1′-cyano nucleoside analogs and uses thereof

Patent metadata

Field	Value
Publication number	US-11939347-B2
Application number	US-202117355813-A
Country	US
Kind code	B2
Filing date	Jun 23, 2021
Priority date	Jun 24, 2020
Publication date	Mar 26, 2024
Grant date	Mar 26, 2024

Abstract

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.

First claim

What is claimed is:

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:

Assignees

• Gilead Sciences Inc

Inventors

• Byun Daniel H
• Chun Byoung-Kwon
• Clarke Michael O
• Jansa Petr
• Kalla Rao V
• Koltun Dmitry
• Mackman Richard L
• Perry Thao D
• Siegel Dustin S
• Simonovich Scott P

Classifications

• 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

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P31/12 Primary

  Antivirals · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K31/675

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