INHIBITORS OF INFLUENZA VIRUSES REPLICATION

• US 20140005197A1
• Filed: 06/14/2013
• Published: 01/02/2014
• Est. Priority Date: 12/16/2010
• Status: Abandoned Application

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Charifson, Paul S., Clark, Michael P., Davies, Ioana, Gao, Huai, Kennedy, Joseph M., Ledeboer, Mark W., Maltais, Francois, Perola, Emanuele
• Application Number:
  US13/918,110
• Publication Number:
  US 20140005197A1
• Time in Patent Office: Days
• US Class Current: 514/242
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 (I) are as described herein. A compound is represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (I) 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 compound represented by Structural Formula (I):

2. The compound of claim 1, wherein:

X is —

Cl, —

Br, —

F, —

CN, —

O(C_1-4 alkyl), C_1-6 alkyl, or C_1-6 haloalkyl;

Ring S is selected from;

6. The compound of claim 2, wherein X is —

Cl, —

Br, —

F, —

CN, —

CH₃, or CF₃.

8. The compound of claim 6, wherein Ring T is an optionally substituted, bridged, C₅-C₁₀ carbocyclic group;

or Ring T is an optionally substituted, monocyclic, C₅-C₈ carbocyclic group.

10. The compound of claim 8, wherein:

Q¹ is —

C(O)—

, —

CO₂—

, —

OC(O)—

, —

O(CR^tR^s)_k—

C(O)O—

, —

C(O)NR′

—

, —

C(O)N(R′

)—

O—

, —

C(O)NRC(O)O—

, —

NRC(O)—

, —

NRC(O)NR′

—

, —

NRCO₂—

, —

OC(O)NR′

—

, —

OSO₂NR′

—

, —

S(O)—

, —

SO₂—

, —

SO₂NR′

—

, —

NRSO₂—

, —

NRSO₂NR′

—

, —

B(O₂)—

, or —

(CR^tR^s)_p—

Y¹—

;

Y¹ is —

C(O)—

, —

CO₂—

, —

OC(O)—

, —

O(CR^tR^s)_k—

C(O)O—

, —

C(O)NR′

—

, —

C(O)N(R′

)—

O—

, —

C(O)NRC(O)O—

, —

NRC(O)—

, —

NRC(O)NR′

—

, —

NRCO₂—

, —

OC(O)NR′

—

, —

OSO₂NR′

—

, —

S(O)—

, —

SO₂—

, —

SO₂NR′

—

, —

NRSO₂—

, —

B(O₂)—

, or —

NRSO₂NR′

—

;

R¹ is independently i) —

H;

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

iii) a C₃-C₈ carbocyclic group or 4-8 membered heterocyclic group, each of which is optionally and independently substituted with one or more instances of J^B;

iv) a phenyl group or 5-6 membered heteroaryl group, each of which is optionally and independently substituted with one or more instances of J^C;

or

optionally R¹, together with R′ and

the nitrogen to which they are attached, form an optionally substituted, 4-8 membered heterocyclic group;

or optionally -Q¹-R¹ forms, together with Ring T, an optionally substituted, 4-10 membered, non-aromatic, spiro ring; and

J^A, J^B, and J^T are each independently oxo or J^C;

J^C is selected from the group consisting of halogen, cyano, R^a, —

OR^b, —

SR^b, —

S(O)R^a, —

SO₂R^a, —

NHR^c, —

C(O)R^b, —

C(O)OR^b, —

OC(O)R^b, —

NHC(O)R^b, —

C(O)NHR^c, —

NHC(O)NHR^c, —

NHC(O)OR^b, —

OCONHR^c, —

NHC(O)NHC(O)OR^b, —

N(CH₃)R^c, —

N(CH₃)C(O)R^b, —

C(O)N(CH₃)R^c, —

N(CH₃)C(O)NHR^c, —

N(CH₃)C(O)OR^b, —

OCON(CH₃)R^c, —

C(O)NHCO₂R^b, —

C(O)N(CH₃)CO₂R^b, —

N(CH₃)C(O)NHC(O)OR^b, —

NHSO₂R^b, —

SO₂NHR^b, —

SO₂N(CH₃)R^b, and —

N(CH₃)SO₂R^b;

optionally, two J^T, two J^A, two J^B, and two J^C, respectively, together with the atom(s) to which they are attached, independently form an optionally substituted, 4-10-membered, non-aromatic ring;

R^a is independently;

i) a C₁-C₆ alkyl group optionally substituted with one or more substituents 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), —

O(C₁-C₄ alkyl), optionally substituted C₃-C₈ carbocyclic group, optionally substituted 4-8 membered heterocyclic group, optionally substituted 5-6 membered heteroaryl, and optionally substituted phenyl group;

ii) an optionally substituted C₃-C₈ carbocyclic group;

iii) optionally substituted 4-8 membered heterocyclic group;

iv) an optionally substituted 5-6 membered heteroaryl group;

v) or optionally substituted phenyl group;

R^b and R^c are each independently R^a or —

H;

or optionally, R^b and R^c, together with the nitrogen atom(s) to which they are attached, each independently form an optionally substituted, 4-8 membered heterocyclic group; and

R and R′

are each and independently —

H or C_1-4 alkyl, or optionally R and R′

, together with the nitrogen to which they are attached, form an optionally substituted 4-8 membered heterocyclic group, or optionally R′

, together with R¹ and the nitrogen to which they are attached, form an optionally substituted 4-8 membered heterocyclic group.

13. The compound of claim 10, wherein:

Q¹ is —

CO₂—

, —

O(CR^tR^s)_k—

C(O)O—

, —

P(O)(OR)O—

, —

OP(O)(OR^a)O—

, —

P(O)₂O—

, —

CO₂SO₂—

, or —

(CR^tR^s)_p—

Y¹—

;

Y¹ is —

CO₂—

, —

O(CR^tR^s)_k—

C(O)O—

, —

P(O)(OR)O—

, —

OP(O)(OR^a)O—

, —

P(O)₂O—

, or —

CO₂SO₂—

; and

Ring S is

15. The compound of claim 13, wherein Ring S is selected from:

16. The compound of claim 15, wherein

20. The compound of claim 16, wherein Ring S is selected from:

21. The compound of claim 20, wherein:

(a) R¹², R¹³, and R¹⁴ are each and independently —

H, halogen, cyano, hydroxy, —

O(C₁-C₆ alkyl), or optionally substituted C₁-C₆ alkyl;

R¹⁵ is —

H or optionally substituted C₁-C₆ alkyl; and

R^t and R^s are each independently —

H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

or

(b) R¹² and R¹³ are each independently —

H, halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —

O(C₁-C₆ alkyl);

R¹⁴ and R¹⁵ are each independently —

H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

R^t and R^s are each independently —

H or C₁-C₆ alkyl.

25. The compound of claim 21, wherein Ring A and R¹⁵, Ring A and R¹⁴, or Ring A and R¹³ independently form an optionally substituted, bridged carbocyclic group.

26. The compound of claim 25, wherein Ring T is:

27. The compound of claim 26, wherein:

R¹⁴ and each R¹⁵ are each independently —

H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

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

H, halogen, hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, or C₁-C₆ haloalkyl.

30. The compound of claim 27, wherein:

Q¹ is independently —

C(O)O—

, —

NHC(O)—

, or —

C(O)NH—

;

R¹ is independently —

H or an optionally substituted C₁-C₆ aliphatic group; and

R and R′

are each and independently —

H or —

CH₃;

or

optionally R¹, together with R′ and

the nitrogen to which they are attached, form an optionally substituted, 4-8 membered heterocyclic group.

32. The compound of claim 30, wherein Ring T is:

34. The compound of claim 32, wherein:

R¹ is H or optionally substituted C_1-6 alkyl;

R¹⁴, R¹⁵, R²¹, R²², R²³, R²⁴, and R²⁵ are each independently —

H, and

q is 1.

36. The compound of claim 21, wherein Ring T is selected from:

38. The compound of claim 36, wherein:

Q¹ is independently —

NRC(O)—

, —

C(O)NR—

, or —

NRC(O)NR′

—

;

R¹⁴ and each R¹⁵ are each independently —

H or C_1-6 alkyl; and

each of Rings A8-A11 is independently and optionally substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and —

O(C₁-C₄ alkyl).

46. A pharmaceutical composition, comprising a compound according to any one of claims 1, 2, 6, 8, 10, 13, 15, 16, 20, 21, 25, 26, 27, 30, 32, 34, 36, 38, 44, and 45, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

47. 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 as described in any one of claims 1, 2, 6, 8, 10, 13, 15, 16, 20, 21, 25, 26, 27, 30, 32, 34, 36, 38, 44, and 45.

50. 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 any one of claims 1, 2, 6, 8, 10, 13, 15, 16, 20, 21, 25, 26, 27, 30, 32, 34, 36, 38, 44, and 45.

51. A method of treating influenza in a patient, comprising administering to said patient an effective amount of a compound as described in any one of claims 1, 2, 6, 8, 10, 13, 15, 16, 20, 21, 25, 26, 27, 30, 32, 34, 36, 38, 44, and 45.

52. A method preparing a compound represented by Structural Formula (I):

54. A method preparing a compound represented by Structural Formula (I):

55. A method preparing a compound represented by Structural Formula (I):

57. A compound represented by Structural Formula (XX):

58. The compound of claim 57, characterized by any one of the following structural formulae:

59. The compound of claim 57, characterized by any one of the following structural formulae:

3. (canceled)

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44. A wherein the compound selected from any of one of the structures depicted below:

45. A compound selected from any of one of the structures depicted below:

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