Biaryl piperidine amide compounds and methods of use thereof

Abstract

The present application is directed to biaryl piperidine amide compounds, or pharmaceutically acceptable salts, solvates, and prodrugs thereof, and methods of use thereof.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or prodrug 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 compound according to  claim 1  of formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
       
     
     
         3 . The compound according to  claim 1  of formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
       
     
     
         4 . The compound according to  claim 1  of a formula selected from: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
       
     
     
         5 . The compound according to  claim 1  of formula (V): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
       
     
     
         6 . The compound 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 compound according to  claim 6 , wherein R 3  is selected from hydrogen, halogen, and CN. 
     
     
         8 . The compound 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 compound 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 compound 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 compound 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 compound 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 . A compound selected from Table 1. 
     
     
         14 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient. 
     
     
         15 . A method of preventing or treating an immune disorder, an inflammatory disorder, or an allergic disorder in a subject comprising administering to the subject an effective amount of a compound according to  claim 1 . 
     
     
         16 . A method of modulating antigen receptor signaling comprising administering a compound according to  claim 1 . 
     
     
         17 . The method of  claim 16  further comprising modulating subsequent biochemical pathways culminating in cellular activation. 
     
     
         18 . The method of  claim 17  further comprising modulating production of a responsive cytokine. 
     
     
         19 . The method of  claim 16 , wherein the antigen receptor is a T cell receptor. 
     
     
         20 . A method of modulating the store-operated calcium (SOC) channel comprising contacting the SOC channel complex, or part thereof, with a compound according to  claim 1 .