Preparation and methods of use for ortho-aryl 5-membered heteroaryl-carboxamide containing multi-targeted kinase inhibitors

Abstract

The present disclosure relates to compounds of the Formula (I): and pharmaceutically acceptable salts, as kinase modulators, compatible with the Type-II inhibition of kinases.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 wherein 
 A is C or N; 
 B, D, and E are each independently selected from CR 0 , N, O, and S; 
 R 0  is selected from H, —F, —Cl, —CH 3 , —C 2 -C 4  linear or branched alkyl, —C 2 -C 4  alkenyl, —C 2 -C 4  alkynyl, —CHR A R B , —Y, —CO(CH 2 ) n Y, —(CH 2 ) n — NR A R B , —[O—(CH 2 ) 2 ] n Y, —(CH 2 ) n SO 2 NR A R B , —S(O) m —(CH 2 ) m —R 1 , —S(O) m R 1 , —NR A R B , —OR 2 , —CH 2 —F, —CH 2 [18]F, —CHF 2 , —CHF[18]F, —CH[18]F 2 , —CF 3 , —CF 2 [18]F, —CF[18]F 2 , and —C[18]F 3 ; 
 provided that R 0  is not CF 3  when A, B, D, and E form a 1H-imidazole ring; 
 Ar is a 6-membered substituted aryl, a 6-membered optionally substituted heteroaryl, a 5 membered optionally substituted heteroaryl, or a 5,6-fused bicyclic optionally substituted heteroaryl ring system; 
 R 1  is independently H, CH 3 , —CH 2 CH 3 , or cyclopropyl; 
 R 2  is independently H, —CH 3 , —(CH 2 ) n —CH 3 , or —(CH 2 ) n —NR A R B ; 
 R A  and R B  are each independently H, CH 3 , —CH 2 CH 3 , or cyclopropyl; R A  and R taken together form a 3-6 membered carbocyclic ring system or 5-7 membered saturated heterocyclic ring system; 
 Y is —CHR 1 R 2 , —CN, —COR 1 , —CONR A R B , —OR 1 , —NR A R B , —NR 1 COR 2 , —S(O) m R 1 , —SO 2 NR A R B , —[O—(CH 2 ) 2 ] n CH 2 F, —S(O) m [11]CH 3 , —[O—(CH 2 ) 2 ] n —CH 2   18 F, —CH 2 —F; —CH 2 [18]F, —CHF 2 , —CHF[18]F, —CH[18]F 2 , —CF 3 , —CF 2 [18]F, —CF[18]F 2 , or —C[18]F 3 ; 
 m is 0, 1, or 2; 
 n is 1, 2, or 3; 
 G is an appropriate group that interacts with the Gatekeeper region in the ATP binding site of a specific kinase or profile of kinases of interest; 
 L is a linker group or ring system; and 
 (H) is an appropriate group that interacts with the Hinge-region in the ATP binding site of a specific kinase or profile of kinases of interest. 
 
     
     
         2 . The compound of  claim 1 , wherein the compound is represented by the structural formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein X is X is —O—, —NR 2 —, or —S—. 
     
     
         3 . The compound of  claim 1 , wherein Ar is of the structural formulae: 
       
         
           
           
               
               
           
         
       
       wherein:
 Z is independently selected from —CH—, —CF—, or —N—; and 
 R 3 , R 4 , and R 5  are each independently selected from H, —CH 3 , —CH 2 CH 3 , cyclopropyl, —F; -[18]F, —Cl, —Br, —CH 2 F, —CH 2 [18]F, —CHF 2 , —CF 3 , —HC═CHR 1 , —CCR 1 ; —CN, —OCF 3 , —NHR 1 —OR 1 , and —S(O) n R 1 . 
 
     
     
         4 . The compound of  claim 1 , wherein G is of the structural formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 R 6 , R 7 , and R 8  are each independently selected from H, —CH 3 , —CH 2 CH 3 , cyclopropyl, —CN; —OR 1 , —(CH 2 ) n OR 1 , —NR A R B , —(CH 2 ) n NR A R B , —S(O) m R 1 , —(CH 2 ) n —S(O) m R 1 , —F, and —Cl. 
 
     
     
         5 . The compound of  claim 1 , wherein G is of the structural formulae: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein L is
 i. a bond, —(CH 2 ) n —, —(CH 2 ) n —O—, -(cis)CH═CH—, -(trans)CH═CH—, —CC—, —OCH 2 —, —OCH(CH 3 )—, —CH(CH 3 )O—, —(CH 2 ) n S(O) m —, —S(O) m (CH 2 ) n —, —(CH 2 ) n NH—, —NH—(CH 2 ) n —, —NHCH(CH 3 )—, —CH(CH 3 )NH—, —NR 1 C(O)—, —C(O)NR 1 —, —XC(O)NH—, —NHC(O)X—, —(CH 2 ) n —CO—, or —CO—(CH 2 ) n —; or   ii. of the structural formulae   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , wherein (H) is of the structural formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 U is —H, F, Cl, —OR 1 , or —NHR 1 ; 
 V and W are each independently selected from —H, —F, —Cl, —CF 3 , —CONHR 2 , —X—R 1 , —X—(CH 2 ) n CN, —X—(CH 2 ) m COR 1 , X—(CH 2 ) m CONR 1 R 2 , —X—CH 2 —(CH 2 ) n OR 1 , —X—CH 2 —(CH 2 ) n NR 1 R 2 , —X—CH 2 —(CH 2 ) n S(O) m R 1 , —X—(CH 2 ) n S(O) m NR 1 R 2 , —O—(CH 2 ) 2 NR 1 R 2 , —O—(CH 2 ) 3 NR 1 R 2 , —O—(CH 2 ) n CONR 1 R 2 , —C 5 -C 6 heteroaryl, —COCH═CH—(CH 2 ) n NR 1 R 2 , and T; and 
 T is: 
 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , wherein (H) is of the structural formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 U is —H, F, Cl, —OR 1 , or —NHR 1 ; 
 V and W are each independently selected from —H, —F, —Cl, —CF 3 , —CONHR 2 , —X—R 2 , —X—(CH 2 ) n CN, —X—(CH 2 ) m COR 1 , X—(CH 2 ) m CONR A R B , —X—CH 2 —(CH 2 ) n OR 1 , —X—CH 2 —(CH 2 ) n NR A R B , —X—CH 2 —(CH 2 ) n S(O) m R 1 , —X—(CH 2 ) n S(O) m NR A R B , —O—(CH 2 ) 2 NR A R B , —O—(CH 2 ) 3 NR A R B , —O—(CH 2 ) n CONR A R B , —C 5 -C 6 heteroaryl, —COCH═CH—(CH 2 ) n NR A R B , and T; and 
 T is: 
 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , wherein the compound is represented by structural Formulae (III) or (IV): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The compound of  claim 1 , wherein the compound is represented by structural Formulae (V) or (VI): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The compound of  claim 9 , wherein the compound is represented by structural Formulae (VII) to (XIV): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, wherein R 11  is selected from H, —CH 3 , —CH 2 CH 3 , cyclopropyl, —F, —Cl, —CN, —OCH 3 , and —S—CH 3 . 
     
     
         12 . The compound of  claim 1 , wherein L is a bond, —O—, —CC—, ═NH—, —S(O) m —, —O—CHR 1 —, —NHCHR 1 —, S(O) m CHR 1 —, —CHR 1 O—, —CHR 1 NH—, or —CHR 1 S(O) m —. 
     
     
         13 . The compound of  claim 1 , wherein L is of the structural formulae: 
       
         
           
           
               
               
           
         
       
       wherein R 12  is selected from H, —CH 3 , —CH 2 —CH 3 , cyclopropyl, —S(O) m R 2 , —O—R 2 , and NR A R B . 
     
     
         14 . The compound of  claim 1 , wherein (H) is of structural formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and V and W are as defined above or are a C 5 -C 6  heteroaryls selected from 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 9 , wherein the compound is of structural formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein R 14  is —(CH 2 ) m —CH 3  or —(CH 2 ) m NR A R B . 
     
     
         16 . The compound of  claim 9 , wherein the compound is of structural formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein R 14  is —(CH 2 ) m —CH 3  or —(CH 2 ) m NR A R B . 
     
     
         17 . The compound of  claim 11 , wherein the compound is of structural formulae (XX)-(XXV): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The compound of  claim 11 , wherein the compound is of structural formulae (XXVI)-(XXVIV): 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 1   17 , wherein L is —O—, —S—, —NH—or —C(O)NR 1 ; and (H) is of the structural formulae 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 1   17 , wherein L is —O—, —NH—, —CC—, or —C(O)NR 1 ; and (H) is of the structural formulae: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 1 , wherein (H) is of structural formulae: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 1 , wherein the compound is selected from the formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The compound of  claim 1 , wherein the compound is selected from the formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         24 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         25 . A method of inhibiting a kinase or profile of kinases in a subject in need thereof, comprising the step of administering to the subject an effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The method of  claim 25 , wherein the kinase is selected from Raf, PI3K, and P38, or combinations thereof. 
     
     
         27 . The method of  claim 25 , wherein the kinases comprise type-III kinases members. 
     
     
         28 . The method of  claim 25 , wherein the kinase is of the TAM and/or MNK family of kinases. 
     
     
         29 . The method of  claim 25 , wherein the subject is suffering from a disease or condition selected from chronic inflammatory conditions, neurodegenerative disorders, cancers, cardiovascular diseases, restenosis after percutaneous coronary intervention, venous bypass graft disease, type-2 diabetes, infectious diseases, and neuropathic pain. 
     
     
         30 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, for use as positron emission tomography tracers.