Small molecule inhibitors of hiv proteases

Abstract

Described herein are compounds, compositions, and methods for treating HIV and related diseases.

1 - 52 . (canceled) 
     
     
         53 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 R 1  is alkyl, cycloalkyl, alkenyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted; 
 X 1  is a bond, O, or an optionally substituted nitrogen; X 2  is CO or SO 2 ; 
 R 2  is selected from the group consisting of hydrogen, alkyl, heteroalkyl, hydroxy, alkoxy, arylalkoxy, amino, aminoalkyl, alkylthio, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, each of which is optionally substituted; or R 2  is a pro-drug moiety; 
 R 3  is hydrogen or alkyl; 
 R 4  and R 5  are, in each instance, independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkoxy, amino, aminoalkyl, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, hydroxyalkyl, nitrile, cyanoalkyl, carboxylic acid or a derivative thereof, and alkylcarboxylic acid or a derivative thereof, each of which is optionally substituted; or R 4  and R 5  are taken together with the attached atoms to foam a carbocycle or heterocycle; 
 X, Y, and Z are taken together with the attached atoms to form a heterocycle or heterobicycle, each of which is optionally substituted; or X, Y, Z, and R 5  are taken together with the attached atoms to form an optionally substituted heterobicycle; providing that X, Y, Z, R 5 , and the attached atoms do not comprise O—O or O—S; and 
 Q is selected from the group consisting of heteroalkyl, hydroxyalkyl, and carboxylic acid or a derivative thereof; 
 providing that the compound is not of the formulae 
 
       
         
           
           
               
               
           
         
       
       wherein R 5  is hydrogen, cyano or CH 2 CH═CH 2 ; n is 1 or 2; R x  is 1-naphthyl or phenyl; and R y  is tosyl or hydrogen. 
     
     
         54 . The compound of  claim 53  wherein X, Y, and Z are each independently selected from the group consisting of a bond, O, S, S(O), SO 2 , optionally substituted nitrogen, and (CR 4 R 5 ) m , where m is 1 to about 3. 
     
     
         55 . The compound of  claim 53  wherein X, Y, and Z are taken together with the attached atoms to form a 5 to 8 membered heterocycle containing 1 or 2 oxygen atoms. 
     
     
         56 . The compound of  claim 53  wherein X, Y, and Z are taken together with the attached atoms to form a 5 to 8 membered heterocycle containing 1 oxygen and 1 nitrogen atom. 
     
     
         57 . The compound of  claim 53  wherein X, Y, and Z are taken together with the attached atoms to form a tetrahydrofuran, dioxolane, tetrahydropyran, dioxane, morpholine, or oxepane, each of which is optionally substituted. 
     
     
         58 . The compound of  claim 53  wherein Z and R 4  are taken together with the attached atoms to form an optionally substituted oxabicyclo-[3.2.1]-octane. 
     
     
         59 . The compound of  claim 53  wherein one of X, Y, or Z is O or NR 2a , where R 2a  is selected from the group consisting of hydrogen, alkyl, heteroalkyl, hydroxy, alkoxy, arylalkoxy, amino, alkylthio, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, each of which is optionally substituted; or R 2a  is a pro-drug moiety; and the others of X, Y, and Z are selected from the group consisting of a bond and (CR 4 R 5 ) m , where m is 1 to about 3. 
     
     
         60 . The compound of  claim 53  wherein X is O; Y is (CR 4 R 5 ) m , where m is 1 to about 3; and Z is a bond. 
     
     
         61 . The compound of  claim 53  wherein Y is O; and X and Z are each (CR 4 R 5 ) m , where m is 1 to about 3. 
     
     
         62 . The compound of  claim 53  wherein each of X and Y is (CR 4 R 5 ) m , where m is 1; and Z is a bond. 
     
     
         63 . The compound of  claim 53  wherein each of X, Y, and Z is (CR 4 R 5 ) m , where m is 1. 
     
     
         64 . The compound of  claim 53  wherein Q is selected from the group consisting of —CH 2 OR 9 , —CO 2 R 9 , —CONR 9 R 10 , —C(O)SR 9 , —C(S)OR 9 , and —C(S)NR 9 R 10 ; where R 9  and R 10  are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, heteroalkyl, and arylalkyl; or one or both of R 9  and R 10  is a pro-drug moiety; or R 9  and R 10  together with the nitrogen to which they are attached form an optionally substituted heterocycle. 
     
     
         65 . The compound of  claim 64  wherein Q is CO 2 R 9 . 
     
     
         66 . The compound of  claim 53  wherein R 1  is optionally substituted aryl. 
     
     
         67 . The compound of  claim 53  wherein X 1  is O and X 2  is C(O). 
     
     
         68 . The compound of  claim 53  wherein X 1  is a bond and X 2  is S(O) 2 . 
     
     
         69 . The compound of  claim 53  wherein R 2  is H. 
     
     
         70 . The compound of  claim 53  wherein R 3  is H. 
     
     
         71 . The compound of  claim 53  wherein R 4  and R 5  are each independently selected from the group consisting of H, alkyl, CN, aryl, heteroaryl, heteroalkyl, arylalkyl, arylheteroalkyl, and heterocyclyl, each of which is optionally substituted. 
     
     
         72 . The compound of  claim 53  wherein one or more of R 4  and R 5  is alkyl substituted with a carboxylic acid or derivative thereof. 
     
     
         73 . The compound of  claim 53  wherein Q is CO 2 R 9 , R 1  is optionally substituted aryl, X 1  is a bond, and X 2  is S(O) 2 . 
     
     
         74 . The compound of  claim 53  of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 R 5  is selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloheteroalkyl, alkenyl, alkoxy, optionally substituted amino, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, nitrile, cyanoalkyl, carboxylic acid, or a derivative thereof, and alkylcarboxylic acid, or a derivative thereof, each of which is optionally substituted; 
 R 7  is selected from the group consisting of hydrogen, hydroxy, alkoxy, optionally substituted alkyl, heteroalkyl, optionally substituted alkylaryl, optionally substituted arylalkyl, optionally substituted alkylheteroaryl, optionally substituted heteroarylalkyl, and NR 9 R 10 , where R 9  and R 10  are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, heteroalkyl, and arylalkyl; or R 9  and R 10  together with the nitrogen to which they are attached form an optionally substituted heterocyclyl; 
 R 8  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, and alkylheteroaryl, each of which is optionally substituted; and 
 R 11  is hydrogen, alkyl, arylalkyl, or a pro-drug moiety. 
 
     
     
         75 . The compound of  claim 74  wherein R 8  is optionally substituted aryl. 
     
     
         76 . The compound of  claim 74  wherein R 8  is naphthyl, quinolinyl or phenyl, each of which is optionally substituted. 
     
     
         77 . The compound of  claim 53  of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 R a  represents from 0 to 3 substituents independently selected in each instance from the group consisting of hydroxy, alkyl, heteroalkyl, alkoxy, aryl, arylalkyl, hydroxy, optionally substituted amino, and thioalkyl, each of which is optionally substituted, or two vicinal R a  together with the attached carbons form a fused ring. 
 
     
     
         78 . The compound of  claim 77  wherein X 2  is SO 2 ; X 1  is a bond; R 3  is hydrogen; R 1  is aryl; and Q is a carboxylic acid or a derivative thereof. 
     
     
         79 . A composition comprising a therapeutically effective amount for treating a patient in need of relief from HIV, AIDS, or an AIDS-related disease of a compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 R 1  is alkyl, cycloalkyl, alkenyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted; 
 X 1  is a bond, O, or an optionally substituted nitrogen; X 2  is CO or SO 2 ; 
 R 2  is selected from the group consisting of hydrogen, alkyl, heteroalkyl, hydroxy, alkoxy, arylalkoxy, amino, aminoalkyl, alkylthio, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, each of which is optionally substituted; or R 2  is a pro-drug moiety; 
 R 3  is hydrogen or alkyl; 
 R 4  and R 5  are, in each instance, independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkoxy, amino, aminoalkyl, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, hydroxyalkyl, nitrile, cyanoalkyl, carboxylic acid or a derivative thereof, and alkylcarboxylic acid or a derivative thereof, each of which is optionally substituted; or R 4  and R 5  are taken together with the attached atoms to form a carbocycle or heterocycle; 
 X, Y, and Z are taken together with the attached atoms to form a heterocycle or heterobicycle, each of which is optionally substituted; or X, Y, Z, and R 5  are taken together with the attached atoms to form an optionally substituted heterobicycle; providing that X, Y, Z, R 5 , and the attached atoms do not comprise O—O or O—S; and 
 Q is selected from the group consisting of heteroalkyl, hydroxyalkyl, and carboxylic acid or a derivative thereof; and 
 one or more carries, diluents, or excipients, or a combination thereof. 
 
     
     
         80 . A method for treating a patient in need of relief from HIV, AIDS, or an AIDS-related disease, the method comprising the step of administering to the patient a therapeutically effective amount of a compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 R 1  is alkyl, cycloalkyl, alkenyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted; 
 X 1  is a bond, O, or an optionally substituted nitrogen; X 2  is CO or SO 2 ; 
 R 2  is selected from the group consisting of hydrogen, alkyl, heteroalkyl, hydroxy, alkoxy, arylalkoxy, amino, aminoalkyl, alkylthio, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, each of which is optionally substituted; or R 2  is a pro-drug moiety; 
 R 3  is hydrogen or alkyl; 
 R 4  and R 5  are, in each instance, independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkoxy, amino, aminoalkyl, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, hydroxyalkyl, nitrile, cyanoalkyl, carboxylic acid or a derivative thereof, and alkylcarboxylic acid or a derivative thereof, each of which is optionally substituted; or R 4  and R 5  are taken together with the attached atoms to foam a carbocycle or heterocycle; 
 X, Y, and Z are taken together with the attached atoms to form a heterocycle or heterobicycle, each of which is optionally substituted; or X, Y, Z, and R 5  are taken together with the attached atoms to form an optionally substituted heterobicycle; providing that X, Y, Z, R 5 , and the attached atoms do not comprise O—O or O—S; and 
 Q is selected from the group consisting of heteroalkyl, hydroxyalkyl, and carboxylic acid or a derivative thereof; or 
 a composition comprising a therapeutically effective amount of the compound and one or more carries, diluents, or excipients, or a combination thereof.