Inhibitors of kidney-type glutaminase, gls-1

Abstract

The present invention relates generally to glutaminase inhibitors of Formula I, Formula II, or Formula III, as well as pharmaceutical compounds containing them and methods of their use.

1 . A compound, or a pharmaceutically acceptable salt, ester, enol ether, enol ester, solvate, hydrate, or prodrug thereof, wherein the compound is selected from the group consisting of:
 (i) a compound of Formula I:   
       
         
           
           
               
               
           
         
         
           wherein: 
           R is selected from the group consisting of monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, and monocyclic or bicyclic heterocyclyl, wherein each monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, and monocyclic or bicyclic heterocyclyl can be optionally substituted from 1 to 4 times with substituents independently selected at each occurrence thereof from the group consisting of H, halogen, C 1-6  alkyl, aryl, —OR 8 , —CF 3 , and —CHF 2 ; 
           R 1  and R 2  are each independently selected from the group consisting of H, halogen, and C 1-6  alkyl; or R 1  and R 2  are combined to form ═O; 
           R 3 —R 7  are each independently selected from the group consisting of H, halogen, —NO 2 , —NR 8 R 9 , —SO 2 NR 8 R 9 , —N 3 , —C(O)R 8 , aryl, heteroaryl, heterocyclyl, 
         
       
       
         
           
           
               
               
           
         
         
            and 
           R 8  and R 9  are each independently selected from the group consisting of H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and aryl; or R 8  and R 9  are combined with the nitrogen to which they are attached to form a heterocyclyl, wherein the heterocyclyl can be optionally substituted with —COOH or —COOMe; 
         
         (ii) a compound of Formula II: 
       
       
         
           
           
               
               
           
         
         
           wherein: 
           the dotted circle identifies an active moiety; 
           X is independently —CR 14a — or —N; 
           R 1a  is independently H, —OH, —OR 14a , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, R 14a C(O)—, R 14a OC(O)—, R 14a S(O)—, or R 14a S(O) 2 —; 
           R 2a , R 3a , R 4a , R 5a , and R 6a  are each independently a photoreactive moiety, H, halogen, —NO 2 , —OH, —OR 14a , —SR 14a , —NH 2 , —NHR 14a , —NR 14a R 15a , R 14a C(O)—, R 14a OC(O), R 14a C(O)O—, C 1 -C 6  alkyl, C 2 -6 alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 4 -C 7  cycloalkylalkyl, aryl C 1 -C 6  alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl with each cyclic unit containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl are optionally substituted with a photoreactive moiety; or R 2a  and R 3a , R 3a  and R 4a , R 4a  and R 5a , or R 5a  and R 6a  are combined to form a heterocyclic ring optionally substituted with a photoreactive moiety; 
           R 7a , R 8a , R 9a , and R 10a  are each independently a photoreactive moiety, H, —OH, —NH 2 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 4 -C 7  cycloalkylalkyl, aryl C 1 -C 6  alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl with each cyclic unit containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the aryl, heteroaryl, and aryl C 1 -C 6  alkyl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of, halogen, —OH, —NH 2 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 6  alkoxy, —SH, and C 1 -C 6  thioalkyl, and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl are optionally substituted with a photoreactive moiety; and 
           R 11a , R 12a , R 13a , R 14a , R 15a , R 16a , and R 17a  are each independently a photoreactive moiety, H, halogen, —OH, —NO 2 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 4 -C 7  cycloalkylalkyl, aryl C 1 -C 6  alkyl, mono or polycyclic aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, and mono or polycyclic aryl are optionally substituted with a photoreactive moiety and each one of R 11a -R 17a  is optionally substituted with —NH 2 , —OH, halogen, —COOH, —NO 2 , and —CN; and 
           wherein the compound comprises at least one photoreactive moiety; and 
         
         (iii) a compound of Formula III: 
       
       
         
           
           
               
               
           
         
         
           wherein: 
           R is selected from the group consisting of monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, and monocyclic or bicyclic heterocyclyl, wherein each monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, and monocyclic or bicyclic heterocyclyl can be optionally substituted from 1 to 4 times with substituents independently selected at each occurrence thereof from the group consisting of H, halogen, C 1-6  alkyl, aryl, —OR 8 , —CF 3 , and —CHF 2 ; 
           R 1  and R 2  are each independently selected from the group consisting of a photoreactive moiety, H, halogen, and C 1-6  alkyl optionally substituted with a photoreactive moiety; or R 1  and R 2  are combined to form ═O; 
           R 3 —R 7  are each independently selected from the group consisting of a photoreactive moiety, H, halogen, —NO 2 , —NR 8 R 9 , —SO 2 NR 8 R 9 , —N 3 , —C(O)R 8 , aryl, heteroaryl, and heterocyclyl, wherein the aryl and heteroaryl are optionally substituted with a photoreactive moiety; and 
           R 8  and R 9  are each independently selected from the group consisting of a photoreactive moiety, H, C 1-6  alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, and aryl, wherein the alkyl, alkenyl, alkynyl, and aryl are optionally substituted with a photoreactive moiety; or R 8  and R 9  are combined with the nitrogen to which they are attached to form a heterocyclyl, wherein the heterocyclyl can be optionally substituted with a photoreactive moiety, —COOH, or —COOMe; and 
           wherein the compound comprises at least one photoreactive moiety; and 
         
         wherein the compound is optionally modified to include a tag and/or an attachment to a solid surface. 
       
     
     
         2 . The compound of  claim 1 , wherein the compound is a compound of Formula I. 
     
     
         3 - 4 . (canceled) 
     
     
         5 . The compound according to  claim 1 , wherein the compound is a compound of Formula II or Formula III. 
     
     
         6 . The compound according to  claim 5 , wherein the photoreactive moiety is selected from the group consisting of aryl azides, diazirines, and benzophenone. 
     
     
         7 . The compound according to  claim 6 , wherein the photoreactive moiety is selected from the group consisting of —N═N + ═N − ; 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound according to  claim 5 , wherein the compound is a compound of Formula II. 
     
     
         9 . (canceled) 
     
     
         10 . The compound according to  claim 5 , wherein the compound is a compound of Formula III. 
     
     
         11 . (canceled) 
     
     
         12 . A pharmaceutical composition comprising:
 a compound of  claim 1 , or a pharmaceutically acceptable salt, ester, enol ether, enol ester, solvate, hydrate, or prodrug thereof.   
     
     
         13 . The pharmaceutical composition of  claim 12  further comprising:
 a pharmaceutically acceptable carrier. 
 
     
     
         14 . A method of treating a subject with a condition mediated by production of glutamate from glutamine by glutaminase GLS1, said method comprising:
 selecting a subject with a condition mediated by production of glutamate from glutamine by glutaminase GLS1 and   administering to said selected subject an inhibitor of glutaminase GLS1 activity under conditions effective to treat the condition mediated by production of glutamate from glutamine, wherein the inhibitor is a compound of  claim 1 , or a pharmaceutically acceptable salt, ester, enol ether, enol ester, solvate, hydrate, or prodrug thereof.   
     
     
         15 . The method of  claim 14 , wherein the condition is a cancer that exhibits active glutaminase GLS1 activity. 
     
     
         16 . The method of  claim 15 , wherein the cancer is selected from the group consisting of breast cancer, brain cancer, lung cancer, ovarian cancer, pancreatic cancer, colon cancer, and multiple myeloma. 
     
     
         17 - 21 . (canceled) 
     
     
         22 . A method of reducing the production of glutamate from glutamine by glutaminase GLS1 in a sample, said method comprising:
 inhibiting glutaminase GLS1 activity in the sample by a method comprising:
 providing a compound and 
 contacting glutaminase GLS1 in the sample with the compound to reduce the production of glutamate from glutamine in the sample, 
 wherein the compound is a compound of  claim 1 , or a pharmaceutically acceptable salt, ester, enol ether, enol ester, solvate, hydrate, or prodrug thereof. 
   
     
     
         23 . A method of detecting glutaminase GLS1 protein in a sample, said method comprising:
 providing a sample potentially containing glutaminase GLS1 protein;   contacting the sample with a compound comprising a photoreactive moiety;   exposing the compound to a light source under conditions effective to form a conjugate between the compound and glutaminase GLS1 protein, if present in the sample, through covalent modification of the photoreactive moiety; and   detecting whether any compound-glutaminase GLS1 protein conjugates are formed, wherein formation of a compound-glutaminase GLS1 protein conjugate indicates the presence of glutaminase GLS1 protein in the sample;   wherein the compound is a compound of  claim 5 , or a pharmaceutically acceptable salt, ester, enol ether, enol ester, solvate, hydrate, or prodrug thereof.   
     
     
         24 . A method of producing a glutaminase inhibitor-glutaminase GLS1 protein conjugate in a sample;
 providing a sample containing one of (i) glutaminase GLS1 protein and (ii) a compound comprising a photoreactive moiety;   contacting the sample with the other of (i) glutaminase GLS1 protein and (ii) a compound comprising a photoreactive moiety; and   exposing the compound to a light source under conditions effective to form a conjugate between the compound and glutaminase GLS1 protein through covalent modification of the photoreactive moiety;   
       wherein the compound is a compound of  claim 5 , or a pharmaceutically acceptable salt, ester, enol ether, enol ester, solvate, hydrate, or prodrug thereof. 
     
     
         25 . The method according to  claim 24  further comprising:
 (i) detecting the compound, the conjugate, and/or the glutaminase GLS1 protein; 
 (ii) quantitating the amount of compound, the conjugate, and/or the glutaminase GLS1 protein present in the sample; 
 (iii) isolating the compound, the conjugate, and/or the glutaminase GLS1 protein from the sample; 
 (iv) purifying the compound, the conjugate, and/or the glutaminase GLS1 protein; or 
 (v) any combination thereof. 
 
     
     
         26 - 39 . (canceled) 
     
     
         40 . The method according to  claim 14 , wherein the glutaminase GLS1 is glutaminase C (“GAC”). 
     
     
         41 . The method according to  claim 14 , wherein the glutaminase GLS1 is brain glutaminase (“KGA”). 
     
     
         42 . The compound according to  claim 1 , wherein the compound is modified to include a tag and/or an attachment to a solid surface. 
     
     
         43 . A pharmaceutically acceptable salt, ester, enol ether, enol ester, solvate, hydrate, or prodrug of a compound according to  claim 1 .