Boronic Acid Inhibitors of HIV Protease

Abstract

Protease inhibitors, particularly aspartyl protease inhibitors, and more particularly HIV protease inhibitors which are boronated to enhance activity or to enhance entry into cells. Compounds, prodrugs and salts thereof of this invention contain phenylboronate groups, in particular p-B(OH) 2 -phenyl groups, benzoxaborole groups or borono-pyridyl groups or analogous groups in which the boronate group is protected. Methods for treating AIDS and ARC as well as providing a method for treating or preventing HIV infection

We claim: 
     
         1 . A compound of formula: 
       
         
           
           
               
               
           
         
         or a salt, ester, solvate or hydrate thereof, 
         wherein: 
         x is 0 or 1 to show the presence or absence of —XX—, 
         —XX— when present is —O—, —CO—, —SO 2 —, —CO—CO—, —O—CO—, —O—SO 2 —, —NR 10 —SO 2 —, —NR 10 —CO— or —NR 10 —CO—CO—; where each R 10  is independently H, C1-C4 alkyl or C1-C4 alkyl substituted with C 3 -C 7  cycloalkyl; 
         R 20 , R 20A  and R 20B  are independently selected from C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, C5-C6-cycloalkenyl, phenyl, C1-C4 alkyl substituted with one or more phenyl, or C3-C6 cycloalkyl groups, a C3-C6 cycloalkyl group substituted with or fused to phenyl or a C5-C6 cycloalkyl group substituted with or fused to a phenyl; 
         R 21  is selected H; —PO 3 (R 3 ) 2 ; or —PO 3 R 3 H or —PO 3 H 2  or pharmaceutically acceptable salts thereof; or an acyl group (—CO—R 22 ), where R 22  is selected from C1-C4 alkyl, C2-C4 alkenyl, or C2-C10 alkyl wherein one or more —CH 2 — groups are replaced with —O—; or a C2-C10 alkyl wherein one or more —CH 2 — groups are replaced with —NH— or one or more —CH 3  groups are replaced with —NR 23 , where R 23  is H or a C1-C4 alkyl; and 
         A is selected from H; Het; C6-C10 aryl; C3-C7 cycloalkyl; C5-C7 cycloalkenyl; C1-C4 alkyl; C2-C4 alkenyl; C1-C4 alkyl substituted with one or more C1-C4 alkoxy, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, C6-C10 aryl, or a Het group, 
         wherein Het is selected from a 5-10 membered saturated, partially saturated or unsaturated cyclic group containing one or more heteroatoms or moieties selected from —N═; —N(R 24 )—; —O—; —S—, —SO—; —SO 2 —, or —CO—, where R 24  is selected from H, C1-C4 alkyl, C1-C4 alkyl substituted with a C3-C7 cycloalkyl group, or C1-C4 alkyl substituted with a C6-C10 aryl group; 
         wherein each R 20 , R 22 , R 23 , R 24 , A or Het group is optionally substituted with one or more oxo, C 1 -C 3 -alkoxy, —OH, —C 1 -C 3  alkyl, —CO—R 25 , —N(R 25 ) 2 , —CO 2 R 25  (or when R 25  is H, pharmaceutically acceptable salts thereof), —NR 25 —CO—R 25 , —CO—N(R 25 ) 2 , —(CH 2 ) r —OH (where r is 1 or 2), —CN, —NO 2 , halo or —CF 3 , and R 25  is selected from H or C 1 -C 3  alkyl, and 
         wherein BBB is a boronated aryl, boronated heteroaryl group or boronate protected derivative thereof other than: 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound, salt, ester, or solvate of  claim 1 , wherein BBB is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The compound, salt, ester, or solvate of  claim 1 , wherein BBB is a boronated aryl or boronated heteroaryl group wherein the boronated is protected. 
     
     
         4 . The compound, salt, ester, or solvate of  claim 1 , wherein BBB is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound, salt, ester, or solvate of  claim 1 , wherein XX is present and is —O—, —CO—, —SO 2 — or —O—CO—. 
     
     
         6 . The compound, salt, ester, or solvate of  claim 1 , wherein XX is present and is —O—CO—. 
     
     
         7 . The compound, salt, ester, or solvate of  claim 1 , wherein A is 5-10 membered saturated, partially saturated or unsaturated cyclic group containing one or more heteroatoms or moieties selected from —N═; —N(R 24 )—; —O—; —S—, —SO—; —SO 2 —, or —CO—, where R 24  is selected from H, C1-C4 alkyl, C1-C4 alkyl substituted with a C3-C7 cycloalkyl group, or C1-C4 alkyl substituted with a C6-C10 aryl group. 
     
     
         8 . The compound, salt, ester, or solvate of  claim 1 , wherein XX is present and is —O—CO—, R 20  is a benzyl group R 20A  is C1-C4 alkyl and R 20B  is hydrogen. 
     
     
         9 . The compound, salt, ester, or solvate of  claim 1 , where R 21  is selected from hydrogen, —PO 3 H 2 , —PO 3 H − , —PO 3   2− , —CH 2 —OPO 3 H 2 , —CH 2 —OPO 3 H − , —CH 2 —OPO 3   2− , —PO 3 (R 31 ) 2 , —PO 3 R 31 H, and pharmaceutically acceptable salts thereof, where R 31  is optionally substituted C1-C6 alkyl or optionally substituted C6-C10 aryl. 
     
     
         10 . The compound, salt, ester, or solvate of  claim 1 , where A is one of: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound, salt, ester, or solvate of  claim 20 , where A is 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1  of formula: 
       
         
           
           
               
               
           
         
         or a salt, ester, or solvate thereof, 
         where R 21  is hydrogen, —PO 3 H 2  or pharmaceutically acceptable salts thereof. 
       
     
     
         13 . The compound, salt, ester, or solvate of  claim 12 , wherein BBB is 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of formula: 
       
         
           
           
               
               
           
         
         or a salt, ester, or solvate thereof, 
         where R 21  is hydrogen, —PO 3 H 2  or pharmaceutically acceptable salts thereof. 
       
     
     
         15 . The compound, salt, ester, or solvate of  claim 14 , wherein BBB is 
       
         
           
           
               
               
           
         
       
     
     
         16 . A pharmaceutical composition comprising a therapeutically effective amount of a compound, salt, ester, or solvate of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         17 . A pharmaceutical composition comprising a therapeutically effective amount of a compound, salt, ester, or solvate of  claim 1 , and a pharmaceutically acceptable carrier and further comprising ritonovir. 
     
     
         18 . A method for treating or preventing HIV infection which comprises administration to a patient in need thereof of a compound, salt, ester, or solvate of  claim 1 . 
     
     
         19 . A method for treating a symptom or disorder associated with HIV infection which comprises administration to a patient in need thereof of a compound, salt, ester, or solvate of  claim 1 . 
     
     
         20 . A compound of formula: 
       
         
           
           
               
               
           
         
       
       or Formula: 
       
         
           
           
               
               
           
         
         or a salt, ester, or solvate thereof, 
         wherein 
         R 40  and R 45  are independently selected from C3-C5 alkyl; C2-C6 haloalkyl; C1-C12 alkyl substituted with halo, —N 3 , phenyl, C3-C7 cycloalkyl, C5-C6 cycloalkenyl, Het, —NH 2 —SO 2 —Het; phenyl, substituted with one or more halo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, C5-C6 cycloalkenyl, Het, or —NH 2 —SO 2 —Het; C3-C12 alkyl wherein one or more —CH 2 — groups are replaced with —O— and/or one or more —CH 3  are replaced with —OH; C2-C12 alkyl wherein one or more —CH 2 — groups are replaced with —NR 41 — and/or one or more —CH 3  are replaced with —N(R 41 ) 2 , where R 41  is H or C1-C4 alkyl; C3-C12 alkyl wherein one or more —CH 2 — groups are replaced with —O— or —NR 41 — and/or one or more —CH 3  are replaced with —OH or —N(R 41 ) 2 , where R 41  is H or C1-C4 alkyl; C2-C12 alkyl wherein one or more —CH 2 — groups are replaced with —CO— or —NR 41 — and/or one or more —CH 3  are replaced with —N(R 41 ) 2 , —OH, —COOH, or —SO 3 H, where R 41  is H or C1-C4 alkyl; or -Het-CO—NH—C1-C3-alkyl; 
         R 50  is C1-C4 alkyl; 
         R 55  is H or C1-C4 alkyl; 
         R 60  is an acyl group, —CO—R 61  where R 61  is H, C1-C6 alkyl, C3-C7 cycloalkyl or C1-C6 alkyl substituted with C3-C7 cycloalkyl or phenyl; 
         R 65  is hydrogen of C1-C4 alkyl; 
         R 66  is —C1-C4 alkyl substituted with Z where Z is —OH, —NH 2 , —PO(OH) 2  or pharmaceutically acceptable salts thereof, or a —COR Q  group where R Q  is C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkyl substituted with C3-C6 cycloalkyl or phenyl, more preferably R 66  is —CH 2 —Z, and yet more preferably Z is —CH 2 —OH; 
         R 70  is H or C1-C6 alkyl and is preferably C1-C6 alkyl, more preferably butyl and yet more preferably —CH 2 —CH 2 (CH 3 ) 2  and 
         BNN is any one of: