MK2 inhibitors, the synthesis thereof, and intermediates thereto

Patent metadata

Field	Value
Publication number	US-12049470-B2
Application number	US-202217587555-A
Country	US
Kind code	B2
Filing date	Jan 28, 2022
Priority date	Feb 1, 2021
Publication date	Jul 30, 2024
Grant date	Jul 30, 2024

Abstract

The present disclosure provides novel synthetic intermediates useful in the synthesis of MK2 kinase inhibitors.

First claim

The invention claimed is:

1. A method of preparing a compound of formula I-a:

or a salt thereof, wherein R 1 is optionally substituted C 1-6 aliphatic;
R 2 is selected from optionally substituted C 1-6 aliphatic and —SO 2 R 2a ; and wherein R 2a is an optionally substituted C 1-6 aliphatic or aryl;
the method comprising:
(a) providing a compound of formula 1-4:

 or a salt thereof; and
(b) contacting the compound of formula 1-4 with a mercaptoacetate ester of formula 1-4-a:

 under conditions suitable to form a compound of formula I-a, or a salt thereof.

2. The method according to claim 1 , wherein R 1 is methyl.

3. The method according to claim 1 , wherein R 2 is benzyl or tosyl.

4. The method according to claim 1 , wherein the compound of formula 1-4, or a salt thereof, is prepared by a method comprising:
(a) providing a compound of formula 1-3:

 or a salt thereof; and
(b) contacting the compound of formula 1-3 with a compound of formula 1-3-a:
R 2 −X   1-3-a

 wherein:
X is a suitable leaving group;
under conditions suitable to form a compound of formula 1-4, or a salt thereof.

5. The method according to claim 4 , wherein R 2 is benzyl or tosyl.

6. The method according to claim 4 , wherein the compound of formula 1-3, or a salt thereof, is prepared by a method comprising:
(a) providing a compound of formula 1-2:

 or a salt thereof; and
(b) contacting the compound of formula 1-2, or a salt thereof, with an acrylate ester of formula 1-2-a:

 wherein:
R 3 is optionally substituted C 1-6 aliphatic;
under conditions suitable to afford a compound of formula 1-3, or a salt thereof.

7. The method according to claim 6 , wherein the compound of formula 1-2, or a salt thereof, is prepared by a method comprising:
(a) providing a compound of formula 1-1:

 or a salt thereof, and
(b) contacting the compound of formula 1-1, or a salt thereof, with a brominating agent under conditions suitable to afford a compound of formula 1-2, or a salt thereof.

8. The method according to claim 2 , wherein R 2 is benzyl.

9. The method according to claim 2 , wherein R 2 is tosyl.

10. The method according to claim 7 , wherein the brominating agent is N-bromosuccinimide or sodium bromate/hydrobromic acid.

11. The method according to claim 9 , wherein the conditions suitable to form a compound of formula 1-a, or a salt thereof, comprise a base.

12. The method according to claim 4 , wherein R 1 is methyl.

13. The method according to claim 12 , wherein R 2 is benzyl.

14. The method according to claim 12 , wherein R 2 is tosyl.

15. The method according to claim 14 , wherein the conditions suitable to form a compound of formula 1-4, or a salt thereof, comprise a palladium catalyst.

16. The method according to claim 6 , wherein R 3 is n-butyl.

17. The method according to claim 6 , wherein the conditions suitable to form a compound of formula 1-4, or a salt thereof, comprise a palladium catalyst.

18. The method according to claim 6 , wherein R 1 is methyl.

19. The method according to claim 18 , wherein R 2 is benzyl or tosyl.

20. The method according to claim 7 , wherein R 2 is benzyl or tosyl.

Assignees

• Celgene Corp

Inventors

• Ruchelman Alexander L
• Coombs John R
• Zhu Keming
• Lim Daniel
• Joe Candice Lee
• George David T
• Zheng Bin
• Lin Dong

Classifications

• C07C255/50

  to carbon atoms of non-condensed six-membered aromatic rings · CPC title

• C07D215/58

  with hetero atoms directly attached to the ring nitrogen atom · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• C07D495/14 Primary

  Ortho-condensed systems · CPC title

• C07C255/58

  containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton · CPC title