Inhibitors of polo-like kinase

Abstract

The present invention provides compounds having a structure according to Formula (I): or a salt or solvate thereof, wherein ring A, E 1 , E 2 , R 1 , R 2 , R 3 and R 4 are defined herein. The invention further provides pharmaceutical compositions including the compounds of the invention and methods of making and using the compounds and compositions of the invention, e.g., in the treatment and prevention of various disorders, such as Parkinson's disease.

1 . A compound having a structure according to Formula (I): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 A is a ring selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted 5- or 6-membered heterocycloalkyl, and substituted or unsubstituted 5- or 6-membered heteroaryl; 
 E 1  is N or CR 5 , wherein R 5  is selected from the group consisting of H, OH, unsubstituted C 1 -C 3  alkoxy, unsubstituted C 1 -C 3  alkyl, unsubstituted C 2 -C 3  alkenyl, unsubstituted C 2 -C 3  alkynyl, C 1 -C 3  haloalkyl and halogen; 
 E 2  is N or CR 5a , wherein R 5a  is selected from the group consisting of H, unsubstituted C 1 -C 4  alkyl, halogen and CN; 
 R 1  is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl; 
 R 2  is selected from the group consisting of H, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, and substituted or unsubstituted 3- to 6-membered heterocycloalkyl; 
 R 4  and R 3 , together with the atoms to which they are attached, are joined to form a substituted or unsubstituted 3- to 8-membered heterocyclic ring; 
 or R 4 , R 2  and R 3 , together with the atoms to which they are attached, are optionally joined to form a substituted or unsubstituted heterocyclic bicyclic ring system of fused 4- to 8-membered rings; and 
 R 25  and R 26  are independently H, substituted or unsubstituted C 3 -C 8  cycloalkyl, or substituted or unsubstituted C 1 -C 10 alkyl. 
 
       
     
     
         2 . The compound of  claim 1  having a structure according to Formula (Ia): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 A, R 1 , R 2 , R 3 , R 4  and R 5  are defined as in  claim 1 . 
 
       
     
     
         3 . The compound of  claim 2 , wherein A is a member selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, N-alkyl-piperazinyl, oxazolidinyl, thiazolidinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl and tetrazolyl, wherein A is substituted or unsubstituted. 
     
     
         4 . The compound of  claim 3 , wherein A is a substituted or unsubstituted ring selected from the group consisting of pyridyl, pyrazolyl and imidazolyl. 
     
     
         5 . The compound of  claim 4 , wherein A is a substituted or unsubstituted ring selected from the group consisting of pyridin-3-yl, pyridin-4-yl, pyrazol-4-yl and imidazol-1-yl. 
     
     
         6 . The compound of  claim 1 , wherein the compound has a structure selected from the group consisting of Formula (XIIa), Formula (XIIb), Formula (XIIc), Formula (XIId), Formula (XIIe), and Formula (XIIf): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 R 2 , R 3  and R 4  are defined as in  claim 1 ; 
 R 6  is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, aryl optionally substituted with one or more independently selected substituents R 27 , heteroaryl optionally substituted with one or more independently selected substituents R 27 , —CN, -halogen, —OR 12 , —SR 12 , —NR 12 R 13 , —C(O)R 14 , —C(O)NR 12 R 13 , —OC(O)NR 12 R 13 , —C(O)OR 12 , —NR 16 C(O)R 14 , —NR 15 C(O)OR 12 , —NR 15 C(O)NR 12 R 13 , —NR 15 C(S)NR 12 R 13 , —NR 15 S(O) 2 R 14 , —S(O) 2 NR 12 R 13 , —S(O)R 14  and —S(O) 2 R 14 ; 
 R 10 , R 10a  and R 16  are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, aryl optionally substituted with one or more independently selected substituents R 27 , heteroaryl optionally substituted with one or more independently selected substituents R 27 , —CN, -halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 22 , —C(O)NR 20 R 21 , —OC(O)NR 20 R 21 , —C(O)OR 20 , —NR 23 C(O)R 22 , —NR 23 C(O)OR 20 , —NR 23 C(O)NR 20 R 21 , —NR 23 C(S)NR 20 R 21 , —NR 23 S(O) 2 R 22 , —S(O) 2 NR 20 R 21 , —S(O)R 22  and —S(O) 2 R 22 ; 
 R 11  is selected from the group consisting of H, —C(O)R 22 , substituted or unsubstituted C 1 -C 6 -alkyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, aryl optionally substituted with one or more independently selected substituents R 27 , 5- or 6-membered heteroaryl optionally substituted with one or more independently selected substituents R 27 , substituted or unsubstituted C 3 -C 8  cycloalkyl and substituted or unsubstituted 3- to 8-membered heterocycloalkyl; 
 each occurrence of R 12 , R 13 , R 15 , R 20 , R 21  and R 23  are independently selected from the group consisting of H, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, aryl optionally substituted with one or more independently selected substituents R 27 , 5- or 6-membered heteroaryl optionally substituted with one or more independently selected substituents R 27 , substituted or unsubstituted C 3 -C 8  cycloalkyl and substituted or unsubstituted 3- to 8-membered heterocycloalkyl; 
 each occurrence of R 14  and R 22  are independently selected from the group consisting of substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, aryl optionally substituted with one or more independently selected substituents R 27 , 5- or 6-membered heteroaryl optionally substituted with one or more independently selected substituents R 27 , substituted or unsubstituted C 3 -C 8  cycloalkyl and substituted or unsubstituted 3- to 8-membered heterocycloalkyl; 
 R 27  at each occurrence is selected from the group consisting of C 1 -C 10  alkyl optionally substituted with one or more independently selected substituents R 28 , 3- to 10-membered heteroalkyl optionally substituted with one or more independently selected substituents R 28 , C 3 -C 8  cycloalkyl optionally substituted with one or more independently selected substituents R 29 , 3- to 8-membered heterocycloalkyl optionally substituted with one or more independently selected substituents R 29 , aryl optionally substituted with one or more independently selected substituents R 29 , heteroaryl optionally substituted with one or more independently selected substituents R 29 , —CN, —NO 2 , -halogen, —OR 30 , —SR 30 , —NR 30 R 31 , —C(O)R 32 , —C(O)NR 33 R 31 , —OC(O)NR 30 R 31 , —C(O)OR 30 , —OC(O)R 32 , —NR 33 C(O)R 32 , —NR 33 C(O)OR 30 , —NR 33 C(O)NR 30 R 31 , —NR 33 C(S)NR 30 R 31 , —NR 33 S(O) 2 R 32 , —S(O) 2 NR 30 R 31 , —S(O)R 32  and —S(O) 2 R 32 ; 
 R 30 , R 31 , R 32  and R 33 , at each occurrence are independently selected from the group consisting of hydrogen, C 1 -C 10  alkyl optionally substituted with one or more independently selected substituents R 28 , 3- to 12-membered heteroalkyl optionally substituted with one or more independently selected substituents R 28 , C 3 -C 8  cycloalkyl optionally substituted with one or more independently selected substituents R 29 , 3- to 8-membered heterocycloalkyl optionally substituted with one or more independently selected substituents R 29 , aryl optionally substituted with one or more independently selected substituents R 29 , and heteroaryl optionally substituted with one or more independently selected substituents R 29 , provided that R 32  is other than hydrogen; 
 R 28  at each occurrence is independently selected from the group consisting of aryl optionally substituted with one or more independently selected substituents R 39 , heteroaryl optionally substituted with one or more independently selected substituents R 39 , —OR 34 , —SR 34 , —NHR 34 , —NR 35 R 34 , —C(O)R 34 , —C(O)OR 34 , —C(O)NHR 34 , —C(O)NR 35 R 34 , —NHC(O)R 34 , —NR 34 C(O)R 34 , —NHC(O)OR 34 , —NR 34 C(O)OR 34 , —NR 34 C(O)OH, —S(O) 2 R 34 , —S(O) 2 NHR 34 , —S(O) 2 NR 35 R 34 , —NHS(O) 2 R 34 , —NR 34 S(O) 2 R 34 , -halogen, —NHC(O)OH, —C(O)OH, —C(O)NH 2 , —S(O) 2 NH 2 , —CN, —NO 2 , ═O, —OH, ═NH, and —NH 2 ; 
 R 29  at each occurrence is independently —R 28  or —R 34 ; 
 R 34  and R 35  are independently selected from the group consisting of aryl optionally substituted with one or more independently selected substituents R 39 , heteroaryl optionally substituted with one or more independently selected substituents R 39 , and C 1 -C 4  alkyl optionally substituted with one or more substituents independently selected from the group consisting of —F, —OH, —NH 2 , unsubstituted C 1 -C 4  alkoxy, C 1 -C 4  haloalkoxy, unsubstituted mono-alkylamino, unsubstituted di-alkylamino, and —NR 36 R 37 ; 
 or —NR 34 R 35  forms a 5-, 6-, or 7-membered heterocycloalkyl optionally substituted with one or more unsubstituted C 1 -C 4  alkyl; 
 —NR 36 R 37  forms a 5-, 6-, or 7-membered heterocycloalkyl optionally substituted with one or more unsubstituted C 1 -C 4  alkyl; 
 R 39  at each occurrence is independently selected from the group consisting of —R 44 , —OR 44 , —SR 44 , —NHR 44 , —NR 44 R 45 , —C(O)R 44 , —C(O)OR 44 , —NHC(O)R 44 , —C(O)NHR 45 , —C(O)NR 44 R 45 , —S(O) 2 R 44 , —NHS(O) 2 R 44 , —S(O) 2 NHR 45 , —S(O) 2 NR 44 R 45 , -halogen, —C(O)OH, —C(O)NH 2 , —CN, —OH, and —NH 2 ; 
 R 44  and R 45  are independently C 1 -C 4  alkyl optionally substituted with one or more independently selected substituents independently selected from the group consisting of —F, —OH, —NH 2 , unsubstituted C 1 -C 4  alkoxy, C 1 -C 4  haloalkoxy, unsubstituted mono-alkylamino, unsubstituted di-alkylamino, and —NR 46 R 47 ; 
 or —NR 44 R 45  forms a 5-, 6-, or 7-membered heterocycloalkyl optionally substituted with one or more unsubstituted C 1 -C 4  alkyl; and 
 —NR 46 R 47  forms a 5-, 6-, or 7-membered heterocycloalkyl optionally substituted with one or more unsubstituted C 1 -C 4  alkyl. 
 
       
     
     
         7 . The compound of  claim 1 , wherein the compound has a structure according to Formula (XV): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 X, is C or N and the dashed line represents a single or double bond; 
 A 3  is a ring selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, imidazole, thiazole, isothiazole, isoxazole, triazole, thiadiazole, benzimidazole, indole, pyrrolo[2,3-b]pyridine, quinoline, pyrrolidine, piperidine, piperazine, and dihydro-imidazole; 
 R 74  is methyl; 
 R 75  is hydrogen, methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 ; 
 R 77  and R 76 , together with the atoms to which they are attached, are joined to form a substituted or unsubstituted 5- to 7-membered heterocyclic ring selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
           represents the core ring of Formula I, wherein the N is attached to R 77  and the C attached to R 76 ; 
           or R 77 , R 75  and R 76 , together with the atoms to which they are attached, are optionally joined to form a substituted or unsubstituted 7-membered heterocyclic ring selected from the group consisting of 
         
       
       
         
           
           
               
               
           
         
         
           represents the core ring of Formula I, wherein the N is attached to R 77  and the C attached to R 76 /R 75 ; 
           wherein 
         
       
       
         
           
           
               
               
           
         
         
           represents the core ring of Formula I, wherein the N is attached to R 77  and the C attached to R 76 /R 75 ; 
           R 78  is hydrogen, —Br, —CN, —CH 3 , —CH 2 CN, —CH 2 CH 2 NH 2 , —OH, —O − , ═O, —OCH 3 , —Obenzyl, —C(O)OH, —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , 
         
       
       
         
           
           
               
               
           
         
         
           —NH 2 , ═NH, —NHCH 3 , —N(CH 3 ) 2 , —NHS(O) 2 CH 3 , —S(O) 2 CH 3 , phenyl, thiazole, pyridine or pyrazine; 
           R 79  is hydrogen, —Cl, —Br, —CH 3 , —CF 3 , —CH 2 NH 2 , —NH 2 , —CH 2 NHC(O)OCHs, —CH 2 NHC(O)CH 3 , —CH 2 NHC(O)phenyl, —CH 2 NHS(O) 2 CH 3 , —CH 2 NHS(O) 2 -phenyl, —NHC(O)CH 3 , —NHC(O)OCH 3 , —NHC(O)phenyl, —NHS(O) 2 CH 3 , —NHS(O) 2 phenyl, —CH≡CHphenyl, cyclopropyl, cyclopentenyl, benzyl, phenyl optionally sub with 1, 2 or 3 substituents R 82 , pyridine optionally substituted with 1 fluoro, pyrimidine, pyrazine, pyridazine, pyrazole, thiazole, oxazole, thiophene optionally substituted with 1 chloro, pyrrolidine, oxazolidinone, pyrrolidinone, dihydropyran, tetrahydropyran, morpholine, 4-methyl-piperazine, pyrrolidine-dione, pyridinone, isoquinoline, or quinoline; 
           R 80  at each occurrence is independently —C(O)NH 2 , fluoro, chloro, cyano, pyrazole, triazole, pyridine or pyrimidine; 
           R 81  is methyl or 2-(trimethylsilyl)ethoxy)methyl, cyclopropyl, or —CH 2 -cyclopropyl; and 
           R 82  at each occurrence is independently selected from the group consisting of fluoro, chloro, bromo, —S(O) 2 CH 3 , —OCF 3 , —CF 3 , —CN, pyridine, triazole, and pyrazole. 
         
       
     
     
         8 . The compound of  claim 7 , wherein the compound has a structure selected from the group consisting of Formula (XVd), 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 Y is O or N—CH 3 ; and 
 X1, A 3 , R 74 , R 75 , R 78 , and R 79 , are as defined for  claim 7 . 
 
       
     
     
         9 . The compound of  claim 8 , wherein the compound has a structure selected from the group consisting of Formula (XVId) 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 X 2  is C or N and the dashed line represents a single or double bond; 
 Y is O or N—CH 3 ; 
 A 4  is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyridin-2-one, pyridin-4-imine, pyrazol-1-yl, pyrazol-4-yl, imidazol-1-yl, thiazol-5-yl, isothiazol-4-yl, isoxazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,3-thiadiazol-5-yl, indol-1-yl, indol-2-yl, indol-7-yl, piperazin-1-yl, 4,5-dihydro-1H-imidazol-1-yl; 
 B is selected from the group consisting of phenyl optionally substituted with 1, 2, or 3 substituents R 89 , pyridin-2-yl, 5-fluoro-pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazin-2-yl, pyridazin-3-yl, pyrazol-1-yl, pyrazol-5-yl, pyrazol-4-yl, thiazol-2-yl, thiazol-4-yl, oxazol-2-yl, pyrrolidin-1-yl, oxazolidin-2-on-3-yl, 2-oxopyrrolidin-1-yl, tetrahydro-2H-pyran-4-yl, morpholin-4-yl, 4-methyl-piperazin-1-yl, quinolin-5-yl, and quinolin-3-yl; 
 R 83  is —CD 3  or —CH 3 ; 
 R 84  is —CD 2 CD 3  or —CH 2 CH 3 ; and 
 R 85  is hydrogen, —CH 3 , —Br, —CN, or —NH 2 . 
 
       
     
     
         10 . The compound of  claim 8 , wherein the compound is selected from the group consisting of:
 (S)-6a-ethyl-5-methyl-2-(2-phenyl-1H-imidazol-1-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one,   (S)-6a-ethyl-5-methyl-2-(5-(thiazol-2-yl)-1H-pyrazol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one,   (S)-6a-ethyl-5,8-dimethyl-2-(2-phenyl-1H-imidazol-1-yl)-7,8,9,10-tetrahydro-5H-pyrazino[2,1-h]pteridin-6(6aH)-one,   (S)-2-(2-(2,4-difluorophenyl)-1H-imidazol-1-yl)-6a-ethyl-5-methyl-6a,7,9,0-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one,   (S)-6a-ethyl-2-(2-(5-fluoropyridin-2-yl)-1H-imidazol-1-yl)-5-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-8(5H)-one,   (S)-6a-ethyl-5-methyl-2-(2-(thiazo-2-yl)-1H-imidazol-1-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one,   (S)-6a-ethyl-5-methyl-2-(3-phenylpyridin-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one,   (S)-6a-ethyl-5-methyl-2-(2-phenylpyridin-3-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one,   (S)-2-(5-(2,4-difluorophenyl)-1H-pyrazol-4-yl)-6a-ethyl-5-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one, and   (S)-2-(2-(2,3-difluorophenyl)-1H-imidazol-1-yl)-6a-ethyl-5-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one,   or a salt thereof.   
     
     
         11 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         12 . A pharmaceutical composition comprising a compound according to  claim 6  and a pharmaceutically acceptable carrier. 
     
     
         13 . A pharmaceutical composition comprising a compound according to  claim 7  and a pharmaceutically acceptable carrier. 
     
     
         14 . A pharmaceutical composition comprising a compound according to  claim 8  and a pharmaceutically acceptable carrier. 
     
     
         15 . A method of treating a neurodegenerative disease comprising administering to a mammalian subject in need thereof a pharmaceutically effective amount of a compound having a structure according to Formula (I): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 A is a ring selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted 5- or 6-membered heterocycloalkyl, and substituted or unsubstituted 5- or 6-membered heteroaryl: 
 E 1  is N or CR 5 , wherein R 5  is selected from the group consisting of H, OH, unsubstituted C 1 -C 3  alkoxy, unsubstituted C 1 -C 3  alkyl, unsubstituted C 2 -C 3  alkenyl, unsubstituted C 2 -C 3  alkynyl, C 1 -C 3  haloalkyl and halogen; 
 E 2  is N or CR 5a , wherein R 5a  is selected from the group consisting of H, unsubstituted C 1 -C 4  alkyl, halogen and CN; 
 R 1  is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl; 
 R 2  is selected from the group consisting of H, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, and substituted or unsubstituted 3- to 6-membered heterocycloalkyl; 
 R 3  is selected from the group consisting of substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, and substituted or unsubstituted 3- to 6-membered heterocycloalkyl; 
 or R 2  and R 3 , together with the carbon atom to which they are attached, are optionally joined to form a substituted or unsubstituted C 3 -C 6  cycloalkyl or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl; 
 R 4  is selected from the group consisting of substituted or unsubstituted C 1 -C 10  alkyl, substituted or unsubstituted C 2 -C 10  alkenyl, substituted or unsubstituted C 2 -C 10  alkynyl, substituted or unsubstituted 3- to 10-membered heteroalkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and —NR 25 R 26 ; 
 R 4  and R 3 , together with the atoms to which they are attached are joined to form a substituted or unsubstituted 3- to 8-membered heterocyclic ring; 
 or R 4 , R 2  and R 3 , together with the atoms to which they are attached, are optionally joined to form a substituted or unsubstituted heterocyclic bicyclic ring system of fused 4- to 8-membered rings; and 
 R 25  and R 26  are independently H, substituted or unsubstituted C 3 -C 8  cycloalkyl, or substituted or unsubstituted C 1 -C 10  alkyl. 
 
       
     
     
         16 . The method of  claim 15 , wherein the disease is an alpha-synucleinopathy. 
     
     
         17 . The method of  claim 16 , wherein the disease is a member selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, PD at risk syndrome, dementia with Lewy bodies, diffuse Lewy body disease, Lewy body dementia, cortical Lewy body disease, senile dementia of Lewy type, Lewy body variant of Alzheimer's disease, diffuse Lewy body type of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. 
     
     
         18 . The method of  claim 17 , wherein the disease is Parkinson's disease. 
     
     
         19 . A method of treating a neurodegenerative disease comprising administering to a mammalian subject in need thereof a pharmaceutically effective amount of a compound according to  claim 6 . 
     
     
         20 . The method of  claim 19 , wherein the disease is an alpha-synucleinopathy. 
     
     
         21 . The method of  claim 20 , wherein the disease is a member selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, PD at risk syndrome, dementia with Lewy bodies, diffuse Lewy body disease, Lewy body dementia, cortical Lewy body disease, senile dementia of Lewy type, Lewy body variant of Alzheimer's disease, diffuse Lewy body type of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. 
     
     
         22 . The method of  claim 21 , wherein the disease is Parkinson's disease. 
     
     
         23 . A method of treating a neurodegenerative disease comprising administering to a mammalian subject in need thereof a pharmaceutically effective amount of a compound having a structure according to Formula (XV): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 X 1  is C or N and the dashed line represents a single or double bond; 
 A 3  is a ring selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, imidazole, thiazole, isothiazole, isoxazole, triazole, thiadiazole, benzimidazole, indole, pyrrolo[2,3-b]pyridine, quinoline, pyrrolidine, piperidine, piperazine, and dihydro-imidazole; 
 R 74  is methyl; 
 R 75  is hydrogen, methyl, ethyl, —CH-cyclopropyl, or —CH 2 CF; 
 R 76  is methyl, ethyl, —CH-cyclopropyl, or —CH 2 CF 3 ; 
 or R 75  and R 76 , together with the carbon atom to which they are attached, are optionally joined to form cyclobutyl; 
 R 77  is selected from the group consisting of —NH 2 , —NHCH 3 ,—NHcyclopropyl, pyrrolidine, —CH 2 -cyclopropyl, —CH(CH 3 )-cyclopropyl, cyclopropyl, cyclobutyl optionally substituted with 1 or 2 fluoro, cyclopentyl optionally substituted with 1 or 2 fluoro, isopropyl, —CH 2 CH 2 CF 3 , tetrahydropyran, tetrahydrofuran, oxetane, phenyl optionally substituted with 1 or 2 substituents R 80 , pyrazole optionally substituted with 1 substituent R 81 , and pyrimidine; 
 or R 77  and R 76 , together with the atoms to which they are attached, are optionally joined to form a substituted or unsubstituted 5- to 7-membered heterocyclic ring selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
           represents the core ring of Formula I, wherein the N is attached to R 77  and the C attached to R 76 ; 
           or R 77 , R 75  and R 76 , together with the atoms to which they are attached, are optionally joined to form a substituted or unsubstituted 7-membered heterocyclic ring selected from the group consisting of 
         
       
       
         
           
           
               
               
           
         
         
           represents the core ring of Formula I, wherein the N is attached to R 77  and the C attached to R 76 /R 75 ; 
           wherein 
         
       
       
         
           
           
               
               
           
         
         
           represents the core ring of Formula I, wherein the N is attached to R 77  and the C attached to R 76 /R 75 ; 
           R 78  is hydrogen, —Br, —CN, —CH 3 , —CH 2 CN, —CH 2 CH 2 NH 2 , —OH, —O − , ═O, —OCH 3 , —Obenzyl, —C(O)OH, —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , 
         
       
       
         
           
           
               
               
           
         
         
           —NH 2 , ═NH, —NHCH 3 , —N(CH 3 ) 2 , —NHS(O) 2 CH 3 , —S(O) 2 CH 3 , phenyl, thiazole, pyridine or pyrazine; 
           R 79  is hydrogen, —Cl, —Br, —CH 3 , —CF 3 , —CH 2 NH 2 , —NH 2 , —CH 2 NHC(O)OCH 3 , —CH 2 NHC(O)CH 3 , —CH 2 NHC(O)phenyl, —CH 2 NHS(O) 2 CH 3 , —CH 2 NHS(O)O 2 phenyl, —NHC(O)CH 3 , —NHC(O)OCH 3 , —NHC(O)phenyl, —NHS(O 2 )CH, —NHS(O) 2 phenyl, —CH≡CHphenyl, cyclopropyl, cyclopentenyl, benzyl, phenyl optionally sub with 1, 2 or 3 substituents R 82 , pyridine optionally substituted with 1 fluoro, pyrimidine, pyrazine, pyridazine, pyrazole, thiazole, oxazole, thiophene optionally substituted with 1 chloro, pyrrolidine, oxazolidinone, pyrrolidinone, dihydropyran, tetrahydropyran, morpholine, 4-methyl-piperazine, pyrrolidine-dione, pyridinone, isoquinoline, or quinoline; 
           R 80  at each occurrence is independently —C(O)NH 2 , fluoro, chloro, cyano, pyrazole, triazole, pyridine or pyrimidine; 
           R 81  is methyl or 2-(trimethylsilyl)ethoxy)methyl, cyclopropyl, or —CH 2 -cyclopropyl; and 
           R 82  at each occurrence is independently selected from the group consisting of fluoro, chloro, bromo, —S(O) 2 CH, —OCF 3 —CF 3 , —CN, pyridine, triazole, and pyrazole. 
         
       
     
     
         24 . The method of  claim 23 , wherein the disease is an alpha-synucleinopathy. 
     
     
         25 . The method of  claim 24 , wherein the disease is a member selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, PD at risk syndrome, dementia with Lewy bodies, diffuse Lewy body disease, Lewy body dementia, cortical Lewy body disease, senile dementia of Lewy type, Lewy body variant of Alzheimer's disease, diffuse Lewy body type of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. 
     
     
         26 . The method of  claim 25 , wherein the disease is Parkinson's disease. 
     
     
         27 . A method of treating a neurodegenerative disease comprising administering to a mammalian subject in need thereof a pharmaceutically effective amount of a compound having a structure selected from the group consisting of Formula (XVa), Formula (XVb), Formula (XVc). Formula (XVd), and Formula (XVe), 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 C is pyrazole, wherein R 81  is bound to either of the nitrogens in the pyrazole ring; 
 Y is O or N—CH 3 ; and 
 X1, A 3 , R 74 , R 75 , R 76 , R 78 , R 79 , R 80  and R 81  are as defined for  claim 23 . 
 
       
     
     
         28 . The method of  claim 27 , wherein the disease is an alpha-synucleinopathy. 
     
     
         29 . The method of  claim 28 , wherein the disease is a member selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, PD at risk syndrome, dementia with Lewy bodies, diffuse Lewy body disease, Lewy body dementia, cortical Lewy body disease, senile dementia of Lewy type, Lewy body variant of Alzheimer's disease, diffuse Lewy body type of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. 
     
     
         30 . The method of  claim 29 , wherein the disease is Parkinson's disease. 
     
     
         31 . A method of treating a neurodegenerative disease comprising administering to a mammalian subject in need thereof a pharmaceutically effective amount of a composition comprising a compound having a structure according to Formula (I): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 A is a ring selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted 5- or 6-membered heterocycloalkyl, and substituted or unsubstituted 5- or 6-membered heteroaryl; 
 E 1  is N or CR 5 , wherein R 5  is selected from the group consisting of H, OH, unsubstituted C 1 -C 3  alkoxy, unsubstituted C 1 -C 3  alkyl, unsubstituted C 2 -C 3  alkenyl, unsubstituted C 2 -C 3  alkynyl, C 1 -C 3  haloalkyl and halogen; 
 E 2  is N or CR 5a , wherein R 5a  is selected from the group consisting of H, unsubstituted C 1 -C 4  alkyl, halogen and CN; 
 R 1  is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl., and substituted or unsubstituted acyl; 
 R 2  is selected from the group consisting of H, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, and substituted or unsubstituted 3- to 6-membered heterocycloalkyl: 
 R 3  is selected from the group consisting of substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, and substituted or unsubstituted 3- to 6-membered heterocycloalkyl: 
 or R 2  and R 3 , together with the carbon atom to which they are attached, are optionally joined to form a substituted or unsubstituted C 3 -C 6  cycloalkyl or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl: 
 R 4  is selected from the group consisting of substituted or unsubstituted C 1 -C 10  alkyl, substituted or unsubstituted C 2 -C 10  alkenyl, substituted or unsubstituted C 2 -C 10  alkynyl, substituted or unsubstituted 3- to 10-membered heteroalkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and —NR 25 R 26 ; 
 R 4  and R 3 , together with the atoms to which they are attached, are joined to form a substituted or unsubstituted 3- to 8-membered heterocyclic ring; 
 or R 4 , R 2  and R 3 , together with the atoms to which they are attached, are optionally joined to form a substituted or unsubstituted heterocyclic bicyclic ring system of fused 4- to 8-membered rings; and 
 R 25  and R 26  are independently H, substituted or unsubstituted C 3 -C 8  cycloalkyl, or substituted or unsubstituted C 1 -C 10  alkyl. 
 
       
     
     
         32 . The method of  claim 31 , wherein the disease is an alpha-synucleinopathy. 
     
     
         33 . The method of  claim 32 , wherein the disease is a member selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, PD at risk syndrome, dementia with Lewy bodies, diffuse Lewy body disease, Lewy body dementia, cortical Lewy body disease, senile dementia of Lewy type, Lewy body variant of Alzheimer's disease, diffuse Lewy body type of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. 
     
     
         34 . The method of  claim 33 , wherein the disease is Parkinson's disease. 
     
     
         35 . A method of treating a neurodegenerative disease comprising administering to a mammalian subject in need thereof a pharmaceutically effective amount of a composition according to  claim 12 . 
     
     
         36 . The method of  claim 35 , wherein the disease is an alpha-synucleinopathy. 
     
     
         37 . The method of  claim 36 , wherein the disease is a member selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, PD at risk syndrome, dementia with Lewy bodies, diffuse Lewy body disease, Lewy body dementia, cortical Lewy body disease, senile dementia of Lewy type, Lewy body variant of Alzheimer's disease, diffuse Lewy body type of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. 
     
     
         38 . The method of  claim 37 , wherein the disease is Parkinson's disease. 
     
     
         39 . A method of treating a neurodegenerative disease comprising administering to a mammalian subject in need thereof a pharmaceutically effective amount of a composition comprising a compound having a structure according to Formula (XV): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 X 1  is C or N and the dashed line represents a single or double bond; 
 A 3  is a ring selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, imidazole, thiazole, isothiazole, isoxazole, triazole, thiadiazole, benzimidazole, indole, pyrrolo[2,3-b]pyridine, quinoline, pyrrolidine, piperidine, piperazine, and dihydro-imidazole; 
 R 74  is methyl; 
 R 75  is hydrogen, methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 ; 
 R 76  is methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 ; 
 or R 75  and R 76 , together with the carbon atom to which they are attached, are optionally joined to form cyclobutyl: 
 R 77  is selected from the group consisting of —NH, —NHCH 3 , —NHcyclopropyl, pyrrolidine, —CH 2 -cyclopropyl, —CH(CH 3 )-cyclopropyl, cyclopropyl, cyclobutyl optionally substituted with 1 or 2 fluoro, cyclopentyl optionally substituted with 1 or 2 fluoro, isopropyl, —CH 2 CH 2 CF 3 , tetrahydropyran, tetrahydrofuran, oxetane, phenyl optionally substituted with 1 or 2 substituents R 80 , pyrazole optionally substituted with 1 substituent R 81 , and pyrimidine; 
 or R 77  and R 76 , together with the atoms to which they are attached, are optionally joined to form a substituted or unsubstituted 5- to 7-membered heterocyclic ring selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
           represents the core ring of Formula I, wherein the N is attached to R 77  and the C attached to R 76 : 
           or R 77 , R 75  and R 76 , together with the atoms to which they are attached, are optionally joined to form a substituted or unsubstituted 7-membered heterocyclic ring selected from the group consisting of 
         
       
       
         
           
           
               
               
           
         
         
           represents the core ring of Formula I, wherein the N is attached to R 77  and the C attached to R 76 /R 75 : 
           wherein 
         
       
       
         
           
           
               
               
           
         
         
           represents the core ring of Formula I, wherein the N is attached to R 77  and the C attached to R 76 /R 75 ; 
           R 78  is hydrogen, —Br, —CN, —CH 3 , —CH 2 CN, —CH 2 CH 2 NH 2 , —OH, —O − , ═O, —OCH 3 , —Obenzyl, —C(O)OH, —C(O)OCH 3 ,—C(O)OCH 2 CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , 
         
       
       
         
           
           
               
               
           
         
         
           —NH 2 , ═NH, —NHCH 3 , —N(CH 3 ) 2 , —NHS(O) 2 CH 3 , —S(O) 2 CH 3 , phenyl, thiazole, pyridine or pyrazine; 
           R 79  is hydrogen, —Cl, —Br, —CH 3 , —CF 3 , —CH 2 NH 2 , —NH 2 , —CH 2 NHC(O)OCH 3 , —CH 2 NHC(O)CH 3 , —CH 2 NHC(O)phenyl, —CH 2 NHS(O) 2 CH 3 , —CH 2 NHS(O) 2 phenyl, —NHC(O)CH 3 , —NHC(O)OCH 3 , —NHC(O)phenyl, —NHS(O) 2 CH 3 ,—NHS(O) 2 phenyl, —CH═CHphenyl, cyclopropyl, cyclopentenyl, benzyl, phenyl optionally sub with 1, 2 or 3 substituents R 82 , pyridine optionally substituted with 1 fluoro, pyrimidine, pyrazine, pyridazine, pyrazole, thiazole, oxazole, thiophene optionally substituted with 1 chloro, pyrrolidine, oxazolidinone, pyrrolidinone, dihydropyran, tetrahydropyran, morpholine, 4-methyl-piperazine, pyrrolidine-dione, pyridinone, isoquinoline, or quinoline; 
           R 80  at each occurrence is independently —C(O)NH 2 , fluoro, chloro, cyano, pyrazole, triazole, pyridine or pyrimidine: 
           R 81  is methyl or 2-(trimethylsilyl)ethoxy)methyl, cyclopropyl, or —CH 2 -cyclopropyl; and 
           R 82  at each occurrence is independently selected from the group consisting of fluoro, chloro, bromo, —S(O) 2 CH 3 , —OCF 3 , —CF 3 , —CN, pyridine, triazole, and pyrazole. 
         
       
     
     
         40 . The method of  claim 39 , wherein the disease is an alpha-synucleinopathy. 
     
     
         41 . The method of  claim 40 , wherein the disease is a member selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, PD at risk syndrome, dementia with Lewy bodies, diffuse Lewy body disease, Lewy body dementia, cortical Lewy body disease, senile dementia of Lewy type, Lewy body variant of Alzheimer's disease, diffuse Lewy body type of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. 
     
     
         42 . The method of  claim 41 , wherein the disease is Parkinson's disease. 
     
     
         43 . A method of treating a neurodegenerative disease comprising administering to a mammalian subject in need thereof a pharmaceutically effective amount of a composition comprising a compound having a structure selected from the group consisting of Formula (XVa), Formula (XVb), Formula (XVc), Formula (XVd), and Formula (XVe), 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 C is pyrazole, wherein R 81  is bound to either of the nitrogens in the pyrazole ring: 
 Y is O or N—CH 3 ; and 
 X1, A 3 , R 74 , R 75 , R 76 , R 78 , R 79 , R 80  and R 81  are as defined for  claim 23 . 
 
       
     
     
         44 . The method of  claim 43 , wherein the disease is an alpha-synucleinopathy. 
     
     
         45 . The method of  claim 44 , wherein the disease is a member selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, PD at risk syndrome, dementia with Lewy bodies, diffuse Lewy body disease, Lewy body dementia, cortical Lewy body disease, senile dementia of Lewy type, Lewy body variant of Alzheimer's disease, diffuse Lewy body type of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. 
     
     
         46 . The method of  claim 45 , wherein the disease is Parkinson's disease. 
     
     
         47 . A method of reducing p-Ser-129-alpha-synuclein concentration in brain tissue of a test animal, the method comprising administering to the test animal a compound having a structure according to Formula (I): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 A is a ring selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted 5- or 6-membered heterocycloalkyl, and substituted or unsubstituted 5- or 6-membered heteroaryl; 
 E 1  is N or CR 5 , wherein R 5  is selected from the group consisting of H, OH, unsubstituted C 1 -C 3  alkoxy, unsubstituted C 1 -C 3  alkyl, unsubstituted —C 2 -C 3  alkenyl, unsubstituted C 2 -C 3  alkynyl, C 1 -C 3  haloalkyl and halogen; 
 E 2  is N or CR 5a , wherein R 5a  is selected from the group consisting of H, unsubstituted C 1 -C 4  alkyl, halogen and CN; 
 R 1  is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl: 
 R 2  is selected from the group consisting of H, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, and substituted or unsubstituted 3- to 6-membered heterocycloalkyl; 
 R 3  is selected from the group consisting of substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 5  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, and substituted or unsubstituted 3- to 6-membered heterocycloalkyl; 
 or R 2  and R 3 , together with the carbon atom to which they are attached, are optionally joined to form a substituted or unsubstituted C 3 -C 6  cycloalkyl or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl; 
 R 4  is selected from the group consisting of substituted or unsubstituted C 1 -C 10  alkyl, substituted or unsubstituted C 2 -C 10  alkenyl, substituted or unsubstituted C 2 -C 10  alkynyl, substituted or unsubstituted 3- to 10-membered heteroalkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and —NR 25 R 26 ; 
 or R 4  and R 3 , together with the atoms to which they are attached, are optionally joined to form a substituted or unsubstituted 3- to 8-membered heterocyclic ring; 
 or R 4 , R 2  and R 3 , together with the atoms to which they are attached, are optionally joined to form a substituted or unsubstituted heterocyclic bicyclic ring system of fused 4- to 8-membered rings; and 
 R 25  and R 26  are independently H, substituted or unsubstituted C 3 -C 8  cycloalkyl, or substituted or unsubstituted C 1 -C 10  alkyl. 
 
       
     
     
         48 . A method of treating a cancer comprising administering to a mammalian subject in need thereof a pharmaceutically effective amount of a compound having a structure according to Formula (I): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 A is a ring selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted 5- or 6-membered heterocycloalkyl, and substituted or unsubstituted 5- or 6-membered heteroaryl; 
 E 1  is N or CR 5 , wherein R 5  is selected from the group consisting of H, OH, unsubstituted C 1 -C 3  alkoxy, unsubstituted C 1 -C 3  alkyl, unsubstituted C 2 -C 3  alkenyl, unsubstituted C 2 -C 3  alkynyl, C 1 -C 3  haloalkyl and halogen; 
 E 2  is N or CR 5a , wherein R 5a  is selected from the group consisting of H, unsubstituted C 1 -C 4  alkyl, halogen and CN; 
 R 1  is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl; 
 R 2  is selected from the group consisting of H, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, and substituted or unsubstituted 3- to 6-membered heterocycloalkyl: 
 R 3  is selected from the group consisting of substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, and substituted or unsubstituted 3- to 6-membered heterocycloalkyl; 
 or R 2  and R 3 , together with the carbon atom to which they are attached, are optionally joined to form a substituted or unsubstituted C 3 -C 6  cycloalkyl or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl; 
 R 4  is selected from the group consisting of substituted or unsubstituted C 1 -C 10  alkyl, substituted or unsubstituted C 2 -C 10  alkenyl, substituted or unsubstituted C 2 -C 10  alkynyl, substituted or unsubstituted 3- to 10-membered heteroalkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and —NR 25 R 26 ; 
 or R 4  and R 3 , together with the atoms to which they are attached, are optionally joined to form a substituted or unsubstituted 3- to 8-membered heterocyclic ring; 
 or R 4 , R 2  and R 3 , together with the atoms to which they are attached, are optionally joined to form a substituted or unsubstituted heterocyclic bicyclic ring system of fused 4- to 8-membered rings; and 
 R 25  and R 26  are independently H, substituted or unsubstituted C 3 -C 8  cycloalkyl, or substituted or unsubstituted C 1 -C 10  alkyl. 
 
       
     
     
         49 . The method of  claim 48 , wherein the cancer is selected from the group consisting of solid tumors, liquid tumors, tumor metastasis, angiogenic disordors, ocular neovasculization, infantile haemangiomas, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, hepatocellular carcinoma, pancreatic carcinoma, brain cancer, non small cell lung cancer, breast cancer, bladder cancer, thyroid cancer, endometrial cancer, prostate cancer, gastric cancer, oropharyngeal cancer, esophageal cancer, head and neck cancer, ovarian carcinomas, papillary carcinomas, colorectal cancers, glioma, glioblastoma, squamous cell carcinoma, hepatoma, melanoma, non-Hodgkins lymphoma, Hodgkin's lymphoma, advanced metastatic cancers, advanced solid tumors, Kaposi's sarcoma, multiple myeloma, and HTLV-1 mediated tumorigenesis. 
     
     
         50 . The method of  claim 49 , wherein the cancer is selected from the group consisting of glioma, glioblastoma, hepatocellular carcinoma, pancreatic carcinoma, colorectal cancer, papillary carcinoma, ovarian carcinoma, non small cell lung cancer, breast cancer, and squamous cell carcinoma. 
     
     
         51 . A method of treating a cancer comprising administering to a mammalian subject in need thereof a pharmaceutically effective amount of a composition comprising a compound having a structure according to Formula (I): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 A is a ring selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted 5- or 6-membered heterocycloalkyl, and substituted or unsubstituted 5- or 6-membered heteroaroyl; 
 E 1  is N or CR 5 , wherein R 5  is selected from the group consisting of H, OH, unsubstituted C 1 -C 3  alkoxy, unsubstituted C 1 -C 3  alkyl, unsubstituted C 2 -C 3  alkenyl, unsubstituted C 2 -C 3  alkynyl, C 1 -C 3  haloalkyl and halogen; 
 E 2  is N or CR 5a , wherein R 5a  is selected from the group consisting of H, unsubstituted C 1 -C 4  alkyl, halogen and CN; 
 R 1  is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl: 
 R 2  is selected from the group consisting of H, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, and substituted or unsubstituted 3- to 6-membered heterocycloalkyl; 
 R 3  is selected from the group consisting of substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, and substituted or unsubstituted 3- to 6-membered heterocycloalkyl; 
 or R 2  and R 3 , together with the carbon atom to which they are attached, are optionally joined to form a substituted or unsubstituted C 3 -C 8 cycloalkynyl or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl; 
 R 4  is selected from the group consisting of substituted or unsubstituted C 1 -C 10  alkyl, substituted or unsubstituted C 2 -C 10  alkenyl, substituted or unsubstituted C 2 -C 10  alkynyl, substituted or unsubstituted 3- to 10-membered heteroalkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and —NR 25 R 26 ; 
 or R 4  and R 3 , together with the atoms to which they are attached, are optionally joined to form a substituted or unsubstituted 3- to 8-membered heterocyclic ring; 
 or R 4 , R 2  and R 3 , together with the atoms to which they are attached, are optionally joined to form a substituted or unsubstituted heterocyclic bicyclic ring system of fused 4- to 8-membered rings; and 
 R 25  and R 26  are independently H, substituted or unsubstituted C 3 -C 8  cycloalkyl, or substituted or unsubstituted C 1 -C 10  alkyl. 
 
       
     
     
         52 . The method of  claim 51 , wherein the cancer is selected from the group consisting of solid tumors, liquid tumors, tumor metastasis, angiogenic disordors, ocular neovasculization, infantile haemangiomas, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, hepatocellular carcinoma, pancreatic carcinoma, brain cancer, non small cell lung cancer, breast cancer, bladder cancer, thyroid cancer, endometrial cancer, prostate cancer, gastric cancer, oropharyngeal cancer, esophageal cancer, head and neck cancer, ovarian carcinomas, papillary carcinomas, colorectal cancers, glioma, glioblastoma, squamous cell carcinoma, hepatoma, melanoma, non-Hodgkins lymphoma, Hodgkin's lymphoma, advanced metastatic cancers, advanced solid tumors, Kaposi's sarcoma, multiple myeloma, and HTLV-1 mediated tumorigenesis. 
     
     
         53 . The method of  claim 52 , wherein the cancer is selected from the group consisting of glioma, glioblastoma, hepatacellular carcinoma, pancreatic carcinoma, colorectal cancer, papillary carcinoma, ovarian carcinoma, non small cell lung cancer, breast cancer, and squamous cell carcinoma.