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Msg  10160 of 10756  at  8/18/2022 6:53:38 AM  by

JBWIN


Building IP: CELG Patent Application re "MK2 INHIBITORS, THE SYNTHESIS THEREOF..."

 
nited States Patent Application20220259222
Kind CodeA1
Ruchelman; Alexander L. ; et al.August 18, 2022

MK2 INHIBITORS, THE SYNTHESIS THEREOF, AND INTERMEDIATES THERETO

Abstract

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


Inventors:Ruchelman; Alexander L.; (Cream Ridge, NJ) ; Coombs; John R.; (New Brunswick, NJ) ; Zhu; Keming; (New Brunswick, NJ) ; Lim; Daniel; (Summit, NJ) ; Joe; Candice Lee; (New Brunswick, NJ) ; George; David T.; (New Brunswick, NJ) ; Zheng; Bin; (Kendall Park, NJ) ; Lin; Dong; (Monmouth Junction, NJ)
Applicant:
NameCityStateCountryType

Celgene Corporation

Summit

NJ

US
Family ID:1000006270244
Appl. No.:17/587555
Filed:January 28, 2022

Related U.S. Patent Documents

Application NumberFiling DatePatent Number
63144361Feb 1, 2021

Current U.S. Class:1/1
Current CPC Class:C07D 215/58 20130101; C07D 495/14 20130101; C07D 495/04 20130101; C07C 255/50 20130101
International Class:C07D 495/14 20060101 C07D495/14; C07C 255/50 20060101 C07C255/50; C07D 215/58 20060101 C07D215/58; C07D 495/04 20060101 C07D495/04

Claims



1. A method of preparing a compound of formula I-a: ##STR00084## or a salt thereof, wherein each of R.sup.1 and R.sup.2 is independently selected from optionally substituted C.sub.1-6 aliphatic; the method comprising: (a) providing a compound of formula 1-4: ##STR00085## or a salt thereof; and (b) contacting the compound of formula 1-4 with a mercaptoacetate ester of formula 1-4-a: ##STR00086## under conditions suitable to form a compound of formula I-a, or a salt thereof.

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

3. The method according to claim 1, wherein R.sup.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: ##STR00087## or a salt thereof; and (b) contacting the compound of formula 1-3 with a compound of formula 1-3-a: R.sup.2-X 1-3-a under conditions suitable to form a compound of formula 1-4, or a salt thereof

5. The method according to claim 4, wherein R.sup.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: ##STR00088## 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: ##STR00089## wherein: R.sup.3 is optionally substituted C.sub.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: ##STR00090## 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. A method of preparing a compound of formula I-b: ##STR00091## or a salt thereof, wherein: R.sup.1 is optionally substituted C.sub.1-6 aliphatic; comprising the steps of: (a) reacting a compound of formula I-a: ##STR00092## or a salt thereof, wherein: R.sup.1 is optionally substituted C.sub.1-6 aliphatic; R.sup.2 is optionally substituted C.sub.1-6 aliphatic or --SO.sub.2R.sup.2a; and R.sup.ea is an optionally substituted C.sub.1-6 aliphatic or aryl; with a compound of formula 1-5 or 1-5-a: ##STR00093## or a salt thereof, wherein: PG.sup.1 is a suitable nitrogen protecting group; and LG.sup.1 is a suitable leaving group; under suitable reaction conditions to afford a compound of formula 1-6: ##STR00094## or a salt thereof; and (b) reacting the compound of formula 1-6 under suitable reaction conditions to afford the compound of formula I-b, or a salt thereof.

9. (canceled)

10. The method of claim 8, wherein PG.sup.1 is Boc.

11. The method of claim 8, wherein R.sup.2 is tosyl.

12. The method of claim 8, wherein R.sup.1 is methyl.

13. The method of claim 8, wherein a compound of formula I-b is provided as a methanesulfonic acid salt or a benzenesulfonic acid salt.

14-17. (canceled)

18. A compound selected from the group consisting of ##STR00095## or a salt thereof, wherein R.sup.1 is selected from optionally substituted C.sub.1-6 aliphatic; R.sup.2 is optionally substituted C.sub.1-6 aliphatic or --SO.sub.2R.sup.2a; R.sup.2a is an optionally substituted C.sub.1-6 aliphatic or aryl; and PG.sup.1 is a suitable nitrogen protecting group.

19. The compound of claim 18, selected from the group consisting of: ##STR00096## or a salt thereof

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

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

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

23. The compound of claim 18, wherein R.sup.2 is benzyl.

24. The compound of claim 18, wherein R.sup.2 is -SO.sub.2(p-tolyl).

25. The compound of claim 18, wherein R.sup.1 is methyl.
Description



CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63/144,361, filed Feb. 1, 2021, which is herein incorporated by reference in its entirety.

TECHNICAL FIELD OF THE INVENTION

[0002] The present disclosure relates to the synthesis of compounds useful as inhibitors of MK2 kinases. The disclosure also provides novel synthetic intermediates useful in the synthesis of MK2 kinase inhibitors.

BACKGROUND OF THE INVENTION

[0003] The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with diseases. One important class of enzymes that has been the subject of extensive study is protein kinases.

[0004] Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).

[0005] Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP K2 or MK2) mediates multiple p38 MAPK-dependent cellular responses. MK2 is an important intracellular regulator of the production of cytokines, such as tumor necrosis factor alpha (TNF-.alpha.), interleukin 6 (IL-6) and interferon gamma (IFN.gamma.), that are involved in many acute and chronic inflammatory diseases, e.g. rheumatoid arthritis and inflammatory bowel disease. MK2 resides in the nucleus of non-stimulated cells and upon stimulation, it translocates to the cytoplasm and phosphorylates and activates tuberin and HSP27. MK2 is also implicated in heart failure, brain ischemic injury, the regulation of stress resistance and the production of TNF-.alpha.. (see Deak et al., EMBO. 17:4426-4441 (1998); Shi et al., Biol. Chem. 383:1519-1536 (2002); Staklatvala., Curr. Opin. Pharmacol. 4:372-377 (2004), and Shiroto et al., J. Mol. Cardiol. 38:93-97 (2005)).

[0006] Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events as described above. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Accordingly, there remains a need to find protein kinase inhibitors useful as therapeutic agents.

SUMMARY OF THE INVENTION

[0007] As described herein, in some embodiments, the present invention provides methods for preparing compounds useful as inhibitors of protein kinases. Such compounds include compound I:

##STR00001##

or a pharmaceutically acceptable salt thereof.

[0008] In particular, in some embodiments, the present disclosure provides methods of preparing a compound of formula I-a:

##STR00002##

or a salt thereof, wherein each of R.sup.1 and R.sup.2 is as defined below and described herein.

[0009] Additionally or alternatively, in some embodiments, the present disclosure provides methods of preparing a compound of formula I-b:

##STR00003##

or a salt thereof, wherein: R.sup.1 is defined below and described herein.

[0010] Additionally or alternatively, in some embodiments, the present disclosure provides methods of preparing a compound of formula I-c:

##STR00004##

or a salt thereof

[0011] In some embodiments, the present disclosure also provides novel intermediates useful in the synthesis of a compound of formula I-a, I-b, or I-c.


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