IP Library › Granted Patent US 10,941,175
Granted Patent B2
US 10,941,175 · App. 16/533,194 · Granted Mar 9, 2021

Pyrrolopyrimidine nucleosides and analogs thereof

Inventors: John Henry Bougher, III (Durham, NC); Ramamurty V S Changalvala (Durham, NC); Aaron Leigh Downey (Durham, NC); John C. Drach (Ann Arbor, MI); Ernest Randall Lanier, Jr. (Durham, NC); Andrew Louis McIver (Durham, NC); Bradley David Robertson (Durham, NC); Dean Wallace Selleseth (Durham, NC); Phiroze Behram Sethna (Durham, NC); Leroy Townsend (Ann Arbor, MI); Roy W. Ware (Durham, NC)
Assignees: Chimerix, Inc.; The Regents of the University of Michigan
C07H19/14C07D239/70C07H19/16A61K31/706A61K31/7052A61K31/7064
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Quick Facts
Patent No.
US 10,941,175
App. No.
16/533,194
Granted
Mar 9, 2021
Kind
B2
Abstract

The present disclosure provides pyrrolopyrimidine nucleoside analogs of the Formula I, Formula IA, Formula IB, or Formula II and phospholipid conjugates and pharmaceutical compositions thereof wherein R c and A are defined herein. Also presented are methods of treating and/or preventing viral infection and/or viral infection-associated disease or disorder with one or more compounds of Formula I, Formula IA, Formula IB, or Formula II.

Claims (47)

1. A compound of the formula:

or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate or mixture thereof, wherein:

each R is independently —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo, R 1 , —OR, —NR 1 R 2 , —SR 1 , —OC(O)R 1 , —C(O)OR 1 , —NHC(O)OR 1 , or —NHC(O)R 1 ;

R a and R b are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo —OR 1 , —NR 1 R 2 , —SR 1 , —OC(O)R, —C(O)OR 1 —NHC(O)OR, or —NHC(O)R 1 ;

R 1 and R 2 are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo, —R 3 , —R 4 , —OR 3 , —NR 3 R 4 , —SR 3 , —OC(O)R 3 ,—C(O)OR 3 , —NHC(O)OR 3 , or —NHC(O)R 3 ;

R 3 and R 4 are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo, aryl, heteroaryl, —OH, —NH 2 , —SH, —OC(O)H,—C(O)OH, —NHC(O)OH, or —NHC(O)H;

R c is independently —H or -D; and

n is independently 0, 1, 2 or 3.

2. The compound claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate or mixture thereof, wherein:

R a and R b are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo —OR 1 , —NR 1 R 2 , —SR 1 , —OC(O)R 1 ,—C(O)OR 1 —NHC(O)OR 1 , or —NHC(O)R 1 ;

R 1 and R 2 are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo, —R 3 , —R 4 , —OR 3 , —NR 3 R 4 , —SR 3 , —OC(O)R 3 ,—C(O)OR 3 , —NHC(O)OR 3 , or —NHC(O)R 3 ;

R 3 and R 4 are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo, aryl, heteroaryl, —OH, —NH 2 , —SH, —OC(O)H,—C(O)OH, —NHC(O)OH, or —NHC(O)H;

R c is independently —H or -D; and

n is independently 0, 1, 2 or 3.

3. The compound claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate or mixture thereof, wherein:

R a and R b are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo —OR 1 , —NR 1 R 2 , —SR 1 , —OC(O)R 1 ,—C(O)OR 1 —NHC(O)OR 1 , or —NHC(O)R 1 ;

R 1 and R 2 are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo, —R 3 , —R 4 , —OR 3 , —NR 3 R 4 , —SR 3 , —OC(O)R 3 ,—C(O)OR 3 , —NHC(O)OR 3 , or —NHC(O)R 3 ;

R 3 and R 4 are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo, aryl, heteroaryl, —OH, —NH 2 , —SH, —OC(O)H,—C(O)OH, —NHC(O)OH, or —NHC(O)H; and

R c is independently —H or -D.

4. The compound claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate or mixture thereof, wherein:

R a and R b are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo —OR 1 , —NR 1 R 2 , —SR 1 , —OC(O)R 1 ,—C(O)OR 1 —NHC(O)OR 1 , or —NHC(O)R 1 ;

R 1 and R 2 are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo, —R 3 , —R 4 , —OR 3 , —NR 3 R 4 , —SR 3 , —OC(O)R 3 ,—C(O)OR 3 , —NHC(O)OR 3 , or —NHC(O)R 3 ;

R 3 and R 4 are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo, aryl, heteroaryl, —OH, —NH 2 , —SH, —OC(O)H,—C(O)OH, —NHC(O)OH, or —NHC(O)H; and

R c is independently —H or -D.

5. The compound claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate or mixture thereof, wherein:

R a and R b are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo —OR 1 , —NR 1 R 2 , —SR 1 , —OC(O)R 1 ,—C(O)OR 1 —NHC(O)OR 1 , or —NHC(O)R 1 ;

R 1 and R 2 are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo, —R 3 , —R 4 , —OR 3 , —NR 3 R 4 , —SR 3 , —OC(O)R 3 ,—C(O)OR 3 , —NHC(O)OR 3 , or —NHC(O)R 3 ;

R 3 and R 4 are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo, aryl, heteroaryl, —OH, —NH 2 , —SH, —OC(O)H,—C(O)OH, —NHC(O)OH, or —NHC(O)H; and

R c is independently —H or -D.

6. The compound claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate or mixture thereof.

7. The compound claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate or mixture thereof.

8. The compound claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate or mixture thereof.

9. The compound of claim 1 , wherein the compound exists in vivo.

10. The compound of claim 1 , wherein the compound is produced in vivo.

11. A method of treating or preventing a viral infection comprising administering to a subject in need thereof an effective amount of a compound of claim 1 a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate or mixture thereof.

12. A method of treating or preventing a viral infection comprising administering to a subject in need thereof an effective amount of a compound that is converted to a compound of claim 1 a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate or mixture thereof in vivo.

13. The method of claim 11 wherein the viral infection is norovirus infection.

14. The method of claim 12 wherein the viral infection is norovirus infection.

15. The compound of claim 8 , wherein the compound exists in vivo.

16. The compound of claim 8 , wherein the compound is produced in vivo.

Assignments (3)
SECURITY AGREEMENT Recorded Sep 4, 2025
From: CHIMERIX, INC.
To: U.S. BANK TRUST COMPANY, NATIONAL ASSOCIATION, AS COLLATERAL TRUSTEE
Reel/Frame 072802/0723 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 7, 2019
From: BOUGHER, JOHN HENRY, III; CHANGALVALA, RAMAMURTY V S; DOWNEY, AARON LEIGH; LANIER, ERNEST RANDALL, JR.; MCIVER, ANDREW LOUIS; ROBERTSON, BRADLEY DAVID; SELLESETH, DEAN WALLACE; SETHNA, PHIROZE BEHRAM; WARE, ROY W.
To: CHIMERIX, INC.
Reel/Frame 049984/0306 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 7, 2019
From: TOWNSEND, LEROY; DRACH, JOHN C.
To: THE REGENTS OF THE UNIVERSITY OF MICHIGAN
Reel/Frame 049984/0378 →