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, X, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 , 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 - 9 . (canceled) 
     
     
         10 . 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: 
         X is C or N and the dashed line represents a single or double bond; 
         A 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 1  is methyl; 
         R 2  is hydrogen, methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 ; 
         R 3  is methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 ; 
         or R 2  and R 3 , together with the carbon atom to which they are attached, are optionally joined to form cyclobutyl; 
         R 4  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 7 , pyrazole optionally substituted with 1 substituent R 8 , and pyrimidine; 
         or R 4  and R 3 , 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 
       
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
       
       resents the core ring of Formula I, i.e. the N attached to R 4  and the C attached to R 3 ;
 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 7-membered heterocyclic ring selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
       
       represents the core ring of Formula I, i.e. the N attached to R 4  and the C attached to R 3 /R 2 ;
 R 5  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 6  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 substituted with 1, 2 or 3 substituents R 9 , 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 7  at each occurrence is independently —C(O)NH 2 , fluoro, chloro, cyano, pyrazole, triazole, pyridine or pyrimidine; 
 R 8  is methyl or 2-(trimethylsilyl)ethoxy)methyl, cyclopropyl, or —CH 2 -cyclopropyl; and 
 R 9  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. 
 
     
     
         11 . The method of  claim 10 , wherein the disease is an alpha-synucleinopathy. 
     
     
         12 . The method of  claim 11 , 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. 
     
     
         13 . The method of  claim 12 , wherein the disease is Parkinson's disease. 
     
     
         14 . 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: 
         X is C or N and the dashed line represents a single or double bond; 
         A 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 1  is methyl; 
         R 2  is hydrogen, methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 ; 
         R 3  is methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 ; 
         or R 2  and R 3 , together with the carbon atom to which they are attached, are optionally joined to form cyclobutyl; 
         R 4  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 7 , pyrazole optionally substituted with 1 substituent R 8 , and pyrimidine; 
         or R 4  and R 3 , 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 
       
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
       
       represents the core ring of Formula I, i.e. the N attached to R 4  and the C attached to R 3 ;
 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 7-membered heterocyclic ring selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
       
       represents the core ring of Formula i.e. the N attached to R 4  and the C attached to R 3 /R 2 ;
 R 5  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, ═NH, —NHCH 3 , —N(CH 3 ) 2 , —NHS(O)CH 3 , —S(O) 2 CH 3 , phenyl, thiazole, pyridine or pyrazine;
 R 6  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) 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 substituted with 1, 2 or 3 substituents R 9 , 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 7  at each occurrence is independently —C(O)NH 2 , fluoro, chloro, cyano, pyrazole, triazole, pyridine or pyrimidine; 
 R 8  is methyl or 2-(trimethylsilyl)ethoxy)methyl, cyclopropyl, or —CH 2 -cyclopropyl; and 
 R 9  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; and 
 a pharmaceutically acceptable carrier. 
 
     
     
         15 . The method of  claim 14 , wherein the disease is an alpha-synucleinopathy. 
     
     
         16 . The method of  claim 15 , 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. 
     
     
         17 . The method of  claim 16 , wherein the disease is Parkinson's disease. 
     
     
         18 . 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 (Ia), Formula (Ib), Formula (Ic), Formula (Id), and Formula (Ie), as follows: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 C is pyrazole, wherein R 8  is bound to either of the nitrogens in the pyrazole ring; 
 Y is O or N—CH 3 ; 
 X is C or N and the dashed line represents a single or double bond; 
 A 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 1  is methyl; 
 R 2  is hydrogen, methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 ; 
 R 3  is methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 ; 
 or R 2  and R 3 , together with the carbon atom to which they attached, are optionally joined to form cyclobutyl; 
 R 5  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 6  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 substituted with 1, 2 or 3 substituents R 9 , 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 7  at each occurrence is independently —C(O)NH 2 , fluoro, chloro, cyano, pyrazole, triazole, pyridine or pyrimidine; and 
 R 8  is methy or 2-(trimethylsilyl)ethoxy)methyl, cyclopropyl, or —CH 2 -cyclopropyl. 
 
     
     
         19 . The method of  claim 18 , wherein the disease is an alpha-synucleinopathy. 
     
     
         20 . The method of  claim 19 , 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. 
     
     
         21 . The method of  claim 20 , wherein the disease is Parkinson's disease. 
     
     
         22 . 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 (Ia), Formula (Ib), Formula (Ic), Formula (Id), and Formula (Ie), as follows: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 C is pyrazole, wherein R 8  is bound to either of the nitrogens in the pyrazole ring; 
 Y is O or N—CH 3 ; 
 X is C or N and the dashed line represents a single or double bond; 
 A 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 1  is methyl; 
 R 2  is hydrogen, methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 ; 
 R 3  is methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 ; 
 or R 2  and R 3 , together with the carbon atom to which the are attached, are optionally joined to form cyclobutyl; 
 R 5  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 6  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, cyclopentyl, benzyl, phenyl optionally substituted with 1, 2 or 3 substituents R 9 , 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 7  at each occurrence is independently —C(O)NH 2 , fluoro, chloro, cyano, pyrazole, triazole, pyridine or pyrimidine; and 
 R 8  is methyl or 2-(trimethylsilyl)ethoxy)methyl, cyclopropyl, or —CH 2 -cyclopropyl; 
 and a pharmaceutically acceptable carrier. 
 
     
     
         23 . The method of  claim 22 , wherein the disease is an alpha-synucleinopathy. 
     
     
         24 . The method of  claim 23 , 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. 
     
     
         25 . The method of  claim 24 , wherein the disease is Parkinson's disease. 
     
     
         26 . 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:
 X is C or N and the dashed line represents a single or double bond; 
 A 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 1  is methyl; 
 R 2  is hydrogen, methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 ; 
 R 3  is methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 ; 
 or R 2  and R 3 , together with the carbon atom to which they are attached, are optionally joined to form cyclobutyl; 
 R 4  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 7 , pyrazole optionally substituted with 1 substituent R 8 , and pyrimidine; 
 or R 4  and R 3 , 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 
 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
       
       represents the core ring of Formula I, i.e. the N attached to R 4  and the C attached to R 3 ;
 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 7-membered heterocyclic ring selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
       
       represents the core ring of Formula I, i.e. the N attached to R 4  and the C attached to R 3 /R 2 ;
 R 5  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 6  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 substituted with 1, 2 or 3 substituents R 9 , 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, pyrrolidin-dione, pyridinone, isoquinoline, or quinoline; 
 R 7  at each occurrence is independently —C(O)NH 2 , fluoro, chloro, cyano, pyrazole, triazole, pyridine or pyrimidine; 
 R 8  is methyl or 2-(trimethylsilyl)ethoxy)methyl, cyclopropyl, or —CH 2 -cyclopropyl; and 
 R 9  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. 
 
     
     
         27 . 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:
 X is C or N and the dashed line represents a single or double bond; 
 A 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 1  is methyl; 
 R 2  is hydrogen, methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 ; 
 R 3  is methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 : 
 or R 2  and R 3 , together with the carbon atom to which they are attached, are optionally joined to form cyclobutyl; 
 R 4  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 7 , pyrazole optionally substituted with 1 substituent R 8 , and pyrimidine; 
 or R 4  and R 3 , 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 
 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
       
       represents the core ring of Formula I, i.e. the N attached to R 4  and the C attached to R 3 ;
 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 7-membered heterocyclic ring selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
       
       represents the core ring of Formula I, i.e. the N attached to R 4  and the C attached to R 3 /R 2 ;
 R 5  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 , —S(O) 2 CH 3 , phenyl, thiazole, pyridine or pyrazine;
 R 6  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, cyclopentyl, benzyl, phenyl, optionally substituted with 1, 2 or 3 substituents R 9 , 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 7  at each occurrence is independently —C(O)NH 12  fluoro, chloro, cyano, pyrazole, triazole, pyridine or pyrimidine; 
 R 8  is methyl or 2-(trimethylsilyl)ethoxy)methyl, cyclopropyl, or —CH 2 -cyclopropyl; and 
 R 9  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. 
 
     
     
         28 . The method of  claim 27 , 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. 
     
     
         29 . The method of  claim 28 , 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. 
     
     
         30 . 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:
 X is C or N and the dashed line represents a single or double bond; 
 A 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 1  is methyl; 
 R 2  is hydrogen, methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 ; 
 R 3  is methyl, ethyl, —CH 2 -cyclopropyl, or —CH 2 CF 3 ; 
 or R 2  and R 3 , together with the carbon atom to which they are attached, are optionally joined to form cyclobutyl; 
 R 4  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 7 , pyrazole optionally substituted with 1 substituent R 8 , and pyrimidine; 
 or R 4  and R 3 , 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 
 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
       
       represents the core ring of Formula I, i.e. the N attached to R 4  and the C attached to R 3 ;
 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 7-membered heterocyclic ring selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
       
       represents the core ring of Formula I, i.e. the N attached to R 4  and the C attached to R 3 /R 2 ;
 R 5  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 6  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 substituted with 1, 2 or 3 substituents R 9 , 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 7  at each occurrence is independently —C(O)NH 2 , fluoro, chloro, cyano, pyrazole, triazole, pyridine or pyrimidine; 
 R 8  is methyl or 2-(trimethylsilyl)ethoxy)methyl cyclopropyl, or —CH 2 -cyclopropyl; and 
 R 9  at each occurrence is independently elected from the group consisting of fluoro, chloro, bromo, —S(O) 2 CH 3 , —OCF 3 , —CF 3 , —CN, pyridine, triazole, and pyrazole; and 
 a pharmaceutically acceptable carrier. 
 
     
     
         31 . The method of  claim 30 , 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. 
     
     
         32 . The method of  claim 31 , 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.