Antiviral compounds

Patent metadata

Field	Value
Publication number	US-12030903-B2
Application number	US-202117178115-A
Country	US
Kind code	B2
Filing date	Feb 17, 2021
Priority date	Feb 18, 2020
Publication date	Jul 9, 2024
Grant date	Jul 9, 2024

Abstract

The present disclosure describes 4′-fluoromethyl nucleosides for treating viral infections, including Dengue.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
Base is

R 1 and R 2 are each independently H or —C(O)R 1A , wherein R 1A is C 1-6 alkyl;
R 3 is —N(H)R 3A ;
R 3A is H, —CH 2 OP(O)(OH) 2 , or —C(O)R 3D , wherein
R 3D is C 6-12 aryl or C 1-6 alkyl optionally substituted with a C 3-6 cycloalkyl;

R 4A is O;
R 4B and R 4C are each independently:
(A) —OH;
(B) —OR 4B1 , wherein R 4B1 is C 6-12 aryl;
(C)

 wherein
subscript m is 0, 1, 2, 3, 4, or 5; and
each R 4D is independently C 1-6 alkyl;
(D)

 wherein
R 4E1 and R 4E2 are each independently H or C 1-6 alkyl;
R 4F1 and R 4F2 together are oxo;
R 4G is C 1-8 alkyl optionally substituted with 1 to 3 R 4G1 , C 3-8 cycloalkyl, or a 3 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, optionally substituted with 1 to 3 R 4G3 ;
each R 4G1 is independently —OH, C 1-6 alkoxy, —(CH 2 OCH 2 ) 1-5 —CH 3 , C 1-3 haloalkyl, or C 3-8 cycloalkyl optionally substituted with 1 to 3 R 4G9 ;
each R 4G3 and R 4G9 is independently C 1-6 alkyl; or

(E) —(OP(O)(OH)) 1-2 —OH; and

R 5A is C 1-6 alkyl substituted with —OP(O)(OH) 2 .

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each H.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each —C(O)R 1A ; and
R 1A is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or t-butyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 and R 2 are each —C(O)R 1A ; and
R 1A is methyl, ethyl, or iso-propyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the formula:

wherein
R 3 is —N(H)R 3A ;
R 3A is H or —C(O)R 3D ; and
R 3D is phenyl or C 1-3 alkyl optionally substituted with a C 3-6 cycloalkyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 3 is —NH 2 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 4B and R 4C are each independently:
(A) —OH;
(B) —OR 4B1 , wherein R 4B1 is naphthyl;

 (C), wherein
subscript m is 0 or 1; and
R 4D is C 1-6 alkyl;

(D)

 wherein
R 4E1 is C 1-3 alkyl;
R 4E2 is H;
R 4F1 and R 4F2 together are oxo;
R 4G is C 1-8 alkyl optionally substituted with 1 R 4G1 , C 4-6 cycloalkyl, or a 4 to 6 membered heterocyclyl having 1 heteroatom selected from N and O, optionally substituted with 1 R 4G3 ;
each R 4G1 is independently —OH, C 1-4 alkoxy, —(CH 2 OCH 2 ) 1-2 -CH 3 , C 1-3 haloalkyl, or C 3-6 cycloalkyl optionally substituted with 1 R 4G9 ;
each R 4G3 and R 4G9 is independently C 1-3 alkyl; or

(E) —(OP(O)(OH)) 1-2 —OH.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 4B is:
(B) —OR 4B1 , wherein R 4B1 is naphthyl; or
(C)

 wherein
subscript m is 0 or 1; and
R 4D is t-butyl; or

(E) —(OP(O)(OH)) 1-2 —OH.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 4C is:
(A) —OH; or
(D)

 wherein
R 4E1 is methyl;
R 4E2 is H;
R 4F1 and R 4F2 together are oxo; and
R 4G is
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexane, 2,2-dimethyl-butyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, or 2-n-propyl-pentyl, each optionally substituted with OH, methoxy, ethoxy, propoxy, butoxy, CF 3 , Me(CH 2 OCH 2 ) 2 —, cyclopropyl or 1-methylcyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl,
pyrrolidinyl, oxetanyl, or tetrahydropyranyl, each optionally substituted with methyl, ethyl, n-propyl or iso-propyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5A is —CH 2 OP(O)(OH) 2 .

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the Formula (Ib):

wherein
R 3A is H; and
R 5A is —CH 2 OP(O)(OH) 2 .

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the Formula (Id):

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the Formula (Ie):

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the Formula (If):

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the Formula (Ig):

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the Formula (Ih):

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the Formula (Ij):

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the Formula (Ik):

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the Formula (Im):

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

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

Assignees

• Gilead Sciences Inc

Inventors

• Byun Daniel H
• Chin Gregory F
• Clarke Michael O
• Goyal Bindu
• Jansa Petr
• Mackman Richard L
• Mish Michael R
• Siegel Dustin S

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P31/12

  Antivirals · CPC title

• C07F9/2458

  of aliphatic amines · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · 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