Antiviral compounds

Patent metadata

Field	Value
Publication number	US-11767337-B2
Application number	US-202117178463-A
Country	US
Kind code	B2
Filing date	Feb 18, 2021
Priority date	Feb 18, 2020
Publication date	Sep 26, 2023
Grant date	Sep 26, 2023

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 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 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 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 4G1 ° 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 compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1A and R 2A are C 1-12 alkyl optionally substituted with 1 to 3 R 1B .

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1A and R 2A are each selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and isopentyl, each optionally substituted with 1 to 3 R 1B .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of R 4B and R 4C is:

and
the other of R 4B and R 4C is:

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4F1 and R 4F2 together are oxo.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4G is C 1-12 alkyl optionally substituted with 1 to 3 R 4G1 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4G is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl or 2-ethyl-butyl, each optionally substituted with 1 to 3 R 4G1 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4G is C 3-7 cycloalkyl optionally substituted with 1 to 3 R 4G2 .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4G is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with 1 to 3 R 4G2 .

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4G is 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, optionally substituted with 1 to 3 R 4G3 .

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4G is a 4-6 membered heterocyclyl having 1 to 2 heteroatoms selected from N and O, optionally substituted with 1 to 3 R 4G3 .

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4G is oxetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each optionally substituted with 1 to 3 R 4G3 .

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5A and R 5B are each —CH 2 OP(O)(OH) 2 .

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, represented by Formula (IIa):

wherein R 5A is —CH 2 OP(O)(OH) 2 .

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, represented by Formula (IIb):

wherein R 5B is —CH 2 OP(O)(OH) 2 .

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1A and R 2A are each independently
methyl optionally substituted with methoxy, methoxyethoxy, or morpholinyl,
ethyl optionally substituted with methoxy,
n-propyl,
isopropyl,
n-butyl,
isobutyl optionally substituted with —OH or —NH 2 ,
tert-butyl,
isopentyl,
oxetanyl,
tetrahydropyranyl,
piperidinyl optionally substituted with methyl, or
phenyl;

R 3 is —N(H)R 3A or —N═C(R 3B ) (R 3C );
R 3A is H, —C(H) 2 OP(O)(OH) 2 , or —C(O)R 3D ;
R 3D is
methyl,
ethyl optionally substituted with methoxy,
isopropyl, or
piperidinyl optionally substituted with methyl;

R 3B is H or methyl;
R 3C is —N(R 3C1 )(R 3C2 );
R 3C1 and R 3C2 are independently H or methyl; or
R 3C1 and R 3C2 together with the atom to which they are attached form a piperazinyl optional

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

• C07F9/6561 Primary

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• A61P31/14

  for RNA viruses · CPC title