Sulfone pyridine alkyl amide-substituted heteroaryl compounds

Patent metadata

Field	Value
Publication number	US-11021462-B2
Application number	US-201816195951-A
Country	US
Kind code	B2
Filing date	Nov 20, 2018
Priority date	Nov 21, 2017
Publication date	Jun 1, 2021
Grant date	Jun 1, 2021

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

We claim:

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 H, CD 3 or C 1-3 alkyl;
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, OH, 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)R c , —NR b C(O)NR 11 R 11 , —S(O) p NR 11 NR 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 , —(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

X is absent, O or NH;
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 alkyoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 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 2 ) 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 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 is independently at each occurrence, 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 is independently at each occurrence, hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or (CH 2 ) r -phenyl substituted with 0-3 R f ;
R f is independently at each occurrence, 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. The compound according to claim 1 of formula II

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein
R 1 is H, CD 3 or C 1-3 alkyl;
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, OH, 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 NR 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 , —(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

X is absent, O or NH;
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 alkyoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 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 2 ) 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 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 is independently at each occurrence, 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 is independently at each occurrence, hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or (CH 2 ) r -phenyl substituted with 0-3 R f ;
R f is independently at each occurrence, 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.

3. The compound according to claim 1 of formula III

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein
R 1 is H, CD 3 or C 1-3 alkyl;

Assignees

• Bristol Myers Squibb Co

Inventors

• Liu Chunjian
• Yang Michael G
• Xiao Zili
• Chen Ling
• Moslin Ryan M
• Tokarski John S
• Weinstein David S
• Wrobleski Stephen T

Classifications

• C07F9/65583

  each of the hetero rings containing nitrogen as ring hetero atom · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P29/00

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

• A61K31/501 Primary

  not condensed and containing further heterocyclic rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title