IP Library › Granted Patent US 8,318,754
Granted Patent B2
US 8,318,754 · App. 12/712,399 · Granted Nov 27, 2012

Pyrimidinecarboxamide derivatives

Assignee: Concert Pharmaceuticals Inc.
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Quick Facts
Patent No.
US 8,318,754
App. No.
12/712,399
Granted
Nov 27, 2012
Kind
B2
Abstract

This disclosure relates to novel HIV integrase inhibitors their derivatives, pharmaceutically acceptable salts, solvates, and hydrates thereof. This disclosure also provides compositions comprising a compound of this disclosure and the use of such compositions in methods of treating HIV infections.

Claims (462)

1. A method of inhibiting the activity of HIV-1 integrase in an HIV-1-infected cell, comprising the step of contacting the cell with one or more compounds of Formula I:

or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the one or more compounds of Formula I are optionally in the presence of a pharmaceutically acceptable carrier, wherein:

each of R 1 , R 2a , R 2b , and R 3 is independently selected from CH 3 , CDH 2 , CD 2 H, and CD 3 ;

Y 1 and Y 2 are each independently selected from H or D;

R 4 is selected from:

and

when each R is CH 3 , at least one of Y 1 and Y 2 is D.

2. The method of claim 1 , wherein each of R 1 , R 2a , R 2b , and R 3 is independently selected from CH 3 , and CD 3 .

3. The method of claim 2 , wherein Y 1 and Y 2 are the same.

4. The method of claim 3 , wherein R 2a and R 2b are the same and are selected from CH 3 and CD 3 .

5. The method of claim 4 , wherein R 4 is selected from

6. The method of claim 5 , wherein R 4 is

and the compound is selected from any one of the compounds set forth in the table below, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

Compound

R 1

R 2a

R 2b

R 3

Y 1

Y 2

101

CD 3

CH 3

CH 3

CH 3

H

H

102

CH 3

CD 3

CD 3

CH 3

H

H

103

CH 3

CH 3

CH 3

CD 3

H

H

104

CH 3

CH 3

CH 3

CH 3

D

D

105

CD 3

CD 3

CD 3

CH 3

H

H

106

CD 3

CH 3

CH 3

CD 3

H

H

107

CD 3

CH 3

CH 3

CH 3

D

D

108

CH 3

CD 3

CD 3

CD 3

H

H

109

CH 3

CD 3

CD 3

CH 3

D

D

110

CH 3

CH 3

CH 3

CD 3

D

D

111

CD 3

CD 3

CD 3

CD 3

H

H

112

CD 3

CH 3

CH 3

CD 3

D

D

113

CH 3

CD 3

CD 3

CD 3

D

D

114

CD 3

CD 3

CD 3

CD 3

D

D

7. The method of claim 5 , wherein R 4

and the compound is selected from any one of the compounds set forth in the table below, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

Compound

R 1

R 2a

R 2b

R 3

Y 1

Y 2

115

CD 3

CH 3

CH 3

CH 3

H

H

116

CH 3

CD 3

CD 3

CH 3

H

H

117

CH 3

CH 3

CH 3

CD 3

H

H

118

CH 3

CH 3

CH 3

CH 3

D

D

119

CD 3

CD 3

CD 3

CH 3

H

H

120

CD 3

CH 3

CH 3

CD 3

H

H

121

CD 3

CH 3

CH 3

CH 3

D

D

122

CH 3

CD 3

CD 3

CD 3

H

H

123

CH 3

CD 3

CD 3

CH 3

D

D

124

CH 3

CH 3

CH 3

CD 3

D

D

125

CD 3

CD 3

CD 3

CD 3

H

H

126

CD 3

CH 3

CH 3

CD 3

D

D

127

CH 3

CD 3

CD 3

CD 3

D

D

128

CD 3

CD 3

CD 3

CD 3

D

D

8. A method of treating an infection in a patient due to HIV-1 integrase, comprising the step of administering to the patient in need thereof one or more compounds of Formula I:

or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the one or more compounds of Formula I are optionally in the presence of a pharmaceutically acceptable carrier, wherein:

each of R 1 , R 2a , R 2b , and R 3 is independently selected from CH 3 , CDH 2 , CD 2 H, and CD 3 ;

Y 1 and Y 2 are each independently selected from H or D;

R 4 is selected from:

and

when each R is CH 3 , at least one of Y 1 and Y 2 is D.

9. The method of claim 8 , wherein each of R 1 , R 2a , R 2b , and R 3 is independently selected from CH 3 , and CD 3 .

10. The method of claim 9 , wherein Y 1 and Y 2 are the same.

11. The method of claim 10 , wherein R 2a and R 2b are the same and are selected from CH 3 and CD 3 .

12. The method of claim 11 , wherein R 4 is selected from

13. The method of claim 12 , wherein R 4 is

and the compound is selected from any one of the compounds set forth in the table below, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

Compound

R 1

R 2a

R 2b

R 3

Y 1

Y 2

101

CD 3

CH 3

CH 3

CH 3

H

H

102

CH 3

CD 3

CD 3

CH 3

H

H

103

CH 3

CH 3

CH 3

CD 3

H

H

104

CH 3

CH 3

CH 3

CH 3

D

D

105

CD 3

CD 3

CD 3

CH 3

H

H

106

CD 3

CH 3

CH 3

CD 3

H

H

107

CD 3

CH 3

CH 3

CH 3

D

D

108

CH 3

CD 3

CD 3

CD 3

H

H

109

CH 3

CD 3

CD 3

CH 3

D

D

110

CH 3

CH 3

CH 3

CD 3

D

D

111

CD 3

CD 3

CD 3

CD 3

H

H

112

CD 3

CH 3

CH 3

CD 3

D

D

113

CH 3

CD 3

CD 3

CD 3

D

D

114

CD 3

CD 3

CD 3

CD 3

D

D

14. The method of claim 12 , wherein R 4 is

and the compound is selected from any one of the compounds set forth in the table below, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

Compound

R 1

R 2a

R 2b

R 3

Y 1

Y 2

115

CD 3

CH 3

CH 3

CH 3

H

H

116

CH 3

CD 3

CD 3

CH 3

H

H

117

CH 3

CH 3

CH 3

CD 3

H

H

118

CH 3

CH 3

CH 3

CH 3

D

D

119

CD 3

CD 3

CD 3

CH 3

H

H

120

CD 3

CH 3

CH 3

CD 3

H

H

121

CD 3

CH 3

CH 3

CH 3

D

D

122

CH 3

CD 3

CD 3

CD 3

H

H

123

CH 3

CD 3

CD 3

CH 3

D

D

124

CH 3

CH 3

CH 3

CD 3

D

D

125

CD 3

CD 3

CD 3

CD 3

H

H

126

CD 3

CH 3

CH 3

CD 3

D

D

127

CH 3

CD 3

CD 3

CD 3

D

D

128

CD 3

CD 3

CD 3

CD 3

D

D

15. The method of claim 1 or claim 8 , further comprising the additional step of contacting the cell with, or co-administering to the patient in need thereof, respectively, a second therapeutic agent selected from one or more of an antiviral agent, an anti-infective, an immunomodulator, an antibiotic, a CCR5 receptor antagonist, a vaccine, a viral protease inhibitor, a nucleoside reverse transcriptase inhibitor and a non-nucleoside reverse transcriptase inhibitor.

16. The method of claim 15 , wherein the second therapeutic agent is selected from one or more of darunavir, ritonavir, and etravirine.

17. A composition comprising a compound of Formula I:

or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the compound of Formula I is optionally in the presence of a pharmaceutically acceptable carrier, wherein:

each of R 1 , R 2a , R 2b , and R 3 is independently selected from CH 3 , CDH 2 , CD 2 H, and CD 3 ;

Y 1 and Y 2 are each independently selected from H or D;

R 4 is selected from:

and

when each R is CH 3 , at least one of Y 1 and Y 2 is D, and a second therapeutic agent selected from an antiviral agent, an anti-infective, an immunomodulator, an antibiotic, a CCR5 receptor antagonist, a vaccine, a viral protease inhibitor, a nucleoside reverse transcriptase inhibitor and a non-nucleoside reverse transcriptase inhibitor.

18. The composition of claim 17 , wherein each of R 1 , R 2a , R 2b , and R 3 is independently selected from CH 3 , and CD 3 .

19. The composition of claim 18 , wherein Y 1 and Y 2 are the same.

20. The composition of claim 19 , wherein R 2a and R 2b are the same and are selected from CH 3 and CD 3 .

Assignments (2)
MERGER Recorded Sep 14, 2023
From: CONCERT PHARMACEUTICALS, INC.
To: SUN PHARMACEUTICAL INDUSTRIES, INC.
Reel/Frame 064907/0514 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 18, 2012
From: HARBESON, SCOTT L.
To: CONCERT PHARMACEUTICALS INC.
Reel/Frame 028067/0315 →
Continuity (3)
Continuation 12169367 · Jul 8, 2008
Provisional Application 60948610 · Jul 9, 2007
Related Publication 20100152214A1 · Jun 17, 2010