Cxcr4 chemokine receptor modulators

Abstract

Provided herein are small molecule modulators of CXCR4 activity (e.g., agonists, antagonists, inverse agonists, partial agonists), and methods of use thereof (e.g., for the treatment of disease).

1 . A composition comprising a compound or Formula (1): 
       
         
           
           
               
               
           
         
         wherein Z is C or N; 
         wherein E is C, S, N, O, or absent; when E is absent Z and (CH 2 ) y  are directly linked by a single covalent bond; 
         wherein G is CH 3 , CN, halogen (e.g., Cl, Br, F, etc.), trihalomethane (e.g., CCl 3 , CBr 3 , CF 3 , etc.), OH, NH 2 , alkyl 1-6 -CH 3 , alkyl 1-6 -CN, alkyl 1-6 -halogen (e.g., Cl, Br, F, etc.), alkyl 1-6 -trihalomethane (e.g., CCl 3 , CBr 3 , CF 3 , etc.), alkyl 1-6 -OH, or alkyl 1-6 -NH 2 ; 
         wherein y is 0-6; 
         wherein 
       
       
         
           
           
               
               
           
         
       
       is any carbocycle, heterocycle, aryl, heteroaryl, or multi-ring systems thereof, and 
       
         
           
           
               
               
           
         
       
       is optionally substituted at any suitable positions with CH 3 , CN, halogen (e.g., Cl, Br, F, etc.), trihalomethane (e.g., CCl 3 , CBr 3 , CF 3 , etc.), OH, NH 2 , alkyl 1-6 -CH 3 , alkyl 1-6 -CN, alkyl 1-6 -halogen (e.g., Cl, Br, F, etc.), alkyl 1-6 -trihalomethane (e.g., CCl 3 , CBr 3 , CF 3 , etc.), alkyl 1-6 -OH, or alkyl 1-6 -NH 2 .
 wherein A is CH 3 , CN, halogen (e.g., Cl, Br, F, etc.), trihalomethane (e.g., CCl 3 , CBr 3 , CF 3 , etc.), OH, NH 2 , alkyl 1-6 -CH 3 , alkyl 1-6 -CN, alkyl 1-6 -halogen (e.g., Cl, Br, F, etc.), alkyl 1-6 -trihalomethane (e.g., CCl 3 , CBr 3 , CF 3 , etc.), alkyl 1-6 -OH, alkyl 1-6 -NH 2 , a carbocycle, a heterocycle, an aryl, a heteroaryl, a multi-ring system thereof, or absent; 
 wherein Y is C, S, O, or absent; 
 wherein X is: 
 
       
         
           
           
               
               
           
         
          NH-alkyl 1-6 , O-alkyl 1-6 , S-alkyl 1-6 , CH 2 -alkyl 1-6 , NH-alkyl 1-6 -O-methyl, O-alkyl 1-6 -O-methyl, S-alkyl 1-6 -O-methyl, CH 2 -alkyl 1-6 -O-methyl, wherein N-dimethyl; and 
         wherein 
       
       
         
           
           
               
               
           
         
       
       is any carbocycle, heterocycle, aryl, heteroaryl, or multi-ring systems thereof,
 and 
 
       
         
           
           
               
               
           
         
       
       is optionally substituted at any suitable positions with CH 3 , CN, halogen (e.g., Cl, Br, F, etc.), trihalomethane (e.g., CCl 3 , CBr 3 , CF 3 , etc.), OH, NH 2 , alkyl 1-6 -CH 3 , alkyl 1-6 -CN, alkyl 1-6 -halogen (e.g., Cl, Br, F, etc.), alkyl 1-6 -trihalomethane (e.g., CCl 3 , CBr 3 , CF 3 , etc.), alkyl 1-6 -OH, or alkyl 1-6 -NH 2 ; or
 a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The composition of  claim 1 , wherein the compound binds to CXCR4 
     
     
         3 . The composition of  claim 1 , wherein the compound is a modulator of CXCR4 activity. 
     
     
         4 . The composition of  claim 3 , wherein the compound is a CXCR4 agonist. 
     
     
         5 . The composition of  claim 3 , wherein the compound is a CXCR4 antagonist. 
     
     
         6 . The composition of  claim 1 , wherein the compound is selected from the compounds of Table 2. 
     
     
         7 . The composition of  claim 6 , wherein the compound is selected from the group consisting of: NUCC-0176286, NUCC-0176287, NUCC-0176288, NUCC-0176289, NUCC-0176290, NUCC-0176291, NUCC-0176292, NUCC-0176293, NUCC-0176294, NUCC-0176295, NUCC-0176296, NUCC-0176297, NUCC-0176298, NUCC-0176299, NUCC-0176300, NUCC-0176301, NUCC-0176302, NUCC-0176303, NUCC-0176304, NUCC-0176305, NUCC-0176306, NUCC-0176307, NUCC-0176308, NUCC-0176309, NUCC-0176310, NUCC-0176311, NUCC-0176312, NUCC-0176313, NUCC-0176314, NUCC-0176315, NUCC-0176316, NUCC-0176317, NUCC-0176318, NUCC-0176319, NUCC-0196315, NUCC-0196316, NUCC-0196317, NUCC-0196318, NUCC-0196319, NUCC-0196320, NUCC-0196321, NUCC-0196322, NUCC-0196323, NUCC-0196324, NUCC-0196325, NUCC-0196326, NUCC-0196327, NUCC-0196328, NUCC-0196329, NUCC-0196330, NUCC-0196331, NUCC-0196332, NUCC-0196333, NUCC-0196334, NUCC-0196335, NUCC-0196336, NUCC-0196337, NUCC-0196338, and NUCC-0196339. 
     
     
         8 . A method of treating a subject comprising administering to the subject a composition of one of  claims 1 - 7 . 
     
     
         9 . The method of  claim 8 , wherein the subject is treated for cancer. 
     
     
         10 . A method of modulating CXCR4 activity comprising contacting CXCR4 with a composition of one of  claims 1 - 7 . 
     
     
         11 . Use of a composition of one of  claims 1 - 7  in the treatment of a disease. 
     
     
         12 . The use of  claim 11 , wherein the disease is a cancer.