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

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- Number: US 9,751,873 B2
- Document ID: US9751873B2
- Status: Granted
- Kind: B2
- Application number: 15/047,523
- Filed: 2016-02-18
- Published: 2016-06-16
- Granted: 2017-09-05
- Earliest claimed: 2014-01-10
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Benjamin Fauber; Alberto Gobbi; Olivier Rene; Monique Bodil van Niel; Emanuela Gancia; Simon Gaines; Tammy Ladduwahetty; David Vesey; Stuart Ward; Paul Winship
- Web page: https://patentgrep.com/patent/US9751873B2

## CPC

- C07D 417/10: linked by a carbon chain containing aromatic rings
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 279/02: 1,2-Thiazines; Hydrogenated 1,2-thiazines
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 487/08: Bridged systems
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D 491/113: with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound of claim 1, 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,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;
(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;
or a stereoisomer or pharmaceutical salt thereof.

### Claim 3

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.

### Claim 4

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.

### Claim 5

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.

### Claim 6

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.

### Claim 7

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.

### Claim 8

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.