Biaryl piperidine amide compounds and methods of use thereof

1. A method of treating an immune disorder associated with T cell activation in a subject comprising administering to the subject an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein

X 1 is selected from CR 1 , N, and N—O;

X 2 is selected from CR 2 , N, and N—O;

X 3 is selected from CR 3 , N, and N—O;

X 4 is selected from CR 4 , N, and N—O;

R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen; halogen; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 1 -C 6 haloalkyl; (C 1 -C 6 alkyl)-OR 20 ; OH; O(C 1 -C 6 alkyl); OCF 3 ; OCF 2 H; OCFH 2 ; CN; N 3 ; NO 2 ; NH 2 ; NH(C 1 -C 6 alkyl); N(C 1 -C 6 alkyl) 2 ; NR 20 C(O)R 20 ; C(O)NR 20 R 20 ; COR 20 ; CO(C 1 -C 6 alkyl); S(O) p R 20 ; NR 20 S(O) p R 20 ; S(O) p NR 20 R 20 ; SR 20 , SCF 3 ; COOR 20 ; OR 20 ; (C 1 -C 6 alkyl)-R 20 ; 3-7 membered saturated, partially saturated, or unsaturated carbocycle; and 3-7 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;

alternatively, two substituents selected from R 1 , R 2 , R 3 , R 4 , and R 5 on two adjacent carbon atoms taken together form a 3-7 membered saturated, partially saturated, or unsaturated carbocycle; or a 3-7 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; where the carbocycle or heterocycle is optionally substituted with one or more R 20 ;

R 20 is independently selected from hydrogen; C 1 -C 6 alkyl; CN; (C 1 -C 6 alkyl)-NR 21 R 21 ; (C 1 -C 6 alkyl)-OR 21 ; 3-7 membered saturated, partially saturated, or unsaturated carbocycle; 3-7 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; (C 1 -C 6 alkyl)-3-7 membered saturated, partially saturated, or unsaturated carbocycle; (C 1 -C 6 alkyl)-3-7 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; where the carbocycle or heterocycle is optionally substituted with one or more R 21 ;

or two R 20 taken together with the carbon atom to which they are attached form a carbonyl;

R 21 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; OH, O—(C 1 -C 6 alkyl), O—(C 2 -C 6 alkenyl), and O—(C 2 -C 6 alkynyl);

Y 6 is independently selected from CR 6 , N, and N—O;

Y 7 is independently selected from CR 7 , N, and N—O;

Y 8 is independently selected from CR 8 , N, and N—O;

Y 9 is independently selected from CR 9 , N, and N—O;

R 6 , R 7 , R 8 , and R 9 are independently selected from hydrogen; halogen; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 1 -C 6 haloalkyl; (C 1 -C 6 alkyl)-R 30 ; (C 1 -C 6 alkyl)-OR 30 ; OH; O(C 1 -C 6 alkyl); OCF 3 ; OCF 2 H; OCFH 2 ; CN; N 3 ; NO 2 ; NH 2 ; NH(C 1 -C 6 alkyl); N(C 1 -C 6 alkyl) 2 ; NR 30 C(O)R 30 ; C(O)NR 30 R 30 ; COR 30 ; CO(C 1 -C 6 alkyl); S(O) q R 30 ; NR 30 S(O) q R 30 ; S(O) q NR 30 R 30 ; SR 30 ; SCF 3 ; and COOR 30 ;

alternatively, two substituents selected from R 6 , R 7 , R 8 , and R 9 on two adjacent carbon atoms taken together form a 3-7 membered saturated, partially saturated, or unsaturated carbocycle; or a 3-7 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; where the carbocycle or heterocycle is optionally substituted with one or more R 30 ;

R 30 is independently selected from hydrogen; C 1 -C 6 alkyl; (C 1 -C 6 alkyl)-R 31 ; (C 1 -C 6 alkyl)-OR 31 ; (C 1 -C 6 alkyl)-NR 31 R 31 ; 3-7 membered saturated, partially saturated, or unsaturated carbocycle; and 3-7 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; where the carbocycle or heterocycle is optionally substituted with one or more R 31 ;

R 31 is independently selected from hydrogen; C 1 -C 6 alkyl; 3-7 membered saturated, partially saturated, or unsaturated carbocycle; and 3-7 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;

G is selected from a bond, O, S, S(O), S(O) 2 , CH 2 , CH 2 CH 2 , and CHCH;

alternatively, G and R a1 together form a 3-7 membered saturated, partially saturated, or unsaturated carbocycle; or a 3-7 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;

A is selected from a bond, CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CHCH, and C≡C;

R a1 and R a2 are independently selected from hydrogen; halogen; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 1 -C 6 haloalkyl; OH; O(C 1 -C 6 alkyl); (C 1 -C 6 alkyl)-OH; (C 1 -C 6 alkyl)-O(C 1 -C 6 alkyl); (C 1 -C 6 alkyl)-3-7 membered saturated, partially saturated, or unsaturated carbocycle; and (C 1 -C 6 alkyl)-3-7 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;

R a3 is selected from hydrogen, halogen, OH, O(C 1 -C 6 alkyl), and C 1 -C 6 alkyl;

R a4 is selected from hydrogen, halogen, and C 1 -C 6 alkyl;

Z 11 is selected from CR 11 , N, and N—O;

Z 12 is selected from CR 12 , N, and N—O;

Z 13 is selected from CR 13 , N, and N—O;

Z 15 is selected from CR 15 , N, and N—O;

R 11 , R 12 , R 13 , R 14 , and R 15 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, (C 1 -C 6 alkyl)-OR 40 , OH, O(C 1 -C 6 alkyl), OCF 3 , OCF 2 H, OCFH 2 , CN, N 3 , NO 2 , NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , NR 40 C(O)R 40 , C(O)NR 40 R 40 , COH, CO(C 1 -C 6 alkyl), S(O) t R 40 , NR 40 S(O) t R 40 , S(O) t NR 40 R 40 , SR 40 , SCF 3 , COOR 40 , COR 40 , and OR 40 ; 3-7 membered saturated, partially saturated, or unsaturated carbocycle; and 3-7 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;

alternatively, two substituents selected from R 11 , R 12 , R 13 , R 14 , and R 15 on two adjacent carbon atoms taken together form a 3-7 membered saturated, partially saturated, or unsaturated carbocycle; or a 3-7 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; where the carbocycle or heterocycle is optionally substituted with one or more R 40 ;

R 40 is independently selected from hydrogen; halogen; C 1 -C 6 alkyl; C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; 3-7 membered saturated, partially saturated, or unsaturated carbocycle; 3-7 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; (C 1 -C 6 alkyl)-3-7 membered saturated, partially saturated, or unsaturated carbocycle; and (C 1 -C 6 alkyl)-3-7 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;

or two R 40 taken together with the carbon atom to which they are attached form a carbonyl;

j is 0, 1, or 2;

p is 0, 1, or 2;

q is 0, 1, or 2; and

t is 0, 1, or 2.

2. The method according to claim 1 , wherein the compound is of formula (II):

or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 , wherein the compound is of formula (III):

or a pharmaceutically acceptable salt thereof.

4. The method according to claim 1 , wherein the compound is of a formula selected from:

or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1 , wherein the compound is of formula (V):

or a pharmaceutically acceptable salt thereof.

6. The method according to claim 1 , wherein R 3 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OH, O(C 1 -C 6 alkyl), OCF 3 , OCF 2 H, OCFH 2 , CN, N 3 , NO 2 , NH 2 , NH(C 1 -C 6 alkyl), and N(C 1 -C 6 alkyl) 2 .

7. The method according to claim 6 , wherein R 3 is selected from hydrogen, halogen, and CN.

8. The method according to claim 1 , wherein R 5 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OH, O(C 1 -C 6 alkyl), OCF 3 , OCF 2 H, OCFH 2 , CN, NH 2 , NH(C 1 -C 6 alkyl), and N(C 1 -C 6 alkyl) 2 .

9. The method according to claim 8 , wherein R 5 is selected from hydrogen, halogen, C 1 -C 6 alkyl, OH, and O(C 1 -C 6 alkyl).

10. The method according to claim 1 , wherein R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OH, O(C 1 -C 6 alkyl), OCF 3 , OCF 2 H, OCFH 2 , CN, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , S(O) q NR 30 R 30 , C(O)NR 30 R 30 , COR 30 , and COOR 30 .

11. The method according to claim 10 , wherein R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OH, O(C 1 -C 6 alkyl), CN, S(O) q NR 30 R 30 , C(O)NR 30 R 30 , COR 30 , and COOR 30 .

12. The method according to claim 11 , wherein R 7 is selected from hydrogen, CF 3 , OH, CN, S(O) 2 NR 30 R 30 , and C(O)NR 30 R 30 .

13. The method according to claim 1 , wherein the compound is of the following structure:

or a pharmaceutically acceptable salt thereof.

14. A method of treating an immune disorder associated with T cell activation in a subject comprising administering to the subject an effective amount of a compound selected from:

Compound

No.

Structure

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444

or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 , wherein the immune disorder is selected from rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis.

16. The method of claim 15 , wherein the immune disorder is rheumatoid arthritis.

17. The method of claim 15 , wherein the immune disorder is inflammatory bowel disease.

18. The method of claim 15 , wherein the immune disorder is multiple sclerosis.

19. The method of claim 14 , wherein the immune disorder is selected from rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis.

20. The method of claim 19 , wherein the immune disorder is rheumatoid arthritis.

21. The method of claim 19 , wherein the immune disorder is inflammatory bowel disease.

22. The method of claim 19 , wherein the immune disorder is multiple sclerosis.