Heterobicyclic pyrazole compounds and methods of use

Abstract

Compounds of Formulas Ia and Ib, and stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting receptor tyrosine kinases and for treating disorders mediated thereby. Methods of using compounds of Formula Ia and Ib, and stereoisomers, geometric isomers, tautomers, solvates and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.

1 . A compound selected from Formulas Ia and Ib: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein: 
         X is O, S or NR 10 ; 
         Z 2  and Z 3  are independently selected from CR 4  and N, wherein zero or one of Z 2  and Z 3  is N; 
         R 1  is H, C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, —C(═O)NR 10 R 11 , or —(CR 14 R 15 ) t NR 10 R 11 , or 
         R 1  is C 3 -C 12  carbocyclyl, C 2 -C 20  heterocyclyl, C 6 -C 20  aryl or C 1 -C 20  heteroaryl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, CF 3 , oxo, —OR 10 , SR 10 , —C(═Y)R 10 , —C(═Y)OR 10 , —C(═Y)NR 10 R 11 , —(CR 14 R 15 ) n —NR 10 R 11 , —NR 10 C(═Y)R 13 , —NR 10 C(═Y)OR 11 , —NR 12 C(═Y)NR 10 R 11 , —NR 12 SO 2 R 10 , —OC(═Y)R 10 , —OC(═Y)OR 10 , —OC(═Y)NR 10 R 11 , —OS(O) 2 (OR 10 ), —OP(═Y)(OR 10 )(OR 11 ), —OP(OR 10 )(OR 11 ), —S(O)R 10 , —S(O) 2 R 10 , —S(O) 2 NR 10 R 11 , —S(O)(OR 10 ), —S(O) 2 (OR 10 ), —SC(═Y)R 10 , —SC(═Y)OR 10 , —SC(═Y)NR 10 R 11 , C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 12  cycloalkyl, C 2 -C 20  heterocyclyl, C 6 -C 20  aryl, C 1 -C 20  heteroaryl, 
       
       —(CR 14 R 15 )—NR 12 C(═O)(CR 14 R 15 )NR 10 R 11 , and (CR 14 R 15 ) t NR 10 R 11 , or
 R 1  is NR x R y ; 
 R 2  is H, CF 3 , CN, —C(═Y)R 10 , —C(═Y)OR 10 , —C(═Y)NR 10 R 11 , —C(═O)NR 12 (CR 14 R 15 ) t NR 10 R 11 , —SR 10 , —S(O)R 10 , —S(O) 2 R 10 , S(O) 2 NR 10 R 11 , —SC(═Y)R 10 , —SC(═Y)OR 10 , C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 12  carbocyclyl, C 2 -C 20  heterocyclyl, C 6 -C 20  aryl, or C 1 -C 20  heteroaryl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, (CH 2 ) n OR 10 , (CH 2 ) n NR 10 R 11 , heteroaryl and heterocyclyl; 
 R 3  is C 3 -C 12  carbocyclyl, C 2 -C 20  heterocyclyl, C 6 -C 20  aryl or C 1 -C 20  heteroaryl, wherein said carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, CF 3 , OR 10 , SR 10 , —C(═Y)R 10 , —C(═Y)OR 10 , —C(═Y)NR 10 R 11 , —NR 10 R 11 , —NR 10 C(═Y)R 13 , —NR 10 C(═Y)OR 11 , —NR 12 C(═Y)NR 10 R 11 , —NR 12 C(═O)C(═O)R 10 R 11 , —NR 12 C(═O)C(═O)OR a , —NR 12 SO 2 R 10 , —NR 12 C(═Y 1 ) (CR 14 R 15 ) n C(═Y 2 )NR 10 R 11 , —NR 12 C(═Y 1 )NR 10 C(═Y 2 )(CR 14 R 15 ) n R 11 , —NR 12 C(═Y 1 ) (CR 14 R 15 ) n C(═Y 2 )(CR 14 R 15 ) m R 10 , —OC(═Y)R 10 , —OC(═Y)OR 10 , —OC(═Y)NR 10 R 11 , —OS(O) 2 (OR 10 ), —OP(═Y)(OR 10 )(OR 11 ), —OP(OR 10 )(OR 11 ), —S(O)R 10 , —S(O) 2 R 10 , —S(O) 2 NR 10 R 11 , —S(O)(OR 10 ), —S(O) 2 (OR 10 ), —SC(═Y)R 10 , —SC(═Y)OR 10 , —SC(═Y)NR 10 R 11 , C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 12  cycloalkyl, C 2 -C 20  heterocyclyl, C 6 -C 20  aryl and C 1 -C 20  heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, OH, C 1 -C 12  alkyl, NR 10 R 11 , and (CR 14 R 15 ) n -aryl; 
 R 4  is H, F, Cl, Br, CF 3 , CN, —C(═Y)R 10 , —C(═Y)OR 10 , —C(═Y)NR 10 R 11 , —NR 10 R 11 , NR 10 C(═Y)R 10 , NR 10 C(═Y)OR 11 , NR 12 C(═Y)NR 10 R 11 , —NR 12 SO 2 NR 10 R 11 , —OR 10 , —OC(═Y)R 10 , —OC(═Y)OR 10 , —OC(═Y)NR 10 R 11 , —C(═O)NR 12 (CR 14 R 15 ) t NR 10 R 11 , —OP(═Y)(OR 10 )(OR 11 ), —OP(OR 10 )(OR 11 ), —SR 10 , —S(O)R 10 , —S(O) 2 R 10 , —S(O) 2 NR 10 R 11 , —SC(═Y)R 10 , —SC(═Y)OR 10 , C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 12  carbocyclyl, C 2 -C 20  heterocyclyl, C 6 -C 20  aryl, or C 1 -C 20  heteroaryl; 
 R 10 , R 11  and R 12  are independently H, C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 12  carbocyclyl, (CR 14 R 15 ) n C 2 -C 20  heterocyclyl, (CR 14 R 15 ) n C 6 -C 20  aryl, or C 1 -C 20  heteroaryl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, SO 2 R c , CN, OR a , NR a R b , C(═O)NR a R b , CR a C(═O)R b , C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 12  carbocyclyl, C 6 -C 20  aryl, and C 1 -C 20  heteroaryl, 
 or R 10  and R 11  together with the nitrogen to which they are attached optionally form a saturated, partially unsaturated or fully unsaturated C 3 -C 20  heterocyclic ring optionally containing one or more additional ring atoms selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, (CH 2 ) n OR a , NR a R b , CF 3 , F, Cl, Br, I, SO 2 R a , C(═O)R a , NR 10 C(═Y)R 11 , C(═Y)NR 10 R 11 , C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 12  cycloalkyl, C 2 -C 20  heterocyclyl, C 6 -C 20  aryl and C 1 -C 20  heteroaryl, 
 or R 10  and R 12  together with the atoms to which they are attached form an oxo-substituted C 3 -C 20  heterocyclic ring optionally fused to a benzene ring; 
 R 13  is H, C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, (CR 14 R 15 ) n -cycloalkyl, (CR 14 R 15 ) n -heterocyclyl, (CR 14 R 15 ) n -aryl, (CR 14 R 15 ) n -heteroaryl, (CR 14 R 15 ) n —O—(CR 14 R 15 ) m -aryl, (CR 14 R 15 ) n —OR 10 , (CR 14 R 15 ) n —NR 10 R 11 , (CR 14 R 15 ) n —NR 10 C(═O)R 11 , or (CR 14 R 15 ) n —NR 10 (SO 2 Me)—R 11 , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and heteroaryl portions are optionally substituted with one or more groups independently selected from F, Cl, Br, I, oxo, SO 2 R c , CN, OR a , C(═O)R a , C(═O)OR a , NR a R b , NR a C(═O)R b , C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 12  cycloalkyl, C 2 -C 20  heterocyclyl, C 6 -C 20  aryl, and C 1 -C 20  heteroaryl; 
 each R 14  and R 15  is independently H, C 1 -C 12  alkyl, or (CH 2 ) t -aryl, 
 or R 14  and R 15  together with the atoms to which they are attached form a saturated or partially unsaturated C 3 -C 12  carbocyclic ring, 
 or R 10  and R 15  together with the atoms to which they are attached form an oxo-substituted saturated or partially unsaturated monocyclic or bicyclic C 1 -C 20  heterocyclic ring optionally further substituted with one or more groups independently selected from F, Cl, Br, I, OR a , C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 12  cycloalkyl, C 2 -C 20  heterocyclyl, C 6 -C 20  aryl, or C 1 -C 20  heteroaryl, wherein said alkyl and aryl are optionally substituted with one or more groups independently selected from F, Cl, Br, and I, 
 or R 14  is null and R 10  and R 15  together with the atoms to which they are attached form a C 1 -C 20  heteroaryl ring having one or more heteroatoms; 
 R a  and R b  are independently H, C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 12  carbocyclyl, C 2 -C 20  heterocyclyl, C 6 -C 20  aryl, or C 1 -C 20  heteroaryl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more alkyl groups; 
 R c  is C 1 -C 12  alkyl or C 6 -C 20  aryl, wherein said alkyl and aryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR a  and C(═O)NR a R b ; 
 R x  is H or C 1 -C 6  alkyl; 
 R y  is (i) (C 1 -C 6  alkyl)NR j R k  wherein R j  and R k  are independently H or C 1 -C 6  alkyl; (ii) C 5 -C 6  cycloalkyl optionally substituted with OH or —OC(═O)CF 3 ; or (iii) a 5-6 membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O and optionally substituted with a halogen group, C 1 -C 6  alkyl, (C 1 -C 6  alkyl)OH, (C 1 -C 6  alkyl)O(C 1 -C 6  alkyl), or C 1 -C 6  fluoroalkyl; 
 Y, Y 1  and Y 2  are independently O or S; 
 t is 1, 2, 3, 4, 5 or 6; and 
 n and m are independently 0, 1, 2, 3, 4, 5 or 6. 
 
     
     
         2 - 73 . (canceled)