Cyclohexyl sulfone RORγ modulators

Patent metadata

Field	Value
Publication number	US-9708253-B2
Application number	US-201515109733-A
Country	US
Kind code	B2
Filing date	Jan 5, 2015
Priority date	Jan 6, 2014
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

Described are RORγ modulators of the formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.

First claim

What is claimed is:

1. The compound having the following formula (I):

or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein
R 1 and R 1′ are, independently at each occurrence, hydrogen, halo, CF 3 , OCF 3 , CN, NO 2 , —(CH 2 ) r OR b , —(CH 2 ) r S(O) p R b , —(CH 2 ) r C(O)R b , —(CH 2 ) r C(O)OR b , —(CH 2 ) r OC(O)R b , —(CH 2 ) r NR 11 R 11 , —(CH 2 ) r C(O)NR 11 R 11 , —(CH 2 ) r NR b C(O)R c , —(CH 2 ) r NR b C(O)OR c , —NR b C(O)NR 11 R 11 , —S(O) p NR 11 R 11 , —NR b S(O) p R c , C 1-6 alkyl substituted with 0-3 R a , C 1-6 haloalkyl, C 2-6 alkenyl substituted with 0-3 R a , C 2-6 alkynyl substituted with 0-3 R a , —(CH 2 ) r -3-14 membered carbocycle substituted with 0-3 R a , or —(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R a ;
R 2 is independently at each occurrence, hydrogen, ═O, —(CH 2 ) r OR 2b , —(CH 2 ) r C(O)R 2b , —(CH 2 ) r OC(O)OR 2b , —(CH 2 ) r OC(O)NR 11 R 11 , —(CH 2 ) r NR 2b C(O)R 2c , —(CH 2 ) r NR 2b C(O)OR 2c , —(CH 2 ) r NR 2b C(O)NR 11 R 11 , —(CH 2 ) r NR 11 R 11 —NR 2 S(O) p R c , —(CH 2 ) r NR 2b S(O) p NR 11 R 11 , C 1-6 alkyl, —(CH 2 )r-3-10 membered carbocycle substituted with 0-3 R2a or —(CH 2 ) r -4-10 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R 2a ; or one R 2 together with an R 2 on an adjacent carbon combine to form a fused ring substituted with 0-3 R 2a , wherein the fused ring is selected from 3-10 membered carbocycle substituted with 0-3 R 2a , or 4-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R 2a ;
R 2a is, independently at each occurrence, hydrogen, ═O, halo, OCF 3 , CN, NO 2 , —(CH 2 ) r OR b , —(CH 2 ) r S(O) p R b , —(CH 2 ) r C(O)R b , —(CH 2 ) r C(O)OR b , —(CH 2 ) r OC(O)R b , —(CH 2 ) r NR 11 R 11 , —(CH 2 ) r C(O)NR 11 R 11 , —(CH 2 ) r NR b C(O)R c , —(CH 2 ) r NR b C(O)OR c , —NR b C(O)NR 11 R 11 , —S(O) p NR 11 R 11 , —NR b S(O) p R c , C 1-6 alkyl substituted with 0-3 R a , C 1-6 haloalkyl, C 2-6 alkenyl substituted with 0-3 R a , C 2-6 alkynyl substituted with 0-3 R a , —(CH 2 ) r -3-14 membered carbocycle substituted with 0-3 R a , or —(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R a ;
R 2b is, independently at each occurrence, hydrogen, CF 3 , —(CH 2 )rOR b , —(CH 2 ) r S(O) p R b , —(CH 2 ) r C(O)R 1d , —(CH 2 ) r C(O)OR b , —(CH 2 )rOC(O)R b , —(CH 2 )rNR 11 R 11 , —(CH 2 ) r C(O)NR 11 R 11 , —(CH 2 )rNR b C(O)R 1c , —(CH 2 )rNR b C(O)OR c , —(CH 2 )rNR b C(O)NR 11 R 11 , —(CH 2 )rS(O) 2 NR 11 R 11 , —(CH 2 )rNR b S(O) 2 R c , C 1-6 alkyl substituted with 0-2 R a , C 1-6 haloalkyl, —(CH 2 ) r -3-14 membered carbocycle substituted with 0-3 R a , or —(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-2 R a ;
R 2c is, independently at each occurrence, hydrogen, C 1-6 alkyl substituted with 0-3 R a , C 2-6 alkenyl substituted with 0-3 R a , C 3-10 cycloalkyl substituted with 0-3 R a , C 6-10 aryl substituted with 0-3 R a , or —(CH 2 ) r -5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , substituted with 0-3 R a ;
R 2d is, independently at each occurrence, hydrogen, C 1-6 alkyl substituted with 0-2 R d , C 1-6 haloalkyl, C(O)NR 11 R 11 , C 3-6 cycloalkyl substituted with 0-2 R d , or (CH 2 ) r -phenyl substituted with 0-2 R a , a 5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R a ;
R 3 is selected from hydrogen, halo, N 3 , CN, —(CH 2 ) r OR 3b , —(CH 2 ) r NR 11 R 11 , C 1-6 alkyl substituted with 0-3 R 3a , and C 3-10 cycloalkyl substituted with 0-3 R 3a ; 4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , substituted with 0-3 R a , or together with the carbon atoms to which they are attached, one R 3 combines with a second R 3 located on an adjacent atom to form a 5-7 membered carbocycle or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatom selected from N, O and S(O)p, each optionally substituted with 0-3 R 3a ;
R 3a is, independently at each occurrence, hydrogen, ═O, halo, OCF 3 , OCHF 2 , CF 3 , CHF 2 , CN, NO 2 , —(CH 2 ) r OR b , —(CH 2 ) r S(O) p R b , —(CH 2 ) r C(O)R b , —(CH 2 ) r C(O)OR b , —(CH 2 ) r OC(O)R b , —(CH 2 ) r NR 11 R 11 , —(CH 2 ) r C(O)NR 11 R 11 , —(CH 2 ) r NR b C(O)R c , —(CH 2 ) r NR b C(O)OR c , —NR b C(O)NR 11 R 11 , —S(O) p NR 11 R 11 , —NR b S(O) p R c , C 1-6 alkyl substituted with 0-3 R a , C 2-6 alkenyl substituted with 0-3 R a , C 2-6 alkynyl substituted with 0-3 R a , C 1-6 haloalkyl, —(CH 2 ) r -3-14 membered carbocycle substituted with 0-3 R a , or a —(CH 2 ) r -5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R a ;
R 3b is, independently at each occurrence, hydrogen, CF 3 , —(CH 2 )rOR b , —(CH 2 ) r S(O) p R b , —(CH 2 ) r C(O)R 1d , —(CH 2 ) r C(O)OR b , —(CH 2 ) r OC(O)R b , —(CH 2 ) r NR 11 R 11 , —(CH 2 ) r C(O)NR 11 R 11 , —(CH 2 ) r NR b C(O)R 1c , —(CH 2 ) r NR b C(O)OR c , —(CH 2 ) r NR b C(O)NR 11 R 11 , —(CH 2 ) r S(O) 2 NR 11 R 11 , —(CH 2 )rNR b S(O) 2 R c , C 1-6 alkyl substituted with 0-3 R a , C 1-6 haloalkyl, —(CH 2 ) r -3-14 membered carbocycle substituted with 0-3 R a , or —(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R a ;
R 11 is, independently at each occurrence, hydrogen, C 1-6 alkyl substituted with 0-3 R f , CF 3 , C 3-10 cycloalkyl substituted with 0-3 R f , —(CH) r -phenyl substituted with 0-3 R d , or —(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R d ;
or one R 11 and a second R 11 , both attached to the same nitrogen atom, combine to form a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R d ;
R a is, independently at each occurrence, hydrogen, ═O, halo, OCF 3 , CF 3 , CHF 2 , CN, NO 2 , —(CH 2 ) r OR b , —(CH 2 ) r S(O) p R b , —(CH 2 ) r C(O)R b , —(CH 2 ) r C(O)OR b , —(CH 2 ) r OC(O)R b , —(CH 2 ) r NR 11 R 11 , —(CH 2 ) r C(O)NR 11 R 11 , —(CH 2 ) r NR b C(O)R c , —(CH 2 ) r NR b C(O)OR c , —NR b C(O)NR 11 R 11 , —S(O) p NR 11 R 11 , —NR b S(O) p R c , C 1-6 alkyl substituted with 0-3 R f , C 1-6 haloalkyl, C 2-6 alkenyl substituted with 0-3 R a , C 2-6 alkynyl substituted with 0-3 R a , —(CH 2 ) r -3-14 membered carbocycle, or —(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R f ;
R b is, independently at each occurrence, hydrogen, C 1-6 alkyl substituted with 0-3 R d , C 1-6 haloalkyl, C 3-6 cycloalkyl substituted with 0-3 R d , —(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R f , or —(CH 2 ) r -6-10 carbocycle substituted with 0-3 R d ;
R c is, independently at each occurrence, C 1-6 alkyl substituted with 0-3 R f , —(CH 2 ) r -C 3-6 cycloalkyl substituted with 0-3 R f , or —(CH 2 ) r -phenyl substituted with 0-3 R f ;
R d is, independently at each occurrence, hydrogen, ═O, halo, OCF 3 , CF 3 , CN, NO 2 , —OR e , —(CH 2 ) r C(O)R c , —NR e R e , —NR e C(O)OR c , C(O)NR e R e , —NR e C(O)R c , CO 2 R c , —NR e SO 2 R c , SO 2 R c , C 1-6 alkyl substituted with 0-3 R f , C 3-6 cycloalkyl substituted with 0-3 R f , —(C

Assignees

• Bristol Myers Squibb Co

Inventors

• Duan Jingwu
• Dhar T G Murali
• Jiang Bin
• Karmakar Ananta
• Gupta Arun Kumar
• Lu Zhonghui
• Weigelt Carolyn A

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P29/00

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

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title