ANTIVIRAL BENZYL-AMINE PHOSPHODIAMIDE COMPOUNDS

• US 20190321380A1
• Filed: 12/19/2017
• Published: 10/24/2019
• Est. Priority Date: 12/22/2016
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: de Lera Ruiz, Manuel, Hartingh, Timothy J., Raheem, Izzat, Schreier, John, Paparin, Jean-Laurent
• Granted Patent: US 11,123,355 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/536 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• 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: A61P 31/20 for DNA viruses
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine
• 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 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.

Claims

1. A compound of structural Formula I:

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R¹ and R² are each independently selected from —

C_1-4alkyl, or R¹ and R² are joined together with the carbon to which they are both attached to form spiro-C_3-6cycloalkyl.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein R¹ and R² are the same moiety selected from —

C_1-4alkyl, or R¹ and R² are joined together with the carbon to which they are both attached to form spiro-C_3-6cycloalkyl

4. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein R⁹ and R¹⁰ are each independently —

H, —

C_1-3alkyl or —

C_1-3alkyl substituted with 1 to 3 of F, or R⁹ and R¹⁰ are joined together with the carbon to which they are both attached to form spiro-C_3-6cycloalkyl.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof wherein R⁹ and R¹⁰ are each independently —

H, —

CH₃ or —

CF₃, or R⁹ and R¹⁰ are joined together with the carbon to which they are both attached to form spiro-C_3-6cycloalkyl.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof wherein R⁹ and R¹⁰ are the same moiety selected from —

C_1-6alkyl.

7. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein R^a is halo, —

CN, —

C_1-3alkyl, —

C_1-3alkyl substituted with 1 to 3 of F, —

OC_1-3alkyl or —

OC_1-3alkyl substituted with 1 to 3 of F.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein R^b is —

H, halo, —

CN, —

C_1-3alkyl, —

C_1-3alkyl substituted with 1 to 3 of F, —

OC_1-3alkyl or —

OC_1-3alkyl substituted with 1 to 3 of F.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R³ is:

(a) —

C_1-8alkyl, —

CH₂CH₂OH, —

CH₂CH₂CH₂OH, —

CH₂CH₂SH, —

CH₂CH₂CH₂SH, —

CH₂CH₂NH₂, —

CH₂CH₂CH₂NH₂,

(b) —

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

OR⁴, —

SR, —

NR⁶R⁷ or —

C_1-3 alkyl,

(c) —

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

OR⁴, —

SR—

NR⁶R⁷ or —

C_1-3 alkyl,

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

OR⁴, —

NR⁶R⁷ or —

C_1-3 alkyl,

(e) —

CH₂CH₂OCH₃, —

CH₂CH₂OCH₂CH₃, —

CH₂CH₂CH₂OCH₃, —

CH₂CH₂CH₂OCH₂CH₃,

—

CH₂CH₂SCH₃, —

CH₂CH₂SCH₂CH₃, —

CH₂CH₂CH₂SCH₃, —

CH₂CH₂CH₂SCH₂CH₃

—

CH₂CH₂NHCH₃, —

CH₂CH₂NHCH₂CH₃, —

CH₂CH₂CH₂NHCH₃, or —

CH₂CH₂CH₂NHCH₂CH₃;

(f) pyridyl, unsubstituted or substituted with one, two or three substituents independently selected from fluoro, chloro, bromo, OR⁴, —

SR, —

NR⁶R⁷ or —

C_1-3alkyl, or

(g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each unsubstituted or substituted with one, two or three substituents independently selected from fluoro, chloro, bromo, OR⁴, —

SR, —

NR⁶R⁷ or —

C_1-3alkyl.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R³ is —

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

C_1-3alkyl-O—

C_1-3alkyl.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R³ is —

C_1-6alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

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

R¹ and R² are both methyl, ethyl, propyl or i-propyl;

R³ is —

C_1-6alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

R⁸ is —

H or —

C_1-3alkyl;

R⁹ is —

H, —

C_1-3alkyl or —

C_1-3alkyl substituted with 1 to 3 of F;

R¹⁰ is —

H, —

C_1-3alkyl or —

C_1-3alkyl substituted with 1 to 3 of F;

or R⁹ and R¹⁰ are joined together with the carbon to which they are both attached to form spiro-C_3-6cycloalkyl;

R^a is halo, —

CN, —

C_1-3alkyl, —

C_1-3alkyl substituted with 1 to 3 of F, —

OC_1-3alkyl or —

OC_1-3alkyl substituted with 1 to 3 of F; and

R^b is —

H, halo, —

CN, —

C_1-3alkyl, —

C_1-3alkyl substituted with 1 to 3 of F, —

OC_1-3alkyl or —

OC_1-3alkyl substituted with 1 to 3 of F.

13. The compound of claim 1 that is

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-chlorophenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-chlorophenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-chlorophenyl)ethyl)(methyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-chlorophenyl)ethyl)(methyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-2,2,2-trifluoro-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-2,2,2-trifluoro-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-3-(6-amino-9H-purin-9-yl)-1,1,1-trifluoropropan-2-yl)oxy)methyl)(((R)-2,2,2-trifluoro-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-3-(6-amino-9H-purin-9-yl)-1,1,1-trifluoropropan-2-yl)oxy)methyl)(((R)-2,2,2-trifluoro-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((4-isopropylbenzyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((4-isopropylbenzyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((4-cyanobenzyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((4-cyanobenzyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((4-(trifluoromethoxy)benzyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((4-(trifluoromethoxy)benzyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((3-fluorobenzyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((3-fluorobenzyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(3-fluorophenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(3-fluorophenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-(3-fluorophenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-(3-fluorophenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-(4-(trifluoromethyl)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-(4-(trifluoromethyl)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-(trifluoromethyl)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-(trifluoromethyl)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-(4-chlorophenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-(4-chlorophenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-(4-methoxyphenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-(4-methoxyphenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-methoxyphenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-methoxyphenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(p-tolyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

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

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

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

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

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

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

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

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

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(2-methyl-4-(trifluoromethoxy)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(2-methyl-4-(trifluoromethoxy)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-2,2,2-trifluoro-1-(3-fluorophenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-2,2,2-trifluoro-1-(3-fluorophenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-cyanophenyl)-2,2,2-trifluoroethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-cyanophenyl)-2,2,2-trifluoroethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-(4-cyanophenyl)-2,2,2-trifluoroethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-(4-cyanophenyl)-2,2,2-trifluoroethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-2,2,2-trifluoro-1-(3-methoxyphenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-2,2,2-trifluoro-1-(3-methoxyphenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-2,2,2-trifluoro-1-(p-tolyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-2,2,2-trifluoro-1-(p-tolyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-2,2,2-trifluoro-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-2,2,2-trifluoro-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-2,2,2-trifluoro-1-(3-methoxyphenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-2,2,2-trifluoro-1-(3-methoxyphenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-chloro-2-methylphenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-chloro-2-methylphenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-(4-chloro-2-methylphenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-(4-chloro-2-methylphenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-cyanophenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-cyanophenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((4-isopropylbenzyl)(methyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((4-isopropylbenzyl)(methyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(methyl((R)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(methyl((R)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-chlorophenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-(4-chlorophenyl)ethyl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((2-(4-chlorophenyl)propan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((2-(4-chlorophenyl)propan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((1-(4-chlorophenyl)cyclopropyl)amino)phosphoryl)amino)-2-methylpropanoate;

or

isopropyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((1-(4-chlorophenyl)cyclopropyl)amino)phosphoryl)amino)-2-methylpropanoate;

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising an effective amount of the compound according to 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. 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, dideoxycytidine, dideoxyinosine, delavirdine, delavirdine mesylate, dolutegravir, doravirine, efavirenz, 4′

-ethynyl-2-fluoro-2′

-deoxyadenosine, elvitegravir, emtricitabine, emivirine, enfuvirtide, 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, or vicriviroc.

17. 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 according to claim 1, or a pharmaceutically acceptable salt thereof.

18. The method of claim 17 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.

19. The method of claim 17 further comprising administering to the subject 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, dideoxycytidine, dideoxyinosine, delavirdine, delavirdine mesylate, dolutegravir, doravirine, efavirenz, 4′

-ethynyl-2-fluoro-2′

-deoxyadenosine, elvitegravir, emtricitabine, emivirine, enfuvirtide, 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, or vicriviroc.

20-21. -21. (canceled)