Substituted reverse pyrimidine bmi-1 inhibitors

Abstract

Amine substituted reverse pyrimidine compounds and forms thereof that inhibit the function and reduce the level of B-cell specific Moloney murine leukemia virus integration site 1 (Bmi-1) protein and methods for their use to inhibit Bmi-1 function and reduce the level of Bmi-1 to treat a cancer mediated by Bmi-1 are described herein.

1 - 20 . (canceled) 
     
     
         21 . A compound, wherein the compound is 5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine, or a pharmaceutically acceptable salt thereof. 
     
     
         22 . A pharmaceutical composition comprising the compound, or pharmaceutically acceptable salt thereof, of  claim 21  and at least one pharmaceutically acceptable excipient. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the pharmaceutical composition comprises about 0.1 ng to about 3500 mg of the compound or pharmaceutically acceptable salt thereof. 
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein the pharmaceutical composition comprises about 5.0 mg to about 1500 mg of the compound or pharmaceutically acceptable salt thereof. 
     
     
         25 . The pharmaceutical composition of  claim 22 , wherein the pharmaceutical composition further comprises one or more additional agents selected from the group consisting of anti-cancer agents, anti-proliferative agents, chemotherapeutic agents, immunomodulatory agents, anti-angiogenic agents, anti-inflammatory agents, alkylating agents, steroidal and non-steroidal anti-inflammatory agents, pain relievers, leukotriene antagonists, β2-agonists, anticholinergic agents, hormonal agents, biological agents, tubulin binding agents, glucocorticoids, corticosteroid agents, antibacterial agents, antihistamines, anti-malarial agents, anti-viral agents, and antibiotics. 
     
     
         26 . The pharmaceutical composition of  claim 22 , wherein the pharmaceutical composition is a solution, emulsion, suspension, tablet, pill, capsule, troche, lozenge, powder, granule, syrup, or elixir. 
     
     
         27 . The pharmaceutical composition of  claim 26 , wherein the pharmaceutical composition is a tablet or a capsule. 
     
     
         28 . The compound of  claim 21 , wherein the compound is 5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine. 
     
     
         29 . A pharmaceutical composition comprising the compound of  claim 28  and at least one pharmaceutically acceptable excipient. 
     
     
         30 . The pharmaceutical composition of  claim 29 , wherein the pharmaceutical composition comprises about 0.1 ng to about 3500 mg of the compound. 
     
     
         31 . The pharmaceutical composition of  claim 30 , wherein the pharmaceutical composition comprises about 5.0 mg to about 1500 mg of the compound. 
     
     
         32 . The pharmaceutical composition of  claim 29 , wherein the pharmaceutical composition further comprises one or more additional agents selected from the group consisting of anti-cancer agents, anti-proliferative agents, chemotherapeutic agents, immunomodulatory agents, anti-angiogenic agents, anti-inflammatory agents, alkylating agents, steroidal and non-steroidal anti-inflammatory agents, pain relievers, leukotriene antagonists, β2-agonists, anticholinergic agents, hormonal agents, biological agents, tubulin binding agents, glucocorticoids, corticosteroid agents, antibacterial agents, antihistamines, anti-malarial agents, anti-viral agents, and antibiotics. 
     
     
         33 . The pharmaceutical composition of  claim 29 , wherein the pharmaceutical composition is a solution, emulsion, suspension, tablet, pill, capsule, troche, lozenge, powder, granule, syrup, or elixir. 
     
     
         34 . The pharmaceutical composition of  claim 33 , wherein the pharmaceutical composition is a tablet or a capsule. 
     
     
         35 . A method of treating a cancer mediated by Bmi-1 in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound are pharmaceutically acceptable salt thereof of  claim 21 . 
     
     
         36 . A method of treating a cancer mediated by Bmi-1 in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 22 . 
     
     
         37 . A method of treating a cancer mediated by Bmi-1 in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 29 .