Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use

Patent metadata

Field	Value
Publication number	US-12110305-B2
Application number	US-202117394630-A
Country	US
Kind code	B2
Filing date	Aug 5, 2021
Priority date	Aug 7, 2020
Publication date	Oct 8, 2024
Grant date	Oct 8, 2024

Abstract

Compounds, compositions, and method useful for treating a viral infection, such as human immunodeficiency virus (HIV) and/or hepatitis B virus (HBV) infection, are disclosed. In particular, prodrugs of phosphonamide nucleotide analogues and methods for their preparation and use as therapeutic or prophylactic agents are disclosed.

First claim

We claim:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein
R 1 and R 2 are independently chosen from C 1-12 alkyl, aryl-C 1-4 alkylene, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkylene, aryl-C 3-7 cycloalkylene, C 7-12 spirocycloalkyl, C 7-12 spirocycloalkyl-C 1-4 alkylene, bridged C 5-10 bicycloalkyl, bridged C 5-10 bicycloalkyl-C 1-4 alkylene, fused C 5-10 bicycloalkyl, C 10-16 dispirocycloalkyl, C 10-16 dispirocycloalkyl-C 1-4 alkylene, bridged C 9-12 tricycloalkyl, bridged C 9-12 tricycloalkyl-C 1-4 alkylene, C 3-7 cycloalkyl-C 3-7 cycloalkylene, and 5- to 7-membered monocyclic heterocyclyl having from 1 to 3 heteroatoms chosen from N, O, and S, wherein each C 1-12 alkyl, aryl-C 1-4 alkylene, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkylene, aryl-C 3-7 cycloalkylene, C 7-12 spirocycloalkyl, and C 7-12 spirocycloalkyl-C 1-4 alkylene is optionally substituted with from one to three R a ;
R 3 , R 4 , R 5 , and R 6 are independently chosen from C 1-4 alkyl, C 3-6 cycloalkyl, and aryl-C 1-4 alkylene, wherein each C 1-4 alkyl, C 3-6 cycloalkyl, and aryl-C 1-4 alkylene is optionally substituted with from one to three R b ; or optionally:
R 3 and R 4 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three R b ; and R 5 and R 6 are independently chosen from C 1-4 alkyl, C 3-6 cycloalkyl, and aryl-C 1-4 alkylene, wherein each C 1-4 alkyl, C 3-6 cycloalkyl, and aryl-C 1-4 alkylene is optionally substituted with from one to three R b ; or
R 3 and R 4 are independently chosen from C 1-4 alkyl, C 3-6 cycloalkyl, and aryl-C 1-4 alkylene, wherein each C 1-4 alkyl, C 3-6 cycloalkyl, and aryl-C 1-4 alkylene is optionally substituted with from one to three R b ; and R 5 and R 6 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three R b ; or
R 3 and R 4 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three R b ; and R 5 and R 6 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three R b ;

B is

R 7 is hydrogen or R 8 ;
R 8 is -L 1 -(L 2 ) m -(L 3 ) n -R 8a ;
L 1 is chosen from a bond, —C(O)—, and —C(O)O—;
L 2 is C 1-6 alkylene;
L 3 is —C(O)O— or

R 8a is chosen from C 1-12 alkyl, aryl, —C(O)-aryl, —C(O)—C 1-4 alkyl, —S—C(O)—C 1-4 alkyl,

 wherein aryl and —C(O)-aryl are optionally substituted with one or two R c ;
each R a is independently chosen from C 1-4 alkyl, halo, C 1-4 haloalkyl, and —O—C 1-4 alkyl;
each R b is independently C 1-4 alkyl;
each R c is independently C 1-4 alkyl or —OC(O)—C 1-4 alkyl;
m and n are independently 0 or 1; and
p is 0, 1, or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently chosen from C 1-8 alkyl, aryl-C 1-4 alkylene, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkylene, aryl-C 3-7 cycloalkylene, C 7-12 spirocycloalkyl, C 7-12 spirocycloalkyl-C 1-4 alkylene, bridged C 5-10 bicycloalkyl, bridged C 5-10 bicycloalkyl-C 1-4 alkylene, fused C 5-10 bicycloalkyl, C 10-16 dispirocycloalkyl, C 10-16 dispirocycloalkyl-C 1-4 alkylene, bridged C 9-12 tricycloalkyl, bridged C 9-12 tricycloalkyl-C 1-4 alkylene, C 3-7 cycloalkyl-C 3-7 cycloalkylene, and 5- to 7-membered monocyclic heterocyclyl having from 1 to 3 heteroatoms chosen from N, O, and S, wherein each C 1-8 alkyl, aryl-C 1-4 alkylene, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkylene, aryl-C 3-7 cycloalkylene, C 7-12 spirocycloalkyl, and C 7-12 spirocycloalkyl-C 1-4 alkylene is optionally substituted with from one to three R a .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently chosen from C 1-8 alkyl, aryl-C 1-4 alkylene, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkylene, aryl-C 3-7 cycloalkylene, C 7-12 spirocycloalkyl, C 7-12 spirocycloalkyl-C 1-4 alkylene, bridged C 5-10 bicycloalkyl-C 1-4 alkylene, fused C 5-10 bicycloalkyl, C 10-16 dispirocycloalkyl-C 1-4 alkylene, bridged C 9-12 tricycloalkyl-C 1-4 alkylene, C 3-7 cycloalkyl-C 3-7 cycloalkylene, and 5- to 7-membered monocyclic heterocyclyl having from 1 to 3 heteroatoms chosen from N, O, and S, wherein each C 1-8 alkyl, aryl-C 1-4 alkylene, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkylene, aryl-C 3-7 cycloalkylene, C 7-12 spirocycloalkyl, and C 7-12 spirocycloalkyl-C 1-4 alkylene is optionally substituted with from one to three R a .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently chosen from C 1-8 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkylene, C 7-12 spirocycloalkyl, C 7-12 spirocycloalkyl-C 1-4 alkylene, and bridged C 5-10 bicycloalkyl-C 1-4 alkylene, wherein each C 1-8 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkylene, C 7-12 spirocycloalkyl, and C 7-12 spirocycloalkyl-C 1-4 alkylene is optionally substituted with from one to three R a .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently chosen from C 5-8 alkyl, C 5-7 cycloalkyl, C 5-7 cycloalkyl-C 1-4 alkylene, C 7-9 spirocycloalkyl, C 7-9 spirocycloalkyl-C 1-4 alkylene, and bridged C 5-7 bicycloalkyl-C 1-4 alkylene, wherein each C 5-8 alkyl, C 5-7 cycloalkyl, C 5-7 cycloalkyl-C 1-4 alkylene, C 7-9 spirocycloalkyl, and C 7-9 spirocycloalkyl-C 1-4 alkylene is optionally substituted with from one to three R a .

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

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are the same.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are the same and chosen from C 1-8 alkyl, aryl-C 1-4 alkylene, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkylene, aryl-C 3-7 cycloalkylene, C 7-12 spirocycloalkyl, C 7-12 spirocycloalkyl-C 1-4 alkylene, bridged C 5-10 bicycloalkyl-C 1-4 alkylene, fused C 5-10 bicycloalkyl, C 10-16 dispirocycloalkyl-C 1-4 alkylene, bridged C 9-12 tricycloalkyl-C 1-4 alkylene, C 3-7 cycloalkyl-C 3-7 cycloalkylene, and 5- to 7-membered monocyclic heterocyclyl having from 1 to 3 heteroatoms chosen from N, O, and S, wherein each C 1-8 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkylene, C 7-12 spirocycloalkyl, and C 7-12 spirocycloalkyl-C 1-4 alkylene is optionally substituted with from one to three R a .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are the same and chosen from C 1-8 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkylene, C 7-12 spirocycloalkyl, C 7-12 spirocycloalkyl-C 1-4 alkylene, and bridged C 5-10 bicycloalkyl-C 1-4 alkylene, wherein each C 1-8 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkylene, C 7-12 spirocycloalkyl, and C 7-12 spi

Assignees

• Gilead Sciences Inc

Inventors

• Byun Daniel H
• Chun Byoung-Kwon
• Clarke Michael O
• Jansa Petr
• Naduthambi Devan
• Squires Neil H

Classifications

• C07F9/65616 Primary

  containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs · CPC title

• A61K45/06

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

• A61P31/18

  for HIV · CPC title

• A61P31/20

  for DNA viruses · CPC title

• A61P31/12 Primary

  Antivirals · CPC title