Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFN alpha responses

Patent metadata

Field	Value
Publication number	US-10000480-B2
Application number	US-201615289437-A
Country	US
Kind code	B2
Filing date	Oct 10, 2016
Priority date	Nov 8, 2012
Publication date	Jun 19, 2018
Grant date	Jun 19, 2018

Abstract

Compounds having the following formula I:

or a stereoisomer or pharmaceutically-acceptable salt thereof, where R 1 , R 2 , R 3 , R 4 , and R 5 are as defined herein, are useful in the modulation of IL-12, IL-23 and/or IFNα, by acting on Tyk-2 to cause signal transduction inhibition.

First claim

What is claimed is:

1. A compound having the following formula I:

or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein:
Y is N or CR 6 ;
R 1 is hydrogen, C 1-3 alkyl or C 3-6 cycloalkyl, each optionally substituted by 0-7 R 1a ;
R 1a at each occurrence is independently hydrogen, deuterium, F, Cl, Br or CN;
R 2 is —C(O)R 2a ; or C 1-6 alkyl, —(CH 2 ) r -3-14 membered carbocycle substituted with 0-1 R 2a or a 5-14 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R 2a ;
R 2a at each occurrence is independently hydrogen, ═O, halo, OCF 3 , CN, NO 2 , —(CH 2 ) r OR b , —(CH 2 ) r SR 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 , —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 0-1 R a or a —(CH 2 ) r -5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-2 R a ;
R 3 is C 3-10 cycloalkyl, C 6-10 aryl or a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 3a ;
R 3a at each occurrence is independently hydrogen, ═O, halo, OCF 3 , CF 3 , CHF 2 , CN, NO 2 , —(CH 2 ) r OR b , —(CH 2 ) r SR 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 , —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 containing 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R a ;
or two R 3a , together with the atoms to which they are attached, combine to form a fused ring wherein said ring is selected from phenyl and a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , each fused ring substituted with 0-3 R a1 ;
R 4 and R 5 are independently hydrogen, C 1-4 alkyl substituted with 0-1 R f , (CH 2 ) r -phenyl substituted with 0-3 R d or a —(CH 2 )-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O) p ;
R 6 is hydrogen, halo, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, OC 1-4 alkyl, CN, NO 2 or OH;
R 11 at each occurrence is independently hydrogen, C 1-4 alkyl substituted with 0-3 R f , CF 3 , C 3-10 cycloalkyl substituted with 0-1 R f , (CH) r -phenyl substituted with 0-3 R d or —(CH 2 ) r -5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R d ;
R a and R a1 at each occurrence are independently hydrogen, F, Cl, Br, OCF 3 , CF 3 , CHF 2 , CN, NO 2 , —(CH 2 ) r OR b , —(CH 2 ) r SR 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 , —S(O)R c , —S(O) 2 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 containing 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R f ;
R b is hydrogen, C 1-6 alkyl substituted with 0-3 R d , C 1-6 haloalkyl, C 3-6 cycloalkyl substituted with 0-2 R d , or —(CH 2 ) r -5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R f or (CH 2 ) r -phenyl substituted with 0-3 R d ;
R c is 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 at each occurrence is independently hydrogen, F, Cl, Br, 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 1-6 alkyl or (CH 2 ) r -phenyl substituted with 0-3 R f ;
R e at each occurrence is independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or (CH 2 ) r -phenyl substituted with 0-3 R f ;
R f independently at each occurrence is hydrogen, halo, CN, NH 2 , OH, C 3-6 cycloalkyl, CF 3 , O(C 1-6 alkyl) or a —(CH 2 ) r -5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O) p ;
p is 0, 1, or 2; and
r is 0, 1, 2, 3, or 4.

2. A compound of claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein R 2 is —C(O)R 2a ; or C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl or pyrrolopyridinyl, each group substituted with 0-4 R 2a .

3. A compound according to claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein both R 4 and R 5 are hydrogen.

4. A compound according to claim 1 , having the following formulae:

or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein:
R 1 is hydrogen or C 1-3 alkyl substituted by 0-7 R 1a ;
R 1a at each occurrence is independently hydrogen, deuterium or halogen;
R 2 is —C(O)R 2a ; or C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl or pyrrolopyridinyl, each group substituted with 0-4 R 2a ;
R 2a at each occurrence is independently hydrogen, ═O, halo, CN, —(CH 2 ) r OR b , —(CH 2 ) r C(O)R b , —NR b C(O)R c , —C(O)OR b , —(CH 2 ) r C(O)NR 11 R 11 , —S(O) p NR 11 R 11 , —C 1-6 alkyl substituted with 0-3 R a , C 1-6 haloalkyl, —(CH 2 ) r -3-14 membered carbocycle substituted with 0-1 R a or a —(CH 2 ) r -5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-2 R a ;
R 3 is C 3-10 cycloalkyl, a C 6-10 aryl, or a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 3a ;
R 3a at each occurrence is independently hydrogen, halo, OCF 3 , CF 3 , CHF 2 , CN, —(CH 2 ) r OR b , —(CH 2 ) r SR b , —(CH 2 ) r C(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 , —S(O) p NR 11 R 11 , —NR b S(O) p R c , —S(O) p R c , C 1-6 alkyl substituted with 0-3 R a , C 1-6 haloalkyl, a —(CH 2 ) r -3-14 membered carbocycle substituted with 0-3 R a or a —(CH 2 ) r -5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R a ;
or two R 3a , together with the atoms to which they are attached, combine to form a fused ring wherein that ring is phenyl or a 5-7 membered heterocycle containing 1-4 heteroatoms selected from N, S or O, each fused ring substituted, as valence allows, by 0-3 R a ;
R 11 at each occurrence is independently hydrogen, C 1-4 alkyl substituted with 0-3 R f or C 3-6 cycloalkyl substituted with 0-1 R f ;
R a at each occurrence is hydrogen, ═O, F, —(CH 2 ) r OR b or C 1-6 alkyl substituted with 0-3 R f ;
R b is hydrogen, C 1-6 alkyl substituted with 0-3 R d , C 1-6 haloalkyl, C 3-6 cycloalkyl substituted with 0-2 R d , or —(CH 2 ) r -5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R f ; or (CH 2 ) r -phenyl substituted with 0-3 R d ;
R c is C 1-6 alkyl

Assignees

• Bristol Myers Squibb Co

Inventors

• Moslin Ryan M
• Weinstein David S
• Wrobleski Stephen T
• Tokarski John S
• Kumar Amit
• Batt Douglas G
• Lin Shuqun
• Liu Chunjian
• Spergel Steven H
• Zhang Yanlei
• Liu Qingjie

Classifications

• A61P37/06

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

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

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title