Compounds inclunding substituted pyridines for inflammation and immune-related uses

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof; wherein:

each of X 1 and X 2 is independently N, C or N + O − , provided that one of X 1 or X 2 is C, and the other is N or N + O − ;

Y 1 is S or CH;

Y 2 is S, N, or CH;

Z is CH 2 , CH 2 CH 2 , CO, thiazolyl, or C≡C;

Y 3 is CH 2 or C═O;

R 1 is heteroaryl, aryl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl, wherein each substituent represented by R 1 is independently and optionally substituted with one to three halo, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, COR 6 , COOR 6 , CON(R 6 ) 2 , N(R 6 ) 2 , NR 6 CON(R 6 ) 2 , NR 6 CSN(R 6 ) 2 , OR 6 , S(O) p R 6 , S(O) p N(R 6 ) 2 , CN, NO 2 , or N 3 ;

R 2 is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, heteroaryl, heteroaryl(C 1 -C 2 )alkyl, heteroaryl(C 2 )alkenyl, heteroaryl(C 2 )alkynyl, aryl(C 1 -C 2 )alkyl, aryl(C 2 )alkenyl, aryl(C 2 )alkynyl, CN, COR 6 , COOR 6 , CON(R 6 ) 2 , CSR 6 , CSOR 6 , or CSN(R 6 ) 2 , wherein each substituent represented by R 2 is independently and optionally substituted with one to three halo, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, COR 6 , COOR 6 , CON(R 6 ) 2 , N(R 6 ) 2 , NR 6 CON(R 6 ) 2 , NR 6 CSN(R 6 ) 2 , OR 6 , SR 6 , CN, NO 2 , or N 3 ;

R 3 is H, halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, heteroaryl, (C 3 -C 7 )cycloalkyl, heterocycloalkyl, COR 6 , COOR 6 , CON(R 6 ) 2 , N(R 6 ) 2 , NR 6 CON(R 6 ) 2 , NR 6 CSN(R 6 ) 2 , OR 6 , S(O) p R 6 , CN, NO 2 , S(O) p N(R 6 ) 2 or N 3 , wherein each substituent represented by R 3 having a hydrogen atom is optionally and independently substituted with halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, —OH, —NH 2 , NH(C 1 -C 3 )alkyl, N((C 1 -C 3 )alkyl) 2 , or CN;

R 4 is H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, heteroaryl, heteroaryl(C 1 -C 2 )alkyl, heteroaryl(C 2 )alkenyl, heteroaryl(C 2 )alkynyl, aryl, aryl(C 1 -C 2 )alkyl, aryl(C 2 )alkenyl, aryl(C 2 )alkynyl, (C 3 -C 7 )cycloalkyl, heterocycloalkyl, OR 6 , or CON(R 6 ) 2 ;

each R 5 is independently halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, heteroaryl, heteroaryl(C 1 -C 2 )alkyl, heteroaryl(C 2 )alkenyl, heteroaryl(C 2 )alkynyl, (C 3 -C 7 )cycloalkyl, heterocycloalkyl, aryl, aryl(C 1 -C 2 )alkyl, aryl(C 2 )alkenyl, aryl(C 2 )alkynyl, (C 1 -C 6 )haloalkyl, COR 6 , COOR 6 , CON(R 6 ) 2 , N(R 6 ) 2 , NR 6 CON(R 6 ) 2 , NR 6 CSN(R 6 ) 2 , OR 6 , S(O) p R 6 , CN, NO 2 or N 3 , wherein each substituent represented by R 5 having a hydrogen atom is optionally an independently substituted with halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, aryl, heteroaryl, (C 3 -C 7 )cycloalkyl, heterocycloalkyl, —OH, —NH 2 , NH(C 1 -C 3 )alkyl, N((C 1 -C 3 )alkyl) 2 , or CN;

each R 6 is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 7 )cycloalkyl, heterocycloalkyl, heteroaryl, heteroaryl(C 1 -C 2 )alkyl, heteroaryl(C 2 )alkenyl, heteroaryl(C 2 )alkynyl, aryl, aryl(C 1 -C 2 )alkyl, aryl(C 2 )alkenyl, or aryl(C 2 )alkynyl or two R 6 substituents attached to the same or adjacent atoms are taken together to form a heterocycloalkyl or heteroaryl;

n is 0, 1, 2, 3, 4, or 5; and

p is 0, 1, or 2;

wherein one but not both of Y 1 and Y 2 is S; and one of the dashed bonds is a double bond, and one is a single bond,

provided that when Z is a bond, Y 2 is CH, X 1 is N, X 2 is C, and R 2 is methyl, then R 1 is other than 1,3-oxazol-5-yl; and

when Z is a bond, Y 2 is CH, X 1 is C, X 2 is N and R 2 is methyl, then R 1 is other than 1-methyl-1H-imidazol-5-yl, 1,3-oxazol-5-yl, isoxazol-5-yl, 1,3-thiazol-2-yl and 1H-imidazol-5-yl.

2. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 1 .

3. A compound selected from the group consisting of:

or pharmaceutically acceptable salts thereof.

4. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 3 .

5. A method of inhibiting cytokine production in a cell, comprising administering to the cell a compound of claim 3 .

6. The method of claim 5 , wherein the cytokine is selected from the group consisting of IL-2, IL-4, IL-5, IL-13, GM-CSF, IFN-γ, TNFα, and combinations thereof.

7. A method of inhibiting immune cell activation comprising administering to an immune cell a compound of claim 3 .

8. A method of modulating a Ca 2+ -release-activated Ca 2+ channel (CRAC) in a cell, wherein the ion channel is involved in immune cell activation, comprising administering to the cell a compound of claim 3 .