Phosphatidylinositol 3-kinase inhibitors

Abstract

The present disclosure provides phosphatidylinositol 3-kinase (PI3K) inhibitors of formula (I), or pharmaceutically acceptable salts or isomers thereof, in which n, m, R 1 , R 2 , R 4 , and R 3 are as defined herein. These compounds are useful for treatment of conditions mediated by one or more PI3K isoforms, such as PI3Kδ. The present disclosure further provides pharmaceutical compositions that include a compound of formula (I), or pharmaceutically acceptable salts or isomers thereof, and methods of using these compounds and compositions to treat conditions mediated by one or more PI3K isoforms, such as PI3Kδ.

What is claimed is: 
     
         1 . A compound having the structure of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, isomer, or a mixture thereof, wherein:
 n is 0, 1, 2, 3, or 4; 
 each R 1  is independently selected from halo, cyano, alkyl, or alkylsulfonyl, wherein the alkyl moiety may be optionally substituted with 1 to 3 halogen; 
 m is 0, 1, 2, or 3; 
 each R 2  is independently selected from halo, —NH 2 , alkoxy, alkyl, or cycloalkyl, wherein the alkyl moiety may be optionally substituted with 1 to 3 halogen; 
 R 3  is hydrogen, alkyl, or cycloalkyl, wherein the alkyl moiety may be optionally substituted with cycloalkyl; and 
 R 4  is cyano, halo, or CONH 2 . 
 
     
     
         2 . The compound of  claim 1 , wherein
 n is 1 or 2;   each R 1  is independently selected from halo, cyano, alkyl, or alkylsulfonyl, wherein the alkyl moiety may be optionally substituted with 1 to 3 halogen;   m is 0, 1, or 2;   each R 2  is independently selected from halo, alkoxy, alkyl, or cycloalkyl, wherein the alkyl moiety may be optionally substituted with 1 to 3 halogen;   R 3  is hydrogen, alkyl, or cycloalkyl, wherein the alkyl moiety may be optionally substituted with cycloalkyl; and   R 4  is cyano.   
     
     
         3 . The compound of  claim 1 , wherein each R 1  is independently selected from halo, cyano, C 1-4 alkyl, C 1-4  haloalkyl, or C 1-4 alkylsulfonyl. 
     
     
         4 . The compound of  claim 3 , wherein each R 1  is independently selected from fluoro, chloro, iodo, bromo, cyano, methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, methylsulfonyl, ethylsulfonyl, or propylsulfonyl. 
     
     
         5 . The compound of  claim 1 , wherein each R 2  is independently selected from halo, —NH 2 , C 1-4 alkoxy, C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl. 
     
     
         6 . The compound of  claim 5 , wherein each R 2  is independently selected from —NH 2 , fluoro, chloro, iodo, bromo, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 
     
     
         7 . The compound of  claim 1 , wherein R 3  is selected from hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl. 
     
     
         8 . The compound of  claim 7 , wherein R 3  is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or C 3-6 cycloalkylC 1-4 alkyl. 
     
     
         9 . The compound of  claim 8 , wherein R 3  is selected from hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, or cyclopropylbutyl. 
     
     
         10 . The compound of  claim 1 , wherein R 4  is selected from cyano, fluoro, chloro, bromo, or CONH 2 . 
     
     
         11 . The compound of  claim 1 , wherein n is 1. 
     
     
         12 . The compound of  claim 1 , wherein n is 2. 
     
     
         13 . The compound of  claim 1 , wherein m is 0. 
     
     
         14 . The compound of  claim 1 , wherein m is 1. 
     
     
         15 . The compound of  claim 1 , wherein m is 2. 
     
     
         16 . The compound of  claim 1 , wherein the compound is a (S)-enantiomer. 
     
     
         17 . The compound of  claim 1 , wherein the compound is a (R)-enantiomer. 
     
     
         18 . The compound of  claim 1 , wherein the compound is an atropisomer. 
     
     
         19 . The compound of  claim 1 , wherein the compound is selected from the group consisting of:
 (S)-2,4-diamino-6-(1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl) (cyclopropyl)methylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)-2-cyclopropylethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(6-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-methyl-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-(methylsulfonyl)-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(4-oxo-3-(pyridin-3-yl)-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazoline-5-carbonitrile;   (S)-2,4-diamino-6-(1-(3-(5-fluoropyridin-3-yl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-3-(5-chloropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-3-(5-methoxypyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-3-(5-(difluoromethyl)pyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-3-(5-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((5-chloro-3-(5-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl) (cyclopropyl)methylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-4-oxo-3-(5-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-3-(5-cyclopropylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((5-chloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl) (cyclopropyl)methylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(8-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5,8-dichloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5,8-difluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl) (cyclopropyl)methylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(cyclopropyl(5,8-dichloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)methylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)-2-cyclopropylethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5,8-dichloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-8-fluoro-3-(5-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl) (cyclopropyl)methylamino)pyrimidine-5-carbonitrile;   (S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazoline-5-carbonitrile;   (S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)propyl)-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazoline-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-6-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((5-chloro-6-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl) (cyclopropyl)methylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-3-(2-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-3-(4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-6-fluoro-3-(4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-3-(5-fluoro-2-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;   (R)-2,4-Diamino-6-((1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (R)-2,4-Diamino-6-((1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;   (R)-2,4-Diamino-6-(((5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl) (cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;   (R)-2,4-Diamino-6-((1-(5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (R)-2,4-diamino-6-((1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (R)-2,4-diamino-6-((1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-Diamino-6-((1-(5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-(methylsulfonyl)-3-(pyridin-3-yl)quinazolin-4(3H)-one;   (S)-2,4-Diamino-6-((1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carboxamide;   (S)-5-Chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(5-fluoropyridin-3-yl)quinazolin-4(3h)-one;   (S)-2-(1-((2,6-Diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-fluoro-3-(pyridin-3-yl)quinazolin-4(3H)-one;   (S)-5-Chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(pyridin-3-yl)quinazolin-4(3H)-one;   (S)-2-(1-((2,6-Diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-6-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazoline-8-carbonitrile;   (S)-2-(1-((2,6-Diamino-5-cyanopyrimidin-4-yl)amino)propyl)-6-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile;   (S)-2-(Cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-6-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile;   (S)-2,4-Diamino-6-((1-(5-chloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methylbutyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-Diamino-6-((1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)-3-methylbutyl)amino)pyrimidine-5-carbonitrile;   (S)-5-Chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-fluoro-3-(pyridin-3-yl)quinazolin-4(3h)-one;   (S)-2,4-diamino-6-((1-(5-bromo-8-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-bromo-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;   (S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-8-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazoline-5-carbonitrile;   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazoline-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-bromo-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-Diamino-6-(((5-chloro-8-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl) (cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-Diamino-6-(((5-chloro-8-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl) (cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(((5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl) (cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(((5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl) (cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-chloro-8-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-chloro-8-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(6-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(6-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-chloro-3-(4,5-dimethylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-chloro-3-(4,5-dimethylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-Diamino-6-((1-(3-(4-methylpyridin-3-yl)-4-oxo-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-Diamino-6-((1-(3-(4-methylpyridin-3-yl)-4-oxo-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-3-(6-aminopyridin-3-yl)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoroquinazolin-4(3H)-one;   (S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-8-chloro-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-3-(6-aminopyridin-3-yl)-5,8-dichloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)quinazolin-4(3H)-one;   (S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5,8-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)quinazolin-4(3H)-one;   (S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)quinazolin-4(3H)-one;   (S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;   (S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-fluoroquinazolin-4(3H)-one;   (S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)quinazolin-4(3H)-one;   (S)-2,4-diamino-6-(((3-(6-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) (cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5,8-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5,8-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(((3-(6-amino-4-methylpyridin-3-yl)-5,8-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl) (cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(((3-(6-amino-4-methylpyridin-3-yl)-5,8-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl) (cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoroquinazolin-4(3H)-one;   (S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5-chloro-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)butyl)quinazolin-4(3H)-one;   (S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile;   (S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)butyl)-6-fluoroquinazolin-4(3H)-one;   (S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5-chloro-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile;   (S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-8-fluoroquinazolin-4(3H)-one;   (S)-2,4-diamino-6-(((3-(6-aminopyridin-3-yl)-5-chloro-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl) (cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(3-(5-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; and   (S)-4-amino-6-((1-(3-(5-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   
       or a pharmaceutically acceptable salt, isomer, or a mixture thereof. 
     
     
         20 . The compound of  claim 19 , wherein the compound is an atropisomer. 
     
     
         21 . A pharmaceutical composition comprising:
 the compound, a pharmaceutically acceptable salt, isomer, or a mixture thereof of  claim 1 ; and at least one pharmaceutically acceptable vehicle.   
     
     
         22 . A method for treating a disease or condition in a human in need thereof, comprising administering to the human a therapeutic effective amount of the compound, a pharmaceutically acceptable salt, isomer, or a mixture thereof of  claim 1 . 
     
     
         23 . The method of  claim 22 , wherein the disease or condition is an inflammatory disorder, an autoimmune disease, or a cancer. 
     
     
         24 . The method of  claim 22 , wherein the disease or condition is lymphoma, multiple myeloma, or leukemia. 
     
     
         25 . The method of any of  claims 22 , wherein the disease or condition is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small-cell lung cancer, colon cancer, systemic lupus erythematosus (SLE), myestenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), Sjoegren's syndrome, autoimmune hemolytic anemia, psoriasis, chronic obstructive pulmonary disease (COPD), or asthma. 
     
     
         26 . The method of  claim 22 , wherein the compound, a pharmaceutically acceptable salt, isomer, or a mixture thereof, is administered intravenously, intramuscularly, parenterally, nasally or orally. 
     
     
         27 . A kit comprises the compound, a pharmaceutically acceptable salt, isomer, or a mixture thereof of  claim 1 , or a label and/or instructions for use.