4′-substituted nucleoside reverse transcriptase inhibitors
View Patent ↗The present invention is directed to 4′-substituted nucleoside derivatives of Formula I and their use in the inhibition of HIV reverse transcriptase, the prophylaxis of infection by HIV, the treatment of infection by HIV, and the prophylaxis, treatment, and delay in the onset or progression of AIDS and/or ARC.
1. A compound of structural Formula I
or a pharmaceutically acceptable salt thereof, wherein:
R is
X is O, S, CH 2 or CF 2 ;
Y is —C≡C—R 8 or —C≡N;
R 1 is —H, —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 ,
or a pro-drug modification of the mono-, di- or triphosphate;
R 2 is —H, —C(O)R 6a , —C(O)OR 6a or —C(O)N(R 6a ) 2 ;
R 3 is —H;
R 4 is —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 haloalkyl, —C 3 -C 7 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, halo, —CN, —NO 2 , —N(R X ) 2 , —NH(C 1 -C 6 alkylene)-(5- or 6-membered monocyclic heteroaryl), —NH(C 1 -C 6 alkylene)-(9- or 10-membered bicyclic heteroaryl), aryl, —NHC(O)OR 6b , —N(C(O)OR 6b ) 2 , —NHC(O)N(R 6b ) 2 , or —NHC(O)R 6b , wherein each of said —C 1 -C 6 alkyl group, said —C 2 -C 6 alkenyl group or said —C 2 -C 6 alkynyl group can be optionally substituted with halo;
R 5 is —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 haloalkyl, —C 3 -C 7 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, halo, —OR X , —CN, —NO 2 , —N(R X ) 2 , —NH(C 1 -C 6 alkylene)-(5- or 6-membered monocyclic heteroaryl), —NH(C 1 -C 6 alkylene)-(9- or 10-membered bicyclic heteroaryl), aryl, —NHC(O)OR 6b , —N(C(O)OR 6b ) 2 , —NHC(O)N(R 6b ) 2 , or —NHC(O)R 6b , wherein each of said —C 1 -C 6 alkyl group, said —C 2 -C 6 alkenyl group or said —C 2 -C 6 alkynyl group can be optionally substituted with halo;
R 6 , R 6a and R 6b are each independently selected at each occurrence from —H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —(C 1 -C 3 alkylene) m -(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) m -(aryl), —(C 1 -C 3 alkylene) m -(4 to 7-membered heterocycloalkyl), —(C 1 -C 3 alkylene) m -(5- or 6-membered monocyclic heteroaryl) or —(C 1 -C 3 alkylene) m -(9- or 10-membered bicyclic heteroaryl), wherein each of said —C 1 -C 6 alkyl, said C 3 -C 7 cycloalkyl group, said aryl group, said 4 to 7-membered heterocycloalkyl group, said -(5- or 6-membered monocyclic heteroaryl group or said 9- or 10-membered bicyclic heteroaryl group can be optionally substituted with R 7 ;
m is an integer selected from 0 (zero) or 1;
R 7 represents from one to five substituent groups, each independently selected from —C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, or a 5-6-member heteroaryl;
R 8 is —H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 3 -C 7 cycloalkyl, aryl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl;
R 9 is —H, halo, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —CN, —OR Y or —N(R Y ) 2 ;
R X is independently selected at each occurrence from —H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, aryl, or 5- or 6-membered monocyclic heteroaryl;
or when either or both of R 4 or R 5 is —N(R X ) 2 , each R X may optionally be joined together with the nitrogen to which they are both attached to form a 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl; and
R Y is —H, —C 1 -C 6 alkyl or —C 1 -C 6 haloalkyl.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R is
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein: R 1 is —H, —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , or a pro-drug modification of
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 1 is
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein:
X is O, S, CH 2 or CF 2 ;
Y is —C≡C—R 8 or —C≡N;
R 1 is —H,
R 2 is —H;
R 3 is —H;
R 4 is —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 haloalkyl, —C 3 -C 7 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, halo, —CN, —NO 2 , —N(R X ) 2 , —NH(C 1 -C 6 alkylene)-(5- or 6-membered monocyclic heteroaryl), —NH(C 1 -C 6 alkylene)-(9- or 10-membered bicyclic heteroaryl), aryl, —NHC(O)OR 6b , —N(C(O)OR 6b ) 2 , —NHC(O)N(R 6b ) 2 , or —NHC(O)R 6b , wherein each of said —C 1 -C 6 alkyl group, said —C 2 -C 6 alkenyl group or said —C 2 -C 6 alkynyl group can be optionally substituted with halo;
R 5 is —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 haloalkyl, —C 3 -C 7 cycloalkyl, a 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, halo, —OR X , —CN, —NO 2 , —N(R X ) 2 , —NH(C 1 -C 6 alkylene)-(5- or 6-membered monocyclic heteroaryl), —NH(C 1 -C 6 alkylene)-(9- or 10-membered bicyclic heteroaryl) or aryl,
wherein each of said —C 1 -C 6 alkyl group, said —C 2 -C 6 alkenyl group or said —C 2 -C 6 alkynyl group can be optionally substituted with halo;
R 8 is —H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 3 -C 7 cycloalkyl, aryl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl;
R 9 is —H, halo, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —CN, —OR Y , or —N(R Y ) 2 ;
R X is independently selected at each occurrence from —H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, aryl, or 5- or 6-membered monocyclic heteroaryl;
or when either or both of R 4 or R 5 is —N(R X ) 2 , each R X may optionally be joined together with the nitrogen to which they are both attached to form a 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl; and
R Y is —H, —C 1 -C 6 alkyl or —C 1 -C 6 haloalkyl.
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein:
R 1 is —H, —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 ,
or a pro-drug modification of the mono-, di- or triphosphate;
R 2 is —H, —C(O)R 6a , —C(O)OR 6a or —C(O)N(R 6a ) 2 ; and
R 4 is —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 haloalkyl, —C 3 -C 7 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, halo, —CN, —NO 2 , —N(R X ) 2 , —NH(C 1 -C 6 alkylene)-(5- or 6-membered monocyclic heteroaryl), —NH(C 1 -C 6 alkylene)-(9- or 10-membered bicyclic heteroaryl), aryl, —NHC(O)OR 6b , —N(C(O)OR 6b ) 2 , —NHC(O)N(R 6b ) 2 , or —NHC(O)R 6b , wherein each of said —C 1 -C 6 alkyl group, said —C 2 -C 6 alkenyl group or said —C 2 -C 6 alkynyl group can be optionally substituted with halo;
R 5 is —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 haloalkyl, —C 3 -C 7 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, halo, —OR X , —CN, —NO 2 , —N(R X ) 2 , —NH(C 1 -C 6 alkylene)-(5- or 6-membered monocyclic heteroaryl), —NH(C 1 -C 6 alkylene)-(9- or 10-membered bicyclic heteroaryl), aryl, —NHC(O)OR 6b , —N(C(O)OR 6b ) 2 , —NHC(O)N(R 6b ) 2 , or —NHC(O)R 6b , wherein each of said —C 1 -C 6 alkyl group, said —C 2 -C 6 alkenyl group or said —C 2 -C 6 alkynyl group can be optionally substituted with halo;
provided that one or more of R 1 , R 2 , R 4 or R 5 is selected as follows:
R 1 is —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 or a pro-drug modification of the mono-, di- or triphosphate; and/or
R 2 is —C(O)R 6a , —C(O)OR 6a or —C(O)N(R 6a ) 2 ; and/or
R 4 is —NHC(O)OR 6b , —N(C(O)OR 6b ) 2 , —NHC(O)N(R 6b ) 2 , or —NHC(O)R 6b ; and/or
R 5 is —NHC(O)OR 6b , —N(C(O)OR 6b ) 2 , —NHC(O)N(R 6b ) 2 , or —NHC(O)R 6b .
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein X is O.
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein Y is —C≡C—R 8 .
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 4 is —N(R X ) 2 , —NHC(O)OR 6b , —N(C(O)OR 6b ) 2 , —NHC(O)N(R 6b ) 2 , or —NHC(O)R 6b .
10. The compound of claim for a pharmaceutically acceptable salt thereof wherein R 4 is —N(R X ) 2 .
11. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 5 is —H, halo, —C 1 -C 6 alkyl, —OR X , —N(R X ) 2 , —NHC(O)OR 6b , —N(C(O)OR 6b ) 2 , —NHC(O)N(R 6b ) 2 , or —NHC(O)R 6b .
12. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 8 is —H.
13. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 9 is —H, halo, —C 1 -C 3 alkyl, —C 1 -C 3 haloalkyl, —CN, —OR Y or —N(R Y ) 2 .
14. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 1 is —H,
15. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein:
X is O;
Y is —CδC—R 8 ;
R 3 is —H;
R 4 is —N(R X ) 2 , —NHC(O)OR 6b , —N(C(O)OR 6b ) 2 , —NHC(O)N(R 6b ) 2 , or —NHC(O)R 6b ;
R 5 is —H, halo, —C 1 -C 6 alkyl, —OR X , —N(R X ) 2 , —NHC(O)OR 6b , —N(C(O)OR 6b ) 2 , —NHC(O)N(R 6b ) 2 , or —NHC(O)R 6b ;
R 8 is —H; and
R 9 is —H, halo, —C 1 -C 3 alkyl, —C 1 -C 3 haloalkyl, —CN, —OR Y or —N(R Y ) 2 .
16. The compound of claim 15 or a pharmaceutically acceptable salt thereof wherein R 4 is —N(R X ) 2 .
17. The compound of claim 16 or a pharmaceutically acceptable salt thereof wherein R 1 is —H.
18. The compound of claim 1 having structural Formula II, III, IV or V,
or a pharmaceutically acceptable salt thereof, wherein:
X is O;
Y is —C≡CH or —C≡N;
R 1 is —H, —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 ,
or a pro-drug modification of the mono-, di- or triphosphate;
R 2 is H, —C(O)R 6a , —C(O)OR 6a or —C(O)N(R 6a ) 2 ;
R 3 is —H;
R 4 is —N(R X ) 2 , —NHC(O)OR 6b or —NHC(O)N(R 6b ) 2 ;
R 5 is —H, halo, —C 1 -C 6 alkyl, —OR X or —N(R X ) 2 ;
R 6 , R 6a , and R 6b are each independently selected at each occurrence from —H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, or a 5- or 6-membered monocyclic heteroaryl, wherein R 6 , R 6a , and R 6b are each optionally substituted with R 7 ;
R 7 is —C 1 -C 6 alkyl, aryl or 5-6 member monocyclic heteroaryl;
R 9 is —H, halo, —C 1 -C 3 alkyl, —C 1 -C 3 haloalkyl, —CN, —OR Y , or —N(R Y ) 2 ;
R X is independently selected at each occurrence from —H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, aryl, or 5- or 6-membered monocyclic heteroaryl;
or when either or both of R 4 or R 5 is —N(R X ) 2 , each R X may optionally be joined together with the nitrogen to which they are both attached to form a 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl; and
R Y is —H, —C 1 -C 6 alkyl or —C 1 -C 6 haloalkyl.
19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —H,
R 2 is H;
R 4 is —NH 2 ;
R 5 is —H, —Cl, —F or —NH 2 ; and
R 9 is —H, —F, —Cl, —I, —Br or —CH 3 .
20. The compound of claim 18 having structural Formula II,
or a pharmaceutically acceptable salt thereof.
21. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —H,
R 2 is H;
R 4 is —NH 2 ;
R 5 is —H, —Cl, —F or —NH 2 ; and
R 9 is —H, —F, —Cl, —I, —Br or —CH 3 .
22. The compound of claim 1 that is:
1)
(2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-
2-(hydroxymethyl)tetrahydrofuran-3-ol;
2)
(2R,3S,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
3)
(2R,3S,5R)-5-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
4)
(2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
5)
(2R,3S,5R)-5-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
6)
(2R,3S,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
7)
(2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
8)
(2R,3S,5R)-5-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-
ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
9)
(2R,3S,5R)-5-(4-amino-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-
ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
10)
(2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxy-
2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile ;
11)
(2R,3S,5R)-5-(4-aminopyrrolo[2,l-f][1,2,4]triazin-7-yl)-2-ethynyl-2-
(hydroxymethyl)tetrahydrofuran-3-ol;
12)
(2R,3S,5R)-5-(4-aminopyrrolo[2,l-f][1,2,4]triazin-7-yl)-3-hydroxy-2-
(hydroxymethyl)tetrahydrofuran-2-carbonitrile ;
13)
((2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-
3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
14)
((2R,3S,5R)-5-(4-arnino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen
triphosphate;
15)
((2R,3S,5R)-5-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen
triphosphate;
16)
((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen
triphosphate;
17)
((2R,3S,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen
triphosphate;
18)
((2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-cyano-
3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen
triphosphate;
19)
((2R,3S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-
2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen
triphosphate;
20)
((2R,35,5R)-5-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)-
2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen
triphosphate;
21)
((2R,3S,5R)-5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-
2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen
triphosphate;
22)
(2R,3S,5R)-5-(4-aminoimidazo[2,1-f] [1,2,4]triazin-7-yl)-
2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
23)
(2R,35,5R)-5-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)-
2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
24. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and further comprising an effective amount of an anti-HIV agent selected from an anti-HIV antiviral agent, an immunomodulator, or anti-infective agent.
25. The pharmaceutical composition of claim 24 wherein the anti-HIV antiviral agent is an HIV protease inhibitor, HIV reverse transcriptase inhibitor, HIV integrase inhibitor, HIV fusion inhibitor, HIV entry inhibitor, or HIV maturation inhibitor.
26. A method for the treatment of infection by HIV or for the treatment of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
27. A method for the prophylaxis of infection by HIV or for the prophylaxis or delay in the onset of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
28. A compound that is:
or a compound that is a pharmaceutically acceptable salt thereof.
29. The compound of claim 28 that is a pharmaceutically acceptable salt of:
30. The compound of claim 28 that is:
31. A pharmaceutical composition comprising an effective amount of a compound of claim 28 and a pharmaceutically acceptable carrier.
32. A pharmaceutical composition comprising an effective amount of a compound of claim 28 and a pharmaceutically acceptable carrier and further comprising an effective amount of an anti-HIV agent selected from an anti-HIV antiviral agent, an immunomodulator, or anti-infective agent.
33. The pharmaceutical composition of claim 32 wherein the anti-HIV antiviral agent is an HIV protease inhibitor, HIV reverse transcriptase inhibitor, HIV integrase inhibitor, HIV fusion inhibitor, HIV entry inhibitor, or HIV maturation inhibitor.
34. A method for the treatment of infection by HIV or for the treatment of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound of claim 28 .
35. A method for the prophylaxis of infection by HIV or for the prophylaxis or delay in the onset of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound of claim 28 .
36. A compound that is:
or a compound that is a pharmaceutically acceptable salt thereof.
37. The compound of claim 36 that is a pharmaceutically acceptable salt of:
38. The compound of claim 36 that is:
39. A pharmaceutical composition comprising an effective amount of a compound of claim 36 and a pharmaceutically acceptable carrier.
40. A pharmaceutical composition comprising an effective amount of a compound of claim 36 and a pharmaceutically acceptable carrier and further comprising an effective amount of an anti-HIV agent selected from an anti-HIV antiviral agent, an immunomodulator, or anti-infective agent.
41. The pharmaceutical composition of claim 40 wherein the anti-HIV antiviral agent is an HIV protease inhibitor, HIV reverse transcriptase inhibitor, HIV integrase inhibitor, HIV fusion inhibitor, HIV entry inhibitor, or HIV maturation inhibitor.
42. A method for the treatment of infection by HIV or for the treatment of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound of claim 36 .
43. A method for the prophylaxis of infection by HIV or for the prophylaxis or delay in the onset of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound of claim 36 .
44. A compound that is:
or compound that is a pharmaceutically acceptable salt thereof.
45. The compound of claim 44 that is a pharmaceutically acceptable salt of:
46. The compound of claim 44 that is:
47. A pharmaceutical composition comprising an effective amount of a compound of claim 44 and a pharmaceutically acceptable carrier.
48. A pharmaceutical composition comprising an effective amount of a compound of claim 44 and a pharmaceutically acceptable carrier and further comprising an effective amount of an anti-HIV agent selected from an anti-HIV antiviral agent, an immunomodulator, or anti-infective agent.
49. The pharmaceutical composition of claim 48 wherein the anti-HIV antiviral agent is an HIV protease inhibitor, HIV reverse transcriptase inhibitor, HIV integrase inhibitor, HIV fusion inhibitor, HIV entry inhibitor, or HIV maturation inhibitor.
50. A method for the treatment of infection by HIV or for the treatment of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound of claim 44 .
51. A method for the prophylaxis of infection by HIV, or for the prophylaxis or delay in the onset of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound of claim 44 .
52. The compound of claim 1 that is:
or a compound that is a pharmaceutically acceptable salt thereof.
53. The compound of claim 52 that is a pharmaceutically acceptable salt of:
54. A compound that is:
55. A pharmaceutical composition comprising an effective amount of a compound of claim 52 and a pharmaceutically acceptable carrier.
56. A pharmaceutical composition comprising an effective amount of a compound of claim 52 and a pharmaceutically acceptable carrier and further comprising an effective amount of an anti-HIV agent selected from an anti-HIV antiviral agent, an immunomodulator, or anti-infective agent.
57. The pharmaceutical composition of claim 56 wherein the anti-HIV antiviral agent is an HIV protease inhibitor, HIV reverse transcriptase inhibitor, HIV integrase inhibitor, HIV fusion inhibitor, HIV entry inhibitor, or HIV maturation inhibitor.
58. A method for the treatment of infection by HIV or for the treatment of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound of claim 52 .
59. A method for the prophylaxis of infection by HIV or for the prophylaxis or delay in the onset of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound of claim 52 .