ARYL SULTAM DERIVATIVES AS RORc MODULATORS

Patent metadata

Field	Value
Publication number	US-2016168141-A1
Application number	US-201615047523-A
Country	US
Kind code	A1
Filing date	Feb 18, 2016
Priority date	Jan 10, 2014
Publication date	Jun 16, 2016
Grant date	—

Abstract

Compounds of the formula I:

or pharmaceutically acceptable salts thereof,

wherein m, n, p, q, r, A, W, X 1 , X 2 , X 3 , X 4 , Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of inflammatory diseases such as arthritis.

First claim

1 - 10 . (canceled)

11 . A compound of formula XXIXa or XXIXb

wherein:
p is from 0 to 2;
s is from 0 to 2;
R 1 , R 2 and R 3 each independently is: hydrogen; or C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo;
each R 9 is independently: C 1-6 alkyl; halo; C 1-6 alkoxy; or cyano; and
each R e 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,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;
(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-(trifluoromethyl)-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-(trifluoromethyl)-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-(trifluoromethyl)-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-(trifluoromethyl)-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.

12 . The compound of claim 11 , wherein the compound is selected from the group consisting of:
(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; (3R,6R)-2-(4-((1R,5 S,6S)-6-(4H-1,2,4-triazol-4-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2,5-difluorobenzyl)-6-phenyl-3-(trifluoromethyl)-1,2-thiazinane 1,1-dioxide; (3R,6S)-2-(4-((1R,5 S,6S)-6-(4H-1,2,4-triazol-4-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2,5-difluorobenzyl)-6-phenyl-3-(trifluoromethyl)-1,2-thiazinane 1,1-dioxide; (3S,6S)-2-[[2,5-difluoro-4-[(1R,5 S)-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,5 S)-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;
or a stereoisomer or pharmaceutical salt thereof.

13 . The compound (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 or a pharmaceutical salt thereof.

14 . The compound (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 or a pharmaceutical salt thereof.

15 . The compound (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-(trifluoromethyl)-1,2-thiazinane 1,1-dioxide or a pharmaceutical salt thereof.

16 . The compound (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-(trifluoromethyl)-1,2-thiazinane 1,1-dioxide
or a pharmaceutical salt thereof.

17 . The compound (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
or a pharmaceutical salt thereof.

18 . The compound (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
or a pharmaceutical salt thereof.

Assignees

• Genentech Inc

Inventors

• Fauber Benjamin
• Gobbi Alberto
• Rene Olivier
• Van Niel Monique Bodil
• Gancia Emanuela
• Gaines Simon
• Ladduwahetty Tammy
• Vesey David
• Ward Stuart
• Winship Paul

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

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

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title