Bicyclic sulfones and sulfoxides and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11072617-B2
Application number	US-201816175206-A
Country	US
Kind code	B2
Filing date	Oct 30, 2018
Priority date	Oct 31, 2017
Publication date	Jul 27, 2021
Grant date	Jul 27, 2021

Abstract

The invention provides novel compounds having the general formula I:wherein R1, RB1, RB2, n, p, q, the A ring and the B ring are as described herein, pharmaceutical compositions including the compounds, and methods of using the compounds.

First claim

We claim:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
the A ring and the B ring are fused to form a polycyclic ring system;
p is 2 and q is 1,
the A ring and the B ring together are selected from the group consisting of:

R 1 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 3 -C 6 cycloalkyl-C 1 -C 3 alkyl, C 1 -C 6 alkyl-N(R 2 ) 2 , C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy-C 1 -C 6 alkyl, phenyl, benzyl, difluoro(phenyl)methyl, 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, and CH 2 -(5 to 6 membered heteroaryl); wherein:
when R 1 is phenyl, benzyl, difluoro(phenyl)methyl, 5 to 6 membered heteroaryl or CH 2 -(5 to 6 membered heteroaryl), the phenyl or heteroaryl moiety of R 1 is optionally, substituted by one or two substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, hydroxyl, hydroxymethyl, methoxymethyl, cyano, trifluoromethyl, difluoromethoxy and trifluoromethoxy; and
when R 1 is cycloalkyl, the cycloalkyl is optionally substituted by by one, two or three substituents independently selected from the group consisting of fluoro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl C 1 -C 6 haloalkoxy, hydroxyl, C 1 -C 6 hydroxyalkyl, and cyano;

n is 1 or 2;
each R 2 is independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkyl; or two R 2 together with the nitrogen atom to which they are both attached form a 4-6 membered heterocyclic ring;
R B1 is independently R 3a and R 3b and each R 3a and R 3b is independently selected from the group consisting of hydrogen, halogen, deutero, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thioalkyl, C 1 -C 6 alkyl-N(R 2 ) 2 , and cyano; and
R B2 is R 4 and R 4 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thioalkyl, C 1 -C 6 alkyl-N(R 2 ) 2 , phenyl, benzyl, CH 2 -(C 3 -C 6 cycloalkyl), CH 2 CH 2 -(C 3 -C 6 cycloalkyl), CH 2 -(4 to 6 membered heterocyclyl), CH 2 CH 2 -(4 to 6 membered heterocyclyl), 5 to 6 membered heteroaryl, and CH 2 -(5 to 6 membered heteroaryl);
wherein when R 4 is phenyl, heteroaryl or benzyl, the phenyl or heteroaryl ring is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, alkoxy, C 1 -C 4 haloalkoxy, and cyano.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the A ring and the B ring together are:

3. The compound of claim 1 wherein:
R 3a and R 3b are selected as follows:
one of R 3a and R 3b is H, and the other is selected from the group consisting of hydrogen, deutero, fluoro, chloro, hydroxyl, cyano, C 1 -C 1 alkyl, C 1 -C 4 haloalkyl, cyclopropyl, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkoxy; or
each of R 3a and R 3b is independently selected from the group consisting of deutero, fluoro; chloro, hydroxyl, cyano, and methyl, provided that R 3a and R 3b cannot both be OH or CN; and
R 4 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, phenyl, and pyridinyl, wherein the phenyl ring or pyridinyl ring is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy; C 1 -C 4 haloalkoxy, and cyano.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b are independently hydrogen or fluorine; and R 4 is selected from the group consisting of ethyl, isopropyl n-propyl, trifluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, optionally substituted phenyl, and optionally substituted pyridine-2-yl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the A ring and the B ring together are selected from the group consisting of:

wherein:
R 3a is hydrogen or fluorine;
each R 5 is selected from the group consisting of hydrogen, fluoro, chloro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy; and
m is 1, 2 or 3.

6. The compound of claim 1 , or a pharmaceutically, acceptable salt thereof, wherein the A ring and the B ring together are:

wherein:
each R 5 is selected from the group consisting of hydrogen, fluoro; chloro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy; and
m is 1, 2 or 3.

7. The compound of claim 1 , or a pharmaceutically, acceptable salt thereof, wherein R 5 is selected from the group consisting of Et, F, Cl, CH 3 , CH 2 CH 3 , OCH 3 , CF 3 , CF 2 H, and OCF 2 H.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is halo.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the A ring and the B ring together are:

10. The compound of claim 1 , or a pharmaceutically, acceptable salt thereof, wherein R 1 is selected from the group consisting of C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, C 3 -C 6 spirocycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 hydroxyalkyl, phenyl, benzyl, and difluoro(phenyl)methyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of methyl, ethyl, tert-butyl, difluoromethyl, trifluoromethyl, cyclopropyl, fluorocyclopropyl, difluorocyclopropyl, phenyl, benzyl, and difluoro(phenyl)methyl.

12. The compound of claim 1 , or a pharmaceutically, acceptable salt thereof, wherein R 1 is selected from the group consisting of ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, fluorocyclopropyl, and difluorocyclopropyl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
2-(difluoromethylsulfinyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole;
2-ethylsulfonyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole;
(5S)-2-[(S)-ethylsulfinyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole;
2-[difluoro(phenyl)methyl]sulfonyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole;
2-[difluoro(phenyl)methyl]sulfinyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole;
2-(difluoromethylsulfonyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole;
(S)-5-(2-fluorophenyl)-2-methylsulfonyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole;
(S)-2-ethylsulfonyl-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole;
2-methylsulfonyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole;
5-phenyl-2-(trifluorotnethylsulfin

Assignees

• Genentech Inc

Inventors

• Patel Snahel
• Hamilton Gregory
• Stivala Craig
• Chen Huifen
• Daniels Blake

Classifications

• C07D249/16

  condensed with carbocyclic rings or ring systems · CPC title

• C07D231/54

  condensed with carbocyclic rings or ring systems · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title