Sigma receptor binders

Abstract

Provided herein, inter alia, are compounds and methods of treating diseases including cancer, neurological disease, alcohol withdrawal, depression and anxiety, and neuropathic pain.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —C(O)R 3 , —OR 3 , —NR 3 R 3A , —C(O)OR 3 , —C(O)NR 3 R 3A , —NO 2 , —SR 3 , —S(O) 1 R 3 , —S(O) n1 OR 3 , —S(O) 1 NR 3 R 3A , —NHNR 3 R 3A , —ONR 3 R 3A , —NHC(O)NR 4 R 4A , —NHC(O)NHNR 3 R 3A , or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heteroalkyl, heterocycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaryl, or a substituted version of any of these groups, or a group of the formula: —Y 1 —(R 5 ) m1 , —OY 1 —(R 5 ) m1 , or —NR 5a Y 1 —(R 5 ) m1 , wherein:
 Y 1  is cycloalkylene, arylene, heterocycloalkylene, heteroarylene, or a substituted version of any of these groups; 
 m 1  is 0, 1, 2, 3, or 4; 
 R 5  is oxo, —CF 3 , —CN, —OH, —NH 2 , —CONH 2 , —S(O) 3 H, —S(O) 2 NH 2 , —NHC(O)NH 2 , —NHC(O)H, —OCHF 2 , alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heteroalkyl, heterocycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or a substituted version of any of these groups; and 
 R 5a  is hydrogen, alkyl, or substituted alkyl; 
 
         R 2  is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heteroalkyl, heterocycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaryl, or a substituted version of any of these groups; 
         n1 and n2 are independently 1 or 2; 
         m is 1, 2, 3 or 4 
         n is 1, 2, 3 or 4; 
         W 1  is CH, C(R 1 ), or N; and 
         W 2  is CH, C(R 1 ), or N; and 
         R 3 , R 3A , R 4  are independently hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —S(O) 2 Cl, —S(O) 3 H, —S(O) 4 H, —S(O) 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHS(O) 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heteroalkyl, heterocycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaryl, or a substituted version of any of these groups 
         provided that R 1  of W 1  is not piperazinyl or 3-methylpiperazinyl, when n is 2. 
       
     
     
         2 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —C(O)R 3 , —OR 3 , —NR 3 R 3A , —C(O)OR 3 , —C(O)NR 3 R 3A , —NO 2 , —SR 3 , —S(O) 1 R 3 , —S(O) n1 OR 3 , —S(O) 1 NR 3 R 3A , —NHNR 3 R 3A , —ONR 3 R 3A , —NHC(O)NHNR 3 R 3A , or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heteroalkyl, heterocycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, a substituted version of any of these groups, or a group of the formula: —Y 1 —(R 5 ) m1 , —OY 1 —(R 5 ) m1 , or —NR 5a Y 1 —(R 5 ) m1 , wherein:
 Y 1  is cycloalkylene, arylene, heterocycloalkylene, heteroarylene, or a substituted version of any of these groups; 
 m 1  is 0, 1, 2, 3, or 4; 
 R 5  is oxo, —CF 3 , —CN, —OH, —NH 2 , —CONH 2 , —S(O) 3 H, —S(O) 2 NH 2 , —NHC(O)NH 2 , —NHC(O)H, —OCHF 2 , alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heteroalkyl, heterocycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or a substituted version of any of these groups; and 
 R 5a  is hydrogen, alkyl, or substituted alkyl; 
 
         R 2  is alkyl, cycloalkyl, heterocycloalkyl or a substituted version of any of these groups; 
         n1 and n2 are independently 1 or 2; 
         m is 1, 2, 3 or 4 
         n is 1, 2, 3 or 4; and 
         R 3 , R 3A , R 4  are independently hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —S(O) 2 Cl, —S(O) 3 H, —S(O) 4 H, —S(O) 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O) NH 2 , —NHS(O) 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heteroalkyl, heterocycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or a substituted version of any of these groups. 
       
     
     
         3 . The compound of  claim 1 , having the structure: 
       
         
           
           
               
               
           
         
         wherein R 1  is halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —C(O)R 3 , —OR 3 , —NR 3 R 3A , —C(O)OR 3 , —C(O)NR 3 R 3A , —NO 2 , —SR 3 , —S(O) n1 R 3 , —S(O) n1 OR 3 , —S(O) n1 NR 3 R 3A , —NHNR 3 R 3A , —ONR 3 R 3A , —NHC(O)NHNR 3 R 3A , or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heteroalkyl, heterocycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, a substituted version of any of these groups, or a group of the formula: —Y 1 —(R 5 ) m1 , —OY 1 —(R 5 ) m1 , or —NR 5a Y 1 —(R 5 ) m1 , wherein:
 Y 1  is cycloalkylene, arylene, heterocycloalkylene, heteroarylene, or a substituted version of any of these groups; 
 m 1  is 0, 1, 2, 3, or 4; 
 R 5  is oxo, —CF 3 , —CN, —OH, —NH 2 , —CONH 2 , —S(O) 3 H, —S(O) 2 NH 2 , —NHC(O)NH 2 , —NHC(O)H, —OCHF 2 , alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heteroalkyl, heterocycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or a substituted version of any of these groups; and 
 R 5a  is hydrogen, alkyl, or substituted alkyl. 
 
       
     
     
         4 . The compound of  claim 1 , wherein R 1  is halogen. 
     
     
         5 . (canceled) 
     
     
         5 . The compound of  claim 1 , wherein R 1  is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heteroalkyl, heterocycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or a substituted version of any of these groups. 
     
     
         6 . (canceled) 
     
     
         7 . The compound of  claim 1 , wherein: R 1  is Cl, F, Br, —OH, —OR 3 , —NR 3 R 3A , or a group of the formula: —Y 1 —(R 5 ) m1 , —OY 1 —(R 5 ) m1 , or —NR 5a Y 1 —(R 5 ) m1 , wherein:
 Y 1  is cycloalkylene, arylene, heterocycloalkylene, heteroarylene, or a substituted version of any of these groups; 
 m 1  is 0, 1, 2, 3, or 4; 
 R 5  is oxo, —CF 3 , —CN, —OH, —NH 2 , —CONH 2 , —S(O) 3 H, —S(O) 2 NH 2 , —NHC(O)NH 2 , —NHC(O)H, —OCHF 2 , alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heteroalkyl, heterocycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or a substituted version of any of these groups; and 
 R 5a  is hydrogen, alkyl, or substituted alkyl. 
 
     
     
         8 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         wherein 
         R 5  is oxo, —CF 3 , —CN, —OH, —NH 2 , —CONH 2 , —S(O) 3 H, —S(O) 2 NH 2 , —NHC(O)NH 2 , —NHC(O)H, —OCHF 2 , alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heteroalkyl, heterocycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or a substituted version of any of these groups; 
         Y selected from the group consisting of arylene, heteroarylene, cycloalkylene, and heterocycloalkylene; and 
         m1 is 0, 1, 2, 3, or 4. 
       
     
     
         9 . The compound  claim 8 , wherein Y is arylene, heterocycloalkylene, or a substituted version of either group. 
     
     
         10 . The compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
         R 5  is oxo, —CF 3 , —CN, —OH, —NH 2 , —CONH 2 , —S(O) 3 H, —S(O) 2 NH 2 , —NHC(O)NH 2 , —NHC(O)H, —OCHF 2 , alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heteroalkyl, heterocycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or a substituted version of any of these groups 
       
     
     
         12 . (canceled) 
     
     
         11 . The compound of  claim 8 , wherein R 5  is halogen, —CF 3 , —CN, —OH, alkyl, cycloalkyl, alkenyl, alkoxy, or a substituted version of any of these groups. 
     
     
         12 . The compound of  claim 11 , wherein R 5  is halogen, —CF 3 , —OH, —OCH 3  or C 1 -C 6  alkyl, cycloalkyl, or alkenyl or 2 to 6 membered alkoxy or a substituted version of any of these groups. 
     
     
         15 .- 17 . (canceled) 
     
     
         18 . The compound of  claim 1 , wherein n is 1 or 2. 
     
     
         19 . (canceled) 
     
     
         20 . The compound of  claim 1 , wherein R 2  is —C(O)OR 4 , alkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or a substituted version of any of these groups. 
     
     
         21 .- 25 . (canceled) 
     
     
         26 . The compound of  claim 1 , wherein R 2  is substituted or unsubstituted C 1 -C 5  alkyl. 
     
     
         27 .- 38 . (canceled) 
     
     
         39 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient or pharmaceutically acceptable salt. 
     
     
         40 . A method of treating a disease or disorder in a subject in need thereof, the method comprising administering an effective amount of a compound of  claim 1 , wherein the disease or disorder is further defined as:
 (A) cancer;   (B) a neurodegenerative disease;   (C) ethanol withdrawal;   (D) anxiety or depression;   (E) neuropathic pain.   
     
     
         41 .- 52 . (canceled) 
     
     
         53 . A method of inhibiting/antagonizing a sigma 2 receptor, the method comprising contacting a sigma 2 receptor with a compound of  claim 1  thereby inhibiting said sigma 2 receptor. 
     
     
         54 .- 65 . (canceled) 
     
     
         66 . The compound of  claim 1 , wherein R 2  is alkyl or substituted alkyl. 
     
     
         67 . The compound of  claim 1 , wherein R 2  is cycloalkyl or substituted cycloalkyl. 
     
     
         68 . The compound of  claim 1 , wherein R 2  is heterocycloalkyl or substituted heterocycloalkyl.