Substituted sulfonamide compounds

Patent metadata

Field	Value
Publication number	US-9580411-B2
Application number	US-201514671643-A
Country	US
Kind code	B2
Filing date	Mar 27, 2015
Priority date	Sep 27, 2012
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

Abstract

The invention is concerned with the compounds of formula (I):

and salts thereof, wherein X, Y, Z, R 1 , R 2 , R 3 , R 3′ , R 4 , R 5 and R 6 are defined in the detailed description and claims. In addition, the present invention relates to methods of manufacturing and using the compounds of Formula (I) as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.

First claim

We claim:

1. A compound of formula (I):

wherein:
R 1 is unsubstituted phenyl, phenyl mono- or bi-substituted independently with halogen or —CN, an unsubstituted five- or six-membered heteroaryl ring or a five- or six-membered heteroaryl ring substituted with lower alkyl, halogen, or haloalkyl;
R 2 is selected from the group consisting of methyl, —CH 2 CF 3 , ethyl, hydroxy-ethyl, propyl, hydroxy-propyl, cyclopropyl, isopropyl, methoxy-ethyl, tert-butyl, oxetan-3-ylmethyl or oxetanyl;
R 3 and R 3′ are each independently selected from the group consisting of hydrogen; deuterium; haloalkyl; cycloalkyl and lower alkyl wherein said haloalkyl, cycloalkyl and lower alkyl is optionally substituted with deuterium, F, Cl, Br, hydroxyl or alkoxy; or R 3 and R 3′ taken together with the carbon to which they are attached form a 3, 4, 5, or 6-membered cycloalkyl optionally substituted with deuterium, F, Cl, Br, hydroxyl or alkoxy;
R 4 is hydrogen or lower alkyl;
and

is selected from:

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 1 is phenyl optionally substituted with cyano, F or Cl, pyrazinyl optionally substituted with F or Cl, pyridinyl optionally substituted with F or Cl, pyrazole optionally substituted with F or Cl, or thienyl, optionally substituted with F or Cl.

3. The compound according to claim 1 , wherein R 1 is phenyl substituted with F or Cl, pyrazinyl substituted with F or Cl, pyridinyl substituted with F or Cl, or thiophenyl substituted with F or Cl.

4. The compound according to claim 1 , wherein R 2 is methyl, —CH 2 CF 3 , ethyl, hydroxy-ethyl, 2-hydroxypropyl, cyclopropyl, isopropyl, 2-methoxyethyl, tert-butyl, methoxymethyl, oxetan-3-ylmethyl, 4-fluorophenyl, or 3-oxetanyl.

5. The compound according to claim 1 , wherein R 3 and R 3′ are both hydrogen.

6. The compound according to claim 1 , wherein one of R 3 or R 3′ is hydrogen and the other is methyl, tert-butyl, cyclopropyl, —CH 2 OH or —CH 2 OCH 3 .

7. The compound according to claim 1 , wherein one of R 3 or R 3′ is hydrogen, deuterium, or methyl, and the other is hydrogen, methyl, isopropyl, cyclopropyl, hydroxymethyl, methoxymethyl, or deuterium; or R 3 and R 3′ taken together with the carbon to which they are attached form a 3-membered cycloalkyl.

8. The compound according to claim 1 , wherein R 4 is hydrogen.

9. The compound according to claim 1 , wherein R 4 is methyl.

10. A compound selected from:
2-(4-fluoro-N-isopropylphenylsulfonamido)-N-(3-(pyrrolidin-1-yl)benzyl)acetamide;
N-(3-cyclopropylbenzyl)-2-(4-fluoro-N-isopropylphenylsulfonamido)acetamide;
R)-2-(4-fluoro-N-isopropylphenylsulfonamido)-N-(3-(2-(2-methylpyrrolidin-1-yl)pyrimidin-5-yl)benzyl)acetamide;
(S)-2-(4-fluoro-N-isopropylphenylsulfonamido)-N-(3-(2-(2-methylpyrrolidin-1-yl)pyrimidin-5-yl)benzyl)acetamide;
2-(4-Fluoro-N-isopropylphenylsulfonamido)-N-((6-(4-(trifluoromethyl)piperidin-1-yl)pyrimidin-4-yl)methyl)acetamide;
N-((6-(4,4-Difluoropiperidin-1-yl)pyrimidin-4-yl)methyl)-2-(4-fluoro-N-isopropylphenylsulfonamido)acetamide;
2-(N-Isopropyl-1-methyl-1H-pyrazole-3-sulfonamido)-N-((4′-(trifluoromethyl)biphenyl-3-yl)methyl)acetamide;
2,2-Dideuterio-2-(4-fluoro-N-isopropylphenylsulfonamido)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)acetamide;
1-(4-Fluoro-N-isopropylphenylsulfonamido)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)cyclopropanecarboxamide;
(6-(6-(Trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl-2-(4-fluoro-N-isopropylphenylsulfonamido)acetate; or
2-[N-(Propan-2-yl)(4-fluorobenzene)sulfonamido]-N-([6-[4-(trifluoromethyl)cyclohex-1-en-1-yl]pyrimidin-4-yl]methyl)acetamide;
or a salt thereof.

11. A compound of formula (I):

wherein:
two of X, Y or Z are N and the other is C or CH;
R 1 is unsubstituted phenyl, phenyl mono- or bi-substituted independently with halogen or —CN, an unsubstituted five- or six-membered heteroaryl ring or a five- or six-membered heteroaryl ring substituted with lower alkyl, halogen, or haloalkyl;
R 2 is selected from the group consisting of methyl, —CH 2 CF 3 , ethyl, hydroxy-ethyl, propyl, hydroxy-propyl, cyclopropyl, isopropyl, methoxy-ethyl, tert-butyl, oxetan-3-ylmethyl or oxetanyl;
R 3 and R 3′ are each independently selected from the group consisting of hydrogen; deuterium; haloalkyl; cycloalkyl and lower alkyl wherein said haloalkyl, cycloalkyl and lower alkyl is optionally substituted with deuterium, F, Cl, Br, hydroxyl or alkoxy; or R 3 and R 3′ taken together with the carbon to which they are attached form a 3, 4, 5, or 6-membered cycloalkyl optionally substituted with deuterium, F, Cl, Br, hydroxyl or alkoxy;
R 4 is hydrogen or lower alkyl;
R 5 is trifluoromethylphenyl, 5-trifluoromethylpyrid-2-yl, 6-trifluoromethylpyrid-3-yl, 6-trifluoromethylpyridazin-3-yl, 2-trifluoromethylpyrimidin-5-yl, 5-trifluoromethylpyrazin-2-yl, pyrrolidino, cyclopropyl, 4,4-difluoropiperidino, 4-trifluoromethylpiperidino, 2-(2-methylpyrrolidino)pyrimidin-5-yl, or 4-trifluoromethylcyclohex-1-ene; and
R 6 is hydrogen, halogen or alkoxy,
or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 11 , wherein R 6 is hydrogen.

13. The compound according to claim 11 , wherein R 6 is F or methoxy.

14. The compound according to claim 11 , wherein R 6 is halogen or alkoxy.

Assignees

• Hoffmann La Roche
• Genentech Inc

Inventors

• Brotherton-Pleiss Christine E
• Chen Huifen
• Chen Shaoqing
• Chen Zhi
• Erickson Shawn David
• Estrada Anthony
• Kim Kyungjin
• Li Hongju
• Lovey Allen John
• Lyssikatos Joseph P
• Qian Yimin
• So Sung-Sau
• Wovkulich Peter Michael
• Yi Lin

Classifications

• A61P43/00

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

• A61P27/16

  Otologicals · CPC title

• A61P29/00

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

• A61P13/02

  of urine or of the urinary tract, e.g. urine acidifiers · CPC title

• A61P11/06

  Antiasthmatics · CPC title