Tetrahydroquinoline compositions as BET bromodomain inhibitors

Patent metadata

Field	Value
Publication number	US-10336722-B2
Application number	US-201815937271-A
Country	US
Kind code	B2
Filing date	Mar 27, 2018
Priority date	Nov 18, 2013
Publication date	Jul 2, 2019
Grant date	Jul 2, 2019

Abstract

The present invention relates to inhibitors of bromo and extra terminal (BET) bromodomains that are useful for the treatment of cancer, inflammatory diseases, diabetes, and obesity, having Formula I:

wherein W, X, Y, Z, R 1 , R 2 , R 5 , and R 8 are as described herein.

First claim

The invention claimed is:

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

Assignees

• Forma Therapeutics Inc

Inventors

• Bair Kenneth W
• Herbertz Torsten
• Kauffman Goss S
• Kayser-Bricker Katherine J
• Luke George P
• Martin Matthew W
• Millan David S
• Schiller Shawn E R
• Talbot Adam C

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title