Tetrahydroquinoline compositions as BET bromodomain inhibitors

1. A composition comprising a compound in an enantiomeric excess (e.e. %) of at least 94% as determined by chiral HPLC analysis, wherein the compound is:

2. The composition of claim 1 , further comprising a compound:

3. The composition of claim 2 , further comprising a compound:

4. The composition of claim 3 , further comprising a compound:

5. The composition of claim 4 , further comprising a compound:

6. The composition of claim 2 , further comprising a compound:

7. The composition of claim 1 , further comprising a compound:

8. The composition of claim 7 , further comprising a compound:

9. The composition of claim 1 , wherein the compound:

is obtained by a process comprising a step of reacting a Boc-protected compound:

with an acid to form the compound:

10. The composition of claim 9 , wherein the process further comprises a step of treating a first tetrahydroquinoline:

with a palladium catalyst and a first base in the presence of a boronic ester:

11. The composition of claim 10 , wherein the process further comprises a step of treating a brominated tetrahydroisoquinoline:

with bromocyclobutane and a second base.

12. The composition of claim 11 , wherein the process further comprises a step of treating a second tetrahydroquinoline:

with a brominating agent.

13. The composition of claim 12 , wherein the process further comprises a step of treating a third tetrahydroquinoline:

or a salt thereof, with cyclopropanecarbonyl chloride and a third base.

14. The composition of claim 9 , wherein the acid is selected from hydrochloric acid and trifluoroacetic acid.

15. A pharmaceutical composition for inhibiting BET in a solid dosage form suitable for oral administration, the pharmaceutical composition comprising a BET inhibitor consisting of a compound:

in an enantiomeric excess (e.e. %) of at least 94% as determined by chiral HPLC analysis, and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15 , wherein the solid dosage form suitable for oral administration is a tablet or capsule.

17. The pharmaceutical composition of claim 16 , wherein the solid dosage form suitable for oral administration comprises a total of about 1 mg to about 250 mg of the compound:

18. A pharmaceutical composition for inhibiting BET, the pharmaceutical composition comprising a pharmaceutically acceptable carrier and from about 5% to about 90% by weight of a BET inhibitor consisting of a compound (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline.

19. The pharmaceutical composition of claim 18 , formulated in a solid dosage form suitable for oral administration, the solid dosage form comprising (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline in an enantiomeric excess (e.e. %) of at least 94% as determined by chiral HPLC analysis, and the pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising about 5% to about 90% by weight of a compound in an enantiomeric excess (e.e. %) of at least 94% as determined by chiral HPLC analysis, wherein the compound is:

21. The pharmaceutical composition of claim 20 , further comprising one or more compounds selected from the group consisting of:

22. The pharmaceutical composition of claim 20 , wherein the compound:

is obtained by a process comprising one or more steps selected from the group consisting of:

(a) reacting a Boc-protected compound:

with an acid to form the compound:

(b) treating a first tetrahydroquinoline:

with a palladium catalyst and a first base in the presence of a boronic ester:

(c) treating a brominated tetrahydroquinoline:

with bromocyclobutane and a second base;

(d) treating a second tetrahydroquinoline:

with a brominating agent; and

(e) treating a third tetrahydroquinoline:

or a salt thereof, with cyclopropanecarbonyl chloride and a third base.

23. A pharmaceutical composition in an oral unit dosage form comprising a total of about 5% to about 90% by weight of a compound in an enantiomeric excess (e.e. %) of at least 94% as determined by chiral HPLC analysis, wherein the compound is:

24. The pharmaceutical composition of claim 23 , comprising the compound:

in an enantiomeric excess (e.e. %) of at least about 97.8% as determined by chiral HPLC analysis.

25. The pharmaceutical composition of claim 24 , wherein the oral unit dosage form is a capsule.

26. A pharmaceutical composition in a unit dosage form comprising (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline in an enantiomeric excess (e.e. %) of at least about 97.8% as determined by chiral HPLC analysis.

27. The pharmaceutical composition of claim 26 , comprising a total of 5% to about 90% by weight of (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline.

28. The pharmaceutical composition of claim 27 , comprising (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline in an enantiomeric excess (e.e. %) of about 99% as determined by chiral HPLC analysis.

29. A pharmaceutical composition in an oral unit dosage form comprising (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline.

30. The pharmaceutical composition of claim 29 , comprising a total of 5% to about 90% by weight of (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline.

31. The pharmaceutical composition of claim 29 comprising a total of about 100, 150, 250, 500, 750, or 1000 mg of (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline.

32. The pharmaceutical composition of claim 31 , comprising (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline in an enantiomeric excess (e.e. %) of at least 94% as determined by chiral HPLC analysis.

33. An inhibitor of BET family bromodomains comprising (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline.

34. A pharmaceutical composition comprising an active substance inhibitor of bromodomain of the BET family proteins, the active substance inhibitor comprising a compound:

35. The pharmaceutical composition of claim 34 , wherein the active substance inhibitor consists essentially of the compound:

36. The pharmaceutical composition of claim 34 , comprising the compound:

in an enantiomeric excess (e.e. %) of at least 94% as determined by chiral HPLC analysis.

37. The pharmaceutical composition of claim 34 , comprising the compound:

in an enantiomeric excess (e.e. %) of at least about 97.8% as determined by chiral HPLC analysis.

38. The pharmaceutical composition of claim 34 , comprising the compound:

in an enantiomeric excess (e.e. %) of about 99% as determined by chiral HPLC analysis.

39. The pharmaceutical composition of claim 35 , comprising a total of about 5% to about 90% by weight of the compound:

40. The pharmaceutical composition of claim 39 , comprising the compound:

in an enantiomeric excess (e.e. %) of at least 94% as determined by chiral HPLC analysis.

41. The pharmaceutical composition of claim 36 , comprising a total of about 5% to about 90% by weight of the compound:

42. The composition of claim 1 , further comprising a compound:

43. The composition of claim 1 , further comprising a compound:

44. The composition of claim 7 , further comprising a compound:

45. The composition of claim 1 , obtained by a process comprising the steps of:

(a) reacting a Boc-protected compound:

with an acid to form the compound:

(b) treating a first tetrahydroquinoline:

with a palladium catalyst and a first base in the presence of a boronic ester

(c) treating a brominated tetrahydroquinoline:

with bromocyclobutane and a second base;

(d) treating a second tetrahydroquinoline:

with a brominating agent; and

(e) treating a third tetrahydroquinoline:

or a salt thereof, with cyclopropanecarbonyl chloride and a third base.

46. The inhibitor of claim 33 , obtained by a process comprising the steps of:

(a) reacting a Boc-protected compound:

with an acid to form (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;

(b) treating a first tetrahydroquinoline:

with a palladium catalyst and a first base in the presence of a boronic ester:

(c) treating a brominated tetrahydroquinoline:

with bromocyclobutane and a second base;

(d) treating a second tetrahydroquinoline:

with a brominating agent; and

(e) treating a third tetrahydroquinoline:

or a salt thereof, with cyclopropanecarbonyl chloride and a third base.

47. The composition of claim 34 , obtained by a process comprising the steps of:

(a) reacting a Boc-protected compound:

with an acid to form the compound:

(b) treating a first tetrahydroquinoline:

with a palladium catalyst and a first base in the presence of a boronic ester

(c) treating a brominated tetrahydroquinoline:

with bromocyclobutane and a second base;

(d) treating a second tetrahydroquinoline:

with a brominating agent; and

(e) treating a third tetrahydroquinoline:

or a salt thereof, with cyclopropanecarbonyl chloride and a third base.