Antiviral compounds
The present disclosure provides compounds for treating a variety of diseases, such as respiratory syncytial virus (RSV), HRV, hMPV, Ebola, Zika, West Nile, Dengue, and HCV.
1. A method of treating a Pneumoviridae virus infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein
Base is
R 1A and R 2A are each independently:
(A) C 1-12 alkyl optionally substituted with 1 to 3 R 1B ,
(B) 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, wherein the 3 to 6 membered heterocyclyl is optionally substituted with 1 to 3 R 1C , or
(C) phenyl, wherein
each R 1B is independently —OH, —NH 2 , C 1-6 alkoxy, methoxyethoxy, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, and
each R 1C is independently C 1-3 alkyl;
R 3 is —N(H)R 3A or —N═C(R 3B )(R 3C );
R 3A is H, —CH 2 OP(O)(OH) 2 , or —C(O)R 3D , wherein
R 3D is C 1-6 alkyl optionally substituted with 1 methoxy, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with C 1-3 alkyl;
R 3B is H or C 1-3 alkyl;
R 3C is —N(R 3C1 ) (R 3C2 );
R 3C1 and R 3C2 are each independently H or C 1-6 alkyl; or
R 3C1 and R 3C2 together with the atom to which they are attached form a 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with C 1-6 alkyl;
R 4A is O or S; and
R 4B and R 4C are each independently
(A) —OH;
(B) —OR 4B1 , wherein
R 4B1 is C 1-6 alkyl optionally substituted with 1 to 3 R 4B2 groups, or C 6-12 aryl,
wherein
each R 4B2 group is independently C 1-6 alkoxy, —S—R 4B3 , or —S(O) 2 -R 4B3 , and
each R 4B3 group is independently C 1-6 alkyl;
(C) wherein
m is 0, 1, 2, 3, 4, or 5; and
each R 4D is independently C 1-3 alkyl optionally substituted with 1 to 3 R 4D1 groups, C 1-3 alkoxy optionally substituted with 1 to 3 R 4D2 groups, or —C(O)N(R 4D3 ) 2 , wherein
each R 4D1 group is independently —NH 2 or —C(O)OR 4D3 ,
each R 4D2 is independently C 1-3 alkoxy, and
each R 4D3 is independently C 1-3 alkyl;
(D) wherein
R 4E1 and R 4E2 are each independently H or C 1-6 alkyl,
R 4P1 and R 4F2 are each independently H or C 1-6 alkyl, or R 4F1 and R 4F2 together are oxo,
R 4G is C 1-12 alkyl optionally substituted with 1 to 3 R 4G1 , C 3-7 cycloalkyl optionally substituted with 1 to 3 R 4G2 , 3 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, optionally substituted with 1 to 3 R 4G3 , or —C(O)R 4G4 ,
each R 4G1 is independently —OH, C 1-6 alkyl, C 1-3 alkoxy, —(CH 2 OCH 2 ) 1-5 -CH 3 , —N(R 4G8 ) 2 , —OP(O)(OH), C 3-7 cycloalkyl optionally substituted with 1 to 3 R409, 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 R 4G10 , or phenyl,
each R 4G2 is independently C 1-6 alkyl, C 1-3 haloalkyl, or —NH 2 ,
each R 4G3 is independently halogen or C 1-3 alkyl;
each R 4G4 is independently C 1-12 alkyl,
each R 4G8 is independently C 1-6 alkyl,
each R 4G9 is independently C 1-3 haloalkyl, or —NH 2 , and
each R 4G10 is independently C 1-3 haloalkyl; or
(E) —(OP(O)(OH) 1-2 —OH; and
R 5A and R 5B are each C 1-6 alkyl substituted with —OP(O)(OH) 2 .
2. The method of claim 1 , wherein the Pneumoviridae virus infection is a respiratory syncytial virus infection.
3. The method of claim 1 , wherein the Pneumoviridae virus infection is human metapneumovirus infection.
4. A method of treating a Picornaviridae virus infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein
Base is
R 1A and R 2A are each independently:
(A) C 1-12 alkyl optionally substituted with 1 to 3 R 1B ,
(B) 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, wherein the 3 to 6 membered heterocyclyl is optionally substituted with 1 to 3 R 1C , or
(C) phenyl, wherein
each R 1B is independently —OH, —NH 2 , C 1-6 alkoxy, methoxyethoxy, or 3 to 6 membered beterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, and
each R 1C is independently C 1-3 alkyl:
R 3 is —N(H)R 3A or —N═C(R 3B )(R 3C );
R 3A is H, —CH 2 OP(O)(OH) 2 , or —C(O)R 3D , wherein
R 3D is C 1-6 alkyl optionally substituted with 1 methoxy, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with C 1-3 alkyl;
R 3B is H or C 1-3 alkyl;
R 3C is —N(R 3C1 )(R 3C2 );
R 3C1 and R 3C2 are each independently H or C 1-6 alkyl; or
R 3C1 and R 3C2 together with the atom to which they are attached form a 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with C 1-6 alkyl;
R 4A is O or S; and
R 4B and R 4C are each independently
(A) —OH;
(B) —OR 4B1 , wherein
R 4B1 is C 1-6 alkyl optionally substituted with 1 to 3 R 4B2 groups, or C 6-12 aryl, wherein
each R 4B2 group is independently C 1-6 alkoxy, —S—R 4B3 , or —S(O) 2 —R 4B3 , and
each R 4B3 group is independently C 1-6 alkyl;
(C) wherein
m is 0, 1, 2, 3, 4, or 5; and
each R 4D is independently C 1-3 alkyl optionally substituted with 1 to 3 R 4D1 groups, C 1-3 alkoxy optionally substituted with 1 to 3 R 4D2 groups, or —C(O)N(R 4D3 ) 2 , wherein
each R 4D1 group is independently —NH 2 or —C(O)OR 4D3 ,
each R 4D2 is independently C 1-3 alkoxy, and
each R 4D3 is independently C 1-3 alkyl;
(D) wherein
R 4E1 and R 4E2 are each independently H or C 1-6 alkyl,
R 4F1 and R 4F2 are each independently H or C 1-6 alkyl, or R 4F1 and R 4F2 together are oxo,
R 4G is C 1-12 alkyl optionally substituted with 1 to 3 R 4G1 , C 3-7 cycloalkyl optionally substituted with 1 to 3 R462, 3 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, optionally substituted with 1 to 3 R 4G3 , or —C(O)R 4G4 ,
each R 4G1 is independently —OH, C 1-6 alkyl, C 1-3 alkoxy, —(CH 2 OCH 2 ) 1-5 -CH 3 , —N(R 4G8 ) 2 , —OP(O)(OH), C 3-7 cycloalkyl optionally substituted with 1 to 3 R 4G9 , 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 R 4G10 , or phenyl,
each R 4G2 is independently C 1-6 alkyl, C 1-3 haloalkyl, or —NH 2 ,
each R 4G3 is independently halogen or C 1-3 alkyl;
each R 4G4 is independently C 1-12 alkyl,
each R 4G8 is independently C 1-6 alkyl,
each R 4G9 is independently C 1-3 haloalkyl, or —NH 2 , and
each R 4G10 is independently C 1-3 haloalkyl; or
(E) —(OP(O)(OH) 1-2 -OH; and
R 5A and R 5B are each C 1-6 alkyl substituted with —OP(O)(OH) 2 .
5. The method of claim 4 , wherein the Picornaviridae virus infection is human rhinovirus infection.
6. A method for the treatment or prophylaxis of an exacerbation of a respiratory condition by a viral infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein
Base is
R 1A and R 2A are each independently:
(A) C 1-12 alkyl optionally substituted with 1 to 3 R 1B ,
(B) 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, wherein the 3 to 6 membered heterocyclyl is optionally substituted with 1 to 3 R 1C , or
(C) phenyl, wherein
each R 1B is independently —OH, —NH 2 , C 1-6 alkoxy, methoxyethoxy, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, and
each R 1C is independently C 1-3 alkyl;
R 3 is —N(H)R 3A or —N═C(R 3B )(R 3C );
R 3A is H, —CH 2 OP(O)(OH) 2 , or —C(O)R 3D , wherein
R 3D is C 1-6 alkyl optionally substituted with 1 methoxy, or 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with C 1-3 alkyl;
R 3B is H or C 1-3 alkyl;
R 3C is —N(R 3C1 )(R 3C2 );
R 3C1 and R 3C2 are each independently H or C 1-6 alkyl; or
R 3C1 and R 3C2 together with the atom to which they are attached form a 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with C 1-6 alkyl;
R 4A is O or S; and
R 4B and R 4C are each independently
(A) —OH;
(B) —OR 4B1 , wherein
R 4B1 is C 1-6 alkyl optionally substituted with 1 to 3 R 4B2 groups, or C 6-12 aryl,
wherein
each R 4B2 group is independently C 1-6 alkoxy, —S—R 4B3 , or —S(O) 2 —R 4B3 , and
each R 4B3 group is independently C 1-6 alkyl;
(C)
wherein
m is 0, 1, 2, 3, 4, or 5; and
each R 4D is independently C 1-3 alkyl optionally substituted with 1 to 3 R 4D1 groups, C 1-3 alkoxy optionally substituted with 1 to 3 R 4D4 groups, or —C(O)N(R 4D3 ) 2 , wherein
each R 4D1 group is independently-NH 2 or —C(O)OR 4D3 ,
each R 4D2 is independently C 1-3 alkoxy, and
each R 4D3 is independently C 1-3 alkyl;
(D)
wherein
R 4E1 and R 4E2 are each independently H or C 1-6 alkyl,
R 4F1 and R 4F2 are each independently H or C 1-6 alkyl, or R 4F1 and R 4F2 together are oxo,
R 4G is C 1-12 alkyl optionally substituted with 1 to 3 R 4G1 , C 3-7 cycloalkyl optionally substituted with 1 to 3 R 4G2 , 3 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, optionally substituted with 1 to 3 R 4G3 , or —C(O)R 4G4 ,
each R 4G1 is independently —OH, C 1-6 alkyl, C 1-3 alkoxy, —(CH 2 OCH 2 ) 1-5 -CH 3 , —N(R 4G8 ) 2 , —OP(O)(OH) 2 , C 3-7 cycloalkyl optionally substituted with 1 to 3 R409, 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 R 4G10 , or phenyl,
each R 4G2 is independently C 1-6 alkyl, C 1-3 haloalkyl or —NH 2 ,
each R 4G3 is independently halogen or C 1-3 alkyl;
each R 4G4 is independently C 1-12 alkyl,
each R 4G8 is independently C 1-6 alkyl,
each R 4G9 is independently C 1-3 haloalkyl, or —NH 2 , and
each R 4G10 is independently C 1-3 haloalkyl; or
(E) —(OP(O)(OH)) 1-2 —OH; and
R 5A and R 5B are each C 1-6 alkyl substituted with —OP(O)(OH) 2
wherein the respiratory condition is chronic obstructive pulmonary disease.
7. The method of claim 6 , wherein the viral infection is caused by respiratory syncytial virus, rhinovirus or metapneumovirus.
8. The method of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
9. The method of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
10. The method of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
11. The method of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
12. The method of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
13. The method of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
14. The method of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
15. The method of claim 6 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
16. The method of claim 6 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 6 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
18. The method of claim 6 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
19. The method of claim 6 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
20. The method of claim 6 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.