1′-cyano nucleoside analogs and uses thereof
Compounds and methods of using said compounds, singly or in combination with additional agents, and pharmaceutical compositions of said compounds for the treatment of viral infections are disclosed.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein
each R 1 and R 2 is independently H, —(CO)C 1 -C 6 alkyl or —(CO)OC 1 -C 6 alkyl, wherein the —(C(O)C 1 -C 6 alkyl or —(CO)OC 1 -C 6 alkyl is optionally substituted with a NH 2 group; or
R 1 and R 2 are combined to form —CO—, —CO—CO—, or —C(O)—C(R 1A )(R 1B )—C(O)—;
wherein each R 1A and R 1B is independently H or C 1 -C 6 alkyl;
R 3A is H or C 1 -C 6 alkyl; wherein the C 1 -C 6 alkyl is optionally substituted with a —OH or phenyl;
R 3B is H or C 1 -C 3 alkyl; and
R 4 is (i) C 1 -C 8 alkyl, (ii) (CR 8 R 9 CR 10 R 11 O) m R 12 , (iii) C 3 -C 10 cycloalkyl, (iv) 4 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, or (v) 5 to 6 membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O and S; wherein the C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4 to 6 membered heterocyclyl, or 5 to 6 membered heteroaryl is optionally substituted with one or two R 4A groups; wherein
each R 4A is independently C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, or 4 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S; wherein the C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, or 4 to 6 membered heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy;
Base is
wherein
R 6 is —N(H)R 6A ; and
each R 6A , R 7A and R 7B is independently H or —CH 2 OP(O)(OH) 2 ;
Ar is C 6 -C 10 aryl or 5 to 10 membered heteroaryl containing one, two, or three heteroatoms selected from the group consisting of O, N, and S;
n is 0, 1, 2, or 3;
each R 5 is independently halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, —COOR 5A , —SO 2 R 5A , 4 to 6 membered heterocycloalkyl containing one, two or three heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing one, two or three heteroatoms selected from N, O, and S; wherein the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, C 1 -C 6 alkoxy, 4 to 6 membered heterocycloalkyl and 5 to 6 membered heteroaryl is optionally substituted with one or two R 5B groups; or
two R 5 groups on adjacent carbon atoms are joined to form a C 5 -C 6 cycloalkyl;
each R 5A is independently C 1 -C 6 alkyl;
each R 5B is independently —OH, —OR 5C , —COOR 5c and —NHCOOR 5D ; wherein R 5C is C 1 -C 6 alkyl and R 5D is C 1 -C 3 alkyl optionally substituted with a phenyl group;
each R 8 , R 9 , R 10 , R 11 and R 12 is independently H or C 1 -C 3 alkyl;
m is 1, 2, 3, 4, or 5;
provided that when R 1 and R 2 are both H then:
(i) n is 1, 2, or 3; or
(ii) R 4 is C 1 -C 8 alkyl substituted with one or two groups independently selected from C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, or 4 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S;
wherein the C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, or 4 to 6 membered heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy; or
(iii) R 4 is (a) —(CR 8 R 9 CR 10 R 11 O) m R 12 , (b) monocyclic C 3 -C 10 cycloalkyl substituted with substituted with one or two R 4A groups, (c) bicyclic C 3 -C 10 cycloalkyl, (d) 4 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, or (e) 5 to 6 membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O and S;
wherein the bicyclic C 3 -C 10 cycloalkyl, 4 to 6 membered heterocyclyl, or 5 to 6 membered heteroaryl is optionally substituted with one or two R 4A groups; or
(iv) Base is
and at least one of R 6A and R 7A is —CH 2 OP(O)(OH) 2 ; or Base is
«and at least one of R 6A and R 7B is —CH 2 OP(O)(OH) 2 .
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula Ia:
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula Ib:
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Base is
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the Base is
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is 5 to 10 membered heteroaryl containing one, two, or three heteroatoms selected from the group consisting of 0, N, and S.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is a C 6 -C 10 aryl; n is 0, 1 or 2; and each R 5 is independently halo, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, or —SO 2 R 5A ; or two R 5 groups on adjacent carbon atoms are joined to form a C 5 -C 6 cycloalkyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is selected from the group consisting of:
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is a phenyl or napthyl; n is 0, 1, or 2; and each R 5 is independently C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; or two R 5 groups on adjacent carbon atoms are joined to form a C 5 -C 6 cycloalkyl.
11. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula II:
12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula IIa:
13. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula IIb:
14. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 3A is C 1 -C 6 alkyl optionally substituted with a —OH or phenyl.
15. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 3A is methyl.
16. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 3B is H.
17. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula III:
18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula IIIa:
19. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula IIIb:
20. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula IIIc:
21. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein
each R 1 and R 2 is independently —(CO)C 1 -C 6 alkyl or —(CO)OC 1 -C 6 alkyl; or
one of R and R 2 is H and the other is —(CO)C 1 -C 6 alkyl or —(CO)OC 1 -C 6 alkyl.
22. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently selected from the group consisting of —COCH(CH 3 ) 2 , —COCH 3 , —COCH 2 CH 3 , —COCH 2 CH(CH 3 ) 2 or —COCH(NH 2 )CH(CH 3 ) 2 .
23. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein one of R 1 and R 2 is H and the other is —(CO)C 1 -C 6 alkyl or —(CO)OC 1 -C 6 alkyl.
24. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein each R 1 and R 2 is independently —(CO)C 1 -C 6 alkyl or —(CO)OC 1 -C 6 alkyl.
25. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein each R 1 and R 2 is independently —(CO)C 1 -C 6 alkyl.
26. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a —(CO)C 1 -C 3 alkyl.
27. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 2 is a —(CO)C 1 -C 3 alkyl.
28. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each —(CO)CH 3 , or R 1 and R 2 are each —(CO)CH 2 CH 3 or R 1 and R 2 are each —(CO)CH(CH 3 ) 2 .
29. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both H and n is 1, 2, or 3.
30. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both H and R 4 is —(CR 8 R 9 CR 10 R 11 O) m R 12 .
31. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both H and Base is
32. The compound of claim 20 , wherein R 1 and R 2 are combined to form —C(O)—, —C(O)—C(O)—, or —C(O)—C(R 1A )(R 1B )—C(O)—, wherein each R 1A and R 1B is independently H or C 1 -C 6 alkyl.
33. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1 -C 8 alkyl optionally substituted with one or two R 4A .
34. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 4A is C 3 -C 10 cycloalkyl or 4 to 6 membered heterocyclyl having one O.
35. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 4A is cyclobutyl, cyclohexyl, cyclooctyl, oxetanyl or tetrahydropyranyl.
36. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of hexyl, methyl, and ethyl.
37. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 4 is 4 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S.
38. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —(CR 8 R 9 CR 10 R 11 O) m R 12 ; wherein each R 1 , R 9 , R 10 , R 11 , and R 12 is independently H or C 1 -C 3 alkyl and m is 1, 2, 3, 4, or 5.
39. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of:
(i) methyl,
(ii) ethyl,
(iii) n-propyl,
(iv) isopropyl,
(xii) cyclobutyl,
(xiii) cyclohexyl,
(xiv) cyclooctyl,
40. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl.
41. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 5 is t-Bu, isopropyl, methyl, or cyclopropyl.
42. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein:
each R 1 and R 2 is independently H, —(CO)C 1 -C 3 alkyl;
R 3A is H or methyl;
R 3B is H or methyl;
R 4 is C 3 -C 8 cycloalkyl;
Ar is C 6 -C 10 aryl;
n is 0 or 1; and
R 5 is C 1 -C 6 alkyl.
43. A pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
44. A method of treating or preventing a viral infection in a human in need thereof, wherein the method comprises administering to the human the compound of claim 1 and wherein the viral infection is a coronavirus infection, pneumoviridae virus infection, picornaviridae virus infection, flaviviridae virus infection, filoviridae virus infection, orthomyxovirus infection, or paramyxoviridae virus infection.
45. The method of claim 44 , wherein the method comprises administering to the human at least one additional therapeutic agent.