CCR9 inhibitors and methods of use thereof
The invention relates to compounds represented by Structural Formula I, which can bind to CCR9 receptors and block the binding of a ligand (e.g., TECK) to the receptors. The invention also relates to a method of inhibiting a function of CCR9, and to the use compounds represented by Structural Formula I in research, therapeutic, prophylactic and diagnostic methods.
1. A compound represented by the following structural formula:
or a pharmaceutically acceptable salts thereof, wherein:
Y is C═O, S(O), or S(O) 2 ;
one of X 1 , X 2 , or X 3 is N, and the other two are CR;
R, for each occurrence, and R 1 are each independently H, an aliphatic group, haloalkyl, aryl, arylalkyl, alkoxy, cycloalkoxy, haloalkoxy, aryloxy, arylalkoxy, alkylthio, halo, nitro, cyano, hydroxy, NR 11 CO 2 R 12 , C(O)N(R 11 ) 2 , C(O)R 12 , CO 2 R 12 , OC(O)N(R 11 ) 2 , OC(O)R 12 , N(R 11 ) 2 , or NR 11 ,C(O)R 12 ; wherein R 11 , for each occurrence is, independently, H or an aliphatic group, and R 12 is an aliphatic group;
R 6 is H, an aliphatic carbonyl group, or an aliphatic ester;
Ar 1 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; and
Ar 2 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, provided that the compound is other than N-(3-benzoyl-6-ethyl-2-methyl-4-pyridinyt)-4-methyl- benzenesulfonamide.
2. The compound of claim 1 , wherein Ar 1 is a substituted or unsubstituted group selected from phenyl, pyrid-4-yl, N-oxido pyrid-4-yl, pyrimidinyl, or pyrazinyl.
3. The compound of claim 2 , wherein R 1 is H, R 6 is H, and Y is C═O, and the compound is represented by one of the following structural formulae:
wherein X 4 is N, N + -O − , or CR;
ring A is unsubstituted or is substituted with one or more independent occurrences of aliphatic, haloalkyl, aryl, arylalkyl, alkoxy, cycloalkoxy, haloalkoxy, aryloxy, arylalkoxy, alkylthio, halo, nitro, cyano, hydroxy, NR 11 CO 2 R 12 , C(O)N(R 11 ) 2 , C(O)R 12 , CO 2 R 12 , OC(O)N(R 11 ) 2 , OC(O)R 12 , N(R 11 ) 2 , or NR 11 C(O)R 12 ; wherein R 11 , for each occurrence is, independently, H or an aliphatic group, and R 12 is an aliphatic group;
ring B is substituted or unsubstituted; and
Ar 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl group.
4. The compound of claim 3 , wherein Ar 2 is a substituted or unsubstituted group selected from phenyl, naplithyl, thienyl, or thianaphthenyl.
5. The compound of claim 3 , wherein Ar 2 is a substituted or unsubstituted group selected from phenyl or pyridyl.
6. The compound of claim 3 , wherein Ar 2 is a substituted or unsubstituted group selected from phenyl or thienyl.
7. The compound of claim 3 , wherein Ar 2 is unsubstituted or is substituted with one or more substituents selected from substituted or unsubstituted aliphatic, aryl, arylalkyl, substituted or unsubstituted alkoxy, aryloxy, arylalkoxy, alkylthio, halo, nitro, cyano, S(O) -(aliphatic), S(O) 2 -(aliphatic), NR 11 S(O) 2 -(aliphatic), C(O)N(R 11 ) 2 , C(O)R 12 , N(R 11 ) 2 , NR 11 C(O) 2 R 12 , and NR 11 C(O)R 12 , wherein R 11 for each occurrence is independently H or an aliphatic group, and R 12 is an aliphatic group.
8. The compound of claim 3 , wherein Ar 2 is unsubstituted or is substituted with one or more substituents selected from aliphatic, alkoxy, or haloalkoxy.
9. The compound of claim 3 , wherein one or both rings A and B are unsubstituted or are independently substituted with a substituent selected from halo, aliphatic, alkoxy, or haloalkyl.
10. The compound of claim 3 , wherein ring A is substituted para to the sulfonamide group with halo, haloalkyl, nitro, cyano, or alkylcarbonyl.
11. The compound of claim 3 , wherein the compound is represented by the following structural formula:
wherein ring A is unsubstituted or is substituted with one or more independent occurrences of aliphatic, haloalkyl, aryl, arylalkyl, alkoxy, cycloalkoxy, haloalkoxy, aryloxy, arylalkoxy, alkylthio, halo, nitro, cyano, hydroxy, NR 11 CO 2 R 12 , C(O)N(R 11 ) 2 , C(O)R 12 , CO 2 R 12 , OC(O)N(R 11 ) 2 , OC(O)R 12 , N(R 11 ) 2 , or NR 1 C(O)R 12 ; wherein R 11 , for each occurrence is, independently, H or an aliphatic group, and R 12 is an aliphatic group;
ring B is substituted or unsubstituted; and
Ar 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl group.
12. The compound of claim 11 , wherein Ar 2 is a substituted or unsubstituted group selected from phenyl, naphthyl, thienyl, or thianaphthenyl.
13. The compound of claim 11 , wherein Ar 2 is a substituted or unsubstituted group selected from phenyl or pyridyl.
14. The compound of claim 11 , wherein Ar 2 is a substituted or unsubstituted group selected from phenyl or thienyl.
15. The compound of claim 11 , wherein Ar 2 is a substituted or unsubstituted phenyl ring and the compound is represented by the following structural formula
16. A compound represented by the following structural formula:
wherein R 8 is H, halo, haloalkyl, nitro, cyano, or alkylcarhonyl.
17. The compound of claim 16 , wherein the compound is represented by the following structural formula:
wherein
R 8 is H, halo, haloalkyl, nitro, or cyano;
m and n are each, independently, 0 or an integer from 1 to 3;
each R 9 is independently, aliphatic, haloalkyl, aryl, arylalkyl, alkoxy, cycloalkoxy, haloalkoxy, aryloxy, arylalkoxy, alkylthio, halo, nitro, cyano, hydroxy, NR 11 CO 2 R 12 , C(O)N(R 11 ) 2 , C(O)R 12 , CO 2 R 12 , OC(O)N(R 11 ) 2 , OC(O)R 12 , N(R, 11 ) 2 , or NR 11 C(O)R 12 ; or two adjacent R 9 groups taken together with the atoms to which they are attached form a fused, saturated, unsaturated or partially unsaturated 5 to 7 membered ring having 0, 1, or 2 heteroatoms selected from N, O, and S;
wherein each R 11 is, independently, selected from H or an aliphatic group; and R 12 is an aliphatic group; and
each R 10 is, independently, halo, aliphatic group, alkoxy, or haloalkyl; or two adjacent R 10 groups taken together with the atoms to which they are attached form a fused, saturated, unsaturated or partially unsaturated 5 to 7 membered ring having 0, 1 or 2 heteroatoms selected from N, O, and S.
18. The compound of claim 17 , wherein:
R 8 is halo, nitro, alkylcarbonyl, or trihaloalkyl; and n is 1 and R 9 is para to the sulfonamide substituent and is an aliphatic, alkoxy, or haloalkoxy group.
19. The compound of claim 18 , wherein R 8 is Cl, Br, or NO 2 .
20. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and the compound of claim 1 .
21. A method of treating inflammatory bowel disease (IBD) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 or a composition of claim 20 .
22. The method of claim 18 , wherein the inflammatory bowel disease is selected from ulcerative colitis, Crohn's disease, ileitis, Celiac disease, nontropical Sprue, enteritis, enteropathy associated with seronegative arthropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchtis resulting after proctocolectomy, and ileoanal anastomosis.
23. The method of claim 22 , wherein the inflammatory disease is Crohn's disease or colitis.
24. The method of claim 22 , wherein the inflammatory disease is Celiac's disease.
25. The compound of claim 1 , wherein the compound has the structure: