Tricyclic heterocycles as BET protein inhibitors

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Cy 1 is a group of Formula Cy 1 -A or Cy 1 -B:

R 1 , R 2 , R 3 , and R 4 are each independently selected from H and C 1-4 alkyl; or R 2 and R 4 are combined to form a bridging —CH 2 — or —CH 2 CH 2 — group;

R 5 is —C(═O)R 5a , —C(═O)OR 5a , —C(═O)NR 5a R 5b , —S(═O) 2 R 5a , or —S(═O)2NR 5a R 5b ;

R 5a is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, (C 1-4 alkoxy)-C 1-4 alkyl-, C 3-6 cycloalkyl, or C 3-6 cycloalkyl-C 1-4 alkyl-;

R 5b is H or C 1-4 alkyl;

R 6 is H or methyl;

R 7 is H, C 1-4 alkyl, —C(═O)R 7a , —C(═O)OR 7a , —C(═O)NR 7a R 7b , —S(═O) 2 R 7a , or —S(═O) 2 NR 7a R 7b ;

R 7a is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, (C 1-4 alkoxy)-C 1-4 alkyl-, C 3-6 cycloalkyl, or C 3-6 cycloalkyl-C 1-4 alkyl-;

R 7b is H or C 1-4 alkyl;

R 8 is H or methyl;

Cy 2 is pyridin-2-yl or pyridin-3-yl, each of which is optionally substituted by F or Cl, wherein said F and Cl are meta or para to the pyridine nitrogen;

R 9 is H, F, or CH 2 OH; and

R 10 is H, —C(═O)NHCH 3 , —C(═O)NHCH 2 CH 3 , —C(═O)NHCH 2 CH 2 CH 3 , or —C(═O)NHCH(CH 3 ) 2 ;

provided:

i) when R 5a is methyl, ethyl or i-propyl, then one of R 2 , R 3 , and R 4 is other than H;

ii) when R 7a is methyl, ethyl, i-propyl, —CF3, or methoxymethyl, then one of R 2 , R 3 , and R 4 is other than H; and

iii) when R 7 and R 8 are both methyl, then one of R 2 , R 3 , and R 4 is other than H.

2. A compound of Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

Cy 1 is a group of Formula Cy 1 -A or Cy 1 -B:

R 1 , R 2 , R 3 , and R 4 are each independently selected from H and C 1-4 alkyl;

or R 2 and R 4 are combined to form a bridging —CH 2 — or —CH 2 CH 2 — group;

R 5 is —C(═O)R 5a , —C(═O)OR 5a , —C(═O)NR 5a R 5b , —S(═O) 2 R 5a , or —S(═O) 2 NR 5a R 5b ;

R 5a is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, (C 1-4 alkoxy)-C 1-4 alkyl-, C 3-6 cycloalkyl, or C 3-6 cycloalkyl-C 1-4 alkyl-;

R 5b is H or C 1-4 alkyl;

R 6 is H or methyl;

R 7 is H, C 1-4 alkyl, —C(═O)R 7a , —C(═O)OR 7a , —C(═O)NR 7a R 7b , —S(═O) 2 R 7a , or —S(═O) 2 NR 7a R 7b ;

R 7a is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, (C 1-4 alkoxy)-C 1-4 alkyl-, C 3-6 cycloalkyl, or C 3-6 cycloalkyl-C 1-4 alkyl-;

R 7b is H or C 1-4 alkyl; and

R 8 is H or methyl;

provided:

i) when R 5a is methyl, ethyl or i-propyl, then one of R 2 , R 3 , and R 4 is other than H;

ii) when R 7a is methyl, ethyl, i-propyl, —CF3, or methoxymethyl, then one of R 2 , R 3 , and R 4 is other than H; and

iii) when R 7 and R 8 are both methyl, then one of R 2 , R 3 , and R 4 is other than H.

3. The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein:

Cy 1 is a group of Formula Cy 1 -A;

R 1 , R 2 , R 3 , and R 4 are each independently selected from H and methyl;

or R 2 and R 4 are combined to form a bridging —CH 2 — group;

R 5 is —C(═O)R 5a , —C(═O)OR 5a , —C(═O)NR 5a R 5b , —S(═O) 2 R 5a , or —S(═O) 2 NR 5a R 5b ;

R 5a is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, (C 1-4 alkoxy)-C 1-4 alkyl-, C 3-6 cycloalkyl, or C 3-6 cycloalkyl-C 1-4 alkyl-;

R 5b is H or methyl;

provided when R 5a is methyl, ethyl or i-propyl, then one of R 2 , R 3 , and R 4 is other than H.

4. The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein:

Cy 1 is a group of Formula Cy 1 -A;

R 1 , R 2 , R 3 , and R 4 are each independently selected from H and methyl;

or R 2 and R 4 are combined to form a bridging —CH 2 — group;

R 5 is —C(═O)R 5a ; and

R 5a is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxyethyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —C(═O)R 5a .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5a is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxyethyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5a is n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxyethyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5a is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5a is n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5a is methyl, ethyl, n-propyl, i-propyl, t-butyl, methoxymethyl, cyclopropyl, or cyclobutyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5a is n-propyl, t-butyl, methoxymethyl, cyclopropyl, or cyclobutyl.

12. The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein:

Cy 1 is a group of Formula Cy 1 -B;

R 1 , R 2 , R 3 , and R 4 are each independently selected from H and methyl;

or R 2 and R 4 are combined to form a bridging —CH 2 — group;

R 6 is H or methyl;

R 7 is H, C 1-4 alkyl, —C(═O)R 7a , —C(═O)OR 7a , —C(═O)NR 7a R 7b , —S(═O) 2 R 7a , or —S(═O) 2 NR 7a R 7b ;

R 7a is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, (C 1-4 alkoxy)-C 1-4 alkyl-, C 3-6 cycloalkyl, or C 3-6 cycloalkyl-C 1-4 alkyl-;

R 7b is H or methyl; and

R 8 is H or methyl;

provided: when R 7a is methyl, ethyl, i-propyl, —CF 3 , or methoxymethyl, then one of R 1 , R 2 , R 3 , and R 4 is other than H; and when R 7 and R 8 are both methyl, then one of R 1 , R 2 , R 3 , and R 4 is other than H.

13. The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein:

Cy 1 is a group of Formula Cy 1 -B;

R 1 , R 2 , R 3 , and R 4 are each independently selected from H and methyl;

or R 2 and R 4 are combined to form a bridging —CH 2 — group;

R 6 is H or methyl;

R 7 is —C(═O)R 7a , —C(═O)NR 7a R 7b ,or —S(═O) 2 R 7a ;

R 7a is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxyethyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl;

R 7b is H or methyl; and

R 8 is H or methyl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —C(═O)R 7a , —C(═O)NR 7a R 7b , or —S(═O) 2 R 7a .

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —C(═O)R 7a .

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7a is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxyethyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7a is n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxyethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7a is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7a is methyl, ethyl, n-propyl, i-propyl, t-butyl, cyclopropyl, or cyclobutyl.

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7a is cyclopropyl.

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7a is cyclobutyl.

22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H.

23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is methyl.

24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7b is H.

25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7b is methyl.

26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4 are each independently selected from H and methyl;

or R 2 and R 4 are combined to form a bridging —CH 2 — group.

27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4 are each independently selected from H and methyl.

28. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 3 , and R 4 is H.

29. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is H.

30. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 10 is H.

31. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 2 is pyridin-2-yl optionally substituted by F or Cl, wherein said F and Cl are meta or para to the pyridine nitrogen.

32. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 2 is pyridin-2-yl.

33. The compound of claim 1 selected from:

(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-(4-isobutyrylpiperazin-1-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;

(4S)-2-[(2R,6S)-4-Acetyl-2,6-dimethylpiperazin-1-yl]-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;

(4S)-2-[(2S)-4-acetyl-2-methylpiperazin-1-yl]-7-(3, 5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;

(4S)-2-(5-acetyl-2, 5-diazabicyclo[2.2.1]hept-2-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1, 4]benzoxazin-2-yl]-4-methylpiperidin-4-yl}acetamide;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}-N-methylacetamide;

(4S)-2-[(3S)-4-acetyl-3-methylpiperazin-1-yl]-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;

(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[(3S)-3-methyl-4-propionylpiperazin-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;

(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[(3S)-4-isobutyryl-3-methylpiperazin-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}butanamide;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}-2,2-dimethylpropanamide;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}cyclopropanecarboxamide;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}cyclobutanecarboxamide;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}ethanesulfonamide;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}-N-methylpropanamide;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}-N-methylbutanamide;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}-N,2-dimethylpropanamide;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}-N,2,2-trimethylpropanamide;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}-N-methylcyclopropanecarboxamide;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}-N-methylcyclobutanecarboxamide;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}-N,N′,N′-trimethylurea;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}-N-methylmethanesulfonamide;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}-N-methylethanesulfonamide;

N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}-N-methylcyclopropanesulfonamide;

(4S)-2-(4-butyrylpiperazin-1-yl)-7-(3, 5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;

(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;

(4S)-2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-′7-(3, 5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;

(4S)-2-[4-(cyclobutylcarbonyl)piperazin-1-yl]-7-(3, 5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine; and

(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(methoxyacetyl)piperazin-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;

or a pharmaceutically acceptable salt of any of the aforementioned.

34. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

35. A method of treating cancer comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is adenocarcinoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer, head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, ocular cancer, optic nerve tumor, oral cancer, ovarian cancer, pituitary tumor, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, sarcoma, skin cancer, spinal tumor, small intestine cancer, stomach cancer, T-cell leukemia, T-cell lymphoma, testicular cancer, thyroid cancer, throat cancer, urogenital cancer, urothelial carcinoma, uterine cancer, vaginal cancer, or Wilms' tumor.

36. A method of treating an autoimmune or inflammatory disease comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the autoimmune or inflammatory disease is selected from allergy, allergic rhinitis, arthritis, asthma, chronic obstructive pulmonary disease, degenerative joint disease, dermatitis, organ rejection, eczema, hepatitis, inflammatory bowel disease, multiple sclerosis, myasthenia gravis, psoriasis, sepsis, sepsis syndrome, septic shock, systemic lupus erythematosus, tissue graft rejection, and type I diabetes.

37. A method of treating a viral infection comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

38. The method of claim 37 , wherein the viral infection is infection with adenovirus, Epstein-Barr virus, hepatitis B virus, hepatitis C virus, a herpes virus, human immunodeficiency virus, human papilloma virus or a pox virus.

39. The compound of claim 1 , wherein the compound is (4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-(4-isobutyrylpiperazin-1-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine, or a pharmaceutically acceptable salt thereof.

40. A pharmaceutical composition comprising a compound of claim 39 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.