Inhibitors of influenza viruses replication

• US 10,874,673 B2
• Filed: 06/25/2018
• Issued: 12/29/2020
• Est. Priority Date: 06/17/2009
• Status: Active Grant

• 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, Davies, Ioana, Duffy, John P., Farmer, Luc J., Gao, Huai, Gu, Wenxin, Jacobs, Dylan H., Kennedy, Joseph M., Ledeboer, Mark W., Ledford, Brian, Maltais, Francois, Perola, Emanuele, Wang, Tiansheng, Wannamaker, M. Woods, Byrn, Randal, Zhou, Yi, Lin, Chao, Jiang, Min, Jones, Steven, Germann, Ursula A., Salituro, Francesco G., Kwong, Ann Dak-Yee
• Primary Examiner(s): Wang, Shengjun
• Application Number:
  US16/016,917
• Publication Number:
  US 20190151314A1
• Time in Patent Office: 918 Days
• Field of Search: 514256
• 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 or reducing the number 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 of Formula (IA):

2. The method of claim 1, wherein R⁴ is:

3. The method of claim 2, wherein ring F is selected from any one of rings F1-F6:

4. The method of claim 1, wherein R⁴ is:

5. The method of claim 4, wherein Q² is independently —

O—

, —

CO₂—

, —

OC(O)—

, —

C(O)NR—

, —

NRC(O)—

, —

NRC(O)NR—

, —

NRCO₂—

, —

OC(O)NR—

, or —

(CR⁶R⁷)_p—

Y¹—

.

6. The method of claim 5, wherein Q² is independently —

O—

or —

CO₂—

.

7. The method of claim 4, wherein:

R⁵ is independently

i) —

H;

ii) an optionally substituted C₁-C₆ alkyl group;

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

or

iv) a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of J^D1.

8. The method of claim 4, wherein:

R¹ is —

H;

R² is —

H, —

CH₃, —

CH₂OH, or —

NH₂;

R³ is —

H, —

F, —

Cl, C₁-C₄ alkyl, or C₁-C₄ 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;

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, an optionally substituted C₃-C₇ non-aromatic carbocycle, an optionally substituted 4-7 membered non-aromatic heterocycle; 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.

9. The method of claim 4, 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-C₇ 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.

10. The method of claim 4, wherein each of J^A is selected from the group consisting of halogen, cyano, hydroxy, C₁-C₆ alkyl, —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

O(C₁-C₄ alkyl), —

C(O)NH₂, —

C(O)NH(C₁-C₄ alkyl), —

C(O)N(C₁-C₄ alkyl)₂, —

C(O)(C₁-C₄-alkyl), —

OC(O)(C₁-C₄ alkyl), —

NHC(O)(C₁-C₄ alkyl), and —

N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl);

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.

11. The method of claim 10, wherein each of J^A is selected from the group consisting of halogen, cyano, hydroxy, —

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, 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).

12. The method of claim 4, 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;

R⁵ is —

H, or an optionally substituted C₁-C₆ alkyl;

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, an 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, hydroxy, and —

O(C₁-C₆ alkyl); and

each of rings G1-G2 is independently a 5-10 membered non-aromatic bridged carbocycle 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.

13. The method of claim 4, wherein x is 0 or 1.

14. The method of claim 4, wherein R³ is methyl or ethyl.

15. The method of claim 1, wherein the compound of Formula (IA) is selected from

16. A method of treating influenza infection in a patient comprising administering to said patient an effective amount of a compound of Formula (IA):

17. The method of claim 16, wherein R⁴ is:

18. The method of claim 17, wherein ring F is selected from any one of rings F1-F6:

19. The method of claim 16, wherein R⁴ is:

20. The method of claim 19, wherein Q² is independently —

O—

, —

CO₂—

, —

OC(O)—

, —

C(O)NR—

, —

NRC(O)—

, —

NRC(O)NR—

, —

NRCO₂—

, —

OC(O)NR—

, or —

(CR⁶R⁷)_p—

Y¹—

.

21. The method of claim 20, wherein Q² is independently —

O—

or —

CO₂—

.

22. The method of claim 19, wherein:

R⁵ is independently

i) —

H;

ii) an optionally substituted C₁-C₆ alkyl group;

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

or

iv) a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of J^D1.

23. The method of claim 19, wherein:

R¹ is —

H;

R² is —

H, —

CH₃, —

CH₂OH, or —

NH₂;

R³ is —

H, —

F, —

Cl, C₁-C₄ alkyl, or C₁-C₄ 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;

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, an optionally substituted C₃-C₇ non-aromatic carbocycle, an optionally substituted 4-7 membered non-aromatic heterocycle; 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.

24. The method of claim 19, 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-C₇ 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.

25. The method of claim 19, wherein each of J^A is selected from the group consisting of halogen, cyano, hydroxy, C₁-C₆ alkyl, —

NH₂, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

O(C₁-C₄ alkyl), —

C(O)NH₂, —

C(O)NH(C₁-C₄ alkyl), —

C(O)N(C₁-C₄ alkyl)₂, —

C(O)(C₁-C₄-alkyl), —

OC(O)(C₁-C₄ alkyl), —

NHC(O)(C₁-C₄ alkyl), and —

N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl);

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.

26. The method of claim 25, wherein each of J^A is selected from the group consisting of halogen, cyano, hydroxy, —

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, 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).

27. The method of claim 19, 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;

R⁵ is —

H, or an optionally substituted C₁-C₆ alkyl;

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, 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, hydroxy, and —

O(C₁-C₆ alkyl); and

each of rings G1-G2 is independently a 5-10 membered non-aromatic bridged carbocycle 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.

28. The method of claim 19, wherein x is 0 or 1.

29. The method of claim 19, wherein R³ is methyl or ethyl.

30. The method of claim 16, wherein the compound of Formula (IA) is selected from