Tricyclic heterocycles as BET protein inhibitors
The present disclosure relates to tricyclic heterocycles which are inhibitors of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and are useful in the treatment of diseases such as cancer.
1. A method of treating a fibrotic condition comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula Ia:
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 provided:
when R 5a is methyl, ethyl or i-propyl, then one of R 1 , R 2 , R 3 , and R 4 is other than H.
2. The method of claim 1 , 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.
3. The method of claim 1 , 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.
4. The method of claim 1 , wherein R 5a is n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
5. The method of claim 1 , wherein R 5a is methyl, ethyl, n-propyl, i-propyl, t-butyl, methoxymethyl, cyclopropyl, or cyclobutyl.
6. The method of claim 1 , wherein R 5a is n-propyl, t-butyl, methoxymethyl, cyclopropyl, or cyclobutyl.
7. The method of claim 1 , wherein each of R 1 , R 2 , R 3 , and R 4 is H.
8. The method of claim 1 wherein the compound of Formula Ia is 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;
(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;
(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;
(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.
9. The method of claim 1 , wherein the fibrotic condition is selected from idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma and cardiac fibrosis.
10. The method of claim 9 , wherein the fibrotic condition is idiopathic pulmonary fibrosis.
11. The method of claim 9 , wherein the fibrotic condition is renal fibrosis.
12. The method of claim 9 , wherein the fibrotic condition is post-operative stricture.
13. The method of claim 9 , wherein the fibrotic condition is keloid formation.
14. The method of claim 9 , wherein the fibrotic condition is scleroderma.
15. The method of claim 9 , wherein the fibrotic condition is cardiac fibrosis.