MK2 inhibitors, synthesis thereof, and intermediates thereto

Patent metadata

Field	Value
Publication number	US-10894796-B2
Application number	US-201816494701-A
Country	US
Kind code	B2
Filing date	Mar 15, 2018
Priority date	Mar 16, 2017
Publication date	Jan 19, 2021
Grant date	Jan 19, 2021

Abstract

The present invention provides methods of preparing a MK2 inhibitor, and intermediates related thereto.

First claim

We claim:

1. A method for preparing compound I:

or a pharmaceutically acceptable salt thereof, comprising the steps of:
reacting a compound of formula 1-11:

or a salt thereof;

with a compound of formula 1-12,

wherein LG 3 is a suitable leaving group;

under suitable reaction conditions to provide compound I, or a pharmaceutically acceptable salt thereof;
wherein the compound of formula 1-11 is prepared by a process comprising:
reacting a compound of formula 1-10:

or a salt thereof, wherein
R′ is hydrogen or optionally substituted C 1-6 aliphatic or aryl;

under suitable reaction conditions to provide a compound of formula 1-11, or a salt thereof.

2. The method according to claim 1 , wherein a compound of formula 1-10 is prepared by a process comprising:
reacting a compound of formula 1-9:

or a salt thereof, wherein
R 1 is a suitable oxygen protecting group; and
PG 1 is a suitable nitrogen protecting group;

under suitable reaction conditions to provide a compound of formula 1-10, or a salt thereof.

3. The method according to claim 2 , wherein the suitable reaction conditions to provide a compound of formula 1-10, or a salt thereof, comprise an acid.

4. The method according to claim 3 , wherein the acid is HCl or BSA.

5. The method according to claim 2 , wherein a compound of formula 1-10 is provided as an HCl salt.

6. The method according to claim 2 , wherein a compound of formula 1-10 is provided as a BSA salt.

7. The method according to claim 2 , wherein a compound of formula 1-9 is prepared by a process comprising:
reacting a compound of formula 1-7:

or a salt thereof;

with a compound of formula 1-8:

or salt thereof, wherein,
LG 2 is a suitable leaving group;

under suitable reaction conditions to provide a compound of formula 1-9, or a salt thereof.

8. The method according to claim 7 , wherein a compound of formula 1-8 is:

9. The method according to claim 7 , wherein a compound of formula 1-7 is prepared by a process comprising:
reacting a compound of formula 1-5:

or a salt thereof, wherein:
LG 1 is a suitable leaving group; and
R 1 is a suitable oxygen protecting group;

with a compound of formula 1-6:

under suitable reaction conditions to provide a compound of formula 1-7.

10. The method according to claim 9 , wherein a compound of formula 1-5 is prepared by a process comprising:
reacting a compound of formula 1-4:

or a salt thereof;

with a compound of formula R 1 OH under suitable reaction conditions to provide a compound of formula 1-5, or a salt thereof.

11. The method according to claim 10 , wherein the suitable reaction conditions to provide a compound of formula 1-5, or a salt thereof, comprise an activating compound.

12. The method according to claim 10 , wherein a compound of formula 1-4 is prepared by a process comprising:
reacting a compound of formula 1-3:

or a salt thereof;

under suitable reaction conditions to provide a compound of formula 1-4, or a salt thereof.

13. The method according to claim 12 , wherein the suitable reaction conditions to provide a compound of formula 1-4, or a salt thereof, comprise a peroxide reagent.

14. The method according to claim 12 , wherein a compound of formula 1-3 is prepared by a process comprising:
reacting a compound of formula 1-2:

or a salt thereof;

under suitable reaction conditions to provide a compound of formula 1-3, or a salt thereof.

15. The method according to claim 14 , wherein the suitable reaction conditions to provide a compound of formula 1-3, or a salt thereof, comprise a nitrite compound.

16. The method according to claim 15 , wherein the suitable reaction conditions to provide a compound of formula 1-3, or a salt thereof, further comprise a bromide source.

17. The method according to claim 14 , wherein the reaction conditions comprise in situ formation of a diazonium intermediate of formula 1-2a:

wherein X″ is a counterion.

18. The method according to claim 14 , wherein a compound of formula 1-2 is prepared by a process comprising:
reacting a compound of formula 1-1:

or a salt thereof;

under suitable reaction conditions to provide a compound of formula 1-2, or a thereof.

19. The method according to claim 18 , wherein the suitable reaction conditions to provide a compound of formula I-2, or a salt thereof, comprise a cyanating agent.

Assignees

• Celgene Car Llc

Inventors

• Feigelson Gregg Brian
• Geherty Maryll E
• Heid Jr Richard Martin
• Kothare Mohit
• Man Hon-Wah
• Ruchelman Alexander L
• Traverse John F
• Yong Kelvin Hin-Yeong
• Zhang Chengmin

Classifications

• C07D495/14 Primary

  Ortho-condensed systems · CPC title