Chemokine CXCR4 Receptor Modulators and Uses Related Thereto

Abstract

The disclosure relates to chemokine CXCR4 receptor modulators and uses related thereto. The receptor modulators can be formulated to form pharmaceutical compositions comprising the disclosed compounds or pharmaceutically acceptable salts or prodrugs thereof. The compositions may be used for managing CXCR4 related conditions, typically prevention or treatment of viral infections abnormal cellular proliferation, retinal degeneration, inflammatory diseases, or as an immunostimulant or immunosuppressant or for managing cancer and may be administered with another active ingredient such as an antiviral agent or chemotherapeutic agent.

1 . A compound of Formula (II) 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 R D  is H or alkyl; 
 R E  is methyl, isopropyl or an amino substituted carbocyclyl; 
 R F  is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         R Z  is H or CH 3 ; 
         W is independently CH or N; 
         R X2  is selected from: (1) optionally substituted aryl, optionally substituted heterocyclyl or optionally substituted amino, wherein the substituents of R X2  are selected from one or more and the same or different R 2 , and (2) CH 2 R Y2 , CH═CHCH 2 R Y2 , OCH 2 CH 2 R Y2 , 
       
       
         
           
           
               
               
           
         
       
       and
 R Y2  is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, oxetane, amino, dimethylamino, methylpiperazine, pyridine, pyridinylmethyl, pyrimidine, trifluoromethylbenzene, H, OH, F, CH 2 OCH 3 , CH 2 F, CF 3 , 
 
       
         
           
           
               
               
           
         
       
       with the proviso that when R D  is H and R E  is CH 3 , then R F  is not 
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound as claimed in  claim 1 , wherein:
 R E  is selected from the group consisting of CH 3 ,   
       
         
           
           
               
               
           
         
         R X2  is selected from the group consisting of CH 2 R Y2 , CH═CHCH 2 R Y2 , OCH 2 CH 2 R Y2 , NHR Y2 , N(R Y2 ) 2 , 
       
       
         
           
           
               
               
           
         
       
       and
 R Y2  is selected from the group consisting of H, OH, F, CH 3 , CH 2 CH 3 , CH 2 OCH 3 , CH 2 F, CF 3 , NH 2 , 
 
       
         
           
           
               
               
           
         
       
       wherein the substituent R Y2  may be individually and independently mono- or di-substituted onto R X2  where appropriate. 
     
     
         3 . The compound as claimed in  claim 1 , wherein R F  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . The compound as claimed in  claim 1 , which is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and salts thereof. 
     
     
         5 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient, diluent, or carrier. 
     
     
         6 . The pharmaceutical composition as claimed in  claim 5 , wherein the compound is in greater than 60%, 70%, 80%, 90%, 95%, or 98% diastereomeric or enantiomeric excess. 
     
     
         7 . The pharmaceutical composition as claimed in  claim 5 , further comprising a second active ingredient, optionally wherein the second active ingredient is an antiviral agent or chemotherapeutic agent. 
     
     
         8 . The pharmaceutical composition as claimed in  claim 7 , wherein the second active ingredient is a CCR5 antagonist. 
     
     
         9 . The pharmaceutical composition as claimed in  claim 5 , wherein the pharmaceutical composition is in the form of an oral formulation. 
     
     
         10 . A method of treating a viral infection, comprising administering a compound of  claim 1  optionally in combination with another active ingredient to a subject in need thereof, wherein the viral infection is CXCR4-related. 
     
     
         11 . The method as claimed in  claim 10 , wherein the viral infection is HIV infection. 
     
     
         12 . The method as claimed in  claim 10 , wherein the compound is administered orally. 
     
     
         13 . A method of treating a cancer comprising administering a compound of  claim 1  optionally in combination with another active ingredient to a subject in need thereof, wherein the cancer is CXCR4-related. 
     
     
         14 . The method as claimed in  claim 13 , wherein the compound is administered orally. 
     
     
         15 . The method as claimed in  claim 13 , wherein the another active ingredient comprises an antiproliferative or antineoplastic drug. 
     
     
         16 . The method as claimed in  claim 15 , wherein the antiproliferative or antineoplastic drug is selected from the group consisting of 5-fluorouracil, gemcitabine, tegafur, raltitrexed, methotrexate, cytosine arabinoside, taxol, and taxotere. 
     
     
         17 . The method as claimed in  claim 13 , wherein the another active ingredient comprises a tyrosine kinase inhibitor, a serine/threonine kinase inhibitor, or a combination thereof. 
     
     
         18 . The method as claimed in  claim 17 , wherein the tyrosine kinase inhibitor is an inhibitor of EGFR family tyrosine kinase. 
     
     
         19 . The method as claimed in  claim 13 , wherein the another active ingredient comprises an antiangiogenic agent. 
     
     
         20 . The method as claimed in  claim 19 , wherein the antiangiogenic agent is an inhibitor of vascular endothelial growth factor. 
     
     
         21 . The method as claimed in  claim 13 , wherein the another active ingredient comprises a cytostatic agent. 
     
     
         22 . The method as claimed in  claim 13 , wherein the another active ingredient comprises an inhibitor of metalloproteinase, an inhibitor of urokinase plasminogen activator receptor, or a combination thereof.