Mk2 degraders and uses thereof

Patent metadata

Field	Value
Publication number	US-2025179075-A1
Application number	US-202519040630-A
Country	US
Kind code	A1
Filing date	Jan 29, 2025
Priority date	Jun 30, 2021
Publication date	Jun 5, 2025
Grant date	—

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

First claim

We claim:

1 . A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
MBM is a MK2 protein binding moiety capable of binding to MK2;
L is a bivalent moiety that connects MBM to DIM; and
DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moeity (LBM), lysine mimetic, and hydrogen.

2 . The compound of claim 1 , wherein the compound of formula I is a compound of formula I-aa-1:

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is a bivalent moiety selected from a covalent bond, —CH 2 —, —CHCF 3 —, —SO 2 —, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR 2 —, —C(O)—, —C(S)—, or

X 2 is a carbon atom or silicon atom;
X 3 is a bivalent moiety selected from —CR 2 —, —NR—, —O—, —S—, or —Si(R 2 )—;
R 1 is hydrogen, halogen, —CN, —OR, —SR, —S(O)R, —S(O) 2 R, —N(R) 2 , —P(O)(OR) 2 , —P(O)(NR 2 )OR, —P(O)(NR 2 ) 2 , —Si(OH) 2 R, —Si(OH)(R) 2 , —Si(R) 3 , or an optionally substituted C1-4 aliphatic;
each R 2 is independently hydrogen, R 6 , halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —Si(R) 3 , —S(O) 2 R, —S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)OR, —C(R) 2 N(R)C(O)R, —C(R) 2 N(R)C(O)N(R) 2 , —OC(O)R, —OC(O)N(R) 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)(NR 2 ), —OP(O)(NR 2 ) 2 —, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —NP(O)R 2 , —N(R)P(O)(OR) 2 , —N(R)P(O)(OR)(NR 2 ), —N(R)P(O)(NR 2 ) 2 , or —N(R)S(O) 2 R;
each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same atom are optionally taken together with their intervening atoms to form an optionally substituted 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic ring or heterocyclic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring A is a bi- or tricyclic ring selected from

wherein
Ring B is a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
R 3 is selected from hydrogen, halogen, —OR, —N(R) 2 , or —SR;
each R 4 is independently hydrogen, R 6 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R;
R 5 is hydrogen, C 1-4 aliphatic, or —CN;
L 1 is a covalent bond or a C 1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(S)—, —C(R) 2 —, —CH(R)—, —C(F) 2 —, —N(R)—, —S(O) 2 — or —(C)═CH—;
m is 0, 1, 2, 3 or 4;
L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C 1-50 hydrocarbon chain, wherein 0-10 methylene units of L are independently replaced by -Cy-, —O—, —N(R)—, —Si(R) 2 —, —Si(OH)(R)—, —Si(OH) 2 —, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR 2 )—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, —N(R)C(O)O—,

each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
Ring X is an optionally substituted ring selected from phenyl, naphthyl, a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
X is an optionally substituted carbon or nitrogen atom;
Y is —O—, —S—, or —N(R′)—;
R is hydrogen, R A , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —SiR 3 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)NROR, —CR 2 NRC(O)R, —CR 2 NRC(O)N(R) 2 , —OC(O)R, —OC(O)N(R) 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)N(R) 2 , —OP(O)(N(R) 2 ) 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)N(R) 2 , —NRS(O) 2 R, —NP(O)(R) 2 , —NRP(O)(OR) 2 , —NRP(O)(OR)N(R) 2 , —NRP(O)(N(R) 2 ) 2 , or —NRS(O) 2 R;
each R A is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L x is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C 1-5 hydrocarbon chain, wherein 0-3 methylene units of L x are independently replaced by —O—, —NR—, —CRF—, —CF 2 —, —C(O)—, —S—, —S(O)—, or —S(O) 2 —;
R x1 and R x2 are, independently, hydrogen or an optionally substituted C 1-6 aliphatic; and
x is 0, 1, 2, 3, or 4.

3 . The compound of claim 2 , wherein the compound is a compo

Assignees

• Kymera Therapeutics Inc

Inventors

• Yang Bin
• Weiss Matthew M
• Zhu Xiao
• Dong Huijun
• Marx Isaac

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D495/12

  in which the condensed system contains three hetero rings · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D471/14

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title