Mk2 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-2024190890-A1
Application number	US-202318495004-A
Country	US
Kind code	A1
Filing date	Oct 26, 2023
Priority date	Oct 27, 2022
Publication date	Jun 13, 2024
Grant date	—

Abstract

The present invention provides compounds, compositions thereof, and methods of using the MK2 inhibitors of the Formula:

First claim

We claim:

1 . A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, provided that when Ring A is a 6-membered heteoaryl ring the 1-3 heteroatoms are each nitrogen;
each R 1 and R 1′ is independently selected from hydrogen and C 1-4 aliphatic substituted with 0-3 instances of R x , or:
R 1 and R 1′ may, together with the intervening atoms to which they are attached, form an optionally substituted 3- to 6-membered saturated, or partially unsaturated, heterocyclyl, carbocycle, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R x is —CN, —NO 2 , halogen, —OR, —SR, —N(R) 2 , —C(O)N(R) 2 , —C(O)OR, —C(O)R, —N(R)C(O)R, —SO 2 N(R) 2 , or —N(R)SO 2 ;
R 2 is halogen, —(CH 2 ) q —CN, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein the alkenyl or alkynyl is optionally substituted with m instances of R y ;
each R y is independently selected from D, halogen, —CN, —CO 2 R, —N(R) 2 , and a 3- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R 3 is independently selected from D, C 1-6 aliphatic, —CN, halogen, —(CH 2 ) q —OR 4 , —N(R) 2 , —C(O)OR, —(CH 2 ) r -Cy, or —O—(CH 2 ) t —R 5 , wherein the C 1-6 aliphatic is optionally substituted with one or more substituents each independently selected from D, halogen and —OR; or:
two R 3 groups, together with the intervening atoms to which they are attached, form an 5- to 6-membered saturated, partially unsaturated, heterocyclic, carbocyclic, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl, carbocyclic, or aryl ring is optionally substituted with one or more substituents each independently selected from halogen, C 1-6 aliphatic, and —OR;

each R 4 is independently selected from hydrogen, C 1-6 aliphatic, and -Cy, wherein the C 1-6 aliphatic is optionally substituted with one or more substituents each independently selected from D, halogen and —OR;
each R 5 is independently selected from —OR and -Cy;
each Cy is independently a ring selected from a 3- to 9-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 3- to 9-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 12-membered saturated or partially unsaturated fused, spirofused, or bridged bicyclic carbocyclic ring, or a 7- to 12-membered saturated or partially unsaturated fused, spirofused, or bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one or more substituents each independently selected from D, halogen, oxo, R, and —(CH 2 ) q —OR;
each R is independently hydrogen or a C 1-6 aliphatic optionally substituted with one or more substituents each selected from D, halogen, —OH, and —O—(C 1-6 aliphatic), or:
two R groups on the same nitrogen are taken together with the nitrogen to form a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur;

each of n, q, and r is independently 0-4; and
t is 1-4.

2 . The compound according to claim 1 , wherein Ring A is selected from:

3 . The compound according to claim 1 , wherein the compound is selected from any of formulae II, III, IV, or V:

or a pharmaceutically acceptable salt thereof.

4 . The compound according to claim 1 , wherein R 2 is halogen.

5 . The compound according to claim 1 , wherein R 2 is —CN.

6 . The compound according to claim 1 , wherein R 2 is C 2-6 aliphatic substituted with m instances of R y , wherein the C 2-6 aliphatic has at least one unit of unsaturation.

7 . The compound according to claim 6 , wherein n is 0.

8 . The compound according to claim 7 , wherein R 2 is selected from:

9 . The compound according to claim 1 , wherein R 2 is selected from:

10 . The compound according to claim 1 , wherein R 2 is selected from

11 . The compound according to claim 1 , wherein the compound is selected from formulae II-a, II-b, II-c, III-a, III-b, IV-a, IV-b, IV-c, V-a, V-b, or V-c:

or a pharmaceutically acceptable salt thereof.

12 . The compound according to claim 1 , wherein the compound is selected from formulae II-a-i, II-a-ii, II-b-i, II-b-ii, II-c-i, II-c-ii, III-a-i, III-b-i, IV-a-i, IV-a-ii, IV-b-i, IV-b-ii, IV-c-i, IV-c-ii, V-a-i, V-b-i, or V-c-i:

or a pharmaceutically acceptable salt thereof.

13 . The compound according to claim 1 , wherein R 3 is selected from —CH 3 , -CD 3 , —CF 2 H, —CF 3 , —CH 2 CH 3 ,

14 . The compound according to claim 1 , wherein R 3 is selected from —OCH 3 , —OCF 2 H, —OCF 3 , —O(CH 2 ) 2 CH 3 , —O(CH 2 ) 2 OCH 2 CH 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 ,

15 . The compound according to claim 1 , wherein R 3 is —(CH 2 ) r -Cy.

16 . The compound according to claim 1 , wherein R 3 is selected from

17 . The compound according to claim 1 , wherein R 3 is selected from

18 . The compound of claim 1 , selected from the group consisting of:
(R)-3-(2-ethynyl-5-fluoropyrimidin-

Assignees

• Bristol Myers Squibb Co
• Celgene Corp

Inventors

• Hu Xirui
• Qiao Lixin
• Seletsky Boris
• Patton Matthew
• Cao Min
• Van Der Mei Farid
• Miao Guobin
• Mcdonald Ivar
• Dzierba Carolyn

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P19/00

  Drugs for skeletal disorders · CPC title