HIV inhibitor compounds
The invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof as described herein. The invention also provides pharmaceutical compositions comprising a compound of Formula I, processes for preparing compounds of Formula I, therapeutic methods for treating the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS symptoms in a mammal using compounds of Formula I.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a 5 to 10-membered heterocycle having 1 to 5 heteroatoms selected from N, O, and S, or a 5 to 10-membered heteroaryl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 5 to 10-membered heterocycle or 5 to 10-membered heteroaryl is optionally substituted with 1 to 5 R a groups;
R 2 and R 3 are each independently C 1-4 alkyl, C 3-6 cycloalkyl, O—R 2A , C 1-2 alkyl-O—R 2A , N—(R 3A ) 2 , or C 1-2 alkyl-N—(R 3A ) 2 ,
wherein each R 2A is independently C 1-4 alkyl, C 3-6 cycloalkyl, or a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, wherein each R 3A is independently hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or COO(R e ),
and wherein each C 3-6 cycloalkyl or 4 to 10-membered heterocyclyl is optionally substituted by 1 to 3 R f groups, wherein each R f is independently C 1-2 alkyl or halogen;
R 4 is hydrogen, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;
R 7 is hydrogen, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;
R 5 , R 6 , R 8 , and R 9 are each independently hydrogen, halo, C 1-2 alkyl, C 1-2 haloalkyl, or C 3-6 cycloalkyl;
and wherein two or more of R 4 , R 5 and R 6 or two or more of R 7 , R 8 , and R 9 optionally join together to form one or more C 3-6 cycloalkyl groups that are optionally substituted with 1 to 4 groups selected from halogen, C 1-2 alkyl, and C 1-2 haloalkyl;
each R 10 is independently halogen, cyano, C 1-4 alkoxy, C 1-6 alkyl, or C 3-6 cycloalkyl;
n is 0 to 4;
each R a is independently halogen, C 1-4 alkyl, C 1-4 alkyl substituted with 1 to 2 groups selected from hydroxyl and C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S which is optionally substituted with R a1 , or O—R 3B ,
wherein R 3B is C 3-6 cycloalkyl optionally substituted with R a1 or a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S optionally substituted with R a1 ,
wherein each R a1 is independently C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, or 4 to 8-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S;
A is ethynyl;
X 1 is a 6 to 10-membered aryl or a 5 to 10-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein each 6 to 10-membered aryl or 5 to 10-membered heteroaryl is optionally substituted with 1 to 4 R b groups;
X 2 is hydrogen or a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 4 to 10-membered heterocyclyl is optionally substituted with one R 11 and optionally substituted with 1 to 5 R b groups;
R 11 is C═O(R c ), CH 2 (R d ), S(O) 1-2 (C 1-4 alkyl), S(O) 1-2 C 3-6 cycloalkyl, a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, or a 5 to 9-membered heteroaryl having 1 to 5 heteroatoms selected from N, O, and S, wherein each 4 to 10-membered heterocyclyl or 5 to 9-membered heteroaryl is optionally substituted with 1 to 5 R b groups;
each R b is independently halogen, oxo, C 1-4 alkyl, C 1-4 alkyl substituted with 1 to 2 groups selected from hydroxyl and C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 alkoxy, or COO(R e );
R c is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, N(R e ) 2 , C 3-6 cycloalkyl, or a 4 to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the C 3-6 cycloalkyl and the 4 to 6-membered heterocyclyl are optionally substituted by 1 to 5 R b groups;
R d is COO(R e ), N(R e ) 2 , C 3-6 cycloalkyl, or a 4 to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the C 3-6 cycloalkyl and the 4 to 6-membered heterocyclyl is optionally substituted by 1 to 5 R b groups;
each R 12 is C 1-2 alkyl, halo, —OC 1-2 alkyl, or cyano;
each p is 0 to 4;
and each R e is independently hydrogen or C 1-4 alkyl.
2. The compound of claim 1 , wherein R 2 and R 3 are each independently C 1-4 alkyl, C 3-6 cycloalkyl, or O—R 2A , wherein R 2A is C 1-4 alkyl, C 3-6 cycloalkyl, or a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S.
3. The compound of claim 1 , wherein R 2 and R 3 are each independently:
4. The compound of claim 1 , wherein R 2 and R 3 are each methoxy.
5. The compound of claim 1 , wherein R 4 is hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl.
6. The compound of claim 1 , wherein R 4 is C 1-4 haloalkyl.
7. The compound of claim 1 , wherein R 4 is CF 3 .
8. The compound of claim 1 , wherein R 1 is hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl.
9. The compound of claim 1 , wherein R 7 is C 1-4 haloalkyl.
10. The compound of claim 1 , wherein R 7 is CF 3 .
11. The compound of claim 1 , wherein R 5 and R 6 are C 1-2 alkyl.
12. The compound of claim 1 , wherein R 5 and R 6 are methyl.
13. The compound of claim 1 , wherein R 8 and R 9 are C 1-2 alkyl.
14. The compound of claim 1 , wherein R 8 and R 9 are methyl.
15. The compound of claim 1 , wherein n is 2.
16. The compound of claim 1 , wherein each R 10 is halogen.
17. The compound of claim 1 , wherein each R 10 is fluoro.
18. The compound of claim 1 , wherein R 1 is a 5 to 6-membered heterocycle having 1 to 3 heteroatoms selected from N, O, and S, or a 5 to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein the 5 to 6-membered heterocycle or 5 to 6-membered heteroaryl is optionally substituted with 1 to 3 R a groups.
19. The compound of claim 1 , wherein R 1 is a 5 to 6-membered heterocycle having 1 to 3 heteroatoms selected from N, O, and S and is optionally substituted with 1 to 3 R a groups.
20. The compound of claim 1 , wherein R 1 is independently:
21. The compound of claim 1 , wherein R 1 is:
22. The compound of claim 1 , wherein R a is independently C 1-4 alkyl, C 1-4 alkyl with 1 to 2 groups selected from hydroxyl and C 1-4 alkoxy, or C 1-4 haloalkyl.
23. The compound of claim 1 , wherein R a is:
24. The compound of claim 1 , wherein R a is C 1-4 haloalkyl.
25. The compound of claim 1 , wherein R a is:
26. The compound of claim 1 , wherein X 1 is a 6-membered aryl or a 5 to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein each 6-membered aryl or 5 to 6-membered heteroaryl is optionally substituted with 1 to 4 R b groups.
27. The compound of claim 1 , wherein X 1 is pyrimidine or pyridine.
28. The compound of claim 1 , wherein X 1 is:
29. The compound of claim 1 , wherein X 2 is a 4 to 10-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S and is optionally substituted with one R 11 and optionally substituted with 1 to 5 R b groups.
30. The compound of claim 1 , wherein X 2 is
wherein:
a) R P1 , R P2 , R P3 , and R P4 are each hydrogen;
b) R P1 and R P3 are taken together to form a —CH 2 — or —CH 2 CH 2 — group and R P2 and R P4 are each hydrogen;
c) R P2 and R P4 are taken together to form a —CH 2 — or —CH 2 CH 2 — group and R P1 and R P3 are each hydrogen;
d) R P1 and R P4 are taken together to form a —CH 2 — group and R P2 and R P3 are each hydrogen; or
e) R P2 and R P3 are taken together to form a —CH 2 — group and R P1 and R P4 are each hydrogen.
31. The compound of claim 30 , wherein:
R P1 and R P3 are taken together to form a —CH 2 — or —CH 2 CH 2 — group and R P2 and R P4 are each hydrogen; or
R P2 and R P4 are taken together to form a —CH 2 — or —CH 2 CH 2 — group and R P1 and R P3 are each hydrogen.
32. The compound of claim 1 , wherein X 2 is:
33. The compound of claim 1 , wherein X 2 is:
34. The compound of claim 33 , wherein R 11 is 4 to 10-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S.
35. The compound of claim 33 , wherein R 11 is a 4 to 6-membered heterocycle having one oxygen.
36. The compound of claim 33 , wherein R 11 is oxetan-3-yl, tetrahydrofuran-3-yl, or tetrahydropyran-4-yl.
37. The compound of claim 1 , wherein p is 0.
38. A compound of any of Examples 1-245 selected from:
or a pharmaceutically acceptable salt thereof.
39. The compound of claim 1 , selected from:
or a pharmaceutically acceptable salt thereof.
40. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
41. The pharmaceutical composition of claim 40 , further comprising one, two, three, or four additional therapeutic agents.
42. A method of treating a human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of a compound of claim 1 ,
or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
43. The method of claim 42 , wherein the method comprises administering the compound, or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents.
44. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ia):
wherein R 10a and R 10b are independently halogen, cyano, C 1-4 alkoxy, C 1-6 alkyl, or C 3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof.
45. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ib):
or a pharmaceutically acceptable salt thereof, wherein:
Z 1 and Z 2 are independently N or CH; and
m is 0 to 2.
46. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula:
or a pharmaceutically acceptable salt thereof, wherein:
Z 1 and Z 2 are independently N or CH.
47. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Id):
or a pharmaceutically acceptable salt thereof.
48. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ie):
49. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a 5 to 10-membered heterocycle having 1 to 5 heteroatoms selected from N, O, and S, or a 5 to 10-membered heteroaryl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 5 to 10-membered heterocycle or 5 to 10-membered heteroaryl is optionally substituted with 1 to 5 R a groups;
R 2 and R 3 are each independently C 1-4 alkyl, C 3-6 cycloalkyl, O—R 2A , C 1-2 alkyl-O—R 2A , N—(R 3A ) 2 , or C 1-2 alkyl-N—(R 3A ) 2 ,
wherein each R 2A is independently C 1-4 alkyl, C 3-6 cycloalkyl, or a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, wherein each R 3A is independently hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or COO(R e ),
and wherein each C 3-6 cycloalkyl or 4 to 10-membered heterocyclyl is optionally substituted by 1 to 3 R f groups, wherein each R f is independently C 1-2 alkyl or halogen;
R 4 is C 1-4 haloalkyl;
R 7 is hydrogen, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;
R 5 , R 6 , R 8 , and R 9 are each independently hydrogen, halo, C 1-2 alkyl, C 1-2 haloalkyl, or C 3-6 cycloalkyl;
and wherein two or more of R 7 , R 8 , and R 9 optionally join together to form one or more C 3-6 cycloalkyl groups that are optionally substituted with 1 to 4 groups selected from halogen, C 1-2 alkyl, and C 1-2 haloalkyl;
each R 10 is independently halogen, cyano, C 1-4 alkoxy, C 1-6 alkyl, or C 3-6 cycloalkyl;
n is 0 to 4;
each R a is independently halogen, C 1-4 alkyl, C 1-4 alkyl substituted with 1 to 2 groups selected from hydroxyl and C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S which is optionally substituted with R a1 , or O—R 3B ,
wherein R 3B is C 3-6 cycloalkyl optionally substituted with R a1 or a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S optionally substituted with R a1 ,
wherein each R a1 is independently C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, or 4 to 8-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S;
A is ethynyl or a bond;
X 1 is a 6 to 10-membered aryl or a 5 to 10-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein each 6 to 10-membered aryl or 5 to 10-membered heteroaryl is optionally substituted with 1 to 4 R b groups;
X 2 is hydrogen or a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 4 to 10-membered heterocyclyl is optionally substituted with one R 11 and optionally substituted with 1 to 5 R b groups;
R 11 is C═O(R c ), CH 2 (R d ), S(O) 1-2 (C 1-4 alkyl), S(O) 1-2 C 3-6 cycloalkyl, a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, or a 5 to 9-membered heteroaryl having 1 to 5 heteroatoms selected from N, O, and S, wherein each 4 to 10-membered heterocyclyl or 5 to 9-membered heteroaryl is optionally substituted with 1 to 5 R b groups;
each R b is independently halogen, oxo, C 1-4 alkyl, C 1-4 alkyl substituted with 1 to 2 groups selected from hydroxyl and C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 alkoxy, or COO(R e );
R c is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, N(R c ) 2 , C 3-6 cycloalkyl, or a 4 to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the C 3-6 cycloalkyl and the 4 to 6-membered heterocyclyl are optionally substituted by 1 to 5 R b groups;
R d is COO(R e ), N(R e ) 2 , C 3-6 cycloalkyl, or a 4 to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the C 3-6 cycloalkyl and the 4 to 6-membered heterocyclyl is optionally substituted by 1 to 5 R b groups;
each R 12 is C 1-2 alkyl, halo, —OC 1-2 alkyl, or cyano;
each p is 0 to 4;
and each R e is independently hydrogen or C 1-4 alkyl.
50. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 49 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
51. The pharmaceutical composition of claim 50 , further comprising one, two, three, or four additional therapeutic agents.
52. A method of treating a human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of a compound of claim 49 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
53. The method of claim 52 , wherein the method comprises administering the compound, or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents.
54. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a 5 to 10-membered heterocycle having 1 to 5 heteroatoms selected from N, O, and S, or a 5 to 10-membered heteroaryl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 5 to 10-membered heterocycle or 5 to 10-membered heteroaryl is optionally substituted with 1 to 5 R a groups;
R 2 and R 3 are each independently C 1-4 alkyl, C 3-6 cycloalkyl, O—R 2A , C 1-2 alkyl-O—R 2A , N—(R 3A ) 2 , or C 1-2 alkyl-N—(R 3A ) 2 ,
wherein each R 2A is independently C 1-4 alkyl, C 3-6 cycloalkyl, or a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S,
wherein each R 3A is independently hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or COO(R e ),
and wherein each C 3-6 cycloalkyl or 4 to 10-membered heterocyclyl is optionally substituted by 1 to 3 R f groups, wherein each R f is independently C 1-2 alkyl or halogen;
R 4 is hydrogen, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;
R 7 is C 1-4 haloalkyl;
R 5 , R 6 , R 8 , and R 9 are each independently hydrogen, halo, C 1-2 alkyl, C 1-2 haloalkyl, or C 3-6 cycloalkyl;
and wherein two or more of R 4 , R 5 and R 6 optionally join together to form one or more C 3-6 cycloalkyl groups that are optionally substituted with 1 to 4 groups selected from halogen, C 1-2 alkyl, and C 1-2 haloalkyl;
each R 10 is independently halogen, cyano, C 1-4 alkoxy, C 1-6 alkyl, or C 3-6 cycloalkyl;
n is 0 to 4;
each R a is independently halogen, C 1-4 alkyl, C 1-4 alkyl substituted with 1 to 2 groups selected from hydroxyl and C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S which is optionally substituted with R a1 , or O—R 3B ,
wherein R 3B is C 3-6 cycloalkyl optionally substituted with R a1 or a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S optionally substituted with R a1 ,
wherein each R a1 is independently C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, or 4 to 8-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S;
A is ethynyl or a bond;
X 1 is a 6 to 10-membered aryl or a 5 to 10-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein each 6 to 10-membered aryl or 5 to 10-membered heteroaryl is optionally substituted with 1 to 4 R b groups;
X 2 is hydrogen or a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 4 to 10-membered heterocyclyl is optionally substituted with one R 11 and optionally substituted with 1 to 5 R b groups;
R 11 is C═O(R c ), CH 2 (R d ), S(O) 1-2 (C 1-4 alkyl), S(O) 1-2 C 3-6 cycloalkyl, a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, or a 5 to 9-membered heteroaryl having 1 to 5 heteroatoms selected from N, O, and S, wherein each 4 to 10-membered heterocyclyl or 5 to 9-membered heteroaryl is optionally substituted with 1 to 5 R b groups;
each R b is independently halogen, oxo, C 1-4 alkyl, C 1-4 alkyl substituted with 1 to 2 groups selected from hydroxyl and C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 alkoxy, or COO(R e );
R c is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, N(R c ) 2 , C 3-6 cycloalkyl, or a 4 to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the C 3-6 cycloalkyl and the 4 to 6-membered heterocyclyl are optionally substituted by 1 to 5 R b groups;
R d is COO(R e ), N(R e ) 2 , C 3-6 cycloalkyl, or a 4 to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the C 3-6 cycloalkyl and the 4 to 6-membered heterocyclyl is optionally substituted by 1 to 5 R b groups;
each R 12 is C 1-2 alkyl, halo, —OC 1-2 alkyl, or cyano;
each p is 0 to 4;
and each R e is independently hydrogen or C 1-4 alkyl.
55. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 54 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
56. The pharmaceutical composition of claim 55 , further comprising one, two, three, or four additional therapeutic agents.
57. A method of treating a human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of a compound of claim 54 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
58. The method of claim 57 , wherein the method comprises administering the compound, or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents.