8-heteroarylpurine mnk2 inhibitors for treating metabolic disorders

Abstract

Compounds of the formula are disclosed as Mnk2 inhibitors which are useful for the treatment and prevention of metabolic disorders such as obesity and diabetes.

1 . A method of treating a disorder selected from the group consisting of type II diabetes, a metabolic disorder, obesity, an eating disorder, cachexia, type I diabetes, osteoarthritis, gallstones, sleep apnea, a neurodegenerative disorder, cancer, acute myeloid leukemia, a disorder associated with MNK1 activity, a disorder associated with MNK2 activity, and a disorder associated with FLT-3 activity, the method comprising administering to a patient in need thereof an effective amount of a composition comprising formula I: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is chosen from aryl, heteroaryl, C 1 -C 10  alkyl, substituted aryl, substituted heteroaryl, and substituted C 1 -C 10  alkyl; 
         n is chosen from 0, 1, and 2; 
         R 1a  is hydrogen or methyl; 
         R 2  is chosen from;
 hydrogen; 
 C 1 -C 6  alkyl; and 
 C 1 -C 6  alkyl substituted with CN, lower alkoxy, or fluorine; and 
 
         R 3  is chosen from aryl substituted with one or two alkoxy, and heteroaryl optionally substituted with one to three substituents chosen from the group consisting of: 
         lower alkyl, hydroxyl, hydroxyloweralkyl, lower alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonyl, and halogen. 
       
     
     
         2 . The method of  claim 1 , wherein:
 R 3  is chosen from heteroaryl optionally substituted with one to three substituents chosen from the group consisting of:   lower alkyl, hydroxy, lower alkoxy, amino, alkylamino, dialkylamino, and acylamino.   
     
     
         3 . The method of  claim 2 , wherein:
 R 1  is chosen from aryl, heteroaryl, and C 1 -C 10  alkyl, each optionally substituted with one to three substituent(s) chosen from the group consisting of:   alkyl, halo, lower alkoxy, haloalkyl, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, mercapto, alkylthio, alkylsulfinyl, alkylsulfonyl, acylamino, acylaminoalkyl, oxaalkyl, heterocyclylalkyl, dialkylaminoalkoxy, (alkyl)(acyl)aminoalkyl, trifluoromethoxy, acylaminoalkoxy, and heterocyclylalkoxy.   
     
     
         4 . The method of  claim 2 , wherein, wherein R 1  is phenyl substituted with one substitutent chosen from the group consisting of: methylenedioxy, halogen, alkyl, aminomethyl, alkylaminomethyl, dialkylaminomethyl, oxaalkyl, dialkylaminoalkoxy, (alkyl)(acyl)aminoalkyl, trifluoromethoxy, acylaminoalkoxy, heterocyclylalkoxy, and 
       
         
           
           
               
               
           
         
       
       wherein 
       
         
           
           
               
               
           
         
       
       is a nitrogen heterocycle; and
 q is 1-3. 
 
     
     
         5 . The method of  claim 2 , wherein R 1  is phenyl or phenyl substituted with methylenedioxy, lower alkyl, halogen, alkyl, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, and acylaminoalkyl. 
     
     
         6 . The method of  claim 2 , wherein R 1  is thienyl and n is 2. 
     
     
         7 . The method of  claim 2 , wherein R 1  is lower alkyl and n is 0. 
     
     
         8 . The method of  claim 2 , wherein R 1a  is H. 
     
     
         9 . The method of  claim 2 , wherein n is zero. 
     
     
         10 . The method of  claim 2 , wherein R 2  is chosen from C 1 -C 3  alkyl, fluorinated C 1 -C 3  alkyl, and cyano C 1 -C 3  alkyl. 
     
     
         11 . The method of  claim 2 , wherein: wherein R 2  is chosen from cyclopropyl, isopropyl, 2-cyanoethyl, ethyl, trifluoroethyl, hydrogen, and methyl. 
     
     
         12 . The method of  claim 2 , wherein R 3  is chosen from nitrogen heteroaryl and substituted nitrogen heteroaryl. 
     
     
         13 . The method of  claim 2 , wherein R 3  is formula II 
       
         
           
           
               
               
           
         
         wherein 
         X is chosen from CH, C-halogen, and nitrogen; 
         Y is chosen from H, halogen, NH 2 , NHMe, NHEt, NMe 2 , NHAc, OH, OMe, OEt, Me, and Et. 
       
     
     
         14 . The method of  claim 13 , wherein Y is chosen from H, NH 2 , and NHMe. 
     
     
         15 . The method of  claim 1 , wherein R 3  is substituted phenyl. 
     
     
         16 . The method of  claim 13 , wherein R 3  is chosen from 4-pyridinyl, 2-aminopyrimidin-4-yl and 2-(methylamino)pyrimidin-4-yl. 
     
     
         17 . The method of  claim 13 , wherein R 3  is chosen from 4-pyridyl, 4-pyrimidinyl, 4-(2-aminopyrimidyl), and 4-(2-aminopyridinyl). 
     
     
         18 . The method of  claim 2 , wherein:
 R 1  is chosen from phenyl and phenyl substituted with alkoxy, halogen, aminoalkyl, or acylaminoalkyl;   n is chosen from 0, 1, and 2;   R 1a  is hydrogen;   R 2  is chosen from cyclopropyl, isopropyl, ethyl, 2-cyano-ethyl, hydrogen, and methyl; and   R 3  is chosen from 4-pyridyl, 4-pyrimidinyl, 4-(2-aminopyrimidyl), and 4-(2-aminopyridinyl).   
     
     
         19 . The method of  claim 1 , wherein the composition is selected from:
 9-Cyclopropyl-8-(2-(methylamino)pyrimidin-4-yl)-N-m-tolyl-9H-purin-2-amine;   N-(4-(9-Methyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)benzyl)-N-methylacetamide;   8-(2-Aminopyridin-4-yl)-9-cyclopropyl-N-(3-methoxyphenyl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-ethyl-N-(4-fluoro-3-methylphenyl)-9H-purin-2-amine;   tert-Butyl 4-(9-cyclopropyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)phenethylcarbamate;   9-Ethyl-N-(4-fluoro-3-methoxyphenyl)-8-(2-(methylamino)pyrimidin-4-yl)-9H-purin-2-amine;   9-Cyclopropyl-N-(3-fluorophenyl)-8-(2-(methylamino)pyrimidin-4-yl)-9H-purin-2-amine;   N-(4-(9-Ethyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)benzyl)-N-methylacetamide;   8-(2-Aminopyrimidin-4-yl)-9-ethyl-N-(4-ethylphenyl)-9H-purin-2-amine;   9-Methyl-N-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Cyclopropyl-8-(pyridin-4-yl)-N-(3-(trifluoromethoxy)phenyl)-9H-purin-2-amine;   9-Ethyl-N-(3-(2-morpholinoethoxy)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Methyl-N-(4-(piperazin-1-ylmethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(3-(2-(Cyclopentylamino)ethyl)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(3-(Aminomethyl)phenyl)-9-cyclopropyl-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Isopropyl-N-(3-methoxyphenyl)-8-(2-(methylamino)pyrimidin-4-yl)-9H-purin-2-amine;   N-(8-(2-Aminopyrimidin-4-yl)-9-cyclopropyl-9H-purin-2-yl)quinolin-6-amine;   N-(3-Chlorophenyl)-9-cyclopropyl-8-(2-(methylamino)pyrimidin-4-yl)-9H-purin-2-amine;   9-Cyclopropyl-N-(4-((methylamino)methyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Cyclopropyl-N-phenethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-ethyl-N-(3-fluorophenyl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-isopropyl-N-(3-methoxyphenyl)-9H-purin-2-amine;   9-Cyclopropyl-N-(3-methoxyphenyl)-8-(2-(methylamino)pyrimidin-4-yl)-9H-purin-2-amine;   9-Ethyl-N-(3-(2-methoxyethoxy)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(3,4-Difluorophenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(2,4-dimethylphenyl)-9-ethyl-9H-purin-2-amine;   9-Ethyl-N-(3-(2-(ethylamino)ethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Methyl-N-(3-(morpholinomethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Methyl-N-(4-(2-(piperidin-1-yl)ethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(4-(Aminomethyl)phenyl)-9-cyclopropyl-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-cyclopropyl-N-(4-fluorophenyl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-ethyl-N-o-tolyl-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-ethyl-N-(3-ethylphenyl)-9H-purin-2-amine;   N-(8-(2-Aminopyrimidin-4-yl)-9-cyclopropyl-9H-purin-2-yl)quinolin-8-amine;   8-(2-Aminopyrimidin-4-yl)-N-(4-fluorophenyl)-9-(2,2,2-trifluoroethyl)-9H-purin-2-amine;   N-(4-(2-Aminoethyl)phenyl)-9-methyl-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Ethyl-N-(3-ethylphenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Isopropyl-N-(3-methoxyphenyl)-8-(pyrimidin-4-yl)-9H-purin-2-amine;   N-(4-(2-(Cyclopropylamino)ethyl)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(8-(2-Aminopyrimidin-4-yl)-9-cyclopropyl-9H-purin-2-yl)isoquinolin-5-amine;   N-(3-(2-(Dimethylamino)ethyl)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-cyclopropyl-N-(3-methoxyphenyl)-9H-purin-2-amine;   9-Ethyl-N-(3-(2-(piperidin-1-yl)ethoxy)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Methyl-N-(4-((methylamino)methyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyridin-4-yl)-9-ethyl-N-(3-ethylphenyl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-ethyl-N-p-tolyl-9H-purin-2-amine;   9-Cyclopropyl-N-(3,4-dimethoxyphenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Methyl-8-(pyridin-4-yl)-N-(4-(2-(pyrrolidin-1-yl)ethyl)phenyl)-9H-purin-2-amine;   9-Ethyl-N-(4-fluorophenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-ethyl-N-(3-fluoro-2-methylphenyl)-9H-purin-2-amine;   9-Methyl-8-(pyridin-4-yl)-N-(3-(2-(pyrrolidin-1-yl)ethyl)phenyl)-9H-purin-2-amine;   N-(3-(Aminomethyl)phenyl)-9-methyl-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Cyclopropyl-N-(4-fluorophenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(4-Methylbenzyl)-9-cyclopropyl-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(4-(9-Ethyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)benzyl)acetamide;   N-(3-(9-Methyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)benzyl)acetamide;   N-(4-(Aminomethyl)phenyl)-9-methyl-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-cyclopropyl-N-(2-(thiophen-2-yl)ethyl)-9H-purin-2-amine;   8-(2-Aminopyridin-4-yl)-9-ethyl-N-(4-fluorophenyl)-9H-purin-2-amine;   N-(3-(2-(Dimethylamino)ethoxy)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Methyl-N-(4-(piperidin-1-ylmethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(3,5-difluorophenyl)-9-ethyl-9H-purin-2-amine;   N-(4-(2-(Dimethylamino)ethyl)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Cyclopropyl-8-(2-(methylamino)pyrimidin-4-yl)-N-phenyl-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(2,5-difluorophenyl)-9-ethyl-9H-purin-2-amine;   9-Cyclopropyl-N-(3-(2-morpholinoethoxy)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(3,4-difluorophenyl)-9-ethyl-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(2,3-difluorophenyl)-9-ethyl-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(4-fluorophenyl)-9-methyl-9H-purin-2-amine;   tert-Butyl 4-(9-cyclopropyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)benzylcarbamate;   9-Cyclopropyl-N-(2,4-dimethoxyphenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Methyl-N-(3-(2-(piperidin-1-yl)ethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(4-(2-Aminoethyl)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Ethyl-N-(3-((ethylamino)methyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-cyclopropyl-N-m-tolyl-9H-purin-2-amine;   N-(4-(9-Methyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)phenethyl)acetamide;   8-(2-Aminopyrimidin-4-yl)-N-(3,4-dimethylphenyl)-9-ethyl-9H-purin-2-amine;   N-(4-Fluorophenyl)-8-(2-(methylamino)pyrimidin-4-yl)-9-(2,2,2-trifluoroethyl)-9H-purin-2-amine;   N-(3-(9-Cyclopropyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)benzyl)acetamide;   (4-(2-(4-Fluorophenylamino)-9-methyl-9H-purin-8-yl)pyridin-2-yl)methanol;   N-(4-((Cyclopentylamino)methyl)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(2-chloro-5-fluorophenyl)-9-cyclopropyl-9H-purin-2-amine;   N-(4-Fluorophenyl)-9-methyl-8-(2-(methylamino)pyrimidin-4-yl)-9H-purin-2-amine;   9-Cyclopropyl-N-(3-methoxyphenyl)-8-(pyrimidin-4-yl)-9H-purin-2-amine;   N 1 -(8-(2-Aminopyrimidin-4-yl)-9-cyclopropyl-9H-purin-2-yl)-N 4 ,N 4  dimethylbenzene-1,4-diamine;   9-Methyl-8-(pyridin-4-yl)-N-(2-(thiophen-2-yl)ethyl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(2,3-dimethylphenyl)-9-ethyl-9H-purin-2-amine;   N-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   3-(2-(3-Methoxyphenylamino)-8-(pyrimidin-4-yl)-9H-purin-9-yl)propanenitrile;   9-Ethyl-N-(3-ethylphenyl)-8-(2-(methylamino)pyrimidin-4-yl)-9H-purin-2-amine;   9-Ethyl-N-(4-((ethylamino)methyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Methyl-N-(4-(2-morpholinoethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Chloropyridin-4-yl)-9-cyclopropyl-N-phenyl-9H-purin-2-amine;   9-Cyclopropyl-8-(1-methyl-1H-pyrrol-2-yl)-N-(2-(thiophen-2-yl)ethyl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-ethyl-N-(3-fluoro-4-methylphenyl)-9H-purin-2-amine;   9-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(3,5-dimethylphenyl)-9-ethyl-9H-purin-2-amine;   9-Methyl-N-(4-(morpholinomethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(3-((Dimethylamino)methyl)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyridin-4-yl)-9-ethyl-N-(4-fluoro-3-methoxyphenyl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(3-chlorophenyl)-9-ethyl-9H-purin-2-amine;   N-(4-(9-Methyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)phenethyl)-N-methylacetamide;   8-(2-Aminopyrimidin-4-yl)-N-(4-chloro-2-fluorophenyl)-9-cyclopropyl-9H-purin-2-amine;   9-Cyclopropyl-N-(4-(2-(methylamino)ethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Cyclopropyl-N-(2-fluorophenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Ethyl-N-(4-(2-(ethylamino)ethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Ethyl-N-(4-((isopropylamino)methyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Methyl-N-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Ethyl-N-(3-fluorophenyl)-8-(2-(methylamino)pyrimidin-4-yl)-9H-purin-2-amine;   N-(4-Fluorophenyl)-9-methyl-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Cyclopropyl-N-phenyl-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(2,3-dihydro-1H-inden-5-yl)-9-ethyl-9H-purin-2-amine;   9-Ethyl-N-(4-(2-methoxyethoxy)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(3-(Aminomethyl)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(3-((Cyclopentylamino)methyl)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Methyl-N-(4-(2-(methylamino)ethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(4-(2-(Cyclopentylamino)ethyl)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Methyl-N-(3-(2-(piperazin-1-yl)ethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(2-Fluorophenethyl)-9-cyclopropyl-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Cyclopropyl-N-(4-fluorophenyl)-8-(2-(methylamino)pyrimidin-4-yl)-9H-purin-2-amine;   9-Cyclopropyl-8-(pyridin-4-yl)-N-(3,4,5-trimethoxyphenyl)-9H-purin-2-amine;   9-Methyl-8-(pyridin-4-yl)-N-(4-(pyrrolidin-1-ylmethyl)phenyl)-9H-purin-2-amine;   9-Cyclopropyl-N-(3-ethylphenyl)-8-(2-(methylamino)pyrimidin-4-yl)-9H-purin-2-amine;   8-(6-Aminopyridin-3-yl)-9-ethyl-N-(4-fluorophenyl)-9H-purin-2-amine;   N 1 -(8-(2-Aminopyrimidin-4-yl)-9-cyclopropyl-9H-purin-2-yl)-N 3 ,N 3 -dimethylbenzene-1,3-diamine;   N-(3-((Cyclopropylamino)methyl)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(2,4-difluorophenyl)-9-ethyl-9H-purin-2-amine;   9-Cyclopropyl-N-(3,5-dimethoxyphenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(4-(9-Cyclopropyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)phenethyl)acetamide;   N-(4-(9-Ethyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)phenethyl)-N-methylacetamide;   N-(4-(9-Methyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)benzyl)acetamide;   9-Ethyl-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(4-(2-Methoxyethoxy)phenyl)-9-methyl-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Chloropyridin-4-yl)-9-isopropyl-N-(3-methoxyphenyl)-9H-purin-2-amine;   8-(2-Aminopyridin-4-yl)-9-isopropyl-N-(3-methoxyphenyl)-9H-purin-2-amine;   9-Ethyl-N-(4-(2-(methylamino)ethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Ethyl-N-(4-(2-morpholinoethoxy)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyridin-4-yl)-N-(3,4-difluorophenyl)-9-ethyl-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(2-chlorophenyl)-9-ethyl-9H-purin-2-amine;   9-Methyl-N-(3-(piperidin-1-ylmethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(6-Aminopyridin-3-yl)-9-ethyl-N-(3-ethylphenyl)-9H-purin-2-amine;   N-(4-(9-Cyclopropyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)benzyl)-N-methylacetamide;   9-Cyclopropyl-8-(pyridin-3-yl)-N-(2-(thiophen-2-yl)ethyl)-9H-purin-2-amine;   N-(2,2-Dimethylbenzo[d][1,3]dioxol-5-yl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(4-(9-Cyclopropyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)phenethyl)-N-methylacetamide;   9-Cyclopropyl-8-(thiazol-2-yl)-N-(2-(thiophen-2-yl)ethyl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(2,6-difluorophenyl)-9-ethyl-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-ethyl-N-(2-fluoro-4-methylphenyl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(4-chlorophenyl)-9-ethyl-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(3-chloro-4-fluorophenyl)-9-cyclopropyl-9H-purin-2-amine;   9-Methyl-N-(3-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Ethyl-N-(3-((isopropylamino)methyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(8-(2-Aminopyrimidin-4-yl)-9-cyclopropyl-9H-purin-2-yl)quinolin-5-amine;   N-(2-(4-(9-Methyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)phenoxy)ethyl)acetamide;   8-(2-Chloropyridin-4-yl)-9-cyclopropyl-N-(3-methoxyphenyl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(2,5-dimethylphenyl)-9-ethyl-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-ethyl-N-(4-fluoro-2-methylphenyl)-9H-purin-2-amine;   N-(4-((Cyclopropylamino)methyl)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-ethyl-N-(2-ethylphenyl)-9H-purin-2-amine;   N-(4-Methoxyphenyl)-9-methyl-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Cyclopropyl-8-(pyrimidin-4-yl)-N-(2-(thiophen-2-yl)ethyl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-ethyl-N-(4-fluoro-3-methoxyphenyl)-9H-purin-2-amine;   9-Cyclopropyl-8-(1-methyl-1H-imidazol-5-yl)-N-(2-(thiophen-2-yl)ethyl)-9H-purin-2-amine;   N-(Benzo[d][1,3]dioxol-5-yl)-9-cyclopropyl-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(4-(2-(Dimethylamino)ethoxy)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(Benzo[d]thiazol-6-yl)-9-cyclopropyl-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Ethyl-N-(4-fluoro-3-methoxyphenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(2,3-dihydro-1H-inden-4-yl)-9-ethyl-9H-purin-2-amine;   N-(3-(2-(Cyclopropylamino)ethyl)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Ethyl-N-(4-fluorophenyl)-8-(2-(methylamino)pyrimidin-4-yl)-9H-purin-2-amine;   9-Ethyl-N-(4-(2-(isopropylamino)ethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(3-chloro-2-fluorophenyl)-9-cyclopropyl-9H-purin-2-amine;   3-(8-(2-Aminopyrimidin-4-yl)-2-(3-methoxyphenylamino)-9H-purin-9-yl)propanenitrile;   8-(2-Aminopyridin-4-yl)-N-(4-fluorophenyl)-9-methyl-9H-purin-2-amine;   N-(4-Fluorophenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(4-Chlorophenyl)-9-cyclopropyl-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-cyclopropyl-N-(3-ethylphenyl)-9H-purin-2-amine;   9-Ethyl-N-(4-((methylamino)methyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(4-Fluorophenyl)-8-(pyridin-4-yl)-9-(2,2,2-trifluoroethyl)-9H-purin-2-amine;   N-(3-(9-Ethyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)benzyl)acetamide;   9-Methyl-8-(pyridin-4-yl)-N-(3-(pyrrolidin-1-ylmethyl)phenyl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-ethyl-N-(5-fluoro-2-methylphenyl)-9H-purin-2-amine;   8-(2-Chloropyridin-4-yl)-9-cyclopropyl-N-(2-(thiophen-2-yl)ethyl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(5-chloro-2-fluorophenyl)-9-cyclopropyl-9H-purin-2-amine;   9-Methyl-N-(3-(2-morpholinoethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Cyclopropyl-N-(2-methoxyphenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Chloropyridin-4-yl)-9-ethyl-N-(3-ethylphenyl)-9H-purin-2-amine;   9-Cyclopropyl-N-(3-methoxyphenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(2-Methoxyphenethyl)-9-cyclopropyl-8-(pyridin-4-yl)-9H-purin-2-amine;   Ethyl-4-(2-(4-fluorophenylamino)-9-methyl-9H-purin-8-yl)picolinate;   8-(2-Aminopyrimidin-4-yl)-N-(2-chloro-4-fluorophenyl)-9-cyclopropyl-9H-purin-2-amine;   N-(4-(2-Aminoethyl)phenyl)-9-cyclopropyl-8-(pyridin-4-yl)-9H-purin-2-amine;   N-Cyclopentyl-9-cyclopropyl-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-cyclopropyl-N-(3-fluorophenyl)-9H-purin-2-amine;   9-Cyclopropyl-8-(pyridin-4-yl)-N-(2-(thiophen-2-yl)ethyl)-9H-purin-2-amine;   8-(2-Aminopyridin-4-yl)-9-cyclopropyl-N-phenyl-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-N-(3-chlorophenyl)-9-cyclopropyl-9H-purin-2-amine;   N-(4-(Aminomethyl)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(4-(9-Methyl-8-(pyridin-4-yl)-9H-purin-2-ylamino)benzyl)-2,2,2-trifluoroacetamide;   9-Ethyl-N-(3-(2-(isopropylamino)ethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   N-(3,4-Difluorophenyl)-9-ethyl-8-(2-(methylamino)pyrimidin-4-yl)-9H-purin-2-amine;   9-Methyl-N-(3-(piperazin-1-ylmethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Cyclopropyl-N-isobutyl-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Ethyl-8-(2-(methylamino)pyrimidin-4-yl)-N-m-tolyl-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-cyclopropyl-N-phenyl-9H-purin-2-amine;   9-Cyclopropyl-8-(1H-pyrrol-2-yl)-N-(2-(thiophen-2-yl)ethyl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-ethyl-N-(4-fluorophenyl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-ethyl-N-m-tolyl-9H-purin-2-amine;   9-Methyl-N-(4-(2-(piperazin-1-yl)ethyl)phenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(Pyridin-4-yl)-N-(2-(thiophen-2-yl)ethyl)-9H-purin-2-amine;   N-(4-((Dimethylamino)methyl)phenyl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-2-amine;   9-Cyclopropyl-N-(4-methoxyphenyl)-8-(pyridin-4-yl)-9H-purin-2-amine;   8-(2-Aminopyrimidin-4-yl)-9-ethyl-N-(5,6,7,8-tetrahydronaphthalen-1-yl)-9H-purin-2-amine.