Antiviral aryl-amide phosphodiamide compounds

1. A compound of structural Formula I:

or a pharmaceutically acceptable salt thereof wherein:

Z is O or S;

R 1 is (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 or (k) heteroaryl;

R 2 is (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 or (k) heteroaryl;

or R 1 and R 2 are joined together with the carbon to which they are both attached to form a —C 3-6 cycloalkyl or a 4 to 6-membered heterocyclic ring;

R 3 is:

(a) aryl unsubstituted or substituted with one, two or three of fluoro, chloro, bromo, —CN, —CF 3 , —OR 5 , —SH, —NR 7a R 8a , —C 1-6 alkyl or —CO 2 —C 1-6 alkyl; or

(b) heteroaryl unsubstituted or substituted with one, two or three of fluoro, chloro, bromo, —CN, —CF 3 , OR 5 , —SH, —NR 7a R 8a , —C 1-6 alkyl or —CO 2 —C 1-6 alkyl;

R 4 is:

(a) —C 1-10 alkyl unsubstituted or substituted with one, two or three of fluoro, chloro, bromo, —OR 6 , —SH, —NR 7b R 8b , —C 3-6 cycloalkyl or spiro-C 3-6 cycloalkyl,

(b) —CH 2 -phenyl unsubstituted or substituted with one, two or three of fluoro, chloro, bromo, —OR 5 , —SH—NR 7b R 8b or —C 1-3 alkyl,

(c) —C 3-8 cycloalkyl unsubstituted or substituted with one, two or three of fluoro, chloro, bromo, —OR 5 , —SH, —NR 7b R 8b or —C 1-3 alkyl,

(d) aryl unsubstituted or substituted with one, two or three of fluoro, chloro, bromo, —OR 5 , —SH, —NR 7b R 8b 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, two or three of fluoro, chloro, bromo, —OR 5 , —SH, —NR 7b R 8b or —C 1-3 alkyl, or

(g) a heterocyclic ring unsubstituted or substituted with one, two or three of fluoro, chloro, bromo, —OR 5 , —SH, —NR 7b R 8b or —C 1-3 alkyl;

R 5 is —H, —CF 3 , —C 1-3 alkyl or —C 3-6 cycloalkyl;

R 6 is —H or —C 3-6 cycloalkyl;

R 7a and R 7b are each independently —H, —C 1-3 alkyl or —C 3-6 cycloalkyl; and

R 8a and R 8b are each independently —H, —C 1-3 alkyl or —C 3-6 cycloalkyl.

2. The compound of claim 1 having the structural Formula Ia:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both the same and are selected from methyl, ethyl, propyl or i-propyl.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both methyl.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl substituted with one, two or three substituents independently selected from fluoro, chloro, bromo, —OR 5 , —C 1-6 alkyl or —CO 2 C 1-6 alkyl.

6. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl mono- or di-substituted with fluoro, chloro, bromo, —OR 5 or —C 1-3 alkyl.

7. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl mono-substituted with fluoro, chloro, bromo, —OR 5 or —C 1-3 alkyl.

8. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl mono-substituted with fluoro, chloro, —OC 1-3 alkyl or —C 1-3 alkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl mono-substituted with fluoro, chloro, —OCH 3 or —CH 3 .

10. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 4 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, two or three substituents independently selected from fluoro, chloro, bromo, —OR 5 , —SH, —NR 7b R 8b or —C 1-3 alkyl,

(c) —C 3-6 cycloalkyl, unsubstituted or substituted with one, two or three substituents independently selected from fluoro, chloro, bromo, —OR 5 , —SH, —NR 7b R 8b 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, OR 5 , —SH, —NR 7b R 8b or —C 1-3 alkyl,

(e) —CH 2 CH 2 OCH 3 , —CH 2 CH 2 OCH 2 CH 3 , —CH 2 CH 2 CH 2 OCH 3 , —CH 2 CH 2 CH 2 OCH 2 CH 3 , —CH 2 CH 2 SCH 3 , —CH 2 CH 2 SCH 2 CH 3 , —CH 2 CH 2 CH 2 SCH 3 , —CH 2 CH 2 CH 2 SCH 2 CH 3 —CH 2 CH 2 NHCH 3 , —CH 2 CH 2 NHCH 2 CH 3 , —CH 2 CH 2 CH 2 NHCH 3 , or —CH 2 CH 2 CH 2 NHCH 2 CH 3 ;

(f) pyridyl, unsubstituted or substituted with one, two or three substituents independently selected from fluoro, chloro, bromo, OR 5 , —SH, —NR 7b R 8b or —C 1-3 alkyl, or

(g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each unsubstituted or substituted with one, two or three substituents independently selected from fluoro, chloro, bromo, OR 5 , —SH, —NR 7b R 8b or —C 1 -_3alkyl.

11. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —C 1-8 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —C 1-3 alkyl-O—C 1-3 alkyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl.

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

R 1 and R 2 are each —CH 3 ;

R 3 is (a) phenyl substituted with one, two or three of fluoro, chloro, —C 1-3 alkyl or —O—C 1-3 alkyl; or (b) a 6-membered heteroaryl comprised of carbon atoms and 2 N atoms, or thienyl; and

R 4 is —C 1-8 alkyl, —C 3-6 cycloalkyl, —C 1-5 alkyl-O—C 1-5 alkyl or a 6-membered heterocyclic ring comprised of carbon atoms and one of O, N or S.

13. The compound of claim 1 selected from:

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

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

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

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

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

methoxy-benzamido)phosphoryl)amino)-2-methylpropanoate;

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

methoxybenzamido)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(4-

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(4-

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

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

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

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

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

isobutyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(4-

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

isobutyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(4-

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

cyclobutyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(4-

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

cyclobutyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(4-

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

cyclopentyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(4-

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

cyclopentyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(4-

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

2-ethoxyethyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(4-

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

2-ethoxyethyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(4-

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

tetrahydro-2H-pyran-4-yl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-

yl)oxy)methyl)(4-chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

tetrahydro-2H-pyran-4-yl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-

yl)oxy)methyl)(4-chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

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

fluorobenzamido)phosphoryl)amino)-2-methylpropanoate;

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

fluorobenzamido)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(4-

fluorobenzamido)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(4-

fluorobenzamido)phosphoryl)amino)-2-methylpropanoate;

2-ethoxyethyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(2-

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

2-ethoxyethyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(2-

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

isopropyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-

yl)oxy)methyl)(pyrimidine-4-carboxamido)phosphoryl)amino)-2-

methylpropanoate;

isopropyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-

yl)oxy)methyl)(pyrimidine-4-carboxamido)phosphoryl)amino)-2-

methylpropanoate;

isopropyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-

yl)oxy)methyl)(pyrazine-2-carboxamido)phosphoryl)amino)-2-

methylpropanoate;

isopropyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-

yl)oxy)methyl)(pyrazine-2-carboxamido)phosphoryl)amino)-2-

methylpropanoate;

pentyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-

yl)oxy)methyl)(thiophene-2-carboxamido)phosphoryl)amino)-2-

methylpropanoate;

pentyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-

yl)oxy)methyl)(thiophene-2-carboxamido)phosphoryl)amino)-2-

methylpropanoate;

pentyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(2-

methoxybenzamido)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(2-

methoxybenzamido)phosphoryl)amino)-2-methylpropanoate;

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

methoxybenzamido)phosphoryl)amino)-2-methylpropanoate;

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

methoxybenzamido)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(4-

methylbenzamido)phosphoryl)amino)-2-methylpropanoate;

pentyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(4-

methylbenzamido)phosphoryl)amino)-2-methylpropanoate;

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

chlorophenylthioamido)phosphoryl)amino)-2-methylpropanoate;

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

chlorophenylthioamido)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(2-

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

propyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(2-

chlorobenzamido)phosphoryl)amino)-2-methylpropanoate;

ethyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(4-(tert-

butyl)benzamido)phosphoryl)amino)-2-methylpropanoate; or

ethyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(4-(tert-

butyl)benzamido)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.