Small molecule BRD4 modulators for HIV epigenetic regulation

Patent metadata

Field	Value
Publication number	US-10975059-B2
Application number	US-201916441748-A
Country	US
Kind code	B2
Filing date	Jun 14, 2019
Priority date	Dec 13, 2017
Publication date	Apr 13, 2021
Grant date	Apr 13, 2021

Abstract

The invention relates generally to novel small molecule BRD4 modulators for HIV, the preparation thereof as well as the use thereof.

First claim

We claim:

1. A compound, or a pharmaceutically acceptable salt thereof, having the formula:

wherein
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently H, —OH, alkyl, alkoxy, halogen, NH 2 , —OCF 3 or —CF 3 ;
R 10 , R 11 and R 12 are independently H, —OH, halogen, alkoxy, —NH 2 , —CF 3 , —(CO)R 13 , where R 13 is alkyl, alkoxy, amino, or alkylamino; —NR 22 R 23 where R 22 and R 23 are independently H, alkyl; or R 22 and R 23 are optionally joined to form a 3-6 membered substituted or unsubstituted heterocycle having 1-3 heteroatoms;
Linker is —(CO)NR 25 —, NR 26 or —R 27 (CO)—, wherein R 25 , R 26 and R 27 are independently H or C 1 -C 6 alkyl; and
n is 0-3.

2. A compound, or a pharmaceutically acceptable salt thereof, having

the formula:
wherein
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently H, —OH, alkyl, alkoxy, halogen, —NH 2 , —OCF 3 or —CF 3 ;
R 10 , R 11 and R 12 are independently H, —OH, halogen, alkoxy, —NH 2 , —CF 3 , —(CO)R 13 where R 13 is alkyl, alkoxy, amino, or alkylamino; —NR 22 R 23 where R 22 and R 23 are independently H, alkyl; or R 22 and R 23 are optionally joined to form a 3-6 membered substituted or unsubstituted heterocycle having 1-3 heteroatoms.

3. The compound of claim 2 , where R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are H and R 3 is —CF 3 or alkoxy:

4. The compound according to claim 2 , where the compound is:

5. A compound, or a pharmaceutically acceptable salt thereof, having the formula:

wherein
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently H, —OH, alkyl, alkoxy, halogen, NH 2 , —OCF 3 or —CF 3 ;
R 10 , R 11 and R 12 are independently H, —OH, halogen, alkoxy, —NH 2 , —CF 3 , —(CO)R 13 where R 13 is alkyl, alkoxy, amino, or alkylamino; —NR 22 R 23 where R 22 and R 23 are independently H, alkyl; or R 22 and R 23 are optionally joined to form a 3-6 membered substituted or unsubstituted heterocycle having 1-3 heteroatoms;
Linker is —NH(CO)NR 24 , wherein R 24 is C 1 -C 6 alkyl;
n is 0-3.

6. A compound, or a pharmaceutically acceptable salt thereof, having the formula:

wherein
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently H, —OH, alkyl, alkoxy, halogen, —NH 2 , —OCF 3 or —CF 3 ;
R 10 , R 11 and R 12 are independently H, —OH, halogen, alkoxy, —NH 2 , —CF 3 , —(CO)R 13 where R 13 is alkyl, alkoxy, amino, or alkylamino; —NR 22 R 23 , where R 22 and R 23 are independently H, alkyl; or R 22 and R 23 are optionally joined to form a 3-6 membered substituted or unsubstituted heterocycle having 1-3 heteroatoms;
Linker is —NH(CO)NH—,
n is 0-3.

7. A method comprising contacting one or more cells with one or more compounds of Formulas I, III, IV, Ia, or Ib, or a pharmaceutically acceptable salt thereof.

8. The method of claim 7 , wherein said compound is any of:

9. The method of claim 7 , wherein said method comprises suppressing HIV.

10. A method of treating HIV comprising administering one or more compounds of Formulas I, III, IV, V, Va′, Vb′, Ia, and Ib, or a pharmaceutically acceptable salt thereof, to a subject.

11. A compound, or a pharmaceutically acceptable salt thereof, having the formula:

wherein R 28 is substituted or unsubstituted aryl, wherein the (*) indicates the presence of a chiral carbon.

12. The compound of claim 11 , wherein R 28 is unsubstituted aryl.

13. The compound of claim 12 , wherein said compound is a (R)- or (S)-enantiomer, or a combination thereof.

14. The compound of claim 13 , wherein said compound is:

wherein the (*) indicates the presence of a chiral carbon.

15. The compound of claim 14 , wherein R 28 is unsubstituted aryl:

Assignees

• Hu Haitao
• Zhou Jia
• Liu Zhiqing
• Univ Texas

Inventors

• Hu Haitao
• Zhou Jia
• Liu Zhiqing

Classifications

• C07D403/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61P31/18 Primary

  for HIV · CPC title

• C07D207/48

  Sulfur atoms · CPC title