Nrf2 regulators

Patent metadata

Field	Value
Publication number	US-10604509-B2
Application number	US-201615736075-A
Country	US
Kind code	B2
Filing date	Jun 15, 2016
Priority date	Jun 15, 2015
Publication date	Mar 31, 2020
Grant date	Mar 31, 2020

Abstract

Provided are aryl analogs, pharmaceutical compositions containing them and their use as NRF2 regulators.

First claim

What is claimed is:

1. A compound of Formula (I)

wherein,
B is —(CH 2 ) 2 -triazolyl which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl, —O—C 1-3 alkyl, CN, —(CH 2 ) 2 —O—(CH 2 ) 2 —OR 4 and halo;
D is —C(O)OH, —C(O)NHSO 2 CH 3, —SO 2 NHC(O)CH 3 , 5-(trifluoromethyl)-4H-1,2,4-triazol-2-yl, or tetrazolyl;
R 1 is independently hydrogen, C 1-3 alkyl, F, or the two R 1 groups together with the carbon to which they are attached form a cyclopropyl group;
R 2 is hydrogen, methyl, CF 3 , or halo;
R 4 is hydrogen or —C 1-3 alkyl;
Linker is —CH 2 —, —CH 2 —N(cyclopropyl)—CH 2 —, —CH 2 —N(CH 3 )—CH 2 — or —N(CH 3 )—CH 2 —;
A is tetrahydrobenzoxazepinyl or tetrahydro-pyrido-oxazepinyl, each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl, C 3-6 spirocycloalkyl, halo, CN, —O—C 1-3 alkyl, —CH 2 —O—CH 3, and OH; and
X is CH;
or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

3. A method for treating heart failure comprising administering to a human in need thereof, a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, of claim 1 .

4. The method of claim 3 wherein the compound, or a pharmaceutically acceptable salt thereof, is administered orally.

5. The method of claim 3 wherein the compound, or a pharmaceutically acceptable salt thereof, is administered intravenously.

6. A compound which is 5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoic acid:

or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, of claim 6 , and one or more pharmaceutically acceptable excipients.

8. A method for treating heart failure comprising administering to a human in need thereof, a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, of claim 6 .

9. The method of claim 8 wherein the compound, or pharmaceutically acceptable salt thereof, is administered orally.

10. The method of claim 8 wherein the compound, or a pharmaceutically acceptable salt thereof, is administered intravenously.

11. An enantiomer of a compound which is 5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoic acid, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof, of claim 11 , and one or more pharmaceutically acceptable excipients.

13. A method for treating heart failure comprising administering to a human in need thereof, a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, of claim 11 .

14. The method of claim 13 wherein the compound, or a pharmaceutically acceptable salt thereof, is administered orally.

15. The method of claim 13 wherein the compound, or a pharmaceutically acceptable salt thereof, is administered intravenously.

16. A compound which is 5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoic acid:

17. A pharmaceutical composition comprising the compound of claim 16 , and one or more pharmaceutically acceptable excipients.

18. A method for treating heart failure comprising administering to a human in need thereof, a therapeutically effective amount of the compound of claim 17 .

19. The method of claim 17 wherein the compound is administered orally.

20. The method of claim 17 wherein the compound is administered intravenously.

21. An enantiomer of a compound which is 5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoic acid.

22. A pharmaceutical composition comprising the compound of claim 21 , and one or more pharmaceutically acceptable excipients.

23. A method for treating heart failrue comprising administering to a human in need thereof, a therapeutically effective amount of the compound claim 21 .

24. The method of claim 22 wherein the compouind is administered orally.

25. The method of claim 22 wherein the compound is administered intravenously.

26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is:
5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-((2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-y1)methyl)-4-methylphenyl)pentanoic acid;
5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoic acid;
5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoic acid;
5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin- 4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoic acid;
5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin- 4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoic acid;
3-(3-((2,2-Dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)- 5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoic acid;
3-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpentanoic acid;
5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpentanoic acid;
3-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-2-methylpentanoic acid;
3-(4-Chloro-3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoic acid;
5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)pentanoic acid;
3-(4-Chloro-3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoic acid;
5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-N-(methylsulfonyl)pentanamide; and
5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][ 1 , 4 ]oxazepin- 4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpentanoic acid.

Assignees

• Glaxosmithkline Ip Dev Ltd
• Astex Therapeutics Ltd

Inventors

• Kerns Jeffrey K
• Callahan James
• Heightman Thomas Daniel
• Woolford Alison Jo-Anne
• Shah Ami Lakdawala
• Davis Roderick S
• Norton David
• Boehm Jeffrey Charles
• Goodwin Nicole Cathleen

Classifications

• C07D487/08

  Bridged systems · CPC title

• C07D255/04

  condensed with carbocyclic rings or ring systems · CPC title

• A61P27/00

  Drugs for disorders of the senses · CPC title

• C07D403/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• A61K9/0019 Primary

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title