4-substituted aminoisoquinoline derivatives

Abstract

This invention relates to 4-substituted isoquinoline compounds and their derivatives and uses thereof for treatment of cancer, for example, acute myeloid leukemia.

1 . A compound represented by a compound of formula (IV) 
       
         
           
           
               
               
           
         
       
       wherein
 W is NR′, alkene, alkyne, C 1-8  alkyl, heteroalkyl containing 1-8 carbon and hetero atoms, cycloalkyl, hetereocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, hetereocycloalkyl, aryl, and heteroaryl optionally form a fused aryl or heteroaryl group with Ring A; 
 U, Y, and Z are each N or CR 6 , wherein R 6  is H or NR a R b ; 
 R 7  and R 8  are each independently H, alkyl, alkenyl, alkynyl, halo, nitro, OR c , SR c , CN, haloalkyl, O-haloalkyl, (CO)R d , NR a R b , NH(CO)R d , NH(CO)OR c , NH(CO)NR a R b , (CO)OR c , (CO)NR a R b , SO 2 NR a R b , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; 
 or R 7  and R 8 , together with the carbon atoms to which they are attached, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each optionally substituted with substituents independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, halo, nitro, OR c , SR c , CN, haloalkyl, O-haloalkyl, NR a R b , (CO)R d , (CO)OR c , (CO)NR a R b , SO 2 NR a R b , and —C(CH 3 )(═N—NHC(NH)NH 2 ; 
 Ring A is a 5- or 6-membered aryl or heteroaryl group, wherein Ring A is optionally substituted with substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halo, nitro, OR c , SR c , CN, haloalkyl, O-haloalkyl, NR m R n , (CO)R d , (CO)OR c , SO 2 NR m R n , (CO)NR m R n , C(NH)NR m R n , NH(CO)R d , NH(CO)OR c , NH(CO)NR m R n , aryl, and heteroaryl; 
 R m  and R n  are each independently 
 H, OH, 
 alkyl, —(CH 2 ) p -T, -aryl-(CH 2 ) p -T, —(CH 2 ) p -aryl-T, -heteroaryl-(CH 2 ) p -T, —(CH 2 ) p -heteroaryl-T, each optionally substituted with alkyl, halo, nitro, CN, haloalkyl, O-haloalkyl, OR c , SR c , NR a R b , (CO)R d , NH(CO)R d , NH(CO)OR c , NH(CO)NR a R b , NHC(NH)NH 2 , (CO)OR c , (CO)NR a R b , SO 2 NR a R b , arylamino, or heteroarylamino, 
 or R m  and R n , together with the nitrogen atom they are attached, form a heterocycloalkyl group, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, nitro, CN, OR c , SR c , COR d , NR a R b , NH(CO)R d , NH(CO)OR c , NH(CO)NR a R b , a guanidine group, (CO)OR c , or (CO)NR a R b ; 
 T is NR a R b , OR c , SR c , O—(CH 2 ) q —NR a R b , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, a guanidine group, or an isonicotinimidamide group; 
 R′ is H, alkyl, or cycloalkyl; 
 R a , R b , R c , and R d  are each independently H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —(CH 2 ) q -cycloalkyl, —(CH) q -heterocycloalkyl, —(CH 2 ) q -aryl, —(CH) q -heteroaryl, —(CO)-alkyl, —(CO)-cycloalkyl, —(CO)-heterocycloalkyl, —(SO 2 )-alkyl, —(SO 2 )-cycloalkyl, or —(SO 2 )-heterocycloalkyl, or R a  and R b , together with the nitrogen atom to which they are attached, form a heterocycloalkyl group, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optioncally substituted with a group consisting of alkyl, halo, nitro, CN, haloalkyl, O-haloalkyl, OH, O-alkyl, SH, S-alkyl, NH 2 , NH(alkyl), and N(alkyl) 2 ; and 
 p and q are each independently 0-8; 
 
       or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer thereof. 
     
     
         2 . The compound of  claim 1 , wherein said compound of formula (IV) is represented by a compound of formula (V) 
       
         
           
           
               
               
           
         
       
       wherein
 W is NR′, —C≡C—, or a heterocycloalkyl group containing a 5- or 6-membered ring, wherein R′ is H or alkyl; 
 U, Y, and Z are each N or CR 6 , wherein R 6  is H or NR a R b ; 
 V, U 1 , Y 1 , and Z 1  are each N or CR 6 ′; 
 R 1 , R 2 , and R 6 ′ are each independently H, alkyl, cycloalkyl, halo, nitro, OR c , SR c , CN, haloalkyl, O-haloalkyl, or NR a R b ; 
 R 3 , R 4 , and R 5  are each independently H, alkyl, cycloalkyl, heterocycloalkyl, halo, nitro, OR c , SR c , CN, haloalkyl, O-haloalkyl, NR m R n , (CO)R d , (CO)OR c , SO 2 NR m R n , (CO)NR m R n , C(NH)NR m R n , NH(CO)R d , NH(CO)OR c , NH(CO)NR m R n , aryl, or heteroaryl; 
 R m  and R n  are each independently 
 H, OH, 
 alkyl, —(CH 2 ) p -T, -aryl-(CH 2 ) p -T, —(CH 2 ) p -aryl-T, -heteroaryl-(CH 2 ) p -T, —(CH 2 ) p -heteroaryl-T, each optionally substituted with alkyl, cycloalkyl, halo, nitro, CN, haloalkyl, O-haloalkyl, OR c , SR c , (CO)R d , NR a R b , NH(CO)R d , NH(CO)OR c , NH(CO)NR a R b , NHC(NH)NH 2 , (CO)OR c , (CO)NR a R b , and SO 2 NR a R b , 
 or R m  and R n , together with the nitrogen atom they are attached, form a heterocycloalkyl group, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, nitro, CN, OR c , SR c , COR d , NR a R b , NH(CO)R d , NH(CO)OR c , NH(CO)NR a R b , a guanidine group, (CO)OR c , and (CO)NR a R b ; 
 T is NR a R b , OR c , SR c , O—(CH 2 ) q —NR a R b , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, a guanidine group, or an isonicotinimidamide group; 
 R a , R b , R c , and R d  are each independently H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —(CH 2 ) q -cycloalkyl, —(CH) q -heterocycloalkyl, —(CH 2 ) q -aryl, —(CH) q -heteroaryl, —(CO)-alkyl, —(CO)-cycloalkyl, or —(CO)-heterocycloalkyl, or R a  and R b , together with the nitrogen atom to which they are attached, form a heterocycloalkyl group, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optioncally substituted with a group consisting of alkyl, halo, nitro, CN, haloalkyl, O-haloalkyl, OH, O-alkyl, SH, S-alkyl, NH 2 , NH(alkyl), and N(alkyl) 2 ; and 
 p and q are each independently 0-5; 
 
       or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer thereof. 
     
     
         3 . The compound of  claim 2 , wherein R 6  is NR a R b . 
     
     
         4 . The compound of  claim 2 , wherein one of R 3 , R 4 , and R 5  is heterocycloalkyl, CN, NR m R n , (CO)R d , (CO)OR c , SO 2 NR m R n , (CO)NR m R n , C(NH)NR m R n , or NH(CO)R d . 
     
     
         5 . The compound of  claim 2 , wherein one of R 3 , R 4 , and R 5  is (CO)NR m R n . 
     
     
         6 . The compound of  claim 5 , wherein R m  is H and R n  is —(CH 2 ) p -T, -aryl-(CH 2 ) p -T, —(CH 2 ) p -aryl-T, or -heteroaryl-(CH 2 ) p -T, each optionally substituted with alkyl, halo, and OR c . 
     
     
         7 . The compound of  claim 6 , wherein T is NR a R b , O—(CH 2 ) q —NR a R b , heterocycloalkyl, aryl, or heteroaryl. 
     
     
         8 . The compound of  claim 5 , wherein R m  and R n , together with the nitrogen atom they are attached, form a heterocycloalkyl group, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, NR a R b , NH(CO)R d , NH(CO)OR c , and NH(CO)NR a R b . 
     
     
         9 . The compound of  claim 2 , wherein R 1  and R 2  are each independently H, alkyl, halo, CN, OR c , SR c , or NR a R b . 
     
     
         10 . The compound of  claim 1 , wherein said compound is a compound of the following formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein
 R 1 , R 2 , R 10 , R 11 , R 12 , and R 13  are each independently H, alkyl, cycloalkyl, halo, nitro, OR c , SR c , CN, haloalkyl, O-haloalkyl, or NR a R b ; 
 R 3 , R 4 , and R 5  are each independently H, alkyl, cycloalkyl, heterocycloalkyl, halo, nitro, OR c , SR c , CN, haloalkyl, O-haloalkyl, NR m R n , (CO)R d , (CO)OR c , SO 2 NR m R n , (CO)NR m R n , C(NH)NR m R n , NH(CO)R d , NH(CO)OR c , NH(CO)NR m R n , aryl, or heteroaryl; 
 R 6  is H or NR a R b ; 
 R m  and R n  are each independently 
 H, OH, 
 alkyl, —(CH 2 ) p -T, -aryl-(CH 2 ) p -T, —(CH 2 ) p -aryl-T, -heteroaryl-(CH 2 ) p -T, —(CH 2 ) p -heteroaryl-T, each optionally substituted with alkyl, cycloalkyl, halo, nitro, CN, haloalkyl, O-haloalkyl, OR c , SR c , (CO)R d , NR a R b , NH(CO)R d , NH(CO)OR c , NH(CO)NR a R b , NHC(NH)NH 2 , (CO)OR c , (CO)NR a R b , and SO 2 NR a R b , 
 or R m  and R n , together with the nitrogen atom they are attached, form a heterocycloalkyl group, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, nitro, CN, OR c , SR c , COR d , NR a R b , NH(CO)R d , NH(CO)OR c , NH(CO)NR a R b , a guanidine group, (CO)OR c , and (CO)NR a R b ; 
 T is NR a R b , OR c , SR c , O—(CH 2 ) q —NR a R b , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, a guanidine group, or an isonicotinimidamide group; 
 R a , R b , R c , and R d  are each independently H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —(CH 2 ) q -cycloalkyl, —(CH) q -heterocycloalkyl, —(CH 2 ) q -aryl, —(CH) q -heteroaryl, —(CO)-alkyl, —(CO)-cycloalkyl, or —(CO)-heterocycloalkyl, or R a  and R b , together with the nitrogen atom to which they are attached, form a heterocycloalkyl group, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optioncally substituted with a group consisting of alkyl, halo, nitro, CN, haloalkyl, O-haloalkyl, OH, O-alkyl, SH, S-alkyl, NH 2 , NH(alkyl), and N(alkyl) 2 ; and 
 p and q are each independently 0-5; 
 
       or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer thereof. 
     
     
         11 . The compound of  claim 1 , wherein said compound is a compound of the following formula: 
       
         
           
           
               
               
           
         
       
       wherein
 V, U 1 , Y 1 , and Z 1  are each N or CR 6 ′, 
 Wherein one of V, U 1 , Y 1 , and Z 1  is N, 
 Wherein V, U 1 , Y 1 , and Z 1  together with the carbon atom they are attached, form a pyridyl group; 
 R 1 , and R 6 ′ are each independently H, alkyl, cycloalkyl, halo, nitro, OR c , SR c , CN, haloalkyl, O-haloalkyl, or NR a R b ; 
 R 3 , R 4 , and R 5  are each independently H, alkyl, cycloalkyl, heterocycloalkyl, halo, nitro, OR c , SR c , CN, haloalkyl, O-haloalkyl, NR m R n , (CO)R d , (CO)OR c , SO 2 NR m R n , (CO)NR m R n , C(NH)NR m R n , NH(CO)R d , NH(CO)OR c , NH(CO)NR m R n , aryl, or heteroaryl; 
 R 6  is H; 
 R m  and R n  are each independently 
 H, OH, 
 alkyl, —(CH 2 ) p -T, -aryl-(CH 2 ) p -T, —(CH 2 ) p -aryl-T, -heteroaryl-(CH 2 ) p -T, —(CH 2 ) p -heteroaryl-T, each optionally substituted with alkyl, cycloalkyl, halo, nitro, CN, haloalkyl, O-haloalkyl, OR c , SR c , (CO)R d , NR a R b , NH(CO)R d , NH(CO)OR c , NH(CO)NR a R b , NHC(NH)NH 2 , (CO)OR c , (CO)NR a R b , and SO 2 NR a R b , 
 or R m  and R n , together with the nitrogen atom they are attached, form a heterocycloalkyl group, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, nitro, CN, OR c , SR c , COR d , NR a R b , NH(CO)R d , NH(CO)OR c , NH(CO)NR a R b , a guanidine group, (CO)OR c , and (CO)NR a R b ; 
 T is NR a R b , OR c , SR c , O—(CH 2 ) q —NR a R b , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, a guanidine group, or an isonicotinimidamide group; 
 R a , R b , R c , and R d  are each independently H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —(CH 2 ) q -cycloalkyl, —(CH) q -heterocycloalkyl, —(CH 2 ) q -aryl, —(CH) q -heteroaryl, —(CO)-alkyl, —(CO)-cycloalkyl, or —(CO)-heterocycloalkyl, or R a  and R b , together with the nitrogen atom to which they are attached, form a heterocycloalkyl group, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optioncally substituted with a group consisting of alkyl, halo, nitro, CN, haloalkyl, O-haloalkyl, OH, O-alkyl, SH, S-alkyl, NH 2 , NH(alkyl), and N(alkyl) 2 ; and 
 p and q are each independently 0-5; 
 
       or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer thereof. 
     
     
         12 . The compound of  claim 1 , wherein said compound is a compound of the following formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein
 V, U 1 , Y 1 , and Z 1  are each N or CR 6 ′; 
 R 1 , R 2 , and R 6 ′ are each independently H, alkyl, cycloalkyl, halo, nitro, OR c , SR c , CN, haloalkyl, O-haloalkyl, or NR a R b ; 
 R 3 , R 4 , and R 5  are each independently H, alkyl, cycloalkyl, heterocycloalkyl, halo, nitro, OR c , SR c , CN, haloalkyl, O-haloalkyl, NR m R n , (CO)R d , (CO)OR c , SO 2 NR m R n , (CO)NR m R n , C(NH)NR m R n , NH(CO)R d , NH(CO)OR c , NH(CO)NR m R n , aryl, or heteroaryl; 
 R 6  is H or NR a R b ; 
 R 7  and R 8  are each independently H, alkyl, alkenyl, alkynyl, halo, nitro, OR c , SR c , CN, haloalkyl, O-haloalkyl, (CO)R d , NR a R b , NH(CO)R d , NH(CO)OR c , NH(CO)NR a R b , (CO)OR c , (CO)NR a R b , SO 2 NR a R b , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; 
 R m  and R n  are each independently 
 H, OH, 
 alkyl, —(CH 2 ) p -T, -aryl-(CH 2 ) p -T, —(CH 2 ) p -aryl-T, -heteroaryl-(CH 2 ) p -T, —(CH 2 ) p -heteroaryl-T, each optionally substituted with alkyl, cycloalkyl, halo, nitro, CN, haloalkyl, O-haloalkyl, OR c , SR c , (CO)R d , NR a R b , NH(CO)R d , NH(CO)OR c , NH(CO)NR a R b , NHC(NH)NH 2 , (CO)OR c  (CO)NR a R b , and SO 2 NR a R b , 
 or R m  and R n , together with the nitrogen atom they are attached, form a heterocycloalkyl group, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, nitro, CN, OR c , SR c , COR d , NR a R b , NH(CO)R d , NH(CO)OR c , NH(CO)NR a R b , a guanidine group, (CO)OR c , and (CO)NR a R b ; 
 T is NR a R b , OR c , SR c , O—(CH 2 ) q —NR a R b , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, a guanidine group, or an isonicotinimidamide group; 
 R a , R b , R c , and R d  are each independently H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —(CH 2 ) q -cycloalkyl, —(CH) q -heterocycloalkyl, —(CH 2 ) q -aryl, —(CH) q -heteroaryl, —(CO)-alkyl, —(CO)-cycloalkyl, or —(CO)-heterocycloalkyl, or R a  and R b , together with the nitrogen atom to which they are attached, form a heterocycloalkyl group, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optioncally substituted with a group consisting of alkyl, halo, nitro, CN, haloalkyl, O-haloalkyl, OH, O-alkyl, SH, S-alkyl, NH 2 , NH(alkyl), and N(alkyl) 2 ; and 
 p and q are each independently 0-5; 
 
       or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer thereof. 
     
     
         13 . The compound of  claim 1 , wherein said compound is a compound of formula (XV) 
       
         
           
           
               
               
           
         
       
       wherein
 R′ is H or alkyl; 
 R 1 , R 2 , R 10 , R 11 , R 12 , and R 13  are each independently H, alkyl, cycloalkyl, halo, nitro, OR c , SR c , CN, haloalkyl, O-haloalkyl, or NR a R b ; 
 R 3 , R 4 , and R 5  are each independently H, alkyl, cycloalkyl, heterocycloalkyl, halo, nitro, OR c , SR c , CN, haloalkyl, O-haloalkyl, NR m R n , (CO)R d , (CO)OR c , SO 2 NR m R n , (CO)NR m R n , C(NH)NR m R n , NH(CO)R d , NH(CO)OR c , NH(CO)NR m R n , aryl, or heteroaryl; 
 R m  and R n  are each independently 
 H, OH, 
 alkyl, —(CH 2 ) p -T, -aryl-(CH 2 ) p -T, —(CH 2 ) p -aryl-T, -heteroaryl-(CH 2 ) p -T, —(CH 2 ) p -heteroaryl-T, each optionally substituted with alkyl, cycloalkyl, halo, nitro, CN, haloalkyl, O-haloalkyl, OR c , SR c , (CO)R d , NR a R b , NH(CO)R d , NH(CO)OR c , NH(CO)NR a R b , NHC(NH)NH 2 , (CO)OR c , (CO)NR a R b , and SO 2 NR a R b , 
 or R m  and R n , together with the nitrogen atom they are attached, form a heterocycloalkyl group, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, nitro, CN, OR c , SR c , COR d , NR a R b , NH(CO)R d , NH(CO)OR c , NH(CO)NR a R b , a guanidine group, (CO)OR c , and (CO)NR a R b ; 
 T is NR a R b , OR c , SR c , O—(CH 2 ) q —NR a R b , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, a guanidine group, or an isonicotinimidamide group; 
 R a , R b , R c , and R d  are each independently H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —(CH 2 ) q -cycloalkyl, —(CH) q -heterocycloalkyl, —(CH 2 ) q -aryl, —(CH) q -heteroaryl, —(CO)-alkyl, —(CO)-cycloalkyl, or —(CO)-heterocycloalkyl, or R a  and R b , together with the nitrogen atom to which they are attached, form a heterocycloalkyl group, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optioncally substituted with a group consisting of alkyl, halo, nitro, CN, haloalkyl, O-haloalkyl, OH, O-alkyl, SH, S-alkyl, NH 2 , NH(alkyl), and N(alkyl) 2 ; and 
 p and q are each independently 0-5, 
 
       or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer thereof. 
     
     
         14 . The compound of  claim 1 , wherein said compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt, N-oxide, hydrate, solvent, tautomer, or optical isomer thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         16 . A method of treating, inhibiting, suppressing, or reducing the severity of cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein said cancer is selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, Lymphoma, Leukemia, colon cancer, head cancer, neck cancer, thyroid cancer, kidney cancer, liver cancer, and stomach cancer. 
     
     
         18 . A method of treating, inhibiting, suppressing, or reducing the severity of a disease or a disorder associated with protein kinase in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of  claim 1 . 
     
     
         19 . The method of  claim 18 , wherein said protein kinase is Abl, Abl2, AFK, ALK, AMPK_group, ATM, ATR, Aurora A, Aurora B, Axl, BCKDK, BLK, BMPR1B, BMX, Brk, BRSK1, BTK, CaM-KIalpha, CaM-KIIalpha, CaMKK_group, CaM-KIV, CaM-KKalpha, CaM-KKbeta, CCDPK, CCRK, CDK1, CDK11, CDK2, CDK4, CDK5, CDK6, CDK7, CDK9, CDK_group, CDPK, Chak1, CHK1, CHK2, CK1 alpha, CK1 delta, CK1 epsilon, CK1_group, CK2 alpha, CK2_beta, CK2_group, CLK1, CSF1R, Csk, DAPK1, DAPK2, DAPK3, DAPK_group, DCAMKL1, DMPK_group, DNA-PK, DYRK1A, DYRK1B, DYRK2, DYRK3, eEF2K, Eg3 kinase, EGFR, EIF2AK2, EphA2, EphA3, EphA4, EphA8, EphB1, EphB2, EphB3, EphB5, ErbB2, FAK, Fer, Fes, FGFR1, FGFR3, FGFR4, FGFR_group, Fgr, FLT1, FLT3, FLT4, Fyn, GRK-1, GRK-2, GRK-3, GRK-4, GRK-5, GRK-6, GRK_group, GSK-3alpha, GSK-3beta, GSK-3_group, HCK, HIPK2, HIPK3, HRI, ICK, IGF1R, IKK-alpha, IKK-beta, IKK-epsilon ILK, InsR, IPL1, IRAK1, IRAK4, ITK, JAK1, JAK2, JAK3, JAK_group, JNK_group, KDR, KIS, Kit, KSR1, Lck, LIMK1, LIMK2, LKB1, LOK, Lyn, MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K6, MAP2K7, MAPK2_group, MAP3K1, MAP3K11, MAP3K14, MAP3K5, MAP3K7, MAP3K8, MAPK3_group, MAP4K1, MAP4K2, MAP4K4, MAPK1, MAPK10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, MAPK4, MAPK6, MAPK7, MAPK8, MAPK9, MAPK_group, MAPKAPK2, MARK_group, Mer, Met, MHCK, MLCK_group, Mnk1, Mnk2, MOS, MRCKa, MST1, MST3, mTOR, NDR1, NDR2, NEK1, NEK2, NEK6, NEK9, NEK_group, NLK, NuaK1, p37 kinase, p38_group, p7056K, p70S6Kb, P70S6K_group, PAK1, PAK2, PAK3, PAK5, PAK6, PAK_group, PASK, P-CIP2, PCTAIRE1, PDGFR alpha, PDGFR beta, PDGFR_group, PDHK1, PDHK2, PDHK3, PDHK4, PDK-1, PDK-2, PDK_group, PHK_group, PIK3CA, PIK3CB, PIK3CD, PIK3CG, Pim-1, PKA alpha, Pka_group, PKB beta, PKB_group, PKC alpha, PKC beta, PKC delta, PKC epsilon, PKC eta, PKC gamma, PKC iota, PKC theta, PKC zeta, PKC_group, PKD1, PKD2, PKD3, PKG1/cGK-1, PKG2/cGK-1, PKG2/cGK_group, PKN1, PLK1, PLK2, PLK3, PRP4, PYK2, RAF1, Ret, ROCK1, ROCK2, Ron, RPL10, RSK-1, RSK-2, RSK-3, RSK-5, SDK1, SGK_group, SIK, Sky, Src, Src_group, STLK3, Syk, TBK1, Tec, TESK1, TESK2, TGFbR1, TGFbR2, Tie1, Tie2, Titin kinase, TNK2, TRKA, TRKB, tropomyosin kinase, TSSK3, TXK, Tyk2, TYK2, VRK1, Wee1, Wnk1, WNK1, Yes, or ZAP70. 
     
     
         20 . The method of  claim 18 , wherein said disease or disorder is cancer, diabetes, malaria, viral infections, cardiovascular and hypertension, CNS and neurodegeneration, osteoporosis, pulmonary fibrosis, retinitis pigmentosis, Wet macular degeneration, Duchenne muscular dystrophy, diabetic eye disease, inflammation and autoimmune, or allergy. 
     
     
         21 . A method of treating, inhibiting, suppressing, or reducing the severity of cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of  claim 15 . 
     
     
         22 . A method of treating, inhibiting, suppressing, or reducing the severity of a disease or a disorder associated with protein kinase in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of  claim 15 .