INHIBITORS OF INFLUENZA VIRUSES REPLICATION

• US 20120171245A1
• Filed: 12/15/2011
• Published: 07/05/2012
• Est. Priority Date: 06/17/2009
• Status: Abandoned Application

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Charifson, Paul S., Clark, Michael P., Bandarage, Upul K., Bethiel, Randy S., Court, John J., Deng, Hongbo, Duffy, John P., Gao, Huai, Ledeboer, Mark W., Ledford, Brian, Maltais, Francois, Perola, Emanuele, Wang, Tiansheng, Byrn, Randal, Zhou, Yi, Lin, Chao, Germann, Ursula A., Davies, Ioana, Farmer, Luc J., Gu, Wenxin, Jacobs, Dylan H., Kennedy, Joseph M., Wannamaker, M. Woods, Jiang, Min, Jones, Steven
• Application Number:
  US13/327,206
• Publication Number:
  US 20120171245A1
• Time in Patent Office: Days
• US Class Current: 424/209.1
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/553 having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/30 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Methods of inhibiting the replication of influenza viruses in a biological sample or patient, of reducing the amount of influenza viruses in a biological sample or patient, and of treating influenza in a patient, comprises administering to said biological sample or patient an effective amount of a compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (IA) are as described herein. A compound is represented by Structural Formula (IA) or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (IA) are as described herein. A pharmaceutical composition comprises an effective amount of such a compound or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

Claims

1. A method of inhibiting the replication of influenza viruses in a biological sample or patient, comprising the step of administering to said biological sample or patient an effective amount of a compound represented by the following structural formula (I):

2. The method of claim 1, represented by Structural Formula (I):

3. The method of claim 2, wherein R¹ is —

H.

4. The method of claim 3, wherein R² is —

H, —

F, —

CH₃, —

CH₂OH, or —

NH₂.

5. The method of claim 4, wherein R² is —

H or —

CH₃.

6. The method of claim 5, wherein R³ is —

H, —

Cl, —

F, —

Br, —

CN, —

CF₃, —

O(C₁-C₄ alkyl), —

OH, —

NH₂, —

NH(C₁-C₄ alkyl) or —

N(C₁-C₄ alkyl)₂.

7. The method of claim 6, wherein R⁴ is:

8. The method of claim 7, wherein:

n and m are each independently 0 or 1 when rings A and B are 3-6 membered;

or n and m are each independently 0, 1 or 2 when rings A and B are 7-10 membered;

provided that if Y¹ is a bond, then R⁵ is neither H nor a C_1-6 aliphatic group; and

provided that if each Q² and Q³ independently is a bond, then R⁵ is neither —

H nor a C_1-6 aliphatic group.

9. The method of claim 8, wherein:

ring A is a C₃-C₈ non-aromatic carbocycle or heterocycle, the carbocycle and heterocycle optionally further substituted with one or more instances of J^A and J^B, respectively;

rings B and C are each independently a 4-8 membered non-aromatic heterocycle optionally and independently further substituted with one or more instances of J^B;

ring D is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of J^D1;

Q¹ is independently a bond, —

O—

, —

S—

, —

NR′

—

, —

C(O)—

, —

C(═

NR)—

, —

CO₂—

, —

OC(O)—

, —

C(O)NR′

—

, —

C(O)NRC(O)O—

, NRC(O)NRC(O)O—

, —

NRC(O)—

, —

NRC(O)NR′

—

, —

NRCO₂—

, —

OC(O)NR′

—

, —

S(O)—

, —

SO₂—

, —

SO₂NR′

—

, —

NRSO₂—

, or —

NRSO₂NR′

—

, or —

(CR⁶R⁷)_p—

Y¹—

;

Q² is independently a bond, —

O—

, —

S—

, —

NR′

—

, —

C(O)—

, —

C(═

NR)—

, —

CO₂—

, —

OC(O)—

, —

C(O)NR′

—

, —

C(O)NRC(O)O—

, NRC(O)NRC(O)O—

, —

NRC(O)—

, —

NRC(O)NR′

—

, —

NRCO₂—

, —

OC(O)NR′

—

, —

S(O)—

, —

SO₂—

, —

SO₂NR′

—

, —

NRSO₂—

, or —

NRSO₂NR′

—

, or —

(CR⁶R⁷)_p—

Y¹—

;

Q³ is independently a bond, —

C(O)—

, —

C(═

NR)—

, —

CO₂—

, —

C(O)NR′

—

, —

SO₂—

, —

SO₂NR′

—

, —

C(O)NRC(O)O—

, or —

(CR⁶R⁷)_p—

Y¹—

;

optionally, each of Q² and Q³, together with R⁵, independently forms a 5-7 membered ring optionally substituted with one or more instances of J^E1;

Y¹ is independently a bond, —

O—

, —

S—

, —

NR′

—

, —

C(O)—

, —

C(═

NR)—

, —

CO₂—

, —

OC(O)—

, —

C(O)NR′

—

, —

C(O)NRC(O)O—

, —

NRC(O)NRC(O)O—

, —

NRC(O)—

, —

NRC(O)NR′

—

, —

NRCO₂—

, —

OC(O)NR′

—

, —

S(O)—

, —

SO₂—

, —

SO₂NR′

—

, —

NRSO₂—

, or —

NRSO₂NR′

—

;

R⁵ is;

i) —

H;

ii) a C₁-C₆ aliphatic group optionally substituted with one or more instances of J^C1;

iii) a C₃-C₈ non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of J^C1;

or iv) a 4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of J^D1;

or

R⁵, together with Q¹, optionally forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of J^E1; and

R⁸ and R⁹ are each independently —

H, halogen, cyano, hydroxy, amino, carboxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ cyanoalkyl, C₂-C₆ alkoxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy, or C₂-C₆ alkoxyalkoxy;

R¹¹, R¹², R¹³ and R¹⁴ are each independently —

H, halogen, or C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy;

each of J^A and J^B is independently selected from the group consisting of halogen, cyano, oxo, —

NCO, and Q¹-R⁵;

or optionally two J^A and two J^B, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of J^E1; and

each of J^C1 and J^D1 is independently selected from the group consisting of halogen, cyano, oxo, R^a, —

OR^b, —

SR^b, —

S(O)R^a, —

SO₂R^a, —

NR^bR^c, —

C(O)R^b, —

C(O)OR^b, —

OC(O)R^b, —

NRC(O)R^b, —

C(O)NR^bR^c, —

NRC(O)NR^bR^c, —

NRC(O)OR^b, —

OCONR^bR^c, —

C(O)NRCO₂R^b, —

NRC(O)NRC(O)OR^b, —

C(O)NR(OR^b), —

SO₂NR^cR^b, —

NRSO₂R^b, —

NRSO₂NR^cR^b, and —

P(O)(OR^a)₂, or optionally, two J^C1 and two J^D1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of J^E1, and fused to the respective ring to which they are attached.

10. The method of claim 9, wherein:

ring A is a C₃-C₈ non-aromatic carbocycle optionally and independently is further substituted with one or more instances of J^A;

rings B and C are each independently a 4-8 membered non-aromatic heterocycle optionally and independently further substituted with one or more instances of J^B;

ring D is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of J^p1;

Q¹ is independently a bond, —

O—

, —

S—

, —

NR′

—

, —

C(O)—

, —

CO₂—

, —

OC(O)—

, —

C(O)NR′

—

, —

C(O)NRC(O)O—

, NRC(O)NRC(O)O—

, —

NRC(O)—

, —

NRC(O)NR′

—

, —

NRCO₂—

, —

OC(O)NR′

—

, —

S(O)—

, —

SO₂—

, —

SO₂NR′

—

, —

NRSO₂—

, or —

NRSO₂NR′

—

, or —

(CR⁶R²)_p—

Y¹—

;

Q² is independently bond, —

O—

, —

S—

, —

NR—

, —

C(O)—

, —

CO₂—

, —

OC(O)—

, —

C(O)NR—

, —

C(O)NRC(O)O—

, —

NRC(O)NRC(O)O—

, —

NRC(O)—

, —

NRC(O)NR—

, —

NRCO₂—

, —

OC(O)NR—

, —

S(O)—

, —

SO₂—

, —

N(R)SO₂—

, —

SO₂NR′

—

, —

NRSO₂NR′

—

, or —

(CR⁶R²)_p—

Y¹—

;

Q³ is independently a bond, —

C(O)—

, —

CO₂—

, —

C(O)NR′

—

, —

SO₂—

, —

SO₂NR′

—

, —

C(O)NRC(O)O—

, or —

(CR⁶R²)_p—

Y¹—

;

optionally, each of Q² and Q³, together with R⁵, independently forms a 5-7 membered ring optionally substituted with one or more instances of J^E1;

Y¹ is independently a bond, —

O—

, —

S—

, —

NR′

—

, —

C(O)—

, —

CO₂—

, —

OC(O)—

, —

C(O)NR′

—

, —

C(O)NRC(O)O—

, —

NRC(O)NRC(O)O—

, —

NRC(O)—

, —

NRC(O)NR′

—

, —

NRCO₂—

, —

OC(O)NR′

—

, —

S(O)—

, —

SO₂—

, —

SO₂NR′

—

, —

NRSO₂—

, or —

NRSO₂NR′

—

;

each of J^A and J^B is independently selected from the group consisting of halogen, cyano, oxo, and Q¹-R⁵;

or optionally two J^A and two J^B, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of J^E1 and fused to the ring to which they are attached; and

each of J^C1 and J^D1 is independently selected from the group consisting of halogen, cyano, oxo, R^a, —

OR^b, —

SR^b, —

S(O)R^a, —

SO₂R^a, —

NR^bR^c, —

C(O)R^b, —

C(O)OR^b, —

OC(O)R^b, —

NRC(O)R^b, —

C(O)NR^bR^c, —

NRC(O)NR^bR^c, —

NRC(O)OR^b, —

OCONR^bR^c, —

C(O)NRCO₂R^b, —

NRC(O)NRC(O)OR^b, —

C(O)NR(OR^b), —

SO₂NR^cR^b, —

NRSO₂R^b, and —

NRSO₂NR^cR^b, or optionally, two J^C1 and two J^D1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of J^E1, and fused to the respective ring to which they are attached.

11. The method of claim 10, wherein:

Z¹ is —

H, C₁-C₆ alkyl, —

O(C₁-C₆ alkyl), —

F, —

Cl, —

CN, —

CO₂H, —

CO₂(C₁-C₆ alkyl), —

CONH₂, —

CONH(C₁-C₆ alkyl), or —

CON(C₁-C₆ alkyl)₂, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

OCO(C₁-C₄ alkyl), —

CO(C₁-C₄ alkyl), —

CO₂H, —

CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy; and

Z² is —

H, C₁-C₆ alkyl, —

O(C₁-C₆ alkyl), —

NH₂, —

NH(C₁-C₆ alkyl), or —

N(C₁-C₆ alkyl)₂, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

OCO(C₁-C₄ alkyl), —

CO(C₁-C₄ alkyl), —

CO₂H, —

CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

12. The method of claim 11, wherein:

Z¹ is —

H, —

F, —

Cl, —

CF₃, —

CH₃, or —

CN; and

Z² is —

H or an optionally substituted C₁-C₆ alkyl.

13. The method of claim 12, wherein:

R² is —

H; and

R³ is —

H, —

F, —

Cl, —

CF₃, —

CH₃, —

C₂H₅, —

NH₂, —

NH(CH₃), or —

N(CH₃)₂.

14. The method of claim 13, wherein:

Z¹ is —

H, —

F, —

Cl, —

CF₃, —

CH₃, or —

CN;

Z² is —

H or C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —

O(C₁-C₄ alkyl);

Z³ is —

H or C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —

O(C₁-C₄ alkyl);

R¹ is —

H;

R² is —

H;

R³ is independently —

H, —

Cl or —

F;

R⁶ and R⁷ are each independently —

H or —

CH₃, or together with the carbon atoms to which they are attached they form a cyclopropane ring;

each R⁸ is independently —

H, halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —

O(C₁-C₄ alkyl), —

NH₂, —

NH(C₁-C₄ alkyl), or —

N(C₁-C₄ alkyl)₂;

each R⁹ is independently —

H or —

CH₃;

R¹¹ and R¹² are each independently —

H or —

CH₃; and

R¹³ and R¹⁴ are each independently —

H or —

CH₃, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

15. The method of claim 11, wherein the compound is represented by any one of the structural formulae below (II), (III), (IV) and (V):

16. The method of claim 15, wherein:

Z¹ is —

H, —

F, —

Cl, —

CF₃, —

CH₃, or —

CN; and

Z² is —

H or an optionally substituted C₁-C₆ alkyl.

17. The method of claim 16, wherein R³ is independently —

H, —

Cl or —

F.

18. The method of claim 17, wherein:

R⁶ and R⁷ are each independently —

H or —

CH₃, or together with the carbon atoms to which they are attached they form a cyclopropane ring;

each R⁸ is independently —

H, halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —

O(C₁-C₄ alkyl), —

NH₂, —

NH(C₁-C₄ alkyl), or —

N(C₁-C₄ alkyl)₂.

each R⁹ is independently —

H or —

CH₃;

R¹¹ and R¹² are each independently —

H or —

CH₃; and

R¹³ and R¹⁴ are each independently —

H or —

CH₃, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

19. The method of claim 18, wherein the compound is represented by the following structural formula (XIA) or (XIB):

29. The method of claim 15, wherein the compound is represented by the following structural formula (XIIA) or (XIIB):

38. The method of claim 15, wherein the compound is represented by the following structural formula (XIII):

39. The method of claim 38, wherein R¹⁰ is —

H or C₁-C₆-alkyl.

43. The method of claim 15, wherein the compound is represented by the following structural formula (XIV):

46. The method of claim 6, wherein R⁴ is:

47. The method of claim 46, wherein ring F is selected from any one of rings F1-F6:

48. The method of claim 47, wherein each rings F1-F6 are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C₁-C₄ alkoxy, and C₁-C₄ alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and —

O(C₁-C₄ alkyl).

49. The method of claim 48, wherein:

R⁹ is independently —

H, halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —

O(C₁-C₄ alkyl), —

NH₂, —

NH(C₁-C₄ alkyl), or —

N(C₁-C₄ alkyl)₂; and

ring E is a C₄-C₈ non-aromatic carbocycle optionally further substituted with one or more instances of J^A.

51. The method of claim 6, wherein R⁴ is:

52. The method of claim 51, wherein R⁴ is:

53. The method of claim 52, wherein

each of R⁸ and R⁹ is independently —

H, halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C_z—

C₄ alkoxyalkyl, —

O(C₁-C₄ alkyl), —

NH₂, —

NH(C₁-C₄ alkyl), or —

N(C₁-C₄ alkyl)₂; and

R²¹, R²², R²³, and R²⁴ are each independently —

H, halogen, —

OH, or C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy.

55. The method of claim 53, wherein:

Q² is independently —

O—

, —

CO₂—

, —

OC(O)—

, —

C(O)NR—

, —

NRC(O)—

, —

NRC(O)NR—

, —

NRCO₂—

, —

OC(O)NR—

, —

CO₂SO₂—

, —

P(O)₂O—

, or —

(CR⁶R⁷)_p—

Y¹—

.

56. The method of claim 55, wherein Q² is independently —

O—

or —

CO₂—

.

60. The method of claim 55, wherein:

R¹ is —

H;

R² is —

H, —

CH₃, —

CH₂OH, or —

NH₂;

R³ is —

H, —

F, —

Cl, C_1-4 alkyl, or C_1-4 haloalkyl;

Z¹ is —

H, —

F, or —

Cl;

Z² is —

H or C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —

O(C₁-C₄ alkyl);

Z³ is —

H or C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —

O(C₁-C₄ alkyl);

R⁵ is;

i) —

H;

ii) an optionally substituted C₁-C₆ alkyl group;

iii) an optionally substituted, C₃-C₇ non-aromatic carbocycle;

iv) an optionally substituted, 4-7 membered non-aromatic heterocycle;

v))an optionally substituted phenyl group;

vi) an optionally substituted 5-6 membered heteroaryl ring;

or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and

said alkyl group represented by R⁵ is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

OCO(O—

C₄ alkyl), —

CO(C₁-C₄ alkyl), —

CO₂H, —

CO₂(O—

C₄ alkyl), C₁-C₄ alkoxy, —

NRCO(C₁-C₄ alkyl), —

CONR(C₁-C₄ alkyl), —

NRCO₂(C₁-C₄ alkyl), a C₃-C₇ non-aromatic carbocycle optionally substituted with one or more instances of J^E1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of J^E1; and

a phenyl optionally substituted with one or more instances of J^E1; and

wherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R⁵ is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —

O(C₁-C₄ alkyl), —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

C(O)(C₁-C₄ alkyl), —

OC(O)(C₁-C₄ alkyl), —

C(O)O(C₁-C₄ alkyl) and —

CO₂H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

OCO(C₁-C₄ alkyl), —

CO(C₁-C₄ alkyl), —

CO₂H, —

CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

62. The method of claim 55, wherein:

R¹ is —

H;

R² is —

H or —

CH₂OH;

R³ is —

H, —

F, or —

Cl;

Z¹ is —

H, —

F, or —

Cl;

Z² is —

H;

Z³ is —

H;

R⁵ is independently;

i) —

H or ii) a C₁-C₆-alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —

O(C₁-C₄ alkyl), —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

C(O)(C₁-C₄ alkyl), —

OC(O)(C₁-C₄ alkyl), —

C(O)O(C₁-C₄ alkyl), —

CO₂H, C₃-C₈ non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl;

wherein each of said alkyl groups referred to in the substituents of the C₁-C₆-alkyl group represented by R⁵ is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

OCO(C₁-C₄ alkyl), —

CO(C₁-C₄ alkyl), —

CO₂H, —

CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy; and

wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl referred to in the substituents of the C₁-C₆-alkyl group represented by R⁵ is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

OCO(C₁-C₄ alkyl), —

CO(C₁-C₄ alkyl), —

CO₂H, —

CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

65. The method of claim 6, wherein:

R⁴ is;

66. The method of claim 65, wherein:

R⁴ is;

67. The method of claim 66, wherein:

R¹ is —

H;

R² is —

H;

R³ is —

H, —

F, or —

Cl;

Z¹ is —

H, —

F, or —

Cl;

Z² is —

H;

Z³ is —

H;

X is —

O—

;

R⁵ is —

H, an optionally substituted C₁-C₆ alkyl, or optionally substituted phenyl;

each R⁸ is independently —

H, halogen, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, or —

O(C₁-C₄ alkyl);

each of R⁹, R¹³, and R¹⁴ is independently —

H or C₁-C₄ alkyl;

R²¹, R²², R²³, R²⁴, and R²⁵ are each independently —

H, halogen, —

OH, C₁-C₆ alkoxy, or C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkyl, and —

O(C₁-C₆ alkyl); and

each rings G1-G5 are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, —

NH₂, —

NH(C₁-C₆ alkyl), —

N(C₁-C₆ alkyl)₂, —

O(C₁-C₆ alkyl), C₁-C₄ alkyl that is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and C₁-C₄ alkoxy.

69. The method of claim 1, further comprising co-administering and additional therapeutic agent.

70. The method of claim 69, wherein the additional therapeutic agent is selected from an antiviral agent or an Influenza vaccine, or both.

145. A pharmaceutical composition, comprising an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt of the same, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

147. The method of claim 1, wherein t is 0 or 1;

and j is 0 or 1.

151. The method of claim 1, wherein the compound is selected from the compounds depicted in FIG. 3, FIG. 4, FIG. 5, FIG. 6, FIG. 7, and FIG. 8, or a pharmaceutically acceptable salt thereof.

152. A method of reducing the amount of influenza viruses in a biological sample or in a patient, comprising administering to said biological sample or patient an effective amount of a compound as described in claim 1, or a combination of said compounds thereof.

153. A method of treating influenza in a patient, comprising administering to said patient an effective amount of a compound as described in claim 1, or a combination of said compounds thereof.

20. (canceled)

21. (canceled)

22. (canceled)

23. (canceled)

24. (canceled)

25. (canceled)

26. (canceled)

27. (canceled)

28. (canceled)

30. (canceled)

31. (canceled)

32. (canceled)

33. (canceled)

34. (canceled)

35. (canceled)

36. (canceled)

37. (canceled)

40. (canceled)

41. (canceled)

42. (canceled)

44. (canceled)

45. (canceled)

50. (canceled)

54. (canceled)

57. (canceled)

58. (canceled)

59. (canceled)

61. (canceled)

63. (canceled)

64. (canceled)

68. (canceled)

71. A compound represented by structural formula (IA):

72. The compound of claim 71, represented by structural formula (I):

73. The compound of claim 72, wherein:

ring A is a C₃-C₈ non-aromatic carbocycle optionally and independently further substituted with one or more instances of J^A;

rings B and C are each independently a 4-8 membered, non-aromatic heterocycle optionally and independently further substituted with one or more instances of J^B;

ring D is a 4-8 membered, non-aromatic heterocycle optionally substituted with one or more instances of J^D1;

each of J^A and J^B is independently selected from the group consisting of halogen, cyano, oxo, and Q¹-R⁵;

or optionally two J^A and two J^B, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of J^E1 and fused to the ring to which they are attached; and

each of J^C1 and J^D1 is independently selected from the group consisting of halogen, cyano, oxo, R^a, —

OR^b, —

SR^b, —

S(O)R^a, —

SO₂R^a, —

NR^bR^c, —

C(O)R^b, —

C(O)OR^b, —

OC(O)R^b, —

NRC(O)R^b, —

C(O)NR^bR^c, —

NRC(O)NR^bR^c, —

NRC(O)OR^b, —

OCONR^bR^c, —

C(O)NRCO₂R^b, —

NRC(O)NRC(O)OR^b, —

C(O)NR(OR^b), —

SO₂NR^cR^b, —

NRSO₂R^b, and —

NRSO₂NR^cR^b, or optionally, two J^C1 and two J^D1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of J^E1, and fused to the respective ring to which they are attached;

Q¹ is independently a bond, —

O—

, —

S—

, —

NR—

, —

C(O)—

, —

CO₂—

, —

OC(O)—

, —

C(O)NR—

, —

C(O)NRC(O)O—

, —

NRC(O)NRC(O)O—

, —

NRC(O)—

, —

NRC(O)NR—

, —

NRCO₂—

, —

OC(O)NR—

, —

S(O)—

, —

SO₂—

, —

N(R)SO₂—

, —

SO₂N(R)—

, —

NRSO₂NR—

, or —

(CR⁶R⁷)_p—

Y¹—

;

Q² is independently a bond, —

O—

, —

S—

, —

NR—

, —

C(O)—

, —

CO₂—

, —

OC(O)—

, —

C(O)NR—

, —

C(O)NRC(O)O—

, —

NRC(O)NRC(O)O—

, —

NRC(O)—

, —

NRC(O)NR—

, —

NRCO₂—

, —

OC(O)NR—

, —

S(O)—

, —

SO₂—

, —

N(R)SO₂—

, —

SO₂N(R)—

, —

NRSO₂NR—

, or —

(CR⁶R⁷)_p—

Y¹—

; and

Q³ is independently a bond, —

C(O)—

, —

CO₂—

, —

C(O)NR—

, —

SO₂—

, —

SO₂N(R)—

, —

C(O)NRC(O)O—

or —

(CR⁶R⁷)_p—

Y¹—

;

or

each of Q² and Q³, together with R⁵, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of J^E1;

each Y¹ is independently a bond, —

O—

, —

S—

, —

NR—

, —

C(O)—

, —

CO₂—

, —

OC(O)—

, —

C(O)NR—

, —

C(O)NRC(O)O—

, —

NRC(O)NRC(O)O—

, —

NRC(O)—

, —

NRC(O)NR—

, —

NRCO₂—

, —

OC(O)NR—

, —

S(O)—

, —

SO₂—

, —

N(R)SO₂—

, —

SO₂N(R)—

, or —

NRSO₂NR—

;

R⁵ is;

i) —

H;

ii) a C₁-C₆ aliphatic group optionally substituted with one or more instances of J^C1;

iii) a C₃-C₈ non-aromatic carbocycle, or 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of J^C1;

or iv) a 4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of J^p1; and

R⁸ and R⁹ are each independently —

H, halogen, cyano, hydroxy, amino, carboxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ cyanoalkyl, C₂-C₆ alkoxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy, or C₂-C₆ alkoxyalkoxy.

74. The compound of any one of claims 71-73, wherein R¹ is —

H or C₁-C₆ alkyl.

75. The compound of claim 74, wherein R¹ is —

H.

76. The compound of claim 75, wherein R² is —

H, —

F, —

CH₃, —

CH₂OH, or —

NH₂.

78. The compound of claim 76, wherein R³ is —

H, —

Cl, —

F, —

Br, —

CN, —

CF₃, —

O(C₁-C₄ alkyl), —

OH, —

NH₂, —

NH(C₁-C₄ alkyl), or —

N(C₁-C₄ alkyl)₂.

79. The compound of claim 73, wherein the compound is represented by the following structural formula (VI):

80. The compound of claim 79, wherein:

Z¹ is —

H, C₁-C₆ alkyl, —

O(C₁-C₆ alkyl), —

F, —

Cl, —

CN, —

CO₂H, —

CO₂(O—

C₆ alkyl), —

CONH₂, —

CONH(C₁-C₆ alkyl), or —

CON(C₁-C₆ alkyl)₂, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

OCO(C₁-C₄ alkyl), —

OCO(C₁-C₄ alkyl), —

CO₂H, —

CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy; and

Z² is —

H, C₁-C₆ alkyl, —

O(C₁-C₆ alkyl), —

NH₂, —

NH(C₁-C₆ alkyl), or —

N(C₁-C₆ alkyl)₂, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

OCO(C₁-C₄ alkyl), —

CO(C₁-C₄ alkyl), —

CO₂H, —

CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

83. The compound of claim 79, wherein:

Z¹ is —

H, —

F, —

Cl, —

CF₃, —

CH₃, or —

CN;

Z² is —

H or C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —

O(C₁-C₄ alkyl);

Z³ is —

H or C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —

O(C₁-C₄ alkyl);

R¹ is —

H;

R² is —

H;

R³ is independently —

H, —

Cl or —

F;

R⁶ and R² are each independently —

H or —

CH₃, or together with the carbon atoms to which they are attached they form a cyclopropane ring;

each R⁸ is independently —

H, halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —

O(C₁-C₄ alkyl), —

NH₂, —

NH(C₁-C₄ alkyl), or —

N(C₁-C₄ alkyl)₂.

each R⁹ is independently —

H or —

CH₃;

R¹¹ and R¹² are each independently —

H or —

CH₃; and

R¹³ and R¹⁴ are each independently —

H or —

CH₃, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

84. The compound of claim 80, wherein the compound is represented by any one of structural formulae (II), (III), (IV) and (V):

85. The compound of claim 84, wherein:

Z¹ is —

H, —

F, —

Cl, —

CF₃, —

CH₃, or —

CN; and

Z² is —

H or an optionally substituted C₁-C₆ alkyl.

86. The compound of claim 85, wherein R³ is —

H, —

Cl or —

F.

87. The compound of claim 86, wherein:

R⁶ and R⁷ are each independently —

H or —

CH₃, or together with the carbon atoms to which they are attached they form a cyclopropane ring;

each R⁸ is independently —

H, halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —

O(C₁-C₄ alkyl), —

NH₂, —

NH(C₁-C₄ alkyl), or —

N(C₁-C₄ alkyl)₂.

each R⁹ is independently —

H or —

CH₃;

R¹¹ and R¹² are each independently —

H or —

CH₃; and

R¹³ and R¹⁴ are each independently —

H or —

CH₃, or optionally R¹³ and R¹⁴, together with the carbon atom to which they are attached, form a cyclopropane ring.

88. The compound of claim 87, wherein the compound is represented by structural formula (XIA) or (XIB):

100. The compound of claim 87, wherein the compound is represented by structural formula (XIIA) or (XIIB):

109. The compound of claim 87, wherein the compound is represented by structural formula (XIII):

110. The compound of claim 109, wherein R¹⁰ is —

H or C₁-C₆-alkyl.

114. The compound of claim 87, wherein the compound is represented by the following structural formula (XIV):

117. The compound of claim 83, wherein R⁴ is:

118. The compound of claim 117, wherein ring F is selected from any one of rings F1-F6:

119. The compound of claim 118, wherein each rings F1-F6 are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C₁-C₄ alkoxy, and C₁-C₄ alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and —

O(C₁-C₄ alkyl).

120. The compound of claim 118, wherein:

R⁹ is independently —

H, halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —

O(C₁-C₄ alkyl), —

NH₂, —

NH(C₁-C₄ alkyl), or —

N(C₁-C₄ alkyl)₂; and

ring E is a C₄-C₈ non-aromatic carbocycle optionally further substituted with one or more instances of J^A.

122. The compound of claim 83, wherein R⁴ is:

123. The compound of claim 122, wherein R⁴ is:

124. The compound of claim 123, wherein:

each of R⁸ and R⁹ is independently —

H, halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C_z—

C₄ alkoxyalkyl, —

O(C₁-C₄ alkyl), —

NH₂, —

NH(C₁-C₄ alkyl), or —

N(C₁-C₄ alkyl)₂; and

R²¹, R²², R²³, and R²⁴ are each independently —

H, halogen, —

OH, or C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy.

126. The compound of claim 124, wherein:

Q² is independently —

O—

, —

CO₂—

, —

OC(O)—

, —

C(O)NR—

, —

NRC(O)—

, —

NRC(O)NR—

, —

NRCO₂—

, —

OC(O)NR—

, —

CO₂SO₂—

, —

P(O)₂O—

, or —

(CR⁶R²)_p—

Y¹—

.

127. The compound of claim 126, wherein Q² is independently —

O—

or —

CO₂—

.

131. The compound of claim 126, wherein:

R¹ is —

H;

R² is —

H, —

CH₃, —

CH₂OH, or —

NH₂;

R³ is —

H, —

F, —

Cl, C_1-4 alkyl, or C_1-4 haloalkyl;

Z¹ is —

H, —

F, or —

Cl;

Z² is —

H or C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —

O(C₁-C₄ alkyl);

Z³ is —

H or C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —

O(C₁-C₄ alkyl);

R⁵ is;

i) —

H;

ii) an optionally substituted C₁-C₆ alkyl group;

iii) an optionally substituted, C₃-C₂ non-aromatic carbocycle;

or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle;

or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and

said alkyl group represented by R⁵ is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

OCO(C₁-C₄ alkyl), —

CO(C₁-C₄ alkyl), —

CO₂H, —

CO₂(C₁-C₄ alkyl), C₁-C₄ alkoxy, a C₃-C₇ non-aromatic carbocycle optionally substituted with one or more instances of J^E1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of J^E1; and

a phenyl optionally substituted with one or more instances of J^E1; and

wherein each of said carbocycles and heterocycles represented by R⁵, and referred to for the substituents of the C₁-C₆ alkyl group represented by R⁵ is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —

O(C₁-C₄ alkyl), —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

C(O)(C₁-C₄ alkyl), —

OC(O)(C₁-C₄ alkyl), —

C(O)O(C₁-C₄ alkyl) and —

CO₂H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

OCO(C₁-C₄ alkyl), —

CO(C₁-C₄ alkyl), —

CO₂H, —

CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

133. The compound of claim 126, wherein:

R¹ is —

H;

R² is —

H or —

CH₂OH;

R³ is —

H, —

F, or —

Cl;

Z¹ is —

H, —

F, or —

Cl;

Z² is —

H;

Z³ is —

H;

R⁵ is independently;

i) —

H or ii) a C₁-C₆-alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —

O(C₁-C₄ alkyl), —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

C(O)(C₁-C₄ alkyl), —

OC(O)(C₁-C₄ alkyl), —

C(O)O(C₁-C₄ alkyl), —

CO₂H, C₃-C₈ non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl;

wherein each of said alkyl groups referred to in the substituents of the C₁-C₆-alkyl group represented by R⁵ is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

OCO(C₁-C₄ alkyl), —

CO(C₁-C₄ alkyl), —

CO₂H, —

CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy; and

wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl referred to in the substituents of the C₁-C₆-alkyl group represented by R⁵ is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

OCO(C₁-C₄ alkyl), —

CO(C₁-C₄ alkyl), —

CO₂H, —

CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

136. The compound of claim 71, wherein:

R⁴ is;

137. The compound of claim 136, wherein:

R⁴ is;

138. The compound of claim 137, wherein:

R¹ is —

H;

R² is —

H;

R³ is —

H, —

F, or —

Cl;

Z¹ is —

H, —

F, or —

Cl;

Z² is —

H;

Z³ is —

H;

X is —

O—

;

R⁵ is —

H, an optionally substituted C₁-C₆ alkyl, or optionally substituted phenyl;

each R⁸ is independently —

H, halogen, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, or —

O(C₁-C₄alkyl);

each of R⁹, R¹³, and R¹⁴ is independently —

H or C₁-C₄ alkyl;

R²¹, R²², R²³, R²⁴, and R²⁵ are each independently —

H, halogen, —

OH, C₁-C₆ alkoxy, or C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C₁-C₆ alkyl, and —

O(C₁-C₆ alkyl); and

each rings G1-G5 are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, —

NH₂, —

NH(C₁-C₆ alkyl), —

N(C₁-C₆ alkyl)₂, —

O(C₁-C₆ alkyl), C₁-C₄ alkyl that is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and C₁-C₄ alkoxy.

143. The compound of claim 71, wherein the compound is selected from any of the structures depicted in FIG. 3, FIG. 4, FIG. 5, and FIG. 6, or a pharmaceutically acceptable salt thereof.

154. A method preparing a compound represented by Structural Formula (IA):

155. A method preparing a compound represented by Structural Formula (IA):

77. (canceled)

81. (canceled)

82. (canceled)

89. (canceled)

90. (canceled)

91. (canceled)

92. (canceled)

93. (canceled)

94. (canceled)

95. (canceled)

96. (canceled)

97. (canceled)

98. (canceled)

99. (canceled)

101. (canceled)

102. (canceled)

103. (canceled)

104. (canceled)

105. (canceled)

106. (canceled)

107. (canceled)

108. (canceled)

111. (canceled)

112. (canceled)

113. (canceled)

115. (canceled)

116. (canceled)

121. (canceled)

125. (canceled)

128. (canceled)

129. (canceled)

130. (canceled)

132. (canceled)

134. (canceled)

135. (canceled)

139. (canceled)

140. (canceled)

141. (canceled)

142. (canceled)

144. A compound selected from any of the structures depicted in FIG. 7 or a pharmaceutically acceptable salt thereof.

146. (canceled)

148. (canceled)

149. (canceled)

150. (canceled)

156. (canceled)