Preparation of condensed triazepine derivatives and their use as BET inhibitors

1. A method of treating a disease selected from the group consisting of a blood cancer, rheumatoid arthritis, acute respiratory distress syndrome, non-alcoholic steatotic hepatitis, idiopathic pulmonary fibrosis, and cardiac fibrosis in advanced heart failure, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of having the following formula (I),

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, and (C 1 -C 6 ) alkyl;

R 3 is selected from the group consisting of (C 1 -C 6 ) alkyl, —OH, and halogen;

R 4 is selected from the group consisting of (C 1 -C 4 ) alkyl and

R 5 is selected from the group consisting of an aryl, a heteroaryl, a benzodioxolane and a benzodioxane, wherein said aryl, heteroaryl, benzodioxolane or benzodioxane is optionally substituted with a halogen or a (C 1 -C 4 )alkoxy group;

R 7 is (C 1 -C 6 ) alkyl.

2. The method according to claim 1 , wherein R 4 is (C 1 -C 4 ) alkyl.

3. The method according to claim 1 , wherein R 4 is

4. The method according to claim 1 , wherein R 7 is (C 1 -C 4 ) alkyl.

5. The method according to claim 1 , wherein R 4 is

and R 7 is ethyl.

6. The method according to claim 1 , wherein R 5 is selected from the group of

wherein W is a halogen.

7. The method according to claim 1 , wherein R 5 is phenyl substituted with a halogen.

8. The method according to claim 1 , wherein R 5 is phenyl substituted with chlorine.

9. The method according to claim 1 , wherein the compound of Formula (I) is a compound of Formula (IIa):

wherein W is a halogen,

or a pharmaceutically acceptable salt thereof.

10. The method according to claim 9 , wherein W is chloro.

11. The method according to claim 1 , wherein R 1 and R 2 are each independently selected from (C 1 -C 3 ) alkyl.

12. The method according to claim 1 , wherein R 1 and R 2 are methyl.

13. The method according to claim 1 , wherein R 3 is (C 1 -C 3 ) alkyl.

14. The method according to claim 1 , wherein R 3 is methyl.

15. The method according to claim 1 , wherein

R 4 is

R 7 is ethyl; and

R 1 , R 2 and R 3 are each methyl.

16. The method according to claim 1 , wherein the compound is selected from the group consisting of

17. The method according to claim 1 , wherein the compound is

18. The method of claim 1 , wherein the subject has, or is at risk of developing, one or more of an acute coronary syndrome, stroke and/or peripheral artery disease.

19. The method of claim 1 , wherein the compound is administered to the subject in combination with an agent selected from an anti-inflammatory agent, an anti-fibrotic agent, an anti-neoplastic agent and an agent which inhibits leukocytic or lymphocytic proliferation, wherein

the anti-inflammatory agent is selected from dexamethasone, prednisolone, indomethacin, naproxene, ibuprofene celecoxib, methotrexate, adalimumab, infliximab and tocilizumab;

the anti-fibrotic agent is selected from pirfenidone and nintedanib;

the anti-neoplastic agent is selected from doxorubicine, trametinib, sonidegib and durvalumab; and

the agent which inhibits leukocytic or lymphocytic proliferation is selected from daunorubicin, cytarabide, platinum salts, and bleomycin.

20. The method of claim 1 , wherein the compound is administered to the subject in combination with an anti-inflammatory agent selected from dexamethasone, prednisolone, indomethacin, naproxene, ibuprofene celecoxib, methotrexate, adalimumab, infliximab and tocilizumab.

21. The method of claim 1 , wherein the compound is administered to the subject in combination with an anti-neoplastic agent selected from doxorubicine, trametinib, sonidegib and durvalumab.

22. The method of claim 1 , wherein the compound is administered in combination with an agent selected from pirfenidone, nintedanib and methotrexate.

23. The method according to claim 1 , wherein the subject is a human.