Hiv integrase inhibitors

Abstract

Compounds of Formula I are inhibitors of HIV integrase and inhibitors of HIV replication: wherein X 1 , X 2 , Y, R 1A , R 1B , R 2 and R 3 are defined herein. The compounds are useful for the prophylaxis or treatment of infection by HIV and the prophylaxis, treatment, or delay in the onset or progression of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se (or as hydrates or solvates thereof) or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Processes for making compounds of Formula I and intermediates thereof are also described.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X 1  and X 2  are each independently H, halogen, or C 1-3  alkyl, such that at least one of X 1  and X 2  is other than H; 
         Y is O; 
         R 1A  is H; 
         R 1B  is H; 
         R 2  is C 1-3  alkyl; and 
         R 3  is C 1-3  alkyl; 
       
     
     
         2 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 X 1  is F or CH 3 ;   X 2  is H, F, or CH 3 , and provided that:
 (A) when X 1  is F, then X 2  is H or CH 3 , and 
 (B) when X 1  is CH 3 , then X 2  is F; 
   Y is O;   R 1A  is H;   R 1B  is H;   R 2  is CH 3 , or CH 2 CH 3 ; and   R 3  is CH 3 ;   
     
     
         3 . A compound according to  claim 2 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1A  and RIB are both H and R 2  is CH 3  or CH 2 CH 3 ; 
       
     
     
         4 . (canceled) 
     
     
         5 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a stereomerically pure compound. 
     
     
         6 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is Compound 4A, Compound 4B, Compound 4C, Compound 4D, Compound 5A, Compound 5B, Compound 5C or Compound 5. 
     
     
         7 . A compound according to  claim 6 , or a pharmaceutically acceptable salt thereof, wherein the compound, Compound 4A, Compound 4B, Compound 4C, Compound 5A, or Compound 5B. 
     
     
         8 - 11 . (canceled) 
     
     
         12 . A compound according to  claim 7 , or a pharmaceutically acceptable salt thereof, wherein the compound is Compound 4A. 
     
     
         13 . A compound according to  claim 12  which is a crystalline form of Compound 4A, wherein the crystalline Compound 4A is characterized by an X-ray powder diffraction pattern obtained using copper K α  radiation which comprises 2Θ values in degrees of about 6.1, 10.4, 12.9, 13.7, 19.4 and 22.9. 
     
     
         14 . A compound according to  claim 7 , or a pharmaceutically acceptable salt thereof, wherein the compound is Compound 4B. 
     
     
         15 . A compound according to  claim 7 , or a pharmaceutically acceptable salt thereof, wherein the compound is Compound 4C. 
     
     
         16 . A compound according to  claim 7 , or a pharmaceutically acceptable salt thereof, wherein the compound is Compound 5A. 
     
     
         17 . A compound according to  claim 16  which is a crystalline form of Compound 5A, wherein the crystalline Compound 5A is characterized by an X-ray powder diffraction pattern obtained using copper K α  radiation which comprises 2θ values in degrees of about 8.4, 8.6, 18.0, 20.5, 20.8, 25.2, 26.1 and 27.2. 
     
     
         18 . A compound according to  claim 16  which is a crystalline form of Compound 5A, wherein the crystalline Compound 5A is characterized by an X-ray powder diffraction pattern obtained using copper K α  radiation which comprises 2θ values in degrees of about 8.4, 8.6, 18.0, 20.4, 20.8, 25.9, 26.2 and 27.1. 
     
     
         19 . A compound according to  claim 7 , or a pharmaceutically acceptable salt thereof, wherein the compound is Compound 5B. 
     
     
         20 - 21 . (canceled) 
     
     
         22 . A compound according to  claim 7 , wherein the compound is stereomerically pure. 
     
     
         23 . A pharmaceutical composition comprising an effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         24 . A method for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         25 - 40 . (canceled)