Antiviral compounds

Patent metadata

Field	Value
Publication number	US-12264173-B2
Application number	US-202318354362-A
Country	US
Kind code	B2
Filing date	Jul 18, 2023
Priority date	Feb 18, 2020
Publication date	Apr 1, 2025
Grant date	Apr 1, 2025

Abstract

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.

First claim

What is claimed is:

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 indepen

Assignees

• Gilead Sciences Inc

Inventors

• Chin Gregory F
• Chun Byoung-Kwon
• Clarke Michael O
• Goyal Bindu
• Hui Hon C
• Jansa Petr
• Mackman Richard L
• Siegel Dustin S
• Yang Hai

Classifications

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61P31/12

  Antivirals · CPC title

• A61K31/661

  Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion {or mevinphos} · CPC title

• A61P31/14

  for RNA viruses · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title