Tropomyosin-related kinase (trk) inhibitors

Abstract

Tropomyosin-related kinase inhibitors (Trk inhibitors) are small molecule compounds useful in the treatment of disease. Trk inhibitors can be used as pharmaceutical agents and in pharmaceutical compositions. Trk inhibitors are useful in the treatment of inflammatory diseases, autoimmune disease, defects of bone metabolism and/or cancer, and are particularly useful in the treatment of osteoarthritis (OA), pain, and pain associated with OA. Trk inhibitors are also useful for inhibiting tropomyosin-related kinase A (TrkA), tropomyosin-related kinase B (TrkB), tropomyosin-related kinase C (TrkC), and/or c-FMS (the cellular receptor for colony stimulating factor-1 (CSF-1)).

1 . A compound comprising the structure of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         n is 1, 2, 3, 4 or 5; 
         m is 0, 1, 2, 3 or 4; 
         Q 1  is H, halo or (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl,
 wherein the (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 3 -C 10 )cycloalkyl, or (C 2 -C 9 )heterocycloalkyl is optionally substituted by one to four groups selected from (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkyl-O—, —OH, —NH 2 , R 7 R 8 N—, R 7 R 8 N(O)C—, R 7 (O)CR 8 N—, F 3 C—, NC—, (C 3 -C 10 )alkyl(O)P—, (C 3 -C 10 )alkyl-S—, (C 3 -C 10 )cycloalkyl-S—, (C 6 -C 14 )aryl-S—, (C 2 -C 9 )heteroalkyl-S—, (C 2 -C 9 )heterocycloalkyl-S—, (C 2 -C 9 )heteroaryl-S—, (C 3 -C 10 )alkyl(O)S—, (C 3 -C 10 )cycloalkyl(O)S—, (C 6 -C 14 )aryl(O)S—, (C 2 -C 9 )heteroalkyl(O)S—, (C 2 -C 9 )heterocycloalkyl(O)S—, (C 2 -C 9 )heteroaryl(O)S—, (C 3 -C 10 )alkyl-O 2 S—, (C 3 -C 10 )cycloalkyl-O 2 S—, (C 6 -C 14 )aryl-O 2 S—, (C 2 -C 9 )heteroalkyl-O 2 S—, (C 2 -C 9 )heterocycloalkyl-O 2 S—, (C 2 -C 9 )heteroaryl-O 2 S—, or R 7 R 8 NO 2 S—, 
 wherein R 7  and R 8  is each independently H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl; 
 
         Q 2  is (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 3 -C 10 )cycloalkyl, or (C 2 -C 9 )heterocycloalkyl, wherein the (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 3 -C 10 )cycloalkyl, or (C 2 -C 9 )heterocycloalkyl is optionally substituted by one to four groups selected from (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkyl-O—, —OH, —NH 2 , R 7 R 8 N—, R 7 R 8 N(O)C—, R 7 (O)CR 8 N—, F 3 C—, NC—, (C 3 -C 10 )alkyl(O)P—, (C 3 -C 10 )alkyl-S—, (C 3 -C 10 )cycloalkyl-S—, (C 6 -C 14 )aryl-S—, (C 2 -C 9 )heteroalkyl-S—, (C 2 -C 9 )heterocycloalkyl-S—, (C 2 -C 9 )heteroaryl-S—, (C 3 -C 10 )alkyl(O)S—, (C 3 -C 10 )cycloalkyl(O)S—, (C 6 -C 14 )aryl(O)S—, (C 2 -C 9 )heteroalkyl(O)S—, (C 2 -C 9 )heterocycloalkyl(O)S—, (C 2 -C 9 )heteroaryl(O)S—, (C 3 -C 10 )alkyl-O 2 S—, (C 3 -C 10 )cycloalkyl-O 2 S—, (C 6 -C 14 )aryl-O 2 S—, (C 2 -C 9 )heteroalkyl-O 2 S—, (C 2 -C 9 )heterocycloalkyl-O 2 S—, (C 2 -C 9 )heteroaryl-O 2 S—, or R 7 R 8 NO 2 S—,
 wherein R 7  and R 8  is each independently H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl; 
 
         X is CH, N, halo or CR 9 ,
 wherein R 9  is (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkyl-O—, —OH, —NH 2 ; 
 
         R 1  is H, halo, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 1 -C 10 )alkylamine, or NH 2 ; 
         R 2  is H, halo, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-O—, or NH 2 ; 
         R 3  and R 4  are each independently H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 1 -C 10 )alkylamine, O—(C 1 -C 10 )alkyl, or NH 2  or R 3  and R 4  are taken together with the carbon to which they are attached to form a 3 to 10 member ring,
 wherein the 3 to 10 member ring is optionally substituted by one to four groups selected from (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkyl-O—, —OH, —NH 2 ; and 
 
         R 5  and R 6  are each independently H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 1 -C 10 )alkylamine, O—(C 1 -C 10 )alkyl, or NH 2  or R 5  and R 6  are taken together with the carbon to which they are attached to form a 3 to 10 member ring,
 wherein the 3 to 10 member ring is optionally substituted by one to four groups selected from (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkyl-O—, —OH, —NH 2 ; 
 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 - 10 . (canceled) 
     
     
         11 . The compound according to  claim 1 , wherein Q 1  is H or (C 6 -C 14 )aryl or (C 2 -C 9 )heteroaryl,
 wherein the (C 6 -C 14 )aryl or (C 2 -C 9 )heteroaryl is optionally substituted by one to four groups selected from (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkyl-O—, —OH, —NH 2 , R 7 R 8 N—, R 7 R 8 N(O)C—, R 7 (O)CR 8 N—, F 3 C—, NC—, (C 3 -C 10 )alkyl(O)P—, (C 3 -C 10 )alkyl-S—, (C 3 -C 10 )cycloalkyl-S—, (C 6 -C 14 )aryl-S—, (C 2 -C 9 )heteroalkyl-S—, (C 2 -C 9 )heterocycloalkyl-S—, (C 2 -C 9 )heteroaryl-S—, (C 3 -C 10 )alkyl(O)S—, (C 3 -C 10 )cycloalkyl(O)S—, (C 6 -C 14 )aryl(O)S—, (C 2 -C 9 )heteroalkyl(O)S—, (C 2 -C 9 )heterocycloalkyl(O)S—, (C 2 -C 9 )heteroaryl(O)S—, (C 3 -C 10 )alkyl-O 2 S—, (C 3 -C 10 )cycloalkyl-O 2 S—, (C 6 -C 14 )aryl-O 2 S—, (C 2 -C 9 )heteroalkyl-O 2 S—, (C 2 -C 9 )heterocycloalkyl-O 2 S—, (C 2 -C 9 )heteroaryl-O 2 S—, or R 7 R 8 NO 2 S—,
 wherein R 7  and R 8  is each independently H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl. 
   
     
     
         12 . (canceled) 
     
     
         13 . The compound according to claim  0 , wherein Q 1  is (C 6 -C 14 )aryl optionally substituted by one to four groups selected from (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkyl-O—, —OH, —NH 2 , R 7 R 8 N—, R 7 R 8 N(O)C—, R 7 (O)CR 8 N—, F 3 C—, NC—, (C 3 -C 10 )alkyl(O)P—, (C 3 -C 10 )alkyl-S—, (C 3 -C 10 )cycloalkyl-S—, (C 6 -C 14 )aryl-S—, (C 2 -C 9 )heteroalkyl-S—, (C 2 -C 9 )heterocycloalkyl-S—, (C 2 -C 9 )heteroaryl-S—, (C 3 -C 10 )alkyl(O)S—, (C 3 -C 10 )cycloalkyl(O)S—, (C 6 -C 14 )aryl(O)S—, (C 2 -C 9 )heteroalkyl(O)S—, (C 2 -C 9 )heterocycloalkyl(O)S—, (C 2 -C 9 )heteroaryl(O)S—, (C 3 -C 10 )alkyl-O 2 S—, (C 3 -C 10 )cycloalkyl-O 2 S—, (C 6 -C 14 )aryl-O 2 S—, (C 2 -C 9 )heteroalkyl-O 2 S—, (C 2 -C 9 )heterocycloalkyl-O 2 S—, (C 2 -C 9 )heteroaryl-O 2 S—, or R 7 R 8 NO 2 S—,
 wherein R 7  and R 8  is each independently H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl. 
 
     
     
         14 . (canceled) 
     
     
         15 . The compound according to  claim 1 , wherein Q 2  is (C 6 -C 14 )aryl or (C 2 -C 9 )heteroaryl,
 wherein the (C 6 -C 14 )aryl or (C 2 -C 9 )heteroaryl is optionally substituted by one to four groups selected from (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkyl-O—, —OH, —NH 2 , R 7 R 8 N—, R 7 R 8 N(O)C—, R 7 (O)CR 8 N—, F 3 C—, NC—, (C 3 -C 10 )alkyl(O)P—, (C 3 -C 10 )alkyl-S—, (C 3 -C 10 )cycloalkyl-S—, (C 6 -C 14 )aryl-S—, (C 2 -C 9 )heteroalkyl-S—, (C 2 -C 9 )heterocycloalkyl-S—, (C 2 -C 9 )heteroaryl-S—, (C 3 -C 10 )alkyl(O)S—, (C 3 -C 10 )cycloalkyl(O)S—, (C 6 -C 14 )aryl(O)S—, (C 2 -C 9 )heteroalkyl(O)S—, (C 2 -C 9 )heterocycloalkyl(O)S—, (C 2 -C 9 )heteroaryl(O)S—, (C 3 -C 10 )alkyl-O 2 S—, (C 3 -C 10 )cycloalkyl-O 2 S—, (C 6 -C 14 )aryl-O 2 S—, (C 2 -C 9 )heteroalkyl-O 2 S—, (C 2 -C 9 )heterocycloalkyl-O 2 S—, (C 2 -C 9 )heteroaryl-O 2 S—, or R 7 R 8 NO 2 S—,
 wherein R 7  and R 8  is each independently H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl. 
   
     
     
         16 . The compound according to claim  0 , wherein Q 2  is (C 6 -C 14 )aryl optionally substituted by one to four groups selected from (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkyl-O—, —OH, —NH 2 , R 7 R 8 N—, R 7 R 8 N(O)C—, R 7 (O)CR 8 N—, F 3 C—, NC—, (C 3 -C 10 )alkyl(O)P—, (C 3 -C 10 )alkyl-S—, (C 3 -C 10 )cycloalkyl-S—, (C 6 -C 14 )aryl-S—, (C 2 -C 9 )heteroalkyl-S—, (C 2 -C 9 )heterocycloalkyl-S—, (C 2 -C 9 )heteroaryl-S—, (C 3 -C 10 )alkyl(O)S—, (C 3 -C 10 )cycloalkyl(O)S—, (C 6 -C 14 )aryl(O)S—, (C 2 -C 9 )heteroalkyl(O)S—, (C 2 -C 9 )heterocycloalkyl(O)S—, (C 2 -C 9 )heteroaryl(O)S—, (C 3 -C 10 )alkyl-O 2 S—, (C 3 -C 10 )cycloalkyl-O 2 S—, (C 6 -C 14 )aryl-O 2 S—, (C 2 -C 9 )heteroalkyl-O 2 S—, (C 2 -C 9 )heterocycloalkyl-O 2 S—, (C 2 -C 9 )heteroaryl-O 2 S—, or R 7 R 8 NO 2 S—,
 wherein R 7  and R 8  is each independently H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl. 
 
     
     
         17 - 19 . (canceled) 
     
     
         20 . The compound according to  claim 1 , wherein R 1  is H, halo, NH 2 , or (C 1 -C 10 )alkyl. 
     
     
         21 - 24 . (canceled) 
     
     
         25 . The compound according to  claim 1 , wherein R 2  is H, halo, (C 1 -C 10 )alkyl, or (C 1 -C 10 )alkyl-O—. 
     
     
         26 - 32 . (canceled) 
     
     
         33 . The compound according to  claim 1  comprising the structure of Formula (II) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         34 . The compound according to claim  0 , wherein
 n is 1;   m is 1;   Q 1  is (C 2 -C 9 )heteroaryl optionally substituted by one to four groups selected from (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkyl-O—, —OH, —NH 2 , R 7 R 8 N—, R 7 R 8 N(O)C—, R 7 (O)CR 8 N—, F 3 C—, NC—, (C 3 -C 10 )alkyl(O)P—, (C 3 -C 10 )alkyl-S—, (C 3 -C 10 )cycloalkyl-S—, (C 6 -C 14 )aryl-S—, (C 2 -C 9 )heteroalkyl-S—, (C 2 -C 9 )heterocycloalkyl-S—, (C 2 -C 9 )heteroaryl-S—, (C 3 -C 10 )alkyl(O)S—, (C 3 -C 10 )cycloalkyl(O)S—, (C 6 -C 14 )aryl(O)S—, (C 2 -C 9 )heteroalkyl(O)S—, (C 2 -C 9 )heterocycloalkyl(O)S—, (C 2 -C 9 )heteroaryl(O)S—, (C 3 -C 10 )alkyl-O 2 S—, (C 3 -C 10 )cycloalkyl-O 2 S—, (C 6 -C 14 )aryl-O 2 S—, (C 2 -C 9 )heteroalkyl-O 2 S—, (C 2 -C 9 )heterocycloalkyl-O 2 S—, (C 2 -C 9 )heteroaryl-O 2 S—, or R 7 R 8 NO 2 S—,
 wherein R 7  and R 8  is each independently H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl; 
   Q 2  is (C 3 -C 10 )cycloalkyl optionally substituted by one to four groups selected from (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkyl-O—, —OH, —NH 2 , R 7 R 8 N—, R 7 R 8 N(O)C—, R 7 (O)CR 8 N—, F 3 C—, NC—, (C 3 -C 10 )alkyl(O)P—, (C 3 -C 10 )alkyl-S—, (C 3 -C 10 )cycloalkyl-S—, (C 6 -C 14 )aryl-S—, (C 2 -C 9 )heteroalkyl-S—, (C 2 -C 9 )heterocycloalkyl-S—, (C 2 -C 9 )heteroaryl-S—, (C 3 -C 10 )alkyl(O)S—, (C 3 -C 10 )cycloalkyl(O)S—, (C 6 -C 14 )aryl(O)S—, (C 2 -C 9 )heteroalkyl(O)S—, (C 2 -C 9 )heterocycloalkyl(O)S—, (C 2 -C 9 )heteroaryl(O)S—, (C 3 -C 10 )alkyl-O 2 S—, (C 3 -C 10 )cycloalkyl-O 2 S—, (C 6 -C 14 )aryl-O 2 S—, (C 2 -C 9 )heteroalkyl-O 2 S—, (C 2 -C 9 )heterocycloalkyl-O 2 S—, (C 2 -C 9 )heteroaryl-O 2 S—, or R 7 R 8 NO 2 S—,
 wherein R 7  and R 8  is each independently H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl; 
   X is N or CH;   R 1  is H or NH 2 ; and   R 2  is H, halo or (C 1 -C 10 )alkyl-O—.   
     
     
         35 - 45 . (canceled) 
     
     
         46 . The compound according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         47 . The compound according to  claim 1 , selected from the group consisting of
 1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo [d]imidazol-2-amine   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin-5-yl)-1H-benzo[d]imidazol-2-amine,   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridine-4-yl)-1H-benzo[d]imidazol-2-amine,   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo [d]imidazol-2-amine,   (5-(2-Amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine oxide,   3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,   1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-benzo[d]imidazole,   3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine,   (5-(2-Amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine oxide,   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)propan-2-amine,   4-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)morpholine,   6-(4-Cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b]pyridine   (S)-1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidine-2-carboxylic acid,   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine   3-(3-Methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,   3-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole,   2-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,3,4-oxadiazole,   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2,3-triazol-4-yl)propan-2-amine, and   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3H-imidazo[4,5-b]pyridine.   
     
     
         48 . A pharmaceutical composition comprising a compound according to  claim 1 . 
     
     
         49 - 50 . (canceled) 
     
     
         51 . A method of treating inflammatory diseases, autoimmune disease, defects of bone metabolism or cancer in a patient in need thereof comprising administering to the patient a compound according to  claim 1 . 
     
     
         52 . (canceled) 
     
     
         53 . A method of treating pain in a patient in need thereof comprising administering to the patient a compound according  claim 1 . 
     
     
         54 . The method of  claim 53 , wherein the pain is post-operative pain. 
     
     
         55 . A method of treating pain associated with osteoarthritis in a patient in need thereof comprising administering to the patient a compound according to  claim 1 . 
     
     
         56 . A method of inhibiting tropomyosin-related kinase A in a patient comprising administering to the patient a compound according to  claim 1 . 
     
     
         57 . A method of inhibiting tropomyosin-related-kinase B in a patient comprising administering to the patient a compound according to  claim 1 . 
     
     
         58 . A method of inhibiting tropomyosin-related kinase C in a patient comprising administering to the patient a compound according to  claim 1 . 
     
     
         59 . A method of inhibiting c-FMS in a patient comprising administering to the patient a compound according to  claim 1 .