ANTIVIRAL OXIME PHOSPHORAMIDE COMPOUNDS

• US 20180362563A1
• Filed: 12/12/2016
• Published: 12/20/2018
• Est. Priority Date: 12/15/2015
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Fu, Wenlang, Guo, Zhiqiang, Qi, Ning, Raheem, Izzat T., Vachal, Petr, Wang, Ming, Schreier, John D.
• Granted Patent: US 10,450,335 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: 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 HV 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:

(a) —

C_1-8alkyl, unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR⁸, —

SH, —

NR⁹R¹⁰, —

C_3-6cycloalkyl or spiro-C_3-6cycloalkyl,

(b) —

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

OR¹¹, —

SH, —

NR⁹R¹⁰ or —

C_1-3alkyl,

(c) —

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

OR¹¹, —

SH, —

NR⁹R¹⁰ or —

C_1-3alkyl,

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

OR¹¹, —

SH, —

NR⁹R¹⁰ 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, —

OR¹¹, —

SH, —

NR⁹R¹⁰ 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, —

OR¹¹, —

SH, —

NR⁹R¹⁰ or —

C_1-3 alkyl.

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

(a) —

C_1-6alkyl unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR⁸, —

SH, —

NR⁹R¹⁰, —

C_3-6cycloalkyl or spiro-C_3-6cycloalkyl,

(b) —

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

OR¹¹, —

SH, —

NR⁹R¹⁰ or —

C_1-3alkyl,

(c) —

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

OR¹¹, —

SH, —

NR⁹R¹⁰ or —

C_1-3alkyl,

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

OR¹¹, —

SH, —

NR⁹R¹⁰ or —

C_1-3alkyl, or

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

OR¹¹, —

SH, —

NR⁹R¹⁰ or —

C_1-3alkyl.

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

R¹ and R² are joined together with the carbon to which they are both attached to form;

(a) —

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

OR¹¹, —

SH, —

NR⁹R¹⁰ or —

C_1-3alkyl,

(b) a 4 to 6-membered heterocyclic ring unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹¹, —

SH, —

NR⁹R¹⁰, —

C_1-3alkyl or —

CH₂-phenyl, or

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R⁴ is —

C_1-4alkyl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R⁵ and R⁶ are each 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 or a 4 to 6-membered heterocyclic ring.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R⁷ is:

(a) —

C_1-10alkyl unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR¹², —

SH, —

NR¹³R¹⁴, —

C_3-6cycloalkyl or spiro-C_3-6cycloalkyl,

(b) —

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

OR¹⁵, —

SH, —

NR¹³R¹⁴ or —

C_1-3alkyl, or

(c) —

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

OR¹⁵, —

SH, —

NR¹³R¹⁴ or —

C_1-3alkyl.

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

R¹ and R² are each independently selected from unsubstituted or substituted —

C_1-6alkyl, unsubstituted or substituted —

CH₂-phenyl, unsubstituted or substituted —

C_3-6cycloalkyl, unsubstituted or substituted phenyl, or unsubstituted or substituted pyridyl;

or

R¹ and R² are joined together with the carbon to which they are both attached to form

(a) —

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

OR¹¹, —

SH, —

NR⁹R¹⁰ or —

C_1-3alkyl;

(b) a 4 to 6-membered heterocyclic ring unsubstituted or substituted with one to three substituents independently selected from fluoro, chloro, bromo, —

OR 1, —

SH, —

NR⁹R¹⁰, —

C_1-3alkyl or —

CH₂-phenyl;

or

9. The compound of claim 1 that is:

pentyl (((R)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((propan-2-ylideneamino)oxy)phosphoryl)-L-alaninate;

pentyl (((S)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((propan-2-ylideneamino)oxy)phosphoryl)-L-alaninate;

isopropyl (((R)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((propan-2-ylideneamino)oxy)phosphoryl)-L-alaninate;

isopropyl (((S)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((propan-2-ylideneamino)oxy)phosphoryl)-L-alaninate;

isopropyl (((R)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((1,3-diphenylpropan-2-ylidene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((S)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((1,3-diphenylpropan-2-ylidene)amino)oxy)phosphoryl)-L-alaninate;

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

hexyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((cyclopentylideneamino)oxy)phosphoryl)amino)-2-methyl-propanoate;

benzyl (((R)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((propan-2-ylideneamino)oxy)phosphoryl)-L-alaninate;

benzyl (((S)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl) ((propan-2-ylideneamino)oxy)phosphoryl)-L-alaninate;

isopropyl (((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((dicyclopentylmethylene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((pentan-3-ylideneamino)oxy)phosphoryl)-L-alaninate;

isopropyl (((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((cyclohexylideneamino)oxy)phosphoryl)-L-alaninate;

isopropyl (((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((tetrahydro-4H-pyran-4-ylidene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((dicyclopropylmethylene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((1-benzylpiperidin-4-ylidene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((R)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((2,6-dimethylheptan-4-ylidene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((S)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((2,6-dimethyl heptan-4-ylidene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((R)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((cyclopentylideneamino)oxy)phosphoryl)-L-alaninate;

isopropyl (((S)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((cyclopentylideneamino)oxy)phosphoryl)-L-alaninate;

isopropyl (((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((diphenylmethylene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((R)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((((E)-1-cyclohexylethylidene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((S)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((((E)-1-cyclohexylethylidene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((R)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((((E)-1-(pyridin-4-yl)ethylidene)amino)oxy)phosphoryl)-L-alaninate and isopropyl;

(((S)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((((E)-1-(pyridin-4-yl)ethylidene)amino)oxy)phosphoryl)-L-alaninate;

pentyl (((R)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((2,6-dimethylheptan-4-ylidene)amino)oxy)phosphoryl)-L-alaninate;

pentyl (((S)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((2,6-dimethyl heptan-4-ylidene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((R)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((((E)-1-phenylethylidene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((S)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((((E)-1-phenylethyl idene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((R)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((((E)-2,3-dihydro-1H-inden-1-ylidene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((S)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((((E)-2,3-dihydro-1H-inden-1-ylidene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((R)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((((E)-3,4-dihydronaphthalen-1(2H)-ylidene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((S)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((((E)-3,4-dihydronaphthalen-1 (2H)-ylidene)amino)oxy)phosphoryl)-L-alaninate;

isopropyl (((R)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((((E)-1-cyclopentylethylidene)amino)oxy)phosphoryl)-L-alaninate

isopropyl (((S)-(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((((E)-1-cyclopentylethylidene)amino)oxy)phosphoryl)-L-alaninate;

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

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

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

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

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

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

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

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

hexyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((2,6-dimethylheptan-4-ylidene)amino)oxy)phosphoryl)amino)-2-methylpropanoate;

hexyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((2,6-dimethylheptan-4-ylidene)amino)oxy)phosphoryl)amino)-2-methylpropanoate;

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

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

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

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

isobutyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((2,6-dimethylheptan-4-ylidene)amino)oxy)phosphoryl)amino)-2-methylpropanoateisobutyl;

isobutyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((2,6-dimethylheptan-4-ylidene)amino)oxy)phosphoryl)amino)-2-methylpropanoateisobutyl;

butyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((2,6-dimethylheptan-4-ylidene)amino)oxy)phosphoryl)amino)-2-methylpropanoate;

butyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((2,6-dimethylheptan-4-ylidene)amino)oxy)phosphoryl)amino)-2-methylpropanoate;

cyclohexyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((2,6-dimethylheptan-4-ylidene)amino)oxy)phosphoryl)amino)-2-methylpropanoate;

cyclohexyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl) (((2,6-dimethyl heptan-4-ylidene)amino)oxy)phosphoryl)amino)-2-methylpropanoate;

cyclobutyl 2-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((2,6-dimethylheptan-4-ylidene)amino)oxy)phosphoryl)amino)-2-methylpropanoate;

cyclobutyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((2,6-dimethylheptan-4-ylidene)amino)oxy)phosphoryl)amino)-2-methylpropanoate;

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

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

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

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

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10 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.

12. The pharmaceutical composition of claim 10 further comprising an effective amount of one or more additional HIV antiviral agent selected from:

13. 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.

14. The method of claim 13 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.

15. The method of claim 13 further comprising an effective amount of one or more additional HIV antiviral agent selected from:

18. A pharmaceutical composition comprising an effective amount of the compound of claim 9, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

19. The pharmaceutical composition of claim 18 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.

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

21. 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 9 or a pharmaceutically acceptable salt thereof.

22. The method of claim 21 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.

23. The method of claim 21 further comprising an effective amount of one or more additional HIV antiviral agent selected from:

16-17. -17. (canceled)