Heterocyclic compounds as anti-viral agents
The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof: which inhibit Respiratory Syncytial Virus (RSV) or HMPV. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from RSV or HMPV infection. The invention also relates to methods of treating an RSV or HMPV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.
1. A compound represented by Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
A is an optionally substituted aryl or optionally substituted heteroaryl;
B is O or S;
R 1 and R 2 are each independently hydrogen, fluorine, or an optionally substituted C 1 -C 4 alkyl;
R 3 is selected from the group consisting of hydrogen, fluorine, hydroxy, and optionally substituted C 1 -C 6 alkoxy;
R 4 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, and optionally substituted C 3 -C 6 heterocyclic;
Z is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, and optionally substituted C 1 -C 6 alkoxyl;
E is an optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 3- to 8 membered heterocyclic;
Y is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted -C 1 -C 6 alkoxy, or optionally substituted C 3 -C 6 cycloalkyl;
G is an optionally substituted heteroaryl; optionally substituted aryl; optionally substituted heteroaryl-C 1 -C 3 -alkyl; or optionally substituted aryl-C 1 -C 3 -alkyl; and
N is 1, 2 or 3.
2. A compound of claim 1 , wherein E is optionally substituted phenyl.
3. The compound of claim 1 , represented by one of Formulae (VIIIa)˜(VIIId), or a pharmaceutically acceptable salt thereof:
wherein A, G, E, and R 4 are as defined in claim 1 .
4. The compound of claim 1 , represented by one of Formula (IXa) or (IXb), or a pharmaceutically acceptable salt thereof:
wherein each R 11 is independently optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 1 -C 6 alkoxyl, optionally substituted —C 3 -C 6 cycloalkyl, halo, —CN, or —NR a R b ; R a and R b are independently selected from hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 3 -C 6 cycloalkyl, alternatively, R a and R b are taken together with nitrogen atom to which they attached to form a heterocyclic ring; m is 0, 1, 2, 3, 4 or 5, A, Y, G, R 3 , and R 4 are as defined in claim 1 .
5. The compound of claim 1 , represented by one of Formulae (XIa)˜(XId), or a pharmaceutically acceptable salt thereof:
wherein R 11 is independently optionally substituted —C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted —C 3 -C 6 cycloalkyl, halo, —CN, or —NR a R b ; R a and R b are independently selected from hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 3 -C 6 cycloalkyl, alternatively, R a and R b are taken together with nitrogen atom to which they attached to form a heterocyclic ring; each p is independently 0, 1, 2 or 3; p′ is 0, or 1; each m is 0, 1, 2, 3, 4 or 5, m′ is independently 0, 1, 2 or 3; and Y, G, R 3 , R 4 , are as defined in claim 1 .
6. The compound of claim 1 , represented by one of Formulae (XIe)˜(XIg), or Formulae (XIj)˜(XIk), or a pharmaceutically acceptable salt thereof:
wherein each R 11 is independently optionally substituted —C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted —C 3 -C 6 cycloalkyl, halo, —CN, or -NR a R b R 12 is hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted —C 3 -C 6 cycloalkyl, halo, —CN, or —NR a R b ; each R a and R b is independently selected from hydrogen, optionally substituted —C 1 -C 6 alkyl, and optionally substituted —C 3 -C 6 cycloalkyl; alternatively, R a and R b are taken together with the nitrogen atom to which they attached to form an optionally substituted heterocyclic ring; R 13 is hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 3 -C 6 cycloalkyl; each p′ is 0, or 1; each m is 0, 1, 2, 3, 4 or 5; and Y, G, R 3 , R 4 , are as defined in claim 1 .
7. The compound of claim 1 , represented by one of Formulae (XIIIa)˜(XIIId), or a pharmaceutically acceptable salt thereof:
wherein R 11 is independently optionally substituted —C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted —C 3 -C 6 cycloalkyl, halo, —CN, or —NR a R b ; R a and R b are independently selected from hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 3 -C 6 cycloalkyl, alternatively, R a and R b are taken together with nitrogen atom to which they attached to form an optionally substituted heterocyclic ring; each m is 0, 1, 2, 3, 4 or 5, and Y, G, and R 4 , are as defined in claim 1 .
8. The compound of claim 1 , represented by one of Formulae (XIIIe)˜(XIIIg) and Formulae (XIIIj)˜(XIIIk), or a pharmaceutically acceptable salt thereof:
wherein R 11 is independently optionally substituted —C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted —C 3 -C 6 cycloalkyl, halo, —CN, or —NR a R b ; R 12 is hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted —C 3 -C 6 cycloalkyl, halo, —CN, or —NR a R b ; each R a and R b is independently selected from hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 3 -C 6 cycloalkyl; alternatively, R a and R b are taken together with nitrogen atom to which they attached to form an optionally substituted heterocyclic ring; R 13 is hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 3 -C 6 cycloalkyl; each m is 0, 1, 2, 3, 4 or 5; and Y, G, R 4 are as defined in claim 1 .
9. The compound of claim 1 , selected from the compounds set forth below, or a pharmaceutically acceptable salt thereof
Compound
Structure
Compound
Structure
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11
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10. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
11. A method of treating an RSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a combination of compounds of claim 1 .
12. The method of claim 11 , further comprising the step of administering to the subject an additional anti-RSV agent.
13. The method of claim 11 , further comprising administering to the subject a steroid anti-inflammatory compound.
14. A method of treating RSV and influenza in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 and a therapeutically effective amount of an anti-influenza agent.
15. The method of claim 12 , wherein the compound and the additional anti-RSV agent are co-formulated.
16. The method of claim 12 , wherein the compound and the additional anti-RSV agent are co-administered.
17. The method of claim 12 , wherein administering the compound allows for administering of the additional anti-RSV agent at a lower dose or frequency as compared to the administering of the additional anti-RSV agent alone that is required to achieve similar results in prophylactically treating an RSV infection in a subject in need thereof.
18. A method of treating an HMPV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a combination of compounds of claim 1 .
19. The method of claim 18 , further comprising the step of administering to the subject an additional anti-HMPV agent.
20. The method of claim 19 , wherein the compound and the additional anti-HMPV agent are co-formulated.
21. The method of claim 19 , wherein the compound and the additional anti-HMPV agent are co-administered.