Pyrrolidinyl sulfone RORγ modulators

Patent metadata

Field	Value
Publication number	US-9458171-B2
Application number	US-201514590233-A
Country	US
Kind code	B2
Filing date	Jan 6, 2015
Priority date	Jan 6, 2014
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

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

The invention claimed is:

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

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from H, halo, C 1-6 alkyl substituted with 0-3 R 1a and —(CR 2e R 2f )r-3-14 membered carbocycle substituted with 0-3 R 1a ;
R 1a is, independently at each occurrence, hydrogen, ═O, halo, CF 3 , OCF 3 , CN, NO 2 , —(CR 2e R 2f )r-OR b , —(CR 2e R 2f )r-S(O) p R b , —(CR 2e R 2f )r-C(O)R b , —(CR 2e R 2f )r-C(O)OR b , —(CR 2e R 2f )r-OC(O)R b , —(CR 2e R 2f )r-NR 11 R 11 , —(CR 2e R 2f )r-C(O)NR 11 R 11 , —(CR 2e R 2f )r-NR b C(O)R c , —(CR 2e R 2f )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 , —(CR 2e R 2f )r-3-14membered carbocycle substituted with 0-3 R a , or —(CR 2e R 2f )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 selected from hydrogen, —(CR 2e R 2f )r-C(O)R 2d , —(CR 2e R 2f )r-C(O)OR 2b , —(CR 2e R 2f )r-C(O)NR 11 R 11 , —(CR 2e R 2f )r-S(O) 2 R 2c , C 1-6 alkyl substituted with 0-3 R 2a , C 2-6 alkenyl substituted with 0-3 R 2a , —(CR 2e R 2f )r-3-10 membered carbocycle substituted with 0-3 R a , and —(CR 2e R 2f )r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R a ;
R 2a is, independently at each occurrence, hydrogen, ═O, halo, OCF 3 , CN, NO 2 , —(CR 2e R 2f )r-OR b , —(CR 2e R 2f )r-S(O) p R b , —(CR 2e R 2f )r-C(O)R b , —(CR 2e R 2f )r-C(O)OR b , —(CR 2e R 2f )r-OC(O)R b , —(CR 2e R 2f )r-NR 11 R 11 , —(CR 2e R 2f )r-C(O)NR 11 R 11 , —(CR 2e R 2f )r-NR b C(O)R c , —(CR 2e R 2f )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 , —(CR 2e R 2f )r-3-14 membered carbocycle substituted with 0-3 R a , or —(CR 2e R 2f )r-4-7 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 , —(CR 2e R 2f ) q OR b , —(CR 2e R 2f ) q S(O) p R b , —(CR 2e R 2f )r-C(O)R 1d , —(CR 2e R 2f )r-C(O)OR b , —(CR 2e R 2f ) q OC(O)R b , —(CR 2e R 2f ) q NR 11 R 11 , —(CR 2e R 2f )r-C(O)NR 11 R 11 , —(CR 2e R 2f ) q NR b C(O)R 1c , —(CR 2e R 2f ) q NR b C(O)OR c , —(CR 2e R 2f ) q NR b C(O)NR 11 R 11 , —(CR 2e R 2f ) q S(O) 2 NR 11 R 11 , —(CR 2e R 2f ) q NR b S(O) 2 R c , C 1-6 alkyl substituted with 0-2 R a , C 1-6 haloalkyl, —(CR 2e R 2f )r-3-14 membered carbocycle substituted with 0-3 R a , or —(CR 2e R 2f )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 —(CR 2e R 2f )r-5-10 membered heterocycle containing 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 , —(CR 2e R 2f )r-C 3-10 cycloalkyl substituted with 0-3 R d , —(CR 2e R 2f )r-phenyl substituted with 0-2 R a , or a —(CR 2e R 2f )r-4-10 membered heterocycle where the heterocycle may be fused, bridged or spirocyclic, containing 1-4 heteroatoms selected from N, O, and S(O) p , substituted with 0-3 R a ;
R 2e and R 2f are, independently at each occurrence, hydrogen, halogen or C 1-6 alkyl;
R 3 is selected from hydrogen, halo, N 3 , CN, —(CR 2e R 2f )r-OR 3b , —(CR 2e R 2f )r-NR 11 R 11 , C 1-6 alkyl substituted with 0-3 R 3a , C 3-10 cycloalkyl substituted with 0-3 R 3a ; and phenyl substituted with 0-3 R 3a , or 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O) p , substituted with 0-3 R 1a , or two R 3 located on adjacent carbon atoms link 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 , both 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 , —(CR 2e R 2f )r-OR b , —(CR 2e R 2f )r-S(O) p R b , —(CR 2e R 2f )r-C(O)R b , —(CR 2e R 2f )r-C(O)OR b , —(CR 2e R 2f )r-OC(O)R b , —(CR 2e R 2f )r-NR 11 R 11 , —(CR 2e R 2f )r-C(O)NR 11 R 11 , —(CR 2e R 2f )r-NR b C(O)R c , —(CR 2e R 2f )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, —(CR 2e R 2f )r-3-14 membered carbocycle substituted with 0-3 R a , or —(CR 2e R 2f )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 , —(CR 2e R 2f ) q OR b , —(CR 2e R 2f ) q S(O) p R b , —(CR 2e R 2f )r-C(O)R 1d , —(CR 2e R 2f )r-C(O)OR b , —(CR 2e R 2f ) q OC(O)R b , —(CR 2e R 2f ) q NR 11 R 11 , —(CR 2e R 2f )r-C(O)NR 11 R 11 , —(CR 2e R 2f ) q NR b C(O)R 1c , —(CR 2e R 2f ) q NR b C(O)OR c , —(CR 2e R 2f ) q NR b C(O)NR 11 R 11 , —(CR 2e R 2f ) q S(O) 2 NR 11 R 11 , —(CR 2e R 2f ) q NR b S(O) 2 R c , C 1-6 alkyl substituted with 0-3 R a , C 1-6 haloalkyl,—(CR 2e R 2f )r-3-14 membered carbocycle substituted with 0-3 R a , or —(CR 2e R 2f )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 , —(CR 2e R 2f )r-phenyl substituted with 0-3 R d , or —(CR 2e R 2f )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 , —(CR 2e R 2f )r-OR b , —(CR 2e R 2f )r-S(O) p R b , —(CR 2e R 2f )r-C(O)R b , —(CR 2e R 2f )r-C(O)OR b , —(CR 2e R 2f )r-OC(O)R b , —(CR 2e R 2f )r-NR 11 R 11 , —(CR 2e R 2f )r-C(O)NR 11 R 11 , —(CR 2e R 2f )r-NR b C(O)R c , —(CR 2e R 2f )r-NR b C(O)OR c , —NR b C(O)NR 11 R 11 , —S(O) pNR 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 , —(CR 2e R 2f )r-3-14 membered carbocycle, or —(CR 2e R 2f )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 , —(CR 2e R 2f )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 —(CR 2e R 2f )r-6-10 membered carbocycle substituted with 0-3 R d ;
R c is, independently at each occurrence, hydrogen, C 1-6 alkyl substituted with 0-3 R f , —(CR 2e R 2f )r-C 3-6 cycloalkyl substituted with 0-3 R f , or —(CR 2e R 2f )r-phenyl substituted with 0-3 R f ;
R d is, independently at each occ

Assignees

• Bristol Myers Squibb Co

Inventors

• Duan Jingwu
• Dhar T G Murali
• Jiang Bin
• Lu Zhonghui
• Xiao Hai-Yun

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• 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

• A61P3/00

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