Compounds useful as antiviral agents, compositions, and methods of use

1. A compound having the formula of:

or an optical isomer, enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof, wherein,

R 1 is an optionally substituted cycloalkyl having from 3 to 20 carbon atoms;

Z is S or NH;

Y is O or S;

R 5 is

a moiety having the formula of:

wherein,

W is selected from the group consisting of O, S, NH, and CH 2 , wherein each of the NH and CH 2 is optionally substituted with an alkyl or aryl;

one of X 1 and X 2 is unsubstituted and is selected from the group consisting of CH, O, S and N,

the other one of X 1 and X 2 is C linked to a substituent R 2 , and R 2 is A-B,

wherein,

A is an optionally substituted aryl, or an optionally substituted alkyl, alkenyl or alkynyl having 1 to 10 carbon atoms; and

B is selected from the group consisting of an alkoxy, a hydroxyl, an acid ester, a carboxyl, an amine, an amide, an ether, an amino acid derivative, an alpha-hydroxy acid, a guanidino, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, and an optionally substituted heterocyclic ring;

X 3 is selected from the group consisting of C and N; and

R 3 is selected from the group consisting of H, a halogen, an amino acid derivative, an acid ester, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclic ring,

wherein the amino acid derivative is selected from the group consisting of

wherein X is O, N or S, and each of R 6 and R 8 is independently a side chain of an amino acid.

2. The compound of claim 1 , wherein the compound of Formula (I) has the formula of:

wherein:

R 3 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocyclic ring.

3. The compound of claim 2 , wherein R 2 has the formula of:

wherein each of A1, B1, C1, D1, E1 is independently selected from the group consisting of N, NH, S, O, CH and CH2, each of NH, CH and CH 2 is optionally independently substituted, and the A 1 B 1 C 1 D 1 E 1 N ring optionally contains one or more double bonds.

4. The compound of claim 3 , wherein,

W is O, S or an optionally substituted NH;

one of X 1 and X 2 is the unsubstituted CH, and the other one of X 1 and X 2 is C—R 2 ;

A is an optionally substituted alkyl having 1 to 10 carbon atoms;

X 3 is C;

R 1 is an optionally substituted fused or bicyclic cycloalkyl ring; and

R 3 is an optionally substituted aryl or an optionally substituted heteroaryl.

5. The compound of claim 1 , wherein R 3 has the formula of:

wherein,

n is an integer of 0 to 3, and

R 4 is independently selected from the group consisting of an alkoxy, a halogen, a hydroxy, an amide, a thio, a nitro, a cyano, an alkyl, an alcohol, an amine, an amino acid derivative, a carboxyl, an acid ester, an alpha-hydroxy acid, an ether, a guanidino, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, and an optionally substituted heterocyclic ring,

wherein the amino acid derivative is selected from the group consisting of

wherein X is O, N or S, and each of R 6 and R 8 is independently a side chain of an amino acid.

6. The compound of claim 5 , wherein,

W is O, S or an optionally substituted NH;

X 3 is C;

Y is S;

Z is S; and

R 1 is an optionally substituted fused or bicyclic cycloalkyl ring.

7. The compound of claim 1 , wherein the compound of Formula (I) has the formula of:

wherein W is O, S or an optionally substituted NH.

8. A compound having the formula of:

wherein,

R 1 is an optionally substituted cycloalkyl having from 3 to 20 carbon atoms;

W is selected from the group consisting of O, S, and an optionally substituted NH;

L 1 is a direct bond or an optionally substituted linking unit, wherein the linking unit consists of 1 to 4 carbon atoms and up to 2 heteroatoms selected from the group consisting of O, N and S; and

R 8 is a side chain of an amino acid.

9. The compound of claim 7 , wherein the compound of Formula (III) has the formula of:

wherein X is O, N or S, and R 6 is a side chain of an amino acid;

wherein R 7 is a side chain of an amino acid;

wherein the morpholine is optionally substituted;

wherein the piperazine is optionally substituted;

wherein the triazole is optionally substituted;

wherein the Ar is an optionally substituted aryl;

in each of Formula (III)(b)(1) to Formula (III)(b)(12), wherein,

n is an integer of 0 to 3; and

R 4 is independently selected from the group consisting of an alkoxy, a halogen, a hydroxy, an amide, a thio, a nitro, a cyano, an alkyl, an alcohol, an amine, an amino acid derivative, a carboxyl, an acid ester, an alpha-hydroxy acid, an ether, a guanidino, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, and an optionally substituted heterocyclic ring,

wherein the amino acid derivative is selected from the group consisting of

wherein X is O, N or S, and each of R 6 and R 8 is independently a side chain of an amino acid.

10. The compound of claim 1 , wherein R 1 is selected from the group consisting of an optionally substituted 5-12 membered monocyclic ring, decalin, norbornane and adamantane.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 .

12. A method of treating a viral infection in a subject having a viral infection comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 11 , wherein the virus is selected from the group consisting of influenza and HIV.

13. The method of claim 12 , further comprising administering to the subject one or more additional agents for treating the viral infection, wherein the additional agent is a nucleoside or nucleotide reverse transcriptase inhibitor, a non nucleoside reverse transcriptase inhibitor, a protease inhibitor, an integrase inhibitor, an RNA polymerase inhibitor, a DNA polymerase inhibitor, a kinase inhibitor, an enzyme inhibitor, an entry inhibitor, an assembly inhibitor, a maturation inhibitor, an M2 inhibitor, or a neuraminidase inhibitor.

14. The method of claim 13 , wherein the additional agent is selected from the group consisting of amantadine, rimantadine, oseltamivir, zanamivir, peramivir, raltegravir, maraviros, enfuviritide, bevirimat, MP-9055, avacavir, zidovudine, emtricitabine, lamivudine, didanosine, tenofovir disoproxil fumarate, a combination of zidovudine and lamivudine, a combination of abacavir and lamivudine, a combination of abacavir and zidovudine and lamivudine, a combination of tenofovir disoproxil fumarate and emtricitabine, stavudine, racivir, amdoxovir, apricitabine, elvucitabine, alpha-epibromide, aldesleukin, HIV-1 Immunogen, BAY 50-4798, IR103, etravirine, delavirdine, efavirenz, nevirapine, rilpivirine, amprenavir, tipranavir, indinavir, saquinavir, a combination of lopinavir and ritonavir, fosamprenavir, ritonavir, darunavir, atazanavir, nelfinavir, enfuvirtude, maraviros, vicriviroc, PRO 140, TNX-355, raltegravir, elvitegravir, bevirimat and hydroxyurea.

15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 8 .

16. A method of treating a viral infection in a subject having a viral infection comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 15 , wherein the virus is selected from the group consisting of influenza and HIV.