ANTIVIRAL PHOSPHODIAMIDE PRODRUGS OF TENOFOVIR

• US 20180362562A1
• Filed: 12/05/2016
• Published: 12/20/2018
• Est. Priority Date: 12/10/2015
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Idenix Pharmaceuticals LLC (Merck & Co., Inc.), Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Raheem, Izzat Tiedje, Hartingh, Timothy J., Schreier, John, Paparin, Jean-Laurent
• Granted Patent: US 10,745,428 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Abstract

Compounds of Formula I and pharmaceutically acceptable salts and co-crystals thereof 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.

Claims

1. A compound of structural Formula I:

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R^A is formula (i):

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R^A is formula (ii):

4. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein R¹ is H or —

C_1-4alkyl and R² is H or —

C_1-4alkyl.

5. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein R³ is

(a) —

C_1-8alkyl, —

CH₂CH₂OH, —

CH₂CH₂CH₂OH, —

CH₂CH₂SH, —

CH₂CH₂CH₂SH, —

CH₂CH₂NH₂, or —

CH₂CH₂CH₂NH₂,

(b) —

CH₂-phenyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁰, —

SH, —

NR⁸R⁹ or —

C_1-3alkyl,

(c) —

C_3-6cycloalkyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁰, —

SH, —

NR⁸R⁹ or —

C_1-3alkyl,

(d) phenyl or naphthyl, each unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁰, —

SH, —

NRR⁹ or —

C_1-3alkyl,

(e) —

CH₂CH₂OCH₃, —

CH₂CH₂CH₂OCH₃, —

CH₂CH₂SCH₃, —

CH₂CH₂CH₂SCH₃, —

CH₂CH₂NHCH₃, —

CH₂CH₂CH₂NHCH₃,

(f) pyridyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁰, —

SH, —

NR⁸R⁹ or —

C_1-3alkyl, or

(g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁰, —

SH, —

NR⁸R⁹ or —

C_1-3alkyl.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof wherein R³ is —

C_1-8alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

7. The compound of any of claim 1 or a pharmaceutically acceptable salt thereof wherein R⁴ and R⁵ are each independently selected from —

CH₃, —

CH₂CH₃, —

C₃alkyl or —

C₄alkyl.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein R⁶ is

(a) —

C_1-8alkyl, —

CH₂CH₂OH, —

CH₂CH₂CH₂OH, —

CH₂CH₂SH, —

CH₂ CH₂CH₂ SH, —

CH₂CH₂NH₂, —

CH₂CH₂CH₂NH₂,

(b) —

CH₂-phenyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁴, —

SH, —

NR¹²R¹³ or —

C_1-3alkyl,

(c) —

C3-6cycloalkyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁴, —

SH, —

NR¹²R¹³ or —

C_1-3alkyl,

(d) phenyl or naphthyl, each unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁴, —

SH, —

NR^—

R¹³ or —

C_1-3alkyl,

(e) —

CH₂CH₂OCH₃, —

CH₂CH₂CH₂OCH₃, —

CH₂CH₂SCH₃, —

CH₂CH₂CH₂SCH₃, —

CH₂CH₂NHCH₃, —

CH₂CH₂CH₂NHCH₃,

(f) pyridyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁴, —

SH, —

NR¹²R¹³ or —

C_1-3alkyl, or

(g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁴, —

SH, —

NR¹²R¹³ or —

C_1-3alkyl.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein R⁶ is —

C_1-8alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein

R¹, if present, is H or —

C_1-4alkyl;

R², if present, is H or —

C_1-4alkyl;

R³ is

(a) —

C_1-8alkyl, —

CH₂CH₂OH, —

CH₂CH₂CH₂OH, —

CH₂CH₂SH, —

CH₂ CH₂CH₂ SH, —

CH₂CH₂NH₂, —

CH₂CH₂CH₂NH₂,

(b) —

CH₂-phenyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁰, —

SH, —

NR⁸R⁹ or —

C_1-3alkyl,

(c) —

C_3-6cycloalkyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁰, —

SH, —

NR⁸R⁹ or —

C_1-3alkyl,

(d) phenyl or naphthyl, each unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁰, —

SH, —

NRR⁹ or —

C_1-3alkyl,

(e) —

CH₂CH₂OCH₃, —

CH₂CH₂CH₂OCH₃, —

CH₂CH₂SCH₃, —

CH₂CH₂CH₂SCH₃, —

CH₂CH₂NHCH₃, —

CH₂CH₂CH₂NHCH₃,

(f) pyridyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁰, —

SH, —

NR⁸R⁹ or —

C_1-3alkyl, or

(g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁰, —

SH, —

NR⁸R⁹ or —

C_1-3alkyl;

R⁴ and R⁵ are both the same moiety which is selected from —

CH₃, —

CH₂CH₃, —

C₃alkyl or —

C₄alkyl;

R⁶ is

(a) —

C_1-8alkyl, —

CH₂CH₂OH, —

CH₂CH₂CH₂OH, —

CH₂CH₂SH, —

CH₂ CH₂CH₂ SH, —

CH₂CH₂NH₂, —

CH₂CH₂CH₂NH₂,

(b) —

CH₂-phenyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁴, —

SH, —

NR¹²R¹³ or —

C_1-3alkyl,

(c) —

C_3-6cycloalkyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁴, —

SH, —

NR¹²R¹³ or —

C_1-3alkyl,

(d) phenyl or naphthyl, each unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁴, —

SH, —

NR¹²R¹³ or —

C_1-3alkyl,

(e) —

CH₂CH₂OCH₃, —

CH₂CH₂CH₂OCH₃, —

CH₂CH₂SCH₃, —

CH₂CH₂CH₂SCH₃, —

CH₂CH₂NHCH₃, —

CH₂CH₂CH₂NHCH₃,

(f) pyridyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁴, —

SH, —

NR¹²R¹³ or —

C_1-3alkyl, or

(g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹⁴, —

SH, —

NR¹²R¹³ or —

C_1-3alkyl.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein

R¹, if present, is H or —

CH₃;

R², if present, is —

C_1-4alkyl;

R³ is —

C_3-8alkyl, cyclobutyl, cyclopentyl or cyclohexyl;

R⁴ and R⁵ are both —

CH₃;

R⁶ is —

C_3-8alkyl, cyclobutyl, cyclopentyl or cyclohexyl.

12. The compound of claim 1 which is selected from the following:

13. The compound of claim 1 which is selected from the following:

isopropyl2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(cyclopentyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(cyclopentyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-butoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-butoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-isobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-isobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(cyclohexyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(cyclohexyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(hexyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(hexyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-oxo-1-(pentyloxy)propan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-oxo-1-(pentyloxy)propan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-butoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-butoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-isobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-isobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-butoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-butoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-oxo-1-(pentyloxy)propan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-oxo-1-(pentyloxy)propan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(hexyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(hexyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(cyclopentyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(cyclopentyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(cyclohexyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(cyclohexyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-oxo-1-(pentyloxy)propan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-oxo-1-(pentyloxy)propan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isobutyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isobutyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

butyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

butyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(cyclopentyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(cyclopentyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(methyl ((R)-1-oxo-1-(pentyloxy)propan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(methyl((R)-1-oxo-1-(pentyloxy)propan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

pentyl (((S)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((2-methyl-1-oxo-1-(pentyloxy)propan-2-yl)amino)phosphoryl)-D-prolinate;

pentyl (((R)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((2-methyl-1-oxo-1-(pentyloxy)propan-2-yl)amino)phosphoryl)-D-prolinate;

cyclohexyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(cyclopentyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

cyclohexyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(cyclopentyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

cyclobutyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(cyclopentyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

cyclobutyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(cyclopentyloxy)-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

a pharmaceutically acceptable salt thereof.

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 further comprising administering to the subject 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.

20. The pharmaceutical composition of claim 14 further comprising an effective amount of one or more additional HIV antiviral agent selected from:

abacavir,

abacavir+lamivudine,

abacavir+lamivudine+zidovudine,

amprenavir,

atazanavir,

AZT,

capravirine,

darunavir,

ddC,

ddI,

ddI (enteric coated),

delavirdine,

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,

lamivudine,

lamivudine+zidovudine,

lopinavir,

lopinavir+ritonavir,

maraviroc,

nelfinavir,

nevirapine,

PPL-100,

raltegravir,

rilpivirine

ritonavir,

saquinavir,

stavudine,

tipranavir,

vicriviroc,

or a pharmaceutically acceptable salt thereof.

18-19. -19. (canceled)