Antiviral prodrugs of tenofovir

• US 10,449,208 B2
• Filed: 08/22/2017
• Issued: 10/22/2019
• Est. Priority Date: 08/25/2016
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Da Costa, Daniel, Dousson, Cyril B., Dukhan, David, Paparin, Jean-Laurent, Rahali, Houcine, Raheem, Izzat
• Primary Examiner(s): Pagano, Alexander R
• Application Number:
  US16/327,631
• Publication Number:
  US 20190183912A1
• Time in Patent Office: 791 Days
• Field of Search: None
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 45/05 Immunological preparations stimulating the reticulo-endothelial system, e.g. against cancer
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• 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 one of R¹ is —

H or —

C_1-4alkyl, and R² is —

H, —

C_1-4alkyl or —

CH₂-phenyl.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein R⁵ and R⁶ are independently selected from —

C_1-4alkyl, or R⁵ and R⁶ are joined together with the carbon to which they are both attached to form —

C_3-6cycloalkyl.

4. The compound of claim 3 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 to three substituents independently selected from fluoro, chloro, bromo, —

OR^8a, —

SH, —

NR^9aR^10a or —

C_1-3alkyl,

(c) —

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

OR^8a, —

SH, —

NR^9aR^10a or —

C_1-3alkyl,

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

OR^8a, —

SH, —

NR^9aR^10a 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, —

OR^8a, —

SH, —

NR^9aR^10a 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, —

OR^8a, —

SH, —

NR^9aR^10a or —

C_1-3alkyl.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof wherein R⁴ is:

(a) —

C_1-8alkyl, —

CH₂CH₂OH, —

CH₂CH₂CH₂OH, —

CH₂CH₂SH, —

CH₂CH₂CH₂SH, —

CH₂CH₂NH₂, —

CH₂CH₂CH₂NH₂,

(b) —

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

OR^8b, —

SH, —

NR^9bR^10b or —

C_1-3alkyl,

(c) —

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

OR^8b, —

SH, —

NR^9bR^10b or —

C_1-3alkyl,

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

OR^8b, —

SH, —

NR^9bR^10b 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, —

OR^8b, —

SH, —

NR^9bR^10b 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, —

OR^8b, —

SH, —

NR^9bR^10b or —

C_1-3alkyl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R³ and R⁴ are each independently unsubstituted or substituted and each is independently selected from —

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

CH2-phenyl.

7. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein R³ and R⁴ are each independently unsubstituted or substituted and each is independently selected from —

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

CH₂-phenyl.

8. The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein R³ and R⁴ are each independently unsubstituted or substituted and each is independently selected from —

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

CH2-phenyl.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R³ and R⁴ are each unsubstituted and independently selected from —

C_2-6alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or —

CH₂-phenyl.

10. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein R³ and R⁴ are each unsubstituted and independently selected from —

C_2-6alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or —

CH₂-phenyl.

11. The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein R³ and R⁴ are each unsubstituted and independently selected from —

C_2-6alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or —

CH₂-phenyl.

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

R¹ is —

H or —

CH_3;

R² is —

H, —

CH₃ or —

CH₂-phenyl;

R³ is selected from —

C_1-8alkyl, —

C_3-6cycloalkyl or —

CH₂-phenyl;

R⁴ is selected from —

C_1-8alkyl or —

C_3-6cycloalkyl; and

R⁵ and R6 are both —

CH₃;

or R⁵ and R⁶ are joined together with the carbon to which they are both attached to form —

C_3-6cycloalkyl.

13. The compound of claim 1 that is:

Isopropyl 2-4(S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-y0oxy)methyl)(((S)-1-isopropoxy-1-oxopropan-2-yl)oxy)phosphoryl)amino)-2-methylpropanoate;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Isopropyl 2-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl) (((R)-1 -is opr op oxy - 1-oxopropan-2-yl)oxy)phosphoryl)amino)-2-methylpropanoate;

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

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

Propyl 2-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-i sopropoxy-1-oxopropan-2-yl)oxy)phosphoryl)amino)-2-methylpropanoate;

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

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

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

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

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

Ethyl 2-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-i sopropoxy-1-oxopropan-2-yl)oxy)phosphoryl)amino)-2-methylpropanoate;

Isobutyl 2-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-ypoxy)methyl)(2-isopropoxy-2-oxoethoxy)phosphoryl)amino)-2-methylpropanoate;

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

Isopropyl 2-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-isopropoxy-1-oxo-3-phenylpropan-2-yl)oxy)phosphoryl)amino)-2-methylpropanoate;

Hexyl 2-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-isopropoxy-1-oxo-3-phenylpropan-2-yl)oxy)phosphoryl)amino)-2-methylpropanoate;

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

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

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

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

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

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

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

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

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

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

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

Isopropyl 1-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(2-isopropoxy-2-oxoethoxy)phosphoryl)amino)cyclopentane-1-carboxylate;

Isopropyl 1-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(2-isopropoxy-2-oxoethoxy)phosphoryl)amino)cyclopropane-1-carboxylate;

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

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

Isopropyl 1-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(2-isopropoxy-2-oxoethoxy)phosphoryl)amino)cyclobutane-1-carboxylate;

Isopropyl 1-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((S)-1-isopropoxy-1-oxopropan-2-yl)oxy)phosphoryl)amino)cyclobutane-l-carboxylate;

Isopropyl 1-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(2-isopropoxy-2-oxoethoxy)phosphoryl)amino)cyclohexane-1-carboxylate;

or

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

or 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.

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