Tricyclic sulfones as RORγ modulators

Patent metadata

Field	Value
Publication number	US-9815859-B2
Application number	US-201615148209-A
Country	US
Kind code	B2
Filing date	May 6, 2016
Priority date	May 7, 2015
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

Abstract

There are described RORγ modulators of the formula (I),

and formula (II)

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. A compound of the formula

wherein
X is —CR 4 R 5 —, —(CR 4 R 5 ) 2 , —OCR 6 R 7 —, —S(O) p CR 6 R 7 — or —NR 6 CR 6 R 7 —;
R 1 is halo, C 1-6 alkyl substituted with 0-3 R 1a , —(CR 2e R 2f )r-3-14 membered carbocycle substituted with 0-3 R 1a or —(CR 2e R 2f )r-5-10 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from the group consisting of N, O, and S(O) p 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 -3-14 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 the group consisting of N, O, and S(O) p substituted with 0-3 R a ;
R 1b is, independently at each occurrence, hydrogen, CD 3 , halo, CF 3 , and C 1 -C 4 alkyl;
R 2 is hydrogen, —(CR 2e R 2f )r-C(O)R 2d , —(CR 2e R 2f )r-C(O)OR 2 b, —(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 , or —(CR 2e R 2f )r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from the group consisting of N, O, P(═O) and S(O) p substituted with 0-4 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-OC(O)NR 11 R 11 , —(CR 2e R 2f )r-OC(O)OR c , —(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 the group consisting of N, O, P(═O) and S(O) p substituted with 0-4 R a ,
R 2b is, independently at each occurrence, hydrogen, CF 3 , —(CR 2e R 2f )qOR b , —(CR 2e R 2f ) q S(O)pR 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 )qS(O) 2 NR 11 R 11 , —(CR 2e R 2f )qNR 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 the group consisting of N, O, P(═O) and S(O) p , substituted with 0-4 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 the group consisting of N, O, P(═O) and S(O) p , substituted with 0-4 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 , where the cycloalkyl ring may be fused, bridged or spirocyclic, —(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 the group consisting of N, O, P(═O) and S(O) p , substituted with 0-4 R a ,
R 2e and R 2f are, independently at each occurrence, hydrogen, halogen or C 1-6 alkyl;
R 3 is, independently at each occurrence, 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 the group consisting of N, O, and S(O) p , substituted with 0-3 R 3a , 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 the group consisting of 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, —(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 the group consisting of 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 )qOR b , —(CR 2e R 2f )qS(O)pR b , —(CR 2e R 2f )r-C(O)R 1d , —(CR 2e R 2f )r-C(O)OR b , —(CR 2e R 2f )qOC(O)R b , —(CR 2e R 2f )qNR 11 R 11 , —(CR 2e R 2f )r-C(O)NR 11 R 11 , —(CR 2e R 2f )qNR b C(O)R 1c , —(CR 2e R 2f )qNR b C(O)OR c , —(CR 2e R 2f )qNR b C(O)NR 11 R 11 , —(CR 2e R 2f )qS(O) 2 NR 11 R 11 , —(CR 2e R 2f )qNR 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 the group consisting of N, O, and S(O)p substituted with 0-3 R a ;
R 4 and R 5 are independently hydrogen, halo, C 1-6 alkyl or C 1-6 haloalkyl, or
R 4 and R 5 together with the carbon atom to which they are attached form a 3- to 6-membered spirocarbocyclyl ring or a spiroheterocyclyl ring;
R 6 and R 7 are independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;
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 the group consisting of N, O, P(═O) and S(O) p substituted with 0-4 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 the group consisting of N, O, P(═O) and S(O) p substituted with 0-4 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

Assignees

• Bristol Myers Squibb Co

Inventors

• Duan Jingwu
• Dhar T G Murali
• Marcoux David
• Shi Qing
• Batt Douglas G
• Liu Qingjie
• Cherney Robert J
• Cornelius Lyndon A M
• Srivastava Anurag S
• Beaudoin Bertrand Myra
• Weigelt Carolyn A

Classifications

• A61P43/00

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

• A61P37/06

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

• A61P37/08

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title