Alkyl amide-substituted pyrimidine compounds useful in the modulation of IL-12, IL-23 and/or IFNα

Patent metadata

Field	Value
Publication number	US-9540333-B2
Application number	US-201314441213-A
Country	US
Kind code	B2
Filing date	Nov 7, 2013
Priority date	Nov 8, 2012
Publication date	Jan 10, 2017
Grant date	Jan 10, 2017

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 sale thereof, wherein:
R 1 is C 1-3 alkyl optionally substituted by 0-7 R 1a ;
R 1a at each occurrence is independently hydrogen, deuterium, F, Cl, Br, CF 3 or CN;
R 2 is —(CH 2 ) r -3-14 membered carbocycle, each group substituted with 0-4 R 2a ;
R 2a at each occurrence is independently hydrogen, ═O, halo, OCF 3 , 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 , —(CH2) r C(O)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 comprising carbon atoms or 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 , 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 comprising carbon atoms and 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 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, S or O said fused ring further substituted by 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 comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p ;
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 comprising carbon atoms and 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 comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R f ;
R b at each occurrence is independently 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 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 -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 , (CH 2 ) r -phenyl substituted with 0-3 R f , or
R d at each occurrence is independently hydrogen, F, Cl, Br, OCF 3 , CF 3 , CN, NO 2 , —OR c , —(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 selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, and (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 heteroaryl comprising carbon atoms and 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 3-6 cycloalkyl or phenyl, each substituted by 0-4 groups selected from 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 formula

or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein:
R 1 is C 1-3 alkyl substituted by 0-7 R 1a ;
R 1a at each occurrence is independently hydrogen or deuterium:
R 2 is C 3-6 cycloalkyl or phenyl, each group substituted by 0-4 groups selected from R 2a ;
R 2a at each occurrence is independently hydrogen, halo, —(CH 2 ) r OR b , —(CH 2 ) r C(O)R 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 comprising carbon atoms and 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 , —(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 comprising carbon atoms and 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 selected from phenyl, or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, S or O substituted by 0-3 R a1 ;
R 11 at each occurrence is independently hydrogen, C 1-4 alkyl substituted with 0-3 R f , or C 3-10 cycloalkyl substituted with 0-1 R f ;
R a and R a1 at each occurrence are independently hydrogen, ═O, F, —(CH 2 ) r OR b or C 1-6 alkyl substituted with 0-3 R f ;
R b at each occurrence is independently 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 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 -phenyl substituted with 0-3 R d ;
R c is C 1-6 alkyl substituted with 0-3 R f ;
R d at each occurrence is independently hydrogen, halo or —OH;
R f at each occurrence is independently hydrogen, halo, CN, OH or O(C 1-6 alkyl);
p is 0, 1 or 2; and
r is 0, 1 or 2.

5. A compoun

Assignees

• Bristol Myers Squibb Co

Inventors

• Santella Joseph B
• Moslin Ryan M
• Weinstein David S
• Wrobleski Stephen T
• Tokarski John S

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/06

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

• C07D239/95

  with hetero atoms directly attached in positions 2 and 4 · CPC title