Difluoroketamide derivatives

Patent metadata

Field	Value
Publication number	US-10428108-B2
Application number	US-201715805521-A
Country	US
Kind code	B2
Filing date	Nov 7, 2017
Priority date	May 11, 2015
Publication date	Oct 1, 2019
Grant date	Oct 1, 2019

Abstract

The invention provides novel compounds having the general formula (I)

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as described herein, compositions including the compounds and methods of using the compounds.

First claim

We claim:

1. A compound of formula (I)

wherein:
R 1 is alkyl, optionally substituted cycloalkyl, haloalkyl, optionally substituted heterocycloalkylalkyl optionally substituted arylalkyl or optionally substituted heteroarylalkyl, wherein each moiety is optionally substituted by one to three substituents independently selected from halogen, alkyl, haloalkyl, cycloalkyl, cyano, hydroxyl, alkoxy, haloalkoxy or phenyl;
R 2 , R 3 R 4 , R 6 , R 7 and R 9 are independently selected from hydrogen, alkyl or cycloalkyl;
R 5 is optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, wherein each moiety is optionally substituted by one to three substituents independently selected from halogen, alkyl, haloalkyl, cycloalkyl, cyano, hydroxyl, alkoxy, haloalkoxy or phenyl;
R 8 is optionally substituted adamantylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted dicycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted diarylalkyl, optionally substituted aryloxyalkyl, optionally substituted diaryloxyalkyl, optionally substituted arylaryloxyalkyl, optionally substituted heteroarylaryloxyalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted arylheteroarylalkyl, optionally substituted arylheteroaryloxyalkyl or optionally substituted aryloxyheteroarylalkyl, wherein each moiety is optionally substituted by one to three substituents independently from selected halogen, alkyl, haloalkyl, cycloalkyl, cyano, hydroxyl, alkoxy, haloalkoxy or phenyl;
wherein a heterocycloalkyl moiety is a ring system of 4 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon, heteroaryl moiety is a ring system of 5 or ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S; the remaining ring atoms being carbon and an aryl moiety is a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms;
or, a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 1 is alkyl, haloalkyl, optionally substituted heterocycloalkylalkyl or optionally substituted phenylalkyl, wherein each moiety is optionally substituted by one to three substituents independently selected from halogen, alkyl, haloalkyl, cycloalkyl, cyano, hydroxyl, alkoxy, haloalkoxy or phenyl.

3. The compound according to claim 2 , wherein R 1 is haloalkyl.

4. The compound according to claim 2 , wherein R 1 is optionally substituted heterocycloalkylalkyl or optionally substituted phenylalkyl.

5. The compound according to claim 2 , wherein R 9 is hydrogen.

6. The compound according to claim 2 , wherein R 2 is alkyl.

7. The compound according to claim 2 , wherein R 3 is hydrogen.

8. The compound according to claim 2 , wherein R 4 is hydrogen.

9. The compound according to claim 2 , wherein R 5 is optionally substituted phenyl or optionally substituted phenylalkyl wherein each moiety is optionally substituted by one to three substituents independently selected from halogen, alkyl, haloalkyl, cycloalkyl, cyano, hydroxyl, alkoxy, haloalkoxy or phenyl.

10. The compound according to claim 9 , wherein each moiety is optionally substituted by one to three substituents independently selected from halogen or alkoxy.

11. The compound according to claim 10 , wherein each moiety is optionally substituted by one to three halogens.

12. The compound according to claim 2 , wherein R 6 is hydrogen.

13. The compound according to claim 2 , wherein R 7 is hydrogen.

14. The compound according to claim 2 , wherein R 8 is optionally substituted phenylalkyl, optionally substituted phenylalkenyl, optionally substituted diphenylalkyl, optionally substituted phenoxyalkyl, optionally substituted pyridinylphenoxyalkyl, optionally substituted phenylpyridinyloxyalkyl or optionally substituted phenylphenoxyalkyl wherein each moiety is optionally substituted by one to three substituents independently selected from halogen, alkyl, haloalkyl, cycloalkyl, cyano, hydroxyl, alkoxy, haloalkoxy or phenyl.

15. The compound according to claim 14 , wherein R 8 is optionally substituted phenylalkyl, optionally substituted phenylalkenyl, optionally substituted diphenylalkyl, optionally substituted phenoxyalkyl or optionally substituted phenylphenoxyalkyl.

16. The compound according to claim 15 , wherein R 8 is optionally substituted phenoxyalkyl or optionally substituted phenylphenoxyalkyl.

17. The compound according to claim 15 , wherein R 8 is phenoxyalkyl or phenylphenoxyalkyl optionally substituted with one to three halogens.

18. The compound according to claim 1 , wherein the compound is of formula (Ia)

19. The compound according to claim 18 , wherein
R 1 is haloalkyl;
R 2 is alkyl;
R 3 R 4 , R 6 , R 7 and R 9 are hydrogen;
R 5 is optionally substituted phenyl or optionally substituted phenylalkyl, wherein each moiety is optionally substituted by one to three independently selected halogens;
R 8 is optionally substituted phenoxyalkyl or optionally substituted phenylphenoxyalkyl, wherein each moiety is optionally substituted by one to three independently selected halogens;
or, pharmaceutically acceptable salt thereof.

20. The compound according to claim 1 which compound is selected from the group consisting of:
(4 S)-4-[[(2 S)-2-[3-(3-chlorophenyl)propanoyl amino]-3-phenylpropanoyl]amino]-2,2-difluoro-5-methyl-N-(2-morpholin-4-ylethyl)-3-oxohexanamide;
(S)-4-((S)-2-((E)-3-(3,5-dichlorophenyl)acrylamido)-2-phenylacetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-(3-(3-chlorophenyl)propanamido)-3-phenylpropanamido)-2,2-difluoro-5-methyl-3-oxo-N-phenethylhexanamide;
(S)-4-((S)-2-(3-(3-chlorophenyl)propanamido)-3-phenylpropanamido)-2,2-difluoro-5-methyl-3-oxo-N-(3,3,3-trifluoropropyl)hexanamide;
(S)-4-((S)-2-(3-(3,4-dichlorophenyl)propanamido)-3-phenylpropanamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-(2-(3-chlorophenoxy)acetamido)-3-phenylpropanamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-(2-(3,4-dichlorophenoxy)acetamido)-3-phenylpropanamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-(3-(3,5-dichlorophenyl)propanamido)-3-phenylpropanamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-(2-(3,5-dichlorophenoxy)acetamido)-3-phenylpropanamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-(3-(3-chlorophenyl)propanamido)-3-phenylpropanamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide;
(S)-4-((S)-2-(2-(3,4-dichlorophenoxy)acetamido)-3-phenylpropanamido)-2,2-difluoro-5-methyl-N-(2-morpholinoethyl)-3-oxohexanamide;
(S)-4-((S)-2-(2-(3-chlorophenoxy)acetamido)-3-phenylpropanamido)-2,2-difluoro-5-methyl-N-(2-morpholinoethyl)-3-oxohexanamide;
(S)-4-((S)-2-(2-(3,5-dichlorophenoxy)acetamido)-3-phenylpropanamido)-2,2-difluoro-5-methyl-N-(2-morpholinoethyl)-3-oxohexanamid

Assignees

• Hoffmann La Roche

Inventors

• Hornsperger Benoit
• Iacone Roberto
• Kitas Eric A
• Maerki Hans P
• Reutlinger Michael
• Mohr Peter

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P29/00

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