Phosphatidylinositol 3-kinase inhibitors

Abstract

The present disclosure provides phosphatidylinositol 3-kinase (PI3K) inhibitors of formula (J), or pharmaceutically acceptable salts thereof, in which A, n, m, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein. These compounds are useful for treatment of conditions mediated by one or more PI3K isoforms. The present disclosure further provides pharmaceutical compositions that include a compound of formula (J), or pharmaceutically acceptable salts thereof, and methods of using these compounds and compositions to treat conditions mediated by one or more PI3K isoforms.

1 - 20 . (canceled) 
     
     
         21 . A method for treating a human, who has or is suspected of having a disease or condition responsive or believed to be responsive to the inhibition of PI3Kδ activity, comprising administering to the human a compound having the structure of formula (J): 
       
         
           
           
               
               
           
         
         wherein: 
         A is N or CH; 
         n is 0, 1, 2, 3, or 4; 
         m is 0, 1, 2, 3, or 4; 
         each R 1  is independently selected from optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, NHC(═O)alkylene-N(R 1x ) 2 , NO 2 , OR 1x , N(R 1x ) 2 , OC(═O)R 1x , C(═O)R 1x , C(═O)OR 1x , aryl-OR 1y , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, NR 1x C(═O)alkylene-C(═O)OR 1x , aryl-O-alkylene-N(R 1x ) 2 , aryl-O—C(═O)R 1x , alkylene-C(═O)OR 1x , alkylene-C(═O)N(R 1x ) 2 , alkylene-C(═O)—Het, O-alkylene-C(═O)OR 1x , alkylene-O-alkylene-C(═O)OR 1x  C(═O)NR 1x SO 2 R 1x , alkylene-N(R 1x ) 2 , alkenylene-N(R 1x ) 2 , C(═O)NR 1x -alkylene-OR 1x , C(═O)NR 1x alkylene-Het, O-alkylene-N(R 1x ) 2 , O-alkylene-CH(OR 1y )CH 2 N(R 1x ) 2 , O-alkylene-Het, O-alkylene-C(═O)OR 1x , O-alkylene-C(═O)—Het, S-alkylene-OR 1x , O-alkylene-OR 1x , O—C 1-6 alkylene-CH(OR 1y )C 1-6 alkylene-OR 1x , O-alkylene-NR 1x C(═O)OR 1x , NR 1x -alkylene-N(R 1x ) 2 , NR 1x C(═O)R 1x , NR 1x C(═O)N(R 1x ) 2 , N(SO 2 -alkyl) 2 , NR 1x (SO 2 -alkyl), SO 2 R 1z , SO 2 N(R 1x ) 2 , alkylene-aryl, alkylene-Het, alkylene-OR 1y , alkylene-N(R 1x ) 2 , C(═O)N(R 1x ) 2 , NHC(═O)alkylene-aryl, aryl-O-alkylene-N(R 1x ) 2 , aryl-OC(═O)R 1y , NHC(═O)alkylene-heterocycloalkyl, NHC(═O)alkylene-Het, O-alkylene-O-alkylene-C(═O)OR 1y , C(═O)alkylene-Het, and NHC(═O)halo-alkyl,
 wherein Het is optionally substituted heteroaryl or optionally substitutedheterocycloalkyl, wherein R 1x  is independently hydrogen, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted aryl, wherein R 1y  is independently hydrogen, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, and wherein R 1z  is independently optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted aryl; 
 
         each R 2  is independently selected from halo, cyano, optionally substituted alkyl, haloalkyl, SO 2 N(R 2x ) 2 , and optionally substituted alkoxy,
 wherein R 2x  is hydrogen, optionally substituted alkyl, or optionally substituted haloalkyl; 
 
         R 3  is hydrogen, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl; 
         R 5  is hydrogen or alkyl, or R 5  and R 3  together with the atoms to which they are attached optionally form an optionally substituted four-, five- or six-membered heterocyclic ring; 
         R 4  is cyano, C(═O)NR 4x R 4y , SO 2 -alkyl, halo, haloalkyl, or C(═O)R 4x , 
         wherein each R 4x  and R 4y  is independently hydrogen, optionally substituted alkyl, or optionally substituted haloalkyl; 
         R 6  is NH 2 , halo, optionally substituted alkyl, or optionally substituted haloalkyl; and 
         R 7  is NH 2 , halo, optionally substituted alkyl, or optionally substituted haloalkyl; 
         provided that when R 5  and R 3  form a 5-membered heterocyclic ring that is optionally substituted with hydroxyl, halo, or methoxy, R 4  is cyano, R 6  is amino, and R 7  is amino, 
         or a pharmaceutically acceptable salt, isomer, or a mixture thereof. 
       
     
     
         22 . The method of  claim 21 , wherein the disease is selected from the group consisting of 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), juvenile myelomonocytic leukemia (JMML), multiple myeloma (MM), Hodgkin lymphoma, indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM), minimal residual disease (MRD), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), lymphoplasmacytic lymphoma, marginal zone lymphoma, Burkitt lymphoma, 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 cancers, CNS cancers, brain tumors, bone cancer, soft tissue sarcoma, systemic lupus erythematosus (SLE), myestenia gravis, rheumatoid arthritis (RA), psoriasis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), Sjoegren's syndrome, psoriasis, autoimmune hemolytic anemia, asthma, and chronic obstructive pulmonary disease (COPD). 
     
     
         23 . A method of inhibiting the activity of a phosphatidylinositol 3-kinase polypeptide by contacting the polypeptide with a compound having the structure of formula (J): 
       
         
           
           
               
               
           
         
         wherein: 
         A is N or CH; 
         n is 0, 1, 2, 3, or 4; 
         m is 0, 1, 2, 3, or 4; 
         each R 1  is independently selected from optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, NHC(═O)alkylene-N(R 1x ) 2 , NO 2 , OR 1x , N(R 1x ) 2 , OC(═O)R 1x , C(═O)R 1x , C(═O)OR 1x , aryl-OR 1y , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, NR 1x C(═O)alkylene-C(═O)OR 1x , aryl-O-alkylene-N(R 1x ) 2 , aryl-O—C(═O)R 1x , alkylene-C(═O)OR 1x , alkylene-C(═O)N(R 1x ) 2 , alkylene-C(═O)—Het, O-alkylene-C(═O)OR 1x , alkylene-O-alkylene-C(═O)OR 1x C(═O)NR 1x SO 2 R 1x , alkylene-N(R 1x ) 2 , alkenylene-N(R 1x ) 2 , C(═O)NR 1x -alkylene-OR 1x , C(═O)NR 1x alkylene-Het, O-alkylene-N(R 1x ) 2 , O-alkylene-CH(OR 1y )CH 2 N(R 1x ) 2 , —O-alkylene-Het, O-alkylene-C(═O)OR 1x , O-alkylene-C(═O)—Het, S-alkylene-OR 1x , O-alkylene-OR 1x , O—C 1-6 alkylene-CH(OR 1y )C 1-6 alkylene-OR 1x , O-alkylene-NR 1x C(═O)OR 1x , NR 1x -alkylene-N(R 1x ) 2 , NR 1x C(═O)R 1x , NR 1x C(═O)N(R 1x ) 2 , N(SO 2 -alkyl) 2 , NR 1x (SO 2 -alkyl), SO 2 R 1z , SO 2 N(R 1x ) 2 , alkylene-aryl, alkylene-Het, alkylene-OR 1y , alkylene-N(R 1x ) 2 , C(═O)N(R 1x ) 2 , NHC(═O)alkylene-aryl, aryl-O-alkylene-N(R 1x ) 2 , aryl-OC(═O)R 1y , NHC(═O)alkylene-heterocycloalkyl, NHC(═O)alkylene-Het, O-alkylene-O-alkylene-C(═O)OR 1y , C(═O)alkylene-Het, and NHC(═O)halo-alkyl,
 wherein Het is optionally substituted heteroaryl or optionally substitutedheterocycloalkyl, wherein R 1x  is independently hydrogen, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted aryl, wherein R 1y  is independently hydrogen, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, and wherein R 1z  is independently optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted aryl; 
 
         each R 2  is independently selected from halo, cyano, optionally substituted alkyl, haloalkyl, SO 2 N(R 2x ) 2 , and optionally substituted alkoxy,
 wherein R 2x  is hydrogen, optionally substituted alkyl, or optionally substituted haloalkyl; 
 
         R 3  is hydrogen, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl; 
         R 5  is hydrogen or alkyl, or R 5  and R 3  together with the atoms to which they are attached optionally form an optionally substituted four-, five- or six-membered heterocyclic ring; 
         R 4  is cyano, C(═O)NR 4x R 4y , SO 2 -alkyl, halo, haloalkyl, or C(═O)R 4x , 
         wherein each R 4x  and R 4y  is independently hydrogen, optionally substituted alkyl, or optionally substituted haloalkyl; 
         R 6  is NH 2 , halo, optionally substituted alkyl, or optionally substituted haloalkyl; and 
         R 7  is NH 2 , halo, optionally substituted alkyl, or optionally substituted haloalkyl; 
         provided that when R 5  and R 3  form a 5-membered heterocyclic ring that is optionally substituted with hydroxyl, halo, or methoxy, R 4  is cyano, R 6  is amino, and R 7  is amino, 
         or a pharmaceutically acceptable salt, isomer, or a mixture thereof. 
       
     
     
         24 . A method of inhibiting excessive or destructive immune reactions or growth or a proliferation of cancer cells, comprising administering an effective amount of a compound having the structure of formula (J): 
       
         
           
           
               
               
           
         
         wherein: 
         A is N or CH; 
         n is 0, 1, 2, 3, or 4; 
         m is 0, 1, 2, 3, or 4; 
         each R 1  is independently selected from optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, NHC(═O)alkylene-N(R 1x ) 2 , NO 2 , OR 1x , N(R 1x ) 2 , OC(═O)R 1x , C(═O)R 1x , C(═O)OR 1x , aryl-OR 1y , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, NR 1x C(═O)alkylene-C(═O)OR 1x , aryl-O-alkylene-N(R 1x ) 2 , aryl-O—C(═O)R 1x , alkylene-C(═O)OR 1x , alkylene-C(═O)N(R 1x ) 2 , alkylene-C(═O)—Het, O-alkylene-C(═O)OR 1x , alkylene-O-alkylene-C(═O)OR 1x C(═O)NR 1x SO 2 R 1x , alkylene-N(R 1x ) 2 , alkenylene-N(R 1x ) 2 , C(═O)NR 1x -alkylene-OR 1x , C(═O)NR 1x alkylene-Het, O-alkylene-N(R 1x ) 2 , O-alkylene-CH(OR 1y )CH 2 N(R 1x ) 2 , O-alkylene-Het, O-alkylene-C(═O)OR 1x , O-alkylene-C(═O)—Het, S-alkylene-OR 1x , O-alkylene-OR 1x , O—C 1-6 alkylene-CH(OR 1y )C 1-6 alkylene-OR 1x , O-alkylene-NR 1x C(═O)OR 1x , NR 1x -alkylene-N(R 1x ) 2 , NR 1x C(═O)R 1x , NR 1x C(═O)N(R 1x ) 2 , N(SO 2 -alkyl) 2 , NR 1x (SO 2 -alkyl) SO 2 R 1z , SO 2 N(R 1x ) 2 , alkylene-aryl, alkylene-Het, alkylene-OR 1y , alkylene-N(R 1x ) 2 , C(═O)N(R 1x ) 2 , NHC(═O)alkylene-aryl, aryl-O-alkylene-N(R 1x ) 2 , aryl-OC(═O)R 1y , NHC(═O)alkylene-heterocycloalkyl, NHC(═O)alkylene-Het, O-alkylene-O-alkylene-C(═O)OR 1y , C(═O)alkylene-Het, and NHC(═O)halo-alkyl,
 wherein Het is optionally substituted heteroaryl or optionally substitutedheterocycloalkyl, wherein R 1x  is independently hydrogen, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted aryl, wherein R 1y  is independently hydrogen, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, and wherein R 1z  is independently optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted aryl; 
 
         each R 2  is independently selected from halo, cyano, optionally substituted alkyl, haloalkyl, SO 2 N(R 2x ) 2 , and optionally substituted alkoxy,
 wherein R 2x  is hydrogen, optionally substituted alkyl, or optionally substituted haloalkyl; 
 
         R 3  is hydrogen, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl; 
         R 5  is hydrogen or alkyl, or R 5  and R 3  together with the atoms to which they are attached optionally form an optionally substituted four-, five- or six-membered heterocyclic ring; 
         R 4  is cyano, C(═O)NR 4x R 4y , SO 2 -alkyl, halo, haloalkyl, or C(═O)R 4x , 
         wherein each R 4x  and R 4y  is independently hydrogen, optionally substituted alkyl, or optionally substituted haloalkyl; 
         R 6  is NH 2 , halo, optionally substituted alkyl, or optionally substituted haloalkyl; and 
         R 7  is NH 2 , halo, optionally substituted alkyl, or optionally substituted haloalkyl; 
         provided that when R 5  and R 3  form a 5-membered heterocyclic ring that is optionally substituted with hydroxyl, halo, or methoxy, R 4  is cyano, R 6  is amino, and R 7  is amino, 
         or a pharmaceutically acceptable salt, isomer, or a mixture thereof. 
       
     
     
         25 - 28 . (canceled) 
     
     
         29 . The method of  claim 21 , wherein the compound is a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         n is 1 or 2; 
         m is 0, 1, or 2; 
         each R 1  is independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-8 heterocycloalkyl, C 3-8 heteroaryl, C 6-10 aryl, halo, cyano, C 6-10 aryl-OR 1y , C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-Het, C 1-6 alkylene-C 3-8 cycloalkyl, C 1-6 alkylene-OR 1y , C 1-6 alkylene-N(R 1x ) 2 , C 2-6 alkenylene-OR 1y , C 2-6 alkenylene-N(R 1x ) 2 , C 1-6 alkylene-C(═O)OR 1x , C 1-6 alkylene-C(═O)N(R 1x ) 2 , C 1-6 alkylene-C(═O)-Het, O—C 1-6 alkylene-C(═O)OR 1x , C 1-6 alkylene-O—C 1-6 alkylene-C(═O)OR 1x , C 1-6 alkenylene-N(R 1x ) 2 , OR 1x , O—C 1-6 alkylene-N(R 1x ) 2 , O—C 1-6 alkylene-CH(OR 1y )CH 2 N(R 1x ) 2 , O—C 1-6 alkylene-Het, O—C 1-6 alkylene-C(═O)OR 1x , O—C 1-6 alkylene-C(═O)—Het, O—C 1-6 alkylene-OR 1x , O—C 1-6 alkylene-CH(OR 1y )C 1-6 alkylene-OR 1x , O—C 2-6 alkenylene-OR 1y , O—C 2-6 alkenylene-N(R 1x ) 2 , O—C 1-6 alkylene-NR 1x C(═O)OR 1x , O—C 1-6 alkylene-O—C 1-6 alkylene-C(═O)OR 1y , SO 2 R 1x , S—C 1-6 alkylene-OR 1z , or SO 2 N(R 1x ) 2 ,
 wherein Het is C 3-8 heteroaryl or C 2-8 heterocycloalkyl, wherein R 1x  is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, C 2-8 heterocycloalkyl, or C 3-8 heteroaryl, wherein R 1y  is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, or C 3-8 heteroaryl, wherein R 1z  is independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, C 2-8 heterocycloalkyl, or C 3-8 heteroaryl, and wherein each of Het, R 1x , R 1y  and R 1z  is optionally substituted with one, two, three, or four members independently selected from halo, oxo, C 1-6 alkyl, and C 6-10 aryl; 
 
         each R 2  is independently halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, or SO 2 N(R 2x ) 2 , wherein R 2x  is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl; 
         R 3  is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, or C 6-10 aryl, wherein the C 1-6 alkyl moiety is optionally substituted with —C(═O)NR 3x R 3y , wherein each R 3x  and R 3y  is independently hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl; 
         R 5  is hydrogen or C 1-6 alkyl, or R 5  and R 3  together with the atoms to which they are attached optionally form a four-, five- or six-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted with one, two, or three members independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, and NR 5x C(O)R 5y  where R 5x  is hydrogen or C 1-6 alkyl, and R 5y  is C 1-6 alkylene-NH 2 , C 1-6  alkylene-C 3-8 cycloalkyl, or C 1-6 haloalkyl; 
         R 4  is cyano, C(═O)NR 4x R 4y , SO 2 —C 1-6 alkyl, halo, C 1-6 haloalkyl, or C(═O)R 4x , wherein each R 4x  and R 4y  is independently hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl; 
         R 6  is NH 2 , halo, C 1-6 alkyl, or C 1-6 haloalkyl; and 
         R 7  is NH 2 , halo, C 1-6 alkyl, or C 1-6 haloalkyl, 
         or a pharmaceutically acceptable salt, isomer, or a mixture thereof. 
       
     
     
         30 . The method of  claim 21 , wherein each R 1  is independently methyl, chloro, fluoro, cyano, tetrahydropyridinyl, —CH 2 —C(═O)OH, —C 2 H 4 —C(═O)OH, —C 3 H 6 —C(═O)OH, —CH 2 —C(═O)NH 2 , —CH 2 —C(═O)N(CH 3 ) 2 , —C 2 H 4 —C(═O)NH 2 , —C 2 H 4 —C(═O)N(CH 3 ) 2 , —C 3 H 6 —C(═O)NH 2 , —C 3 H 6 —C(═O)N(CH 3 ) 2 , —CH 2 —C(═O)—Het, C 2 H 4 —C(═O)—Het, —C 3 H 6 —C(═O)—Het, O—CH 2 —C(═O)OC 3 H 7 , O—C 2 H 4 —C(═O)OC 3 H 7 , O—C 3 H 6 —C(═O)OC 3 H 7 , —CH 2 —Het, —C 2 H 4 -Het, —C 3 H 6 -Het, —CH 2 -cyclopropyl, —C 2 H 4 -cyclopropyl, —C 3 H 6 -cyclopropyl, —CH 2 -cyclobutyl, —C 2 H 4 -cyclobutyl, —C 3 H 6 -cyclobutyl, —CH 2 — cyclopentyl, —C 2 H 4 -cyclopentyl, —C 3 H 6 -cyclopentyl, —CH 2 -cyclohexyl, —C 2 H 4 -cyclohexyl, —C 3 H 6 -cyclohexyl, O—CH 2 —NH 2 , O—C 2 H 4 —NH 2 , O—C 3 H 6 —NH 2 , O—CH 2 —N(CH 3 ) 2 , O—C 2 H 4 —N(CH 3 ) 2 , O—C 3 H 6 —N(CH 3 ) 2 , O—CH 2 —Het, O—C 2 H 4 -Het, O—C 3 H 6 -Het, O—CH 2 —C(═O)OH, O—C 2 H 4 —C(═O)OH, O—C 3 H 6 —C(═O)OH, O—CH 2 —C(═O)OCH 3 , O—C 2 H 4 —C(═O)OCH 3 , O—C 3 H 6 —C(═O)OCH 3 , O—CH 2 —C(═O)—Het, O—CH 2 C(CH 3 )(CH 2 OH) 2 , S—C 2 H 4 OH, S—C 3 H 6 OH, SO 2 -phenyl, SO 2 -methylphenyl, —SO 2 — ethylphenyl, —SO 2 -cyclopropyl, —SO 2 -cyclobutyl, —SO 2 -cyclopentyl, —SO 2 C 2 H 4 -Het, —SO 2 CH 3 , —SO 2 C 2 H 5 , —SO 2 C 3 H 7 , —SO 2 C 2 H 4 OH, or —SO 2 C 3 H 6 OH; wherein Het is independently selected from piperidinyl, morpholinyl, piperazinyl, azepanyl, imidazolyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl, wherein each of the piperidinyl, morpholinyl, piperazinyl, azepanyl, imidazolyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl moieties is optionally substituted with one, two, three, or four members independently selected from fluoro, chloro, methyl, ethyl, propyl, oxo, and phenyl. 
     
     
         31 . The method of  claim 21 , wherein each R 2  is independently fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, or SO 2 NH 2 . 
     
     
         32 . The method of  claim 21 , wherein R 3  is methyl, ethyl, propyl, —CH 2 —C(═O)NH 2 , —C 2 H 4 —C(═O)NH 2 , —C 3 H 6 —C(═O)NH 2 , —CH 2 —C(═O)N(CH 3 ) 2 , —C 2 H 4 —C(═O)N(CH 3 ) 2 , —C 3 H 6 —C(═O)N(CH 3 ) 2 , cyclopropyl, cyclobutyl, or phenyl. 
     
     
         33 . The method of  claim 21 , wherein R 3  is —CH 2 —C(═O)NH 2 , —C 2 H 4 —C(═O)NH 2 , —C 3 H 6 —C(═O)NH 2 , —CH 2 —C(═O)N(CH 3 ) 2 , —C 2 H 4 —C(═O)N(CH 3 ) 2 , —C 3 H 6 —C(═O)N(CH 3 ) 2 , cyclopropyl, cyclobutyl, or phenyl. 
     
     
         34 . The method of  claim 21 , wherein, R 3  is methyl, ethyl, or cyclopropyl. 
     
     
         35 . The method of  claim 21 , wherein R 4  is cyano, chloro, bromo, iodo, or C(═O)CH 3 . 
     
     
         36 . The method of  claim 21 , wherein R 5  is hydrogen, methyl, ethyl, or propyl. 
     
     
         37 . The method of  claim 21 , wherein R 6  and R 7  are independently NH 2 , chloro, fluoro, methyl, ethyl, or propyl. 
     
     
         38 . The method of  claim 21 , wherein R 5  and R 3  together with the atoms to which they are attached optionally form a heterocyclic ring, wherein the heterocyclic ring is selected from azetidinyl, morpholinyl, and pyrrolidinyl, wherein each of the azetidinyl, morpholinyl, and pyrrolidinyl moieties is optionally substituted with 1, 2 or 3 groups which are independently C 1-4  alkyl, methoxy, ethoxy, halo, N(CH 3 )C(═O)CH 2 NH 2 , N(CH 3 )C(═O)CHF 2 , N(CH 3 )C(═O)CH 2 CF 3 , N(CH 3 )C(═O)cyclopropyl, NHC(═O)CH 2 NH 2 , NHC(═O)CHF 2 , NHC(═O)CH 2 CF 3 , NHC(═O)CH 2 cyclopropyl, or NHC(═O)cyclopropyl. 
     
     
         39 . The method of  claim 38 , wherein each R 1  is independently chloro, fluoro, cyano, methyl, SO 2 -phenyl, —SO 2 CH 3 , or —C 3 H 6 —C(═O)OH. 
     
     
         40 . The method of  claim 21 , wherein:
 R 3  is methyl;   n is 1 or 2;   and one R 1  is tetrahydropyridinyl, CH 2 —C(═O)OH, —C 2 H 4 —C(═O)OH, —C 3 H 6 —C(═O)OH, —CH 2 —C(═O)NH 2 , —CH 2 —C(═O)N(CH 3 ) 2 , —C 2 H 4 —C(═O)NH 2 , —C 2 H 4 —C(═O)N(CH 3 ) 2 , —C 3 H 6 —C(═O)NH 2 , —C 3 H 6 —C(═O)N(CH 3 ) 2 , —CH 2 —C(═O)—Het, C 2 H 4 —C(═O)—Het, —C 3 H 6 —C(═O)—Het, O—CH 2 —C(═O)OC 3 H 7 , O—C 2 H 4 —C(═O)OC 3 H 7 , O—C 3 H 6 —C(═O)OC 3 H 7 , —CH 2 —Het, —C 2 H 4 -Het, —C 3 H 6 -Het, —CH 2 -cyclopropyl, —C 2 H 4 -cyclopropyl, —C 3 H 6 -cyclopropyl, —CH 2 -cyclobutyl, —C 2 H 4 -cyclobutyl, —C 3 H 6 -cyclobutyl, —CH 2 -cyclopentyl, —C 2 H 4 -cyclopentyl, —C 3 H 6 -cyclopentyl, —CH 2 -cyclohexyl, —C 2 H 4 -cyclohexyl, —C 3 H 6 -cyclohexyl, O—CH 2 —NH 2 , O—C 2 H 4 —NH 2 , O—C 3 H 6 —NH 2 , O—CH 2 —N(CH 3 ) 2 , O—C 2 H 4 —N(CH 3 ) 2 , O—C 3 H 6 —N(CH 3 ) 2 , O—CH 2 —Het, O—C 2 H 4 -Het, O—C 3 H 6 -Het, O—CH 2 —C(═O)OH, O—C 2 H 4 —C(═O)OH, O—C 3 H 6 —C(═O)OH, O—CH 2 —C(═O)OCH 3 , O—C 2 H 4 —C(═O)OCH 3 , O—C 3 H 6 —C(═O)OCH 3 , O—CH 2 —C(═O)-Het, O—CH 2 C(CH 3 )(CH 2 OH) 2 , S—C 2 H 4 OH, S—C 3 H 6 OH, SO 2 -phenyl, SO 2 -methylphenyl, —SO 2 — ethylphenyl, —SO 2 -cyclopropyl, —SO 2 -cyclobutyl, —SO 2 -cyclopentyl, —SO 2 C 2 H 4 -Het, —SO 2 CH 3 , —SO 2 C 2 H 5 , —SO 2 C 3 H 7 , —SO 2 C 2 H 4 OH, or —SO 2 C 3 H 6 OH; wherein Het is independently selected from piperidinyl, morpholinyl, piperazinyl, azepanyl, imidazolyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl, wherein each of the piperidinyl, morpholinyl, piperazinyl, azepanyl, imidazolyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl moieties is optionally substituted with one, two, three, or four members independently selected from fluoro, chloro, methyl, ethyl, propyl, oxo, or phenyl.   
     
     
         41 . The method of  claim 21 , wherein:
 each R 1  is independently methyl, chloro, fluoro, or cyano;   R 3  is methyl or ethyl;   R 4  is cyano or halo;   R 6  is NH 2 , halo, or C 1-4  alkyl; and   R 7  is NH 2 , halo, or C 1-4  alkyl;   wherein only one of R 6  and R 7  is NH 2 .   
     
     
         42 . The method of  claim 21 , wherein the compound is an (S)-enantiomer or a pharmaceutically acceptable salt thereof. 
     
     
         43 . The method of  claim 21 , wherein the compound is an (R)-enantiomer or a pharmaceutically acceptable salt thereof. 
     
     
         44 . The method of  claim 21 , wherein the compound is selected from the group consisting of:
 (S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile;   (S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile;   (S)-2,4-diamino-6-(((5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)(phenyl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-5-carbonitrile;   (S)-2,4-diamino-6-((cyclopropyl(3-(3-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((cyclopropyl(3-(2-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((cyclopropyl(3-(2-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((cyclopropyl(3-(2,6-difluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-6-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile;   (S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-6-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazoline-8-carbonitrile;   (S)-3-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-3-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)-N,N-dimethylpropanamide   (S)-3-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-3-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)-N,N-dimethylpropanamide;   (S)-2,4-diamino-6-(((3-(3-cyano-5-fluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((cyclopropyl(3-(3,5-difluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(((5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((cyclopropyl(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((cyclopropyl(5-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((cyclopropyl(6-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2-(1-((5-acetyl-2,6-diaminopyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one,   2,4-diamino-6-((2S)-2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-4-methoxypyrrolidin-1-yl)pyrimidine-5-carbonitrile;   (S)-2-(1-((6-amino-5-bromo-2-methylpyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;   (S)-2-(1-((6-amino-5-bromo-2-methylpyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;   (S)-2,4-diamino-6-((1-(5-(2-morpholinoethoxy)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-(2-(azepan-1-yl)ethoxy)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(2-(pyrrolidin-1-yl)ethoxy)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-isopropyl 2-((2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-5-yl)oxy)acetate;   (S)-2,4-diamino-6-((1-(4-oxo-5-(2-(2-oxopyrrolidin-1-yl)ethoxy)-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-(2-(dimethylamino)ethoxy)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(4-oxo-5-(2-oxo-2-(piperidin-1-yl)ethoxy)-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-(3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(2-(piperidin-1-yl)ethoxy)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(2-(4-phenylpiperazin-1-yl)ethoxy)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-(2-(2-methyl-1H-imidazol-1-yl)ethoxy)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   2,4-diamino-6-(((1S)-1-(5-(2-(1-methylpyrrolidin-2-yl)ethoxy)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-((3-methyloxetan-3-yl)methoxy)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-(2-morpholino-2-oxoethoxy)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-(2-(4-methylpiperidin-1-yl)-2-oxoethoxy)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-3-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-5-yl)propanamide;   (S)-3-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-5-yl)propanamide;   (S)-3-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-5-yl)propanamide;   (S)-3-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-5-yl)propanamide;   (S)-3-(2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-5-yl)propanamide;   (S)-3-(2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-5-yl)propanamide;   (S)-3-(2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-5-yl)propanamide;   (S)-3-(2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-5-yl)propanamide;   (S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(3-(piperidin-1-yl)propyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-(3-(4,4-difluoropiperidin-1-yl)propyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   2,4-diamino-6-(((1S)-1-(5-(3-(3,5-dimethylmorpholino)propyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(8-fluoro-4-oxo-3-phenyl-5-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-4-oxo-5-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-(3-(2,2-dimethylmorpholino)propyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-(3-(3,3-dimethylmorpholino)propyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(3-(2,2,6,6-tetrafluoromorpholino)propyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((cyclopropyl(4-oxo-3-phenyl-5-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((cyclopropyl(4-oxo-3-phenyl-5-(3-(piperidin-1-yl)propyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((cyclopropyl(8-fluoro-4-oxo-3-phenyl-5-(3-(pyrrolidinn-1-yl)propyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((cyclopropyl(8-fluoro-4-oxo-3-phenyl-5-(3-(piperidin-1-yl)propyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2-amino-4-chloro-6-((cyclopropyl(4-oxo-3-phenyl-5-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-(3-morpholinopropyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-4-((1-(5-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)-2,6-diaminopyrimidine-5-carbonitrile;   (S)-4-((1-(5-(3-(2-oxa-6-azaspiro[3.4]octan-6-yl)propyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)-2,6-diaminopyrimidine-5-carbonitrile;   (S)-4-((1-(5-(3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)-2,6-diaminopyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-(3-cyclohexylpropyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2-amino-4-chloro-6-((1-(5-chloro-8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)azetidin-1-yl)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)azetidin-1-yl)pyrimidine-5-carbonitrile;   (S)-4-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-5-yl)butanoic acid;   (S)-4-(2-(1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-2-yl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-5-yl)butanoic acid;   (S)-4-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-5-yl)butanoic acid;   (S)-2,4-diamino-6-(2-(3-(3-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(2-(3-(2-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(2-(3-(2-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(2-(3-(2,6-difluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-4-oxo-5-(phenylsulfonyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(2-(3-(3-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-5-((2-hydroxyethyl)sulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-5-((2-hydroxyethyl)thio)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(5-(cyclopentylsulfonyl)-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-4-oxo-5-(o-tolylsulfonyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-4-oxo-5-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(2-(5-chloro-3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(2-(8-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(2-(3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(2-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;   (S)-2,4-diamino-6-(2-(5-chloro-3-(3-cyano-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;   (S)-2-(1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-2-yl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-8-carbonitrile;   (S)-2-(1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-2-yl)-3-(3-(difluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile   (S)-3-(5,8-dichloro-2-(1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-2-yl)-4-oxoquinazolin-3 (4H)-yl)benzenesulfonamide;   (S)-3-(5,8-dichloro-2-(1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-2-yl)-4-oxoquinazolin-3 (4H)-yl)benzenesulfonamide;   (S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   2,4-diamino-6-((2S,4R)-2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-4-methylpyrrolidin-1-yl)pyrimidine-5-carbonitrile;   2,4-diamino-6-((2S,4R)-2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-4-fluoropyrrolidin-1-yl)pyrimidine-5-carbonitrile;   (S)-2-amino-4-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-methylpyrimidine-5-carbonitrile;   (S)-2-(1-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;   (S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)-2-methylpyrimidine-5-carbonitrile;   (S)-4-amino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)-2-methylpyrimidine-5-carbonitrile   (R)-5-chloro-2-(4-(2,6-diamino-5-chloropyrimidin-4-yl)morpholin-3-yl)-3-phenylquinazolin-4(3H)-one (0);   (S)-2-amino-4-chloro-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2-amino-4-chloro-6-((1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2-amino-4-chloro-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;   (S)-4-amino-2-chloro-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2-amino-4-chloro-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)-2-fluoropyrimidine-5-carbonitrile;   N-((3R,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2,2-difluoroacetamide;   N-((3S,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2,2,2-trifluoroacetamide;   N-((3R,5S)-5-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2,2-difluoroacetamide;   N-((3R,5S)-5-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2,2-difluoroacetamide;   N-((3R,5S)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)-5-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-3-yl)-2,2-difluoroacetamide;   N-((3R,5S)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)-5-(3-(3-(difluoromethyl)-5-fluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-3-yl)-2,2-difluoroacetamide;   N-((3R,5S)-5-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2,2-difluoro-N-methylacetamide;   N-((3R,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2-cyclopropylacetamide;   2-amino-N-((3R,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)acetamide; and   2-amino-N-((3R,5S)-5-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)acetamide,   or a pharmaceutically acceptable salt thereof.