US 9,751,873 B2 · Aryl sultam derivatives as RORc modulators

Abstract

Compounds of the formula I: or pharmaceutically acceptable salts thereof, wherein m, n, p, q, r, A, W, X1, X2, X3, X4, Y, Z, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of inflammatory diseases such as arthritis.

A compound of formula XXIXa or XXIXb

wherein:
p is from 0 to 2;
s is from 0 to 2;
R1, R2 and R3 each independently is:
hydrogen;
or C1-6alkyl which may be unsubstituted or substituted one or more times with halo;
each R9 is independently:
C1-6alkyl;
halo;
C1-6alkoxy;
or cyano;
and
each Re is halo;
wherein the compound is selected from the group consisting of:
(1S,5R,6S)-3- [2,3-Difluoro-4- ((3S,6R)-3- methyl-1,1- dioxo-6-phenyl-[1,2]thiazinan-2- ylmethyl)- phenyl]- 6-[1,2,4]triazol- 4-yl-3-aza-bicyclo- [3.1.0]hexane;
(1S,5R,6S)-3- [2,3-Difluoro- 4-((3S,6S)-3- methyl-1,1- dioxo-6-phenyl- [1,2]-thiazinan- 2-ylmethyl)-phenyl]-6- [1,2,4]triazol- 4-yl-3-aza- bicyclo- [3.1.0]hexane;
(1R,5S,6S)-3- [2,5-Difluoro- 4-((3S,6R)-3- methyl-1,1- dioxo-6-phenyl- [1,2]-thiazinan- 2-ylmethyl)- phenyl]- 6-[1,2,4]triazol- 4-yl-3-aza- bicyclo- [3.1.0]hexane;
(1S,5R,6S)-3- [2,5-Difluoro- 4-((3S,6S)-3-methyl- 1,1-dioxo-6-phenyl-[1,2]- thiazinan-2-ylmethyl)- phenyl]-6- [1,2,4]triazol- 4-yl-3-aza- bicyclo- [3.1.0]hexane;
(1R,5S,6S)-3- [2,6-Difluoro- 4-((3S,6S)-3- methyl- 1,1-dioxo-6- phenyl-[1,2]- thiazinan-2-ylmethyl)- phenyl]-6- [1,2,4]triazol- 4-yl-3-aza- bicyclo- [3.1.0]hexane;
(1R,5S,6S)-3- [2,6-Difluoro- 4-((3S,6R)-3- methyl-1,1- dioxo-6- phenyl-[1,2]- thiazinan-2- ylmethyl)- phenyl]-6- [1,2,4]triazol- 4-yl-3-aza- bicyclo- [3.1.0]hexane;
(1S,5R,6S)-3- [2-Fluoro-4- ((3S,6R)- 3-methyl-1,1- dioxo-6-phenyl-[1,2]thiazinan- 2-ylmethyl)- phenyl]-6- [1,2,4]triazol- 4-yl-3-aza- bicyclo- [3.1.0]hexane;
(1S,5R,6S)-3- [2-Fluoro-4- ((3S,6R)- 3-methyl-1,1- dioxo-6-phenyl- [1,2]thiazinan- 2-ylmethyl)- phenyl]-6- [1,2,4]triazol- 4-yl-3-aza- bicyclo- [3.1.0]hexane;
(3R,6R)-2-(4- ((1R,5S,6S)- 6-(4H-1,2,4- triazol-4-yl)-3- azabicyclo- [3.1.0]-hexan- 3-yl)-2,5- difluorobenzyl)- 6-phenyl-3- (trifluoro- methyl)- 1,2-thiazinane 1,1-dioxide;
(3R,6S)-2-(4- ((1R,5S,6S)-6- (4H-1,2,4- triazol-4-yl)-3- azabicyclo- [3.1.0]-hexan- 3-yl)-2,5- difluorobenzyl)- 6-phenyl-3- (trifluoro- methyl)-1,2- thiazinane 1,1-dioxide;
(3R,6R)-2-(4- ((1R,5S,6S)-6- (4H-1,2,4- triazol-4-yl)-3- azabicyclo- [3.1.0]-hexan- 3-yl)-2- fluorobenzyl)- 6-phenyl-3- (trifluoro- methyl)- 1,2-thiazinane 1,1-dioxide;
(3R,6S)-2-(4- ((1R,5S,6S)-6- (4H-1,2,4- triazol-4-yl)-3- azabicyclo- [3.1.0]-hexan- 3-yl)-2- fluorobenzyl)- 6-phenyl-3- (trifluoro- methyl)- 1,2-thiazinane 1,1-dioxide;
(3S,6S)-2-[[2,5- difluoro-4- [(1R,5S)-6- (1,2,4-triazol- 4-yl)-3- azabicyclo- [3.1.0]- hexan-3- yl]phenyl]- methyl]- 3-ethyl-6- phenyl- thiazinane 1,1-dioxide;
(3S,6R)-2-[[2,5- difluoro-4- [(1R,5S)-6- (1,2,4-triazol- 4-yl)-3- azabicyclo- [3.1.0]- hexan-3- yl]phenyl]- methyl]- 3-ethyl-6- phenyl- thiazinane 1,1-dioxide;
(3S,6R)-3-ethyl- 2-[[2-fluoro-4- [(1R,5S)-6- (1,2,4-triazol- 4-yl)-3- azabicyclo- [3.1.0]- hexan-3- yl]phenyl]- methyl]- 6-phenyl- thiazinane 1,1-dioxide;
and
(3S,6S)-3-ethyl- 2-[[2-fluoro-4- [(1R,5S)-6- (1,2,4-triazol- 4-yl)-3- azabicyclo- [3.1.0]- hexan-3- yl]phenyl]- methyl]- 6-phenyl- thiazinane 1,1-dioxide;
or a stereoisomer or pharmaceutical salt thereof.

29 more elements

Aryl sultam derivatives as RORc modulators

Life of this patent

Aryl sultam derivatives as RORc modulators

Life of this patent

Abstract

Claims8