New difluoroketamide derivatives as htra1 inhibitors

Patent metadata

Field	Value
Publication number	US-2018371015-A1
Application number	US-201816121244-A
Country	US
Kind code	A1
Filing date	Sep 4, 2018
Priority date	Mar 4, 2016
Publication date	Dec 27, 2018
Grant date	—

Abstract

wherein R1, R2, R3, R4, R5, R6, R7, R3, R8, R9, R10, R11 and R23 are as described herein, compositions including the compounds and methods of using the compounds.

First claim

1 . Compounds of formula (I)

wherein
R 1 is selected from
i) C 1-6 -alkyl,
ii) C 3-8 -cycloalkyl substituted with R 24 , R 25 and R 26 ,
iii) halo-C 1-6 -alkyl,
iv) heterocycloalkyl-C 1-6 -alkyl substituted with R 24 , R 25 and R 26 ,
v) aryl-C 1-6 -alkyl substituted with R 24 , R 25 and R 26 , and
vi) heteroaryl-C 1-6 -alkyl substituted with R 24 , R 25 and R 26 ;

R 2 , R 3 , R 4 , R 6 , R 7 , R 9 , R 10 and R 23 are independently selected from
i) H,
ii) C 1-6 -alkyl, and
iii) C 3-8 -cycloalkyl;

R 5 is selected from
i) aryl substituted with R 12 , R 13 and R 14 ,
ii) aryl-C 1-6 -alkyl substituted with R 12 , R 13 and R 14 ,
iii) heteroaryl substituted with R 12 , R 13 and R 14 , and
iv) heteroaryl-C 1-6 -alkyl substituted with R 12 , R 13 and R 14 ;

R 8 is selected from
i) H,
ii) hydroxy,
iii) amino-C 1-6 -alkyl substituted on the nitrogen atom by one or two substituents selected from H, C 1-6 -alkylcarbonyl, C 1-6 -alkoxycarbonyl, C 1-6 -alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R 15 , R 16 and R 17 ,
iv) aminocarbonyl substituted on the nitrogen atom by one or two substituents selected from H, C 1-6 -alkylcarbonyl, C 1-6 -alkoxycarbonyl, C 1-6 -alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R 15 , R 16 and R 17 ,
v) aminocarbonyl-C 1-6 -alkyl substituted on the nitrogen atom by one or two substituents selected from H, C 1-6 -alkylcarbonyl, C 1-6 -alkoxycarbonyl, C 1-6 -alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R 15 , R 16 and R 17 ,
vi) carboxy,
vii) carboxy-C 1-6 -alkyl,
viii) C 1-6 -alkoxy,
ix) C 1-6 -haloalkoxy,
x) C 1-6 -alkoxycarbonyl,
xi) C 1-6 -alkoxycarbonyl-C 1-6 -alkyl,
xii) C 3-8 -cycloalkyl,
xiii) aryl substituted with R 15 , R 16 and R 17 ,
xiv) aryl-C 1-6 -alkyl substituted with R 15 , R 16 and R 17 ,
xv) aryl-C 1-6 -alkoxy substituted with R 15 , R 16 and R 17 ,
xvi) heteroaryl substituted with R 15 , R 16 and R 17 ,
xvii) heteroaryl-C 1-6 -alkyl substituted with R 15 , R 16 and R 17 , and
xviii) heteroaryl-C 1-6 -alkoxy substituted with R 15 , R 16 and R 17
xix) heterocycloalkyl substituted with R 15 , R 16 and R 17 ,
xx) heterocycloalkyl-C 1-6 -alkyl substituted with R 15 , R 16 and R 17 , and
xxi) heterocycloalkyl-C 1-6 -alkoxy substituted with R 15 , R 16 and R 17 ;

R 11 is selected from
i) amino-C 1-6 -alkyl substituted on the nitrogen atom by R 21 and R 22 ,
ii) C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 ,
iii) C 3-8 -cycloalkyl-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 ,
iv) C 3-8 -cycloalkyl(halo)-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 ,
v) aryl substituted with R 18 , R 19 and R 20 ,
vi) aryl-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 ,
vii) aryl-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 ,
viii) aryl-heterocycloalkyl substituted with R 18 , R 19 and R 20 ,
ix) aryl(halo)-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 ,
x) aryl(halo)-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 ,
xi) aryl(halo)-heterocycloalkyl substituted with R 18 , R 19 and R 20
xii) aryloxy-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 ,
xiii) aryloxy-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 ,
xiv) aryloxy-heterocycloalkyl substituted with R 18 , R 19 and R 20 ,
xv) aryloxy(halo)-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 ,
xvi) aryloxy(halo)-heterocycloalkyl substituted with R 18 , R 19 and R 20 ,
xvii) aryloxy(halo)-C 1-6 -alkyl,
xviii) heterocycloalkyl substituted with R 18 , R 19 and R 20 ,
xix) heterocycloalkyl-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 ,
xx) heterocycloalkyl-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 ,
xxi) heterocycloalkyl(halo)-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 ,
xxii) heterocycloalkyl(halo)-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 ,
xxiii) heteroaryl substituted with R 18 , R 19 and R 20 ,
xxiv) heteroaryl-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 ,
xxv) heteroaryl-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 ,
xxvi) heteroaryl(halo)-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 ,
xxvii) heteroaryl(halo)-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 ,
xxviii) heteroaryloxy-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 ,
xxix) heteroaryloxy-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 ,
xxx) heteroaryloxy(halo)-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 , and
xxxi) heteroaryloxy(halo)-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 ;

R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 24 , R 25 and R 26 are independently selected from i) H,
ii) cyano,
iii) halogen,
iv) oxo,
v) C 1-6 -alkyl,
vi) amino substituted on the nitrogen atom by two substituents independently selected from H, C 1-6 -alkyl, C 1-6 -alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl,
vii) amino-C 1-6 -alkyl substituted on the nitrogen atom by two substituents independently selected from H, C 1-6 -alkyl, C 1-6 -alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl,
viii) C 1-6 -alkyl,
ix) halo-C 1-6 -alkyl,
x) C 3-8 -cycloalkyl,
xi) C 1-6 -alkoxycarbonyl-C 1-6 -alkyl,
xii) carboxy-C 1-6 -alkyl,
xiii) C 1-6 -alkoxycarbonyl-C 1-6 alkylaminocarbonyl-C 1-6 alkyl,
xiv) carboxy-C 1-6 -alkylaminocarbonyl-C 1-6 alkyl,
xv) C 1-6 -alkoxy,
xvi) halo-C 1-6 -alkoxy,
xvii) C 1-6 -alkoxycarbonyl-C 1-6 -alkoxy,
xviii) carboxy-C 1-6 -alkoxy,
xix) C 1-6 alkoxycarbonyl-C 1-6 alkylaminocarbonyl-C 1-6 alkoxy, and
xx) carboxy-C 1-6 alkylaminocarbonyl-C 1-6 alkoxy;
xxi) heterocycloalkyl;

R 21 and R 22 are independently selected from
i) H,
ii) C 1-6 -alkoxycarbonyl,
iii) carboxy-C 1-6 -alkyl,
iv) arylcarbonyl, and
v) heteroarylcarbonyl;

or pharmaceutically acceptable salts;

2 . A compound according to claim 1 , wherein
R 1 is halo-C 1-6 -alkyl; R 2 is selected from
i) C 1-6 -alkyl, and
ii) C 3-8 -cycloalkyl;
R 3 , R 4 , R 6 , R 7 , R 9 , R 10 and R 23 are H; R 5 is phenyl substituted with R 12 , R 13 and R 14 ; R 8 is selected from
i) H,
ii) hydroxy,
iii) phenyl substituted with R 15 , R 16 and R 17 ;
R 11 is selected rom
i) amino-C 1-6 s-alkyl substituted on the nitrogen atom by R 21 and R 22 ,
ii) phenyl substituted with R 18 , R 19 and R 20 ,
iii) phenyl-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 ,
iv) phenyl-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 ,
v) phenyl(halo)-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 ,
vi) heteroaryl substituted with R 18 , R 19 and R 20 , wherein heteroaryl is selected from pyrazinyl, pyridinyl, pyrimidinyl and thiophenyl,
R 12 is selected from
i) H, and
ii) C 1-6 -alkoxy;
R 13 , R 14 , R 17 and R 20 are H; R 15 is selected from
i) C 1-6 -alkyl,
ii) cyano,
iii) halogen, and
iv) carboxy-C 1-6 -alkoxy;
R 16 is selected from
i) H, and
ii) halogen;
R 18 is selected from
i) H,
ii) halogen,
iii) halo-C 1-6 -alkoxy,
iv) cyano,
v) amino substituted on the nitrogen atom by two C 1-6 -alkyl,
vi) C 1-6 -alkoxycarbonyl-C 1-6 -alkoxy,
vii) carboxy-C 1-6 -alkoxy, and
viii) morpholinyl;
R 19 is selected from
i) H and
ii) halogen;
R 21 is pyridinylcarbonyl; R 22 is H; or pharmaceutically acceptable salts.

3 . A compound according to any one of claims 1 to 2 , wherein R 1 is halo-C 1-6 -alkyl.

Assignees

• Hoffmann La Roche

Inventors

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

Classifications

• A61P43/00

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

• A61P27/02

  Ophthalmic agents · CPC title

• A61P29/00

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

• C07K5/06078

  and aromatic or cycloaliphatic · CPC title

• C07K5/0819

  with the first amino acid being acidic · CPC title