Difluoroketamide derivatives as HtrA1 inhibitors

Patent metadata

Field	Value
Publication number	US-11059858-B2
Application number	US-201816121244-A
Country	US
Kind code	B2
Filing date	Sep 4, 2018
Priority date	Mar 4, 2016
Publication date	Jul 13, 2021
Grant date	Jul 13, 2021

Abstract

The invention provides novel compounds having the general formula (I)wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R23 are as described herein, compositions including the compounds and methods of using the compounds.

First claim

The invention claimed is:

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, 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 the arylcarbonyl and the 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 the arylcarbonyl and the 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 the arylcarbonyl and the 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 ,
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 8 , 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 8 , 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,
xx) carboxy-C 1-6 -alkylaminocarbonyl-C 1-6 -alkoxy, and
xxi) heterocycloalkyl; and
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.

2. The compound or a pharmaceutically acceptable salt thereof 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, and
iii) phenyl 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) 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 , and
vi) heteroaryl substituted with R 18 , R 19 and R 20 , wherein the he

Assignees

• Hoffmann La Roche

Inventors

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

Classifications

• C07K5/0815

  with the first amino acid being basic · CPC title

• C07K5/06191

  containing heteroatoms different from O, S, or N · CPC title

• C07K5/06026

  the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala · CPC title

• C07K5/0606

  the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr · CPC title

• C07K5/06078

  and aromatic or cycloaliphatic · CPC title