) hydroxy,
(b) C 1-4 alkoxy,
(c) cyano,
(d) OCOR 11 wherein R 11 is phenyl, or
(e) SO 2 R 12 wherein R 12 is C 1-4 alkyl,
(4) C 1-4 haloalkyl wherein the haloalkyl is optionally substituted by hydroxy,
(5) C 1-4 alkoxy wherein the alkoxy is optionally substituted by 1 to 3 halogen,
(6) COR 13 wherein R 13 is
(a) hydroxy, or
(b) NR 14 R 15 wherein R 14 and R 15 are each independently hydrogen or C 1-4 alkyl,
(7) cyano,
(8) SO 2 R 16 wherein R 16 is C 1-4 alkyl,
(9) C 3-4 cycloalkyl wherein the cycloalkyl is optionally substituted by hydroxy, or
(10) triazolyl, or
two R 1 bonded to the same carbon atom are taken together to form oxo;
R 2 in the number of n are each independently
(1) halogen, or
(2) C 1-4 alkoxy, or
two R 2 bonded to the same carbon atom are taken together to form C 3-4 cycloalkane with the carbon atom to which they are bonded;
R 3 and R 4 are each independently
(1) hydrogen, or
(2) C 1-4 alkyl, or
R 3 and R 4 are taken together to form C 3-4 cycloalkane with the carbon atom to which they are bonded;
R 5 is hydrogen or C 1-4 alkyl;
R 6 is C 1-4 haloalkyl;
R 7 is hydrogen or halogen;
L is linear C 1-4 alkylene;
m is 0, 1, 2, 3 or 4; and
n is 0, 1, 2 or 3.
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.
3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L is ethylene or trimethylene.
4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen.
5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 in the number of n are each independently halogen, or two R 2 bonded to the same carbon atom are taken together to form C 3-4 cycloalkane with the carbon atom to which they are bonded.
6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is represented by Formula [III]:
wherein
R 2a in the number of n1 are each independently halogen;
L a is ethylene or trimethylene; and
n1 is 0, 1 or 2.
7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
Cy 1 is
(1) C 3-7 cycloalkyl,
(2) 4 to 7-membered heterocycloalkyl containing one or two heteroatoms independently selected from the group consisting of oxygen and sulfur atoms (the sulfur atom may be oxidized), as a ring constituting atom besides carbon atom(s),
(3) C 7-11 spirocycloalkyl, or
(4) 7 to 11-membered spiroheterocycloalkyl containing one to three oxygen atoms as a ring constituting atom besides carbon atom(s).
8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 is
(1) monofluoromethyl,
(2) difluoromethyl, or
(3) trifluoromethyl.
9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each independently
(1) hydrogen, or
(2) methyl, or
R 3 and R 4 are taken together to form cyclopropane with the carbon atom to which they are bonded.
10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 in the number of m are each independently
(1) halogen,
(2) hydroxy,
(3) C 1-6 alkyl wherein the alkyl is optionally substituted by
(a) hydroxy,
(b) C 1-4 alkoxy,
(c) cyano, or
(d) SO 2 R 12 wherein R 12 is C 1-4 alkyl,
(4) C 1-4 haloalkyl wherein the haloalkyl is optionally substituted by hydroxy,
(5) C 1-4 alkoxy wherein the alkoxy is optionally substituted by 1 to 3 halogen,
(6) COR 13 wherein R 13 is
(a) hydroxy, or
(b) NR 14 R 15 wherein R 14 and R 15 are each independently hydrogen or C 1-4 alkyl,
(7) cyano,
(8) SO 2 R 16 wherein R 16 is C 1-4 alkyl, or
(9) C 3-4 cycloalkyl wherein the cycloalkyl is optionally substituted by hydroxy, or two R 1 bonded to the same carbon atom are taken together to form oxo.
11. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. A method for treating a disease selected from the group consisting of pulmonary arterial hypertension, psoriasis and systemic lupus erythematosus in a mammal, which comprises administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof to the mammal.
14. A compound of the following formula or a pharmaceutically acceptable salt thereof:
15. A compound of the following formula or a pharmaceutically acceptable salt thereof:
16. A compound of the following formula or a pharmaceutically acceptable salt thereof:
17. A compound of the following formula or a pharmaceutically acceptable salt thereof:
18. A compound of the following formula or a pharmaceutically acceptable salt thereof:
19. A compound of the following formula or a pharmaceutically acceptable salt thereof:
20. A compound of the following formula or a pharmaceutically acceptable salt thereof:
21. A compound of the following formula or a pharmaceutically acceptable salt thereof:
22. A compound of the following formula or a pharmaceutically acceptable salt thereof:
23. A compound of the following formula or a pharmaceutically acceptable salt thereof:
24. A compound of the following formula:
25. A compound of the following formula:
26. A compound of the following formula:
27. A compound of the following formula:
28. A compound of the following formula:
29. A compound of the following formula:
30. A compound of the following formula:
31. A compound of the following formula:
32. A compound of the following formula:
33. A compound of the following formula:
34. A pharmaceutical composition comprising the compound according to any one of claims 14 - 23 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
35. A method for treating a disease selected from the group consisting of pulmonary arterial hypertension, psoriasis and systemic lupus erythematosus in a mammal, which comprises administering a therapeutically effective amount of the compound according to any one of claims 14 - 23 or a pharmaceutically acceptable salt thereof to the mammal.
36. A pharmaceutical composition comprising the compound according to any one of claims 24 - 33 and a pharmaceutically acceptable carrier.
37. A method for treating a disease selected from the group consisting of pulmonary arterial hypertension, psoriasis and systemic lupus erythematosus in a mammal, which comprises administering a therapeutically effective amount of the compound according to any one of claims 24 - 33 to the mammal.
38. A method for treating a disease selected from the group consisting of acute myeloid leukemia, colon cancer, pancreatic cancer, osteosarcoma, breast cancer, chronic myelogenous leukemia, multiple myeloma, diffuse large B-cell lymphoma and myeloproliferative neoplasm in a mammal, which comprises administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof to the mammal.
39. A method for treating a disease selected from the group consisting of acute myeloid leukemia, colon cancer, pancreatic cancer, osteosarcoma, breast cancer, chronic myelogenous leukemia, multiple myeloma, diffuse large B-cell lymphoma and myeloproliferative neoplasm in a mammal, which comprises administering a therapeutically effective amount of the compound according to any one of claims 14 - 23 or a pharmaceutically acceptable salt thereof to the mammal.
40. A method for treating a disease selected from the group consisting of acute myeloid leukemia, colon cancer, pancreatic cancer, osteosarcoma, breast cancer, chronic myelogenous leukemia, multiple myeloma, diffuse large B-cell lymphoma and myeloproliferative neoplasm in a mammal, which comprises administering a therapeutically effective amount of the compound according to any one of claims 24 - 33 to the mammal.