Antiviral beta-amino acid ester phosphodiamide compounds

Abstract

Compounds of Formula I: and their pharmaceutically acceptable salts are useful for the inhibition of HIV reverse transcriptase. The compounds may also be useful for the prophylaxis or treatment of infection by HIV and in the prophylaxis, delay in the onset or progression, and treatment of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antiviral agents, immunomodulators, antibiotics or vaccines.

1 . A compound of structural Formula I: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         R 1  and R 2  are each independently selected from (a) H, (b) —C 1-4 alkyl, (c) —C 1-4 alkyl substituted with —OH, —SH, —SCH 3 , —NH 2  or —NH—C(═NH)—NH 2 , (d) —CH 2 -phenyl, (e) —CH 2 -phenol, (f) —(CH 2 ) 1-2 —COOH, (g) —(CH 2 ) 1-2 —CONH 2 , (h) —CH 2 -1H-indole, (i) —CH 2 -imidazole, (j) aryl (for example but not limited to phenyl or naphthyl) or (k) heteroaryl (for example but not limited to pyridine); 
         R 3  is
 (a) —C 1-10 alkyl unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 10a , —SH, —NR 11 R 12 , —C 3-6 cycloalkyl or spiro-C 3-6 cycloalkyl, 
 (b) —CH 2 -phenyl unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15a , —SH, —NR 11 R 12  or —C 1-3 alkyl, 
 (c) —C 3-8 cycloalkyl unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15a , —SH, —NR 11 R 12  or —C 1-3 alkyl, 
 (d) aryl unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15a , —SH, —NR 11 R 12  or —C 1-3 alkyl, 
 (e) —C 1-5 alkyl-X—C 1-5 alkyl wherein X is O, S or NH, 
 (f) heteroaryl unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15a , —SH, —NR 11 R 12  or —C 1-3 alkyl, or 
 (g) a heterocyclic ring unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15a , —SH, —NR 11 R 12  or —C 1-3 alkyl; 
 
         R A  is an L-amino acid ester residue of formula (i), a D-amino acid ester residue of formula (ii), a glycine ester residue of formula (iii), a geminally di-substituted amino acid ester residue of formula (iv), a beta amino acid ester residue of formula (v), or an L-proline ester residue of formula (vi): 
       
       
         
           
           
               
               
           
         
         R 4  is (a) —C 1-4 alkyl, (b) —C 1-4 alkyl substituted with —OH, —SH, —SCH 3 , —NH 2 , —NH—C(═NH)—NH 2 , (c) —CH 2 -phenyl, (d) —CH 2 -phenol, (e) —(CH 2 ) 1-2 —COOH, (f) —(CH 2 ) 1-2 —CONH 2 , (g) —CH 2 -1H-indole, (h) —CH 2 -imidazole, (i) aryl (for example but not limited to phenyl or naphthyl) or (j) heteroaryl (for example but not limited to pyridine); 
         R 5  and R 6  are each independently selected from (a) —C 1-4 alkyl, (b) —C 1-4 alkyl substituted with —OH, —SH, —SCH 3 , —NH 2 , —NH—C(═NH)—NH 2 , (c) —CH 2 -phenyl, (d) —CH 2 -phenol, (e) —(CH 2 ) 1-2 —COOH, (f) —(CH 2 ) 1-2 —CONH 2 , (g) —CH 2 -1H-indole, (h) —CH 2 -imidazole, (i) aryl (for example but not limited to phenyl or naphthyl) or (j) heteroaryl (for example but not limited to pyridine); 
         or R 5  and R 6  are joined together with the carbon to which they are both attached to form —C 3-6 cycloalkyl or a 4 to 6-membered heterocyclic ring; 
         R 7  and R 8  are each independently selected from (a) H, (b) —C 1-4 alkyl, (c) —C 1-4 alkyl substituted with —OH, —SH, —SCH 3 , —NH 2  or —NH—C(═NH)—NH 2 , (d) —CH 2 -phenyl, (e) —CH 2 -phenol, (f) —(CH 2 ) 1-2 —COOH, (g) —(CH 2 ) 1-2 —CONH 2 , (h) —CH 2 -1H-indole, (i) —CH 2 -imidazole, (j) aryl (for example but not limited to phenyl or naphthyl) or (k) heteroaryl (for example but not limited to pyridine); 
         R 9  is
 (a) —C 1-10 alkyl unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 10b , —SH, —NR 13 R 14 , —C 3-6 cycloalkyl or spiro-C 3-6 cycloalkyl, 
 (b) —CH 2 -phenyl unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15b , —SH, —NR 13 R 14  or —C 1-3 alkyl, 
 (c) —C 3-8 cycloalkyl unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15b , —SH, —NR 13 R 14  or —C 1-3 alkyl, 
 (d) aryl unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15b , —SH, —NR 13 R 14  or —C 1-3 alkyl, 
 (e) —C 1-5 alkyl-X—C 1-5 alkyl wherein X is O, S or NH; 
 (f) heteroaryl unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15b , —SH, —NR 13 R 14  or —C 1-3 alkyl, or 
 (g) a heterocyclic ring unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15b , —SH, —NR 13 R 14  or —C 1-3 alkyl; 
 
         R 10a  and R 10b  are each independently selected from —H or —C 3-6 cycloalkyl; 
         R 11  and R 12  are each independently selected from —H, —C 1-3 alkyl or —C 3-6 cycloalkyl; 
         R 13  and R 14  are each independently selected from —H, —C 1-3 alkyl or —C 3-6 cycloalkyl; and 
         R 15a  and R 15b  are each independently selected from —H, —C 1-3 alkyl or —C 3-6 cycloalkyl. 
       
     
     
         2 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein one of R 1  and R 2  is H, and the other is H or —C 1-4 alkyl. 
     
     
         3 . The compound of  claim 2  or a pharmaceutically acceptable salt thereof wherein R 3  is
 (a) —C 1-8 alkyl, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH 2 SH, —CH 2 CH 2 CH 2 SH, —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , 
 (b) —CH 2 -phenyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15a , —SH, —NR 11 R 12  or —C 1-3 alkyl, 
 (c) —C 3-6 cycloalkyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15a , —SH, —NR 11 R 12  or —C 1-3 alkyl, 
 (d) phenyl or naphthyl, each unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15a , —SH, —NR 11 R 12  or —C 1-3 alkyl, 
 (e) —CH 2 CH 2 OCH 3 , —CH 2 CH 2 CH 2 OCH 3 , —CH 2 CH 2 SCH 3 , —CH 2 CH 2 CH 2 SCH 3 , —CH 2 CH 2 NHCH 3 , —CH 2 CH 2 CH 2 NHCH 3 , 
 (f) pyridyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15a , —SH, —NR 11 R 12  or —C 1-3 alkyl, or 
 (g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15a , —SH, —NR 11 R 12  or —C 1-3 alkyl. 
 
     
     
         4 . The compound of  claim 3  or a pharmaceutically acceptable salt thereof wherein R 3  is —C 1-8 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 
     
     
         5 . The compound of  claim 4  or a pharmaceutically acceptable salt thereof wherein R 3  is —C 3-8 alkyl. 
     
     
         6 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein R 9  is
 (a) —C 1-8 alkyl, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH 2 SH, —CH 2 CH 2 CH 2 SH, —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , 
 (b) —CH 2 -phenyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15b , —SH, —NR 13 R 14  or —C 1-3 alkyl, 
 (c) —C 3-6 cycloalkyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15b , —SH, —NR 13 R 14  or —C 1-3 alkyl, 
 (d) phenyl or naphthyl, each unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15b , —SH, —NR 13 R 14  or —C 1-3 alkyl, 
 (e) —CH 2 CH 2 OCH 3 , —CH 2 CH 2 CH 2 OCH 3 , —CH 2 CH 2 SCH 3 , —CH 2 CH 2 CH 2 SCH 3 , —CH 2 CH 2 NHCH 3 , —CH 2 CH 2 CH 2 NHCH 3 , 
 (f) pyridyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15b , —SH, —NR 13 R 14  or —C 1-3 alkyl, or 
 (g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —OR 15b , —SH, —NR 13 R 14  or —C 1-3 alkyl. 
 
     
     
         7 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein R A  is: 
       
         
           
           
               
               
           
         
         and R 9  is —C 1-8 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 
       
     
     
         8 . The compound of  claim 2  or a pharmaceutically acceptable salt thereof, wherein R A  is: 
       
         
           
           
               
               
           
         
         R 4  is —C 1-4 alkyl and 
         R 9  is —C 1-8 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. 
       
     
     
         9 . The compound of  claim 2  or a pharmaceutically acceptable salt thereof, wherein R A  is: 
       
         
           
           
               
               
           
         
         R 5  and R 6  are each independently selected from —CH 3 , —CH 2 CH 3 , —C 3 alkyl or —C 4 alkyl, and R 9  is —C 1-8 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 
       
     
     
         10 . The compound of  claim 2  or a pharmaceutically acceptable salt thereof, wherein R A  is: 
       
         
           
           
               
               
           
         
         R 7  is H or —C 1-4 alkyl, 
         R 8  is H or —C 1-4 alkyl, and 
         R 9  is —C 1-8 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 
       
     
     
         11 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein:
 R 1  is H or —C 1-4 alkyl; R 2  is H or —C 1-4 alkyl; 
 R 3  is —C 1-8 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; 
 R 4  is —CH 3 ; 
 R 5  and R 6  are both —CH 3 ; 
 R 7  is H or —C 1-4 alkyl; R 8  is H or —C 1-4 alkyl; and 
 R 9  is —C 1-8 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 
 
     
     
         12 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein:
 one of R 1  and R 2  is H, and the other is methyl or i-propyl; 
 R 3  is i-propyl; 
 R 4  is —CH 3 ; 
 R 5  and R 6  are both —CH 3 ; 
 R 7  is H or —C 1-4 alkyl; R 8  is H or —C 1-4 alkyl; and 
 R 9  is —C 3-8 alkyl, cyclobutyl, cyclopentyl or cyclohexyl. 
 
     
     
         13 . (canceled) 
     
     
         14 . A pharmaceutical composition comprising an effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         15 . The pharmaceutical composition of  claim 14  further comprising an effective amount of one or more additional HIV antiviral agent selected from HIV protease inhibitors, HIV integrase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, HIV fusion inhibitors and HIV entry inhibitors. 
     
     
         16 . A method for the prophylaxis or treatment of infection by HIV or for the prophylaxis, treatment, or delay in the onset of AIDS in a subject in need thereof which comprises administering to the subject an effective amount of the compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The method of  claim 16  wherein the subject is human. 
     
     
         18 . The method of  claim 17  further comprising administering to the human an effective amount of one or more additional HIV antiviral agent selected from HIV protease inhibitors, HIV integrase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, HIV fusion inhibitors and HIV entry inhibitors. 
     
     
         19 - 21 . (canceled) 
     
     
         22 . The pharmaceutical composition of  claim 14  further comprising an effective amount of one or more additional HIV antiviral agent selected from: abacavir, abacavir sulfate, abacavir+lamivudine, abacavir+lamivudine+zidovudine, amprenavir, atazanavir, atazanavir sulfate, AZT, capravirine, darunavir, ddC, ddI, delavirdine, delavirdine mesylate, dolutegravir, doravirine, efavirenz, efavirenz+emtricitabine+tenofovir DF, 4′-ethynyl-2-fluoro-2′-deoxyadenosine, elvitegravir, emtricitabine, emtricitabine+tenofovir DF, emvirine, enfuvirtide, enteric coated didanosine, etravirine, fosamprenavir calcium, indinavir, indinavir sulfate, lamivudine, lamivudine+zidovudine, lopinavir, lopinavir+ritonavir, maraviroc, nelfinavir, nelfinavir mesylate, nevirapine, PPL-100, raltegravir, rilpivirine, ritonavir, saquinavir, saquinavir mesylate, stavudine, tipranavir and vicriviroc.