Imidazopyrazine Tyrosine Kinase Inhibitors

Abstract

Compounds of the formula and pharmaceutically acceptable salts thereof, wherein Q 1 and R 1 are defined herein, inhibit the IGF-1R enzyme and are useful for the treatment and/or prevention of various diseases and conditions that respond to treatment by inhibition of tyrosine kinases.

1 . A compound represented by Formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 Q 1  is aryl 1 , heteroaryl 1 , cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which is optionally substituted by one to five independent G 1  substituents; 
 R 1  is alkyl, cycloalkyl, bicycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, or heterobicycloalkyl, any of which is optionally substituted by one or more independent G 11  substituents; 
 G 1  and G 41  are each independently halo, oxo, —CF 3 , —OCF 3 , —OR 2 , —NR 2 R 3 (R 3a ) j1 , —C(O)R 2 , —CO 2 R 2 , —CONR 2 R 3 , —NO 2 , —CN, —S(O) j1 R 2 , —SO 2 NR 2 R 3 , NR 2 (C═O)R 3 , NR 2 (C═O)OR 3 , NR 2 (C═O)NR 2 R 3 , NR 2 S(O) j1 R 3 , —(C═S)OR 2 , —(C═O)SR 2 , —NR 2 (C═NR 3 )NR 2a R 3a , —NR 2 (C═NR 3 )OR 2a , —NR 2 (C═NR 3 )SR 3a , —O(C═O)R 2 , —O(C═O)NR 2 R 3 , —O(C═O)SR 2 , —S(C═O)OR 2 , —S(C═O)NR 2 R 3 , C 0-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyC 1-10 alkyl, C 1-10 alkoxyC 2-10 alkenyl, C 1-10 alkoxyC 2-10 alkynyl, C 1-10 alkylthioC 1-10 alkyl, C 1-10 alkylthioC 2-10 alkenyl, C 1-10 alkylthioC 2-10 alkynyl, cycloC 3-8 alkyl, cycloC 3-8 alkenyl, cycloC 3-8 alkylC 1-10 alkyl, cycloC 3-8 alkenylC 1-10 alkyl, cycloC 3-8 alkylC 2-10 alkenyl, cycloC 3-8 alkenylC 2-10 alkenyl, cycloC 3-8 alkylC 2-10 alkynyl, cycloC 3-8 alkenylC 2-10 alkynyl, heterocyclyl-C 0-10 alkyl, heterocyclyl-C 2-10 alkenyl, or heterocyclyl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, oxo, —CF 3 , —OCF 3 , —OR 222 , —NR 222 R 333 (R 333a ) j1a , —C(O)R 222 , —CO 2 R 222 , —CONR 222 R 333 , —NO 2 , —CN, —S(O) j1a R 222 , —SO 2 NR 222 R 333 , NR 222 (C═O)R 333 , NR 222 (C═O)OR 333 , NR 222 (C═O)NR 222 R 333 , NR 222 S(O) j1a R 333 , —(C═S)OR 222 , —(C═O)SR 222 , —NR 222 (C═NR 333 )NR 222a R 333a , —NR 222 (C═NR 333 )OR 222a , —NR 222 (C═N 333 )SR 333a , —O(C═O)OR 222 , —O(C═O)NR 222 R 333 , —O(C═O)SR 222 , —S(C═O)OR 222 , or —S(C═O)NR 222 R 333  substituents; or —(X 1 ) n —(Y 1 ) m —R 4 ; or aryl-C 0-10 alkyl, aryl-C 2-10 alkenyl, or aryl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, —CF 3 , —OCF 3 , —OR 222 , —NR 222 R 333 (R 333a ) j2a , —C(O)R 222 , —CO 2 R 222 , —CONR 222 R 333 , —NO 2 , —CN, —S(O) j2a R 222 , —SO 2 NR 222 R 333 , NR 222 (C═O)R 333 , NR 222 (C═O)OR 333 , NR 222 (C═O)NR 222 R 333 , NR 222 S(O) j2a R 333 , —(C═S)OR 222 , —(C═O)SR 222 , —NR 222 (C═NR 333 )NR 222a R 333a , —NR 222 (C═N 333 )OR 222a , —NR 222 (C═NR 333 )SR 333a , —O(C═O)OR 222 , —O(C═O)NR 222 R 333 , —O(C═O)SR 222 , —S(C═O)OR 222 , or —S(C═O)NR 222 R 333  substituents; or hetaryl-C 0-10 alkyl, hetaryl-C 2-10 alkenyl, or hetaryl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, —CF 3 , —OCF 3 , —OR 222 , —NR 222 R 333 (R 333a ) j3a , —C(O)R 222 , —CO 2 R 222 , —CONR 222 R 333 , —NO 2 , —CN, —S(O) j3a R 222 , —SO 2 NR 222 R 333 , NR 222 (C═O)R 333 , NR 222 (C═O)OR 333 , NR 222 (C═O)NR 222 R 333 , NR 222 S(O) j3a R 333 , —(C═S)OR 222 , —(C═O)SR 222 , —NR 222 (C═N 333 )NR 222a R 333a , —NR 222 (C═NR 333 )OR 222a , —NR 222 (CNR 333 )SR 333a , —O(C═O)OR 222 , —O(C═O)NR 222 R 333 , —O(C═O)SR 222 S(C═O)OR 222 , or S(C═)NR 222 R 333  substituents; 
 G 11  is halo, oxo, —CF 3 , —OCF 3 , —OR 21 , —NR 21 R 31 (R 3a1 ) j4 , —C(O)R 21 , —CO 2 R 21 , —CONR 21 R 31 , —NO 2 , —CN, —S(O) j4 R 21 , —SO 2 NR 21 R 31 , NR 21 (C═O)R 31 , NR 21 (C═O)OR 31 , NR 21 (C═O)NR 21 R 31 , NR 21 S(O) j4 R 31 , —(C═S)OR 21 , —(C═O)SR 21 , —NR 21 (C═NR 31 )NR 2a1 R 3a1 , —NR 21 (C═NR 31 )OR 2a1 , —NR 21 (C═NR 31 )SR 3a1 , —O(C═O)OR 21 , —O(C═O)NR 21 R 31 , —O(C═O)SR 21 , —S(C═O)OR 21 , —S(C═O)NR 21 R 31 , —P(O)OR 21 OR 31 , C 0-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyC 1-10 alkyl, C 1-10 alkoxyC 2-10 alkenyl, C 1-10 alkoxyC 2-10 alkynyl, C 1-10 alkylthioC 1-10 alkyl, C 1-10 alkylthioC 2-10 alkenyl, C 1-10 alkylthioC 2-10 alkynyl, cycloC 3-8 alkyl, cycloC 3-8 alkenyl, cycloC 3-8 alkylC 1-10 alkyl, cycloC 3-8 alkenylC 1-10 alkyl, cycloC 3-8 alkylC 2-10 alkenyl, cycloC 3-8 alkenylC 2-10 alkenyl, cycloC 3-8 alkylC 2-10 alkynyl, cycloC 3-8 alkenylC 2-10 alkynyl, heterocyclyl-C 0-10 alkyl, heterocyclyl-C 2-10 alkenyl, or heterocyclyl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, oxo, —CF 3 , —OCF 3 , —OR 2221 , —NR 2221 R 3331 (R 333a1 ) j4a , —C(O)R 2221 , —CO 2 R 2221 , —CONR 2221 R 3331 , —NO 2 , —CN, —S(O) j4a R 2221 , —SO 2 NR 2221 R 3331 , NR 2221 (C═O)R 3331 , NR 2221 (C═O)OR 3331 , NR 2221 (C═O)NR 2221 R 3331 , NR 2221 S(O) j4a R 3331 , —(C═O)SR 2221 , —NR 2221 (C═NR 3331 )NR 222a1 R 333a1 , —NR 2221 (C═NR 3331 )OR 222a1 , —NR 2221 (C═NR 3331 )SR 333a1 , —O(C═O)OR 2221 , —O(C═O)NR 2221 R 3331 , —O(C═O)SR 2221 , —S(C═O)OR 2221 , —P(O)OR 2220 R 333 , or —S(C═O)NR 222 R 331  substituents; or aryl-C 0-10 alkyl, aryl-C 2-10 alkenyl, or aryl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, —CF 3 , —OCF 3 , —OR 2221 , —NR 2221 R 3331 (R 333a1 ) j5a , —C(O)R 2221 , —CO 2 R 2221 , —CONR 2221 R 3331 , —NO 2 , —CN, —S(O) j5a R 2221 , —SO 2 NR 2221 R 3331 , NR 2221 (C═O)R 3331 , NR 2221 (C═O)OR 3331 , NR 2221 (C═O)NR 2221 R 3331 , NR 2221 S(O) j5a R 3331 , —(C═S)OR 2221 , —(C═O)SR 2221 , —NR 2221 (C═NR 3331 )NR 222a1 R 333a1 , —NR 2221 (C═NR 3331 )OR 222a1 , —NR 2221 (C═NR 3331 )SR 333a1 , —O(C═O)OR 2221 , —O(C═O)NR 2221 R 3331 , —O(C═O)SR 2221 , —S(C═O)OR 2221 , —P(O)OR 2221 R 3331 , or —S(C═O)NR 2221 R 3331  substituents; or hetaryl-C 0-10 alkyl, hetaryl-C 2-10 alkenyl, or hetaryl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, —CF 3 , —OCF 3 , —OR 2221 , —NR 2221 R 3331 (R 333a1 ) j6a , —C(O)R 2221 , —CO 2 R 2221 , —CONR 2221 R 3331 , —NO 2 , —CN, —S(O) j6a R 2221 , —SO 2 NR 2221 R 3331 , NR 2221 (C═O)R 3331 , NR 2221 (C═O)OR 3331 , NR 2221 (C═O)NR 2221 R 3331 , NR 2221 S(O) j6a R 3331 , —(C═S)OR 2221 , —(C═O)SR 2221 , —NR 2221 (C═NR 3331 )NR 222a1 R 333a1 , —NR 2221 (C═NR 3331 )OR 222a1 , —NR 2221 (C═NR 3331 )SR 333a1 , —O(C═O)OR 2221 , —O(C═O)NR 2221 R 3331 , —O(C═O)SR 2221 , —S(C═O)OR 2221 , —P(O)OR 2221 R 3331 , or —S(C═O)NR 2221 R 3331  substituents; or G 11  is taken together with the carbon to which it is attached to form a double bond which is substituted with R 5  and G 111 ; 
 R 2 R 2a , R 3 , R 3a , R 222 , R 222a R 333 , R 333a , R 21 , R 2a1 , R 31 , R 3a1 , R 2221 R 222a1 , R 3331  and R 333a1  are each independently equal to C 0-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyC 1-10 alkyl, C 1-10 alkoxyC 2-10 alkenyl, C 1-10 alkoxyC 2-10 alkynyl, C 1-10 alkylthioC 1-10 alkyl, C 1-10 alkylthioC 2-10 alkenyl, C 1-10 alkylthioC 2-10 alkynyl, cycloC 3-8 alkyl, cycloC 3-8 alkenyl, cycloC 3-8 alkylC 1-10 alkyl, cycloC 3-8 alkenylC 1-10 alkyl, cycloC 3-8 alkylC 2-10 alkenyl, cycloC 3-8 alkenylC 2-10 alkenyl, cycloC 3-8 alkylC 2-10 alkynyl, cycloC 3-8 alkenylC 2-10 alkynyl, heterocyclyl-C 0-10 alkyl, heterocyclyl-C 2-10 alkenyl, or heterocyclyl-C 2-10 alkynyl, any of which is optionally substituted by one or more G 111  substituents; or aryl-C 0-10 alkyl, aryl-C 2-10 alkenyl, or aryl-C 2-10 alkynyl, hetaryl-C 0-10 alkyl, hetaryl-C 2-10 alkenyl, or hetaryl-C 2-10 alkynyl, any of which is optionally substituted by one or more G 111  substituents; or in the case of —NR 2 R 3 (R 3a ) j1  or —NR 222 R 333 (R 333a ) j1a  or —NR 222 R 333 (R 333a ) j2a  or —NR 2221 R 3331 (R 333a1 ) j3a  or —NR 2221 R 3331 (R 333a1 ) j4a  or —NR 2221 R 3331 (R 333a1 ) or NR 2221 R 3331 (R 333a1 ) j6a , R 2  and R 3  or R 222  and R 333  or R 2221  and R 3331  taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted by one or more G 111  substituents; 
 X 1  and Y 1  are each independently —O—, —NR 7 —, —S(O) j7 —, —CR 5 R 6 —, —N(C(O)OR 7 )—, —N(C(O)R 7 )—, —N(SO 2 R 7 )—, —CH 2 O—, —CH 2 S—, —CH 2 N(R 7 )—, —CH(NR 7 )—, —CH 2 N(C(O)R 7 )—, —CH 2 N(C(O)OR 7 )—, —CH 2 N(SO 2 R 7 )—, —CH(NHR 7 )—, —CH(NHC(O)R 7 )—, —CH(NHSO 2 R 7 )—, —CH(NHC(O)OR 7 )—, —CH(OC(O)R 7 )—, —CH(OC(O)NHR 7 )—, —CH═CH—, —C≡C—, —C(═NOR 7 )—, —C(O)—, —CH(OR 7 )—, —C(O)N(R 7 )—, —N(R 7 )C(O)—, —N(R 7 )S(O)—, —N(R 7 )S(O) 2 — —OC(O)N(R 7 )—, —N(R 7 )C(O)N(R 7 )—, —NR 7 C(O)O—, —S(O)N(R 7 )—, —S(O) 2 N(R 7 )—, —N(C(O)R 7 )S(O)—, —N(C(O)R 7 )S(O) 2 —, —N(R 7 )S(O)N(R 7 )—, —N(R 7 )S(O) 2 N(R 7 )—, —C(O)N(R 7 )C(O)—, —S(O)N(R 7 )C(O)—, —S(O) 2 N(R 7 )C(O)—, —OS(O)N(R 7 )—, —OS(O) 2 N(R 7 )—, —N(R 7 )S(O)O—, —N(R 7 )S(O) 2 O—, —N(R 7 )S(O)C(O)—, —N(R 7 )S(O) 2 C(O)—, —SON(C(O)R 7 )—, —SO 2 N(C(O)R 7 )—, —N(R 7 )SON(R 7 )—, —N(R 7 )SO 2 N(R 7 )—, —C(O)O—, —N(R 7 )P(OR 8 )O—, —N(R 7 )P(OR 8 )—, —N(R 7 )P(O)(OR 8 )O—, —N(R 7 )P(O)(OR 8 )—, —N(C(O)R 7 )P(OR 8 )O—, —N(C(O)R 7 )P(OR 8 )—, —N(C(O)R 7 )P(O)(OR 8 )O—, —N(C(O)R 7 )P(OR 8 )—, —CH(R 7 )S(O)—, —CH(R 7 )S(O) 2 —, —CH(R 7 )N(C(O)OR 7 )—, —CH(R 7 )N(C(O)R 7 )—, —CH(R 7 )N(SO 2 R 7 )—, —CH(R 7 )O—, —CH(R 7 )S—, —CH(R 7 )N(R 7 )—, —CH(R 7 )N(C(O)R 7 )—, —CH(R 7 )N(C(O)OR 7 )—, —CH(R 7 )N(SO 2 R 7 )—, —CH(R 7 )C(═NOR 7 )—, —CH(R 7 )C(O)—, —CH(R 7 )CH(OR 7 )—, —CH(R 7 )C(O)N(R 7 )—, —CH(R 7 )N(R 7 )C(O)—, —CH(R 7 )N(R 7 )S(O)—, —CH(R 7 )N(R 7 )S(O) 2 —, —CH(R 7 )OC(O)N(R 7 )—, —CH(R 7 )N(R 7 )C(O)N(R 7 )—, —CH(R 7 )NR 7 C(O)O—, —CH(R 7 )S(O)N(R 7 )—, —CH(R 7 )S(O) 2 N(R 7 )—, —CH(R 7 )N(C(O)R 7 )S(O)—, —CH(R 7 )N(C(O)R 7 )S(O)—, —CH(R 7 )N(R 7 )S(O)N(R 7 )—, —CH(R 7 )N(R 7 )S(O) 2 N(R 7 )—, —CH(R 7 )C(O)N(R 7 )C(O)—, —CH(R 7 )S(O)N(R 7 )C(O)—, —CH(R 7 )S(O) 2 N(R 7 )C(O)—, —CH(R 7 )OS(O)N(R 7 )—, —CH(R 7 )OS(O) 2 N(R 7 )—, —CH(R 7 )N(R 7 )S(O)O—, —CH(R 7 )N(R 7 )S(O) 2 O—, —CH(R 7 )N(R 7 )S(O)C(O)—, —CH(R 7 )N(R 7 )S(O) 2 C(O)—, —CH(R 7 )SON(C(O)R 7 )—, —CH(R 7 )SO 2 N(C(O)R 7 )—, —CH(R 7 )N(R 7 )SON(R 7 )—, —CH(R 7 )N(R 7 )SO 2 N(R 7 )—, —CH(R 7 )C(O)O—, —CH(R 7 )N(R 7 )P(OR 8 )O—, —CH(R 7 )N(R 7 )P(OR 8 )—, —CH(R 7 )N(R 7 )P(O)(OR 8 )O—, —CH(R 7 )N(R 7 )P(O)(OR 8 )—, —CH(R 7 )N(C(O)R 7 )P(OR 8 )O—, —CH(R 7 )N(C(O)R 7 )P(OR 8 )—, —CH(R 7 )N(C(O)R 7 )P(O)(OR 8 )O—, or —CH(R 7 )N(C(O)R 7 )P(OR 8 )—; 
 or X 1  and Y 1  are each independently represented by one of the following structural formulas: 
 
     
       
         
         
             
             
         
       
       R 10 , taken together with the phosphinamide or phosphonamide, is a 5-, 6-, or 7-membered aryl, heteroaryl or heterocyclyl ring system; 
       R 5 , R 6 , and G 111  are each independently a C 0-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyC 1-10 alkyl, C 1-10 alkoxyC 2-10 alkenyl, C 1-10 alkoxyC 2-10 alkynyl, C 1-10 alkylthioC 1-10 alkyl, C 1-10 alkylthioC 2-10 alkenyl, C 1-10 alkylthioC 2-10 alkynyl, cycloC 3-8 alkyl, cycloC 3-8 alkenyl, cycloC 3-8 alkylC 1-10 alkyl, cycloC 3-8 alkenylC 1-10 alkyl, cycloC 3-8 alkylC 2-10 alkenyl, cycloC 3-8 alkenylC 2-10 alkenyl, cycloC 3-8 alkylC 2-10 alkynyl, cycloC 3-8 alkenylC 2-10 alkynyl, heterocyclyl-C 0-10 alkyl, heterocyclyl-C 2-10 alkenyl, or heterocyclyl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, —CF 3 , —OCF 3 , —OR 77 , —NR 77 R 87 , —C(O)R 77 , —CO 2 R 77 , —CONR 77 R 87 , —NO 2 , —CN, —S(O) j5a R 77 , —SO 2 NR 77 R 87 , NR 77 (C═O)R 87 , NR 77 (C═O)OR 87 , NR 77  (C═O)NR 78 R 87 , NR 77 S(O) j5a R 87 , —(C═S)OR 77 , —(C═O)SR 77 , —NR 77 (C═NR 87 )NR 78 R 88 , —NR 77 (C═NR 87 )OR 78 , —NR 77 (C═NR 87 )SR 78 , —O(C═O)OR 77 , —O(C═O)NR 77 R 87 , —O(C═O)SR 77 , —S(C═O)OR 77 , —P(O)OR 77 OR 87 , or —S(C═O)NR 77 R 87  substituents; or aryl-C 0-10 alkyl, aryl-C 2-10 alkenyl, or aryl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, —CF 3 , —OCF 3 , —OR 77 , —NR 77 R 87 , —C(O)R 77 , —CO 2 R 77 , —CONR 77 R 87 , —NO 2 , —CN, —S(O) j5a R 77 , —SO 2 NR 77 R 87 , NR 77 (C═O)R 87 , NR 77 (C═O)OR 87 , NR 77 (C═O)NR 78 R 87 , NR 77 S(O) j5a R 87 , —(C═S)OR 77 , —(C═O)SR 77 , —NR 77 (C═NR 87 )NR 78 R 88 , —NR 77 (C═NR 87 )OR 78 , —NR 77 (C═NR 87 )SR 78 , —O(C═O)OR 77 , —O(C═O)NR 77 R 87 , —O(C═O)SR 77 , —S(C═O)OR 77 , —P(O)OR 77 OR 87 , or —S(C═O)NR 77 R 87  substituents; or hetaryl-C 0-10 alkyl, hetaryl-C 2-10 alkenyl, or hetaryl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, —CF 3 , —OCF 3 , —OR 77 , —NR 77 R 87 , —C(O)R 77 , —CO 2 R 77 , —CONR 77 R 87 , —NO 2 , —CN, —S(O) j5a R 77 , —SO 2 NR 77 R 87 , NR 77 (C═O)R 87 , NR 77 (C═O)OR 87 , NR 77 (C═O)NR 78 R 87 , NR 77 S(O) j5a R 87 , —(C═S)OR 77 , —(C═O)SR 77 , —NR 77 (C═NR 87 )NR 78 R 88 , —NR 77 (C═NR 87 )OR 78 , —NR 77 (C═NR 87 )SR 78 , —O(C═O)OR 77 , —O(C═O)NR 77 R 87 , —O(C═O)SR 77 , —S(C═O)OR 77 , —P(O)OR 77 OR 87 , or —S(C═O)NR 77 R 87  substituents; or R 5  with R 6  taken together with the respective carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted with R 69 ; or R 5  with R 6  taken together with the respective carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated heterocyclic ring, wherein said ring is optionally substituted with R 69 ; 
       R 7  and R 8  are each independently H, acyl, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl or cycloalkyl, any of which is optionally substituted by one or more G 111  substituents; 
       R 4  is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which is optionally substituted by one or more G 41  substituents; 
       R 69  is equal to halo, —OR 78 , —SH, —NR 78 R 88 , —CO 2 R 78 , —CONR 78 R 88 , —NO 2 , —CN, —S(O) j8 R 78 , —SO 2 NR 78 R 88 , C 0-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyC 1-10 alkyl, C 1-10 alkoxyC 2-10 alkenyl, C 1-10 alkoxyC 2-10 alkynyl, C 1-10 alkylthioC 1-10 alkyl, C 1-10 alkylthioC 2-10 alkenyl, C 1-10 alkylthioC 2-10 alkynyl, cycloC 3-8 alkyl, cycloC 3-8 alkenyl, cycloC 3-8 alkylC 1-10 alkyl, cycloC 3-8 alkenylC 1-10 alkyl, cycloC 3-8 alkylC 2-10 alkenyl, cycloC 3-8 alkenylC 2-10 alkenyl, cycloC 3-8 alkylC 2-10 alkynyl, cycloC 3-8 alkenylC 2-10 alkynyl, heterocyclyl-C 0-10 alkyl, heterocyclyl-C 2-10 alkenyl, or heterocyclyl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, —OR 778 , —SO 2 NR 778 R 888 , or —NR 778 R 888  substituents; or aryl-C 0-10 alkyl, aryl-C 2-10 alkenyl, or aryl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, —OR 778 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, haloC 1-10 alkyl, haloC 2-10 alkenyl, haloC 2-10 alkynyl, —COOH, C 1-4 alkoxycarbonyl, —CONR 778 R 888 , —SO 2 NR 778 R 888 , or —NR 778 R 888  substituents; or hetaryl-C 0-10 alkyl, hetaryl-C 2-10 alkenyl, or hetaryl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, —OR 778 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, haloC 1-10 alkyl, haloC 2-10 alkenyl, haloC 2-10 alkynyl, —COOH, C 1-4 alkoxycarbonyl, —CONR 778 R 888 , —SO 2 NR 778 R 888 , or —NR 778 R 888  substituents; or mono(C 1-6 alkyl)aminoC 1-6 alkyl, di(C 1-6 alkyl)aminoC 1-6 alkyl, mono(aryl)aminoC 1-6 alkyl, di(aryl)aminoC 1-6 alkyl, or —N(C 1-6 alkyl)-C 1-6 alkyl-aryl, any of which is optionally substituted with one or more independent halo, cyano, nitro, —OR 778 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, haloC 1-10 alkyl, haloC 2-10 alkenyl, haloC 2-10 alkynyl, —COOH, C 1-4 alkoxycarbonyl, —CONR 778 R 888 , —SO 2 NR 778 R 888 , or —NR 778 R 888  substituents; or in the case of —NR 78 R 88 , R 78  and R 88  taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C 1-10 alkoxy, —SO 2 NR 778 R 888 , or —NR 778 R 888  substituents; 
       R 77 , R 78 , R 87 , R 88 , R 778 , and R 888  are each independently C 0-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyC 1-10 alkyl, C 1-10 alkoxyC 2-10 alkenyl, C 1-10 alkoxyC 2-10 alkynyl, C 1-10 alkylthioC 1-10 alkyl, C 1-10 alkylthioC 2-10 alkenyl, C 1-10 alkylthioC 2-10 alkynyl, cycloC 3-8 alkyl, cycloC 3-8 alkenyl, cycloC 3-8 alkylC 1-10 alkyl, cycloC 3-8 alkenylC 1-10 alkyl, cycloC 3-8 alkylC 2-10 alkenyl, cycloC 3-8 alkenylC 2-10 alkenyl, cycloC 3-8 alkylC 2-10 alkynyl, cycloC 3-8 alkenylC 2-10 alkynyl, heterocyclyl-C 0-10 alkyl, heterocyclyl-C 2-10 alkenyl, heterocyclyl-C 2-10 alkynyl, C 1-10 alkylcarbonyl, C 2-10 alkenylcarbonyl, C 2-10 alkynylcarbonyl, C 1-10 alkoxycarbonyl, C 1-10 alkoxycarbonylC 1-10 alkyl, monoC 1-6 alkylaminocarbonyl, diC 1-6 alkylaminocarbonyl, mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or C 1-10 alkyl(aryl)aminocarbonyl, any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C 1-10 alkoxy, —SO 2 N(C 0-4 alkyl)(C 0-4 alkyl), or —N(C 0-4 alkyl)(C 0-4 alkyl) substituents; or aryl-C 0-10 alkyl, aryl-C 2-10 alkenyl, or aryl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, —O(C 0-4 alkyl), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, haloC 1-10 alkyl, haloC 2-10 alkenyl, haloC 2-10 alkynyl, —COOH, C 1-4 alkoxycarbonyl, —CON(C 0-4 alkyl)(C 0-10 alkyl), —SO 2 N(C 0-4 alkyl)(C 0-4 alkyl), or —N(C 0-4 alkyl)(C 0-4 alkyl) substituents; or hetaryl-C 0-10 alkyl, hetaryl-C 2-10 alkenyl, or hetaryl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, —O(C 0-4 alkyl), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, haloC 1-10 alkyl, haloC 2-10 alkenyl, haloC 2-10 alkynyl, —COOH, C 1-4 alkoxycarbonyl, —CON(C 0-4 alkyl)(C 0-4 alkyl), —SO 2 N(C 0-4 alkyl)(C 0-4 alkyl), or —N(C 0-4 alkyl)(C 0-4 alkyl) substituents; or mono(C 1-6 alkyl)aminoC 1-6 alkyl, di(C 1-6 alkyl)aminoC 1-6 alkyl, mono(aryl)aminoC 1-6 alkyl, di(aryl)aminoC 1-6 alkyl, or —N(C 1-6 alkyl)-C 1-6 alkyl-aryl, any of which is optionally substituted with one or more independent halo, cyano, nitro, —O(C 0-4 alkyl), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, haloC 1-10 alkyl, haloC 2-10 alkenyl, haloC 2-10 alkynyl, —COOH, C 1-4 alkoxycarbonyl, —CON(C 0-4 alkyl)(C 0-4 alkyl), —SO 2 N(C 0-4 alkyl)(C 0-4 alkyl), or —N(C 0-4 alkyl)(C 0-4 alkyl) substituents; and 
       n, m, j1, j1a, j2a, j3a, j4, j4a, j5a, j6a, j7, and j8 are each independently equal to 0, 1, or 2. 
     
   
   
       2 - 59 . (canceled) 
   
   
       60 . A method of inhibiting protein kinase activity comprising administering a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       61 . The method of  claim 60  wherein said protein kinase is IGF-1R. 
   
   
       62 . The method of  claim 60  wherein the activity of said protein kinase affects hyperproliferative disorders. 
   
   
       63 . The method of  claim 60  wherein the activity of said protein kinase influences angiogenesis, vascular permeability, immune response, cellular apoptosis, tumor growth, or inflammation. 
   
   
       64 . A method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       65 . The method of  claim 64  wherein said protein kinase is IGF-1R. 
   
   
       66 . The method of  claim 64  wherein the condition mediated by protein kinase activity is a hyperproliferative disorder. 
   
   
       67 . The method of  claim 64  wherein the activity of said protein kinase influences angiogenesis, vascular permeability, immune response, cellular apoptosis, tumor growth, or inflammation. 
   
   
       68 . The method of  claim 64  wherein the protein kinase is a protein serine/threonine kinase or a protein tyrosine kinase. 
   
   
       69 . The method of  claim 64  wherein the condition mediated by protein kinase activity is one or more ulcers. 
   
   
       70 . The method of  claim 69  wherein the ulcer or ulcers are caused by a bacterial or fungal infection; or the ulcer or ulcers are Mooren ulcers; or the ulcer or ulcers are a symptom of ulcerative colitis. 
   
   
       71 . The method of  claim 64  wherein the condition mediated by protein kinase activity is Lyme disease, sepsis or infection by Herpes simplex, Herpes Zoster, human immunodeficiency virus, parapoxvirus, protozoa, or toxoplasmosis. 
   
   
       72 . The method of  claim 64  wherein the condition mediated by protein kinase activity is von Hippel Lindau disease, pemphigoid, psoriasis, Paget's disease, or polycystic kidney disease. 
   
   
       73 . The method of  claim 64  wherein the condition mediated by protein kinase activity is fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, asthma, exudtaes, ascites, pleural effusions, pulmonary edema, cerebral edema or edema following burns, trauma, radiation, stroke, hypoxia, or ischemia. 
   
   
       74 . The method of  claim 64  wherein the condition mediated by protein kinase activity is ovarian hyperstimulation syndrome, preeclainpsia, menometrorrhagia, or endometriosis. 
   
   
       75 . The method of  claim 64  wherein the condition mediated by protein kinase-activity is chronic inflammation, systemic lupus, glomerulonephritis, synovitis, inflammatory bowel disease, Crohn's disease, glomerulonephritis, rheumatoid arthritis and osteoarthritis, multiple sclerosis, or graft rejection. 
   
   
       76 . The method of  claim 64  wherein the condition mediated by protein kinase activity is sickle cell anaemia. 
   
   
       77 . The method of  claim 64  wherein the condition mediated by protein kinase activity is an ocular condition. 
   
   
       78 . The method of  claim 77  wherein the ocular condition is ocular or macular edema, ocular neovascular disease, seleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser treatment complications, conjunctivitis, Stargardt's disease, Eales disease, retinopathy, or macular degeneration. 
   
   
       79 - 100 . (canceled)