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US-20260125397-A1 - MK2 DEGRADERS AND USES THEREOF

US20260125397A1US 20260125397 A1US20260125397 A1US 20260125397A1US-20260125397-A1

Abstract

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

Inventors

  • Isaac Marx
  • Bin Yang
  • Thijs Beuming

Assignees

  • KYMERA THERAPEUTICS, INC.

Dates

Publication Date
20260507
Application Date
20240103

Claims (20)

  1. 1 . 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)—; 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 C 1-4 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 an optionally substituted phenyl, bicyclic ring 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, —NR 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)NROR, —OC(O)R, —OC(O)NR 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)NR 2 , or —NRS(O) 2 R; R 5 is hydrogen, C 1 0.4 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)—, —CR 2 —, —CHR—, —C(F) 2 —, —NR—, —S(O) 2 — or —R═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—, —NR—, —SiR 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)—, 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 x1 )—; R x 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)NR 2 , —C(O)NROR, —CR 2 NRC(O)R, —CR 2 NRC(O)NR 2 , —OC(O)R, —OC(O)NR 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)NR 2 , —OP(O)(NR 2 ) 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)NR 2 , —NRS(O) 2 R, —NP(O)R 2 , —NRP(O)(OR) 2 , —NRP(O)(OR)NR 2 , —NRP(O)(NR 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 is hydrogen or an optionally substituted C 1-6 aliphatic; and x is 0, 1, 2, 3, or 4.
  2. 2 . The compound of claim 1 , wherein the compound is a compound of any one of the following formulae: or a pharmaceutically acceptable salt.
  3. 3 . The compound of any one of claims 1-2 2 wherein R is hydrogen.
  4. 4 . The compound of any one of claims 1-3 , wherein R 1 is methyl.
  5. 5 . A compound of formula I-bb-1; or a pharmaceutically acceptable salt, 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, —NR 2 , —P(O)(OR) 2 , —P(O)(NR 2 )OR, —P(O)(NR 2 ) 2 , —Si(OH) 2 R, —Si(OH)R 2 , —SiR 3 , or an optionally substituted C 1-4 aliphatic; each R 2 is independently hydrogen, R 6 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —SiR 3 , —S(O):R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)NROR, —CR 2 NRC(O)R, —CR 2 NRC(O)NR 2 , —OC(O)R, —OC(O)NR 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)(NR 2 ), —OP(O)(NR 2 ) 2 —, —NRC(O)OR, —NRC(O)R, —NRC(O)NR 2 , —NRS(O) 2 R, —NP(O)R 2 , —NRP(O)(OR) 2 , —NRP(O)(OR)(NR 2 ), —NRP(O)(NR 2 ) 2 , or —NRS(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 an optionally substituted phenyl, bicyclic ring 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, —NR 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)NROR, —OC(O)R, —OC(O)NR 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)NR 2 , or —NRS(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)—, —CR 2 —, —CHR—, —C(F) 2 —, —NR—, —S(O) 2 — or —R═CH—; n is 0, 1, 2, 3 or 4; L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C 1 so hydrocarbon chain, wherein 0-10 methylene units of L are independently replaced by —Cy—, —O—, —NR—, —SiR 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 —, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(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 Y is —CH═CH—, —NH—, —O—, or —S—; Ring W is a bivalent ring selected from phenylenyl, naphthylenyl, a 5-10 membered heteroarylenyl 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 carbocyclylenyl or heterocyclylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring X is a 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: R v , R w , and R x are, independently, 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)NR 2 , —C(O)NROR, —OC(O)R, —OC(O)NR 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)NR 2 , —OP(O)(NR 2 ) 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)NR 2 , —NRS(O) 2 R, —NP(O)R 2 , —NRP(O)(OR) 2 , —NRP(O)(OR)NR 2 , —NRP(O)(NR 2 ) 2 , or —NRS(O) 2 R; or: two R v groups on the same or different atoms are optionally taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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 5-9 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; v is 0, 1, 2, 3, or 4; w is 0, 1, 2, 3, or 4; x is 0, 1, 2, 3, or 4; and m is 0, 1,2,3, or 4.
  6. 6 . The compound of claim 5 , wherein the compound is a compound of any one of the following formulae: or a pharmaceutically acceptable salt.
  7. 7 . The compound of any one of claims 5-6 , wherein R w and R x are, independently, hydrogen, R A , halogen, —CN, —CF 3 or —OR.
  8. 8 . The compound of any one of claims 1-7 , wherein Ring A is
  9. 9 . The compound of any one of claims 1-8 , wherein Ring B is benzo.
  10. 10 . The compound of any one of claims 1-9 , wherein R 4 is methyl.
  11. 11 . The compound of any one of claims 1-7 , wherein Ring A is N.
  12. 12 . The compound of claim 11 , wherein Ring B is benzo.
  13. 13 . The compound of any one of claims 1-7 , wherein Ring A is
  14. 14 . The compound of any one of claims 1-13 , wherein L is
  15. 15 . The compound of claim 1 , wherein said compound is selected from any one of the compounds depicted in Table 1, or a pharmaceutically acceptable salt thereof.
  16. 16 . A pharmaceutical composition comprising a compound according to any one of claims 1-15 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  17. 17 . The pharmaceutical composition according to claim 16 , further comprising an additional therapeutic agent.
  18. 18 . A method of degrading MK2 protein in a patient or biological sample comprising administering to said patient, or contacting said biological sample with a compound according to any one of claims 1-15 , or a pharmaceutical composition thereof.
  19. 19 . A method of treating an MK2-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound according to any one of claims 1-15 , or a pharmaceutical composition thereof.
  20. 20 . The method of claim 19 , further comprising administration of an additional therapeutic agent.

Description

RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Application No. 63/478,471, filed Jan. 4, 2023. the entire contents of which are hereby incorporated by reference. TECHNICAL FIELD OF THE INVENTION The present invention relates to compounds and methods useful for the modulation of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAP kinase-2 or MK2) via ubiquitination and/or degradation by compounds according to the present invention. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders. BACKGROUND OF THE INVENTION Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. There are over 600 E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s. U-box E3s, monomeric RING E3s and multi-subunit E3s. See generally Li et al. (PLOS One, 2008, 3. 1487) titled “Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling.”; Bemdsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307) titled “New insights into ubiquitin E3 ligase mechanism”; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) titled “RING domain E3 ubiquitin ligases.”; Spratt et al. (Biochem. 2014, 458, 421-437) titled “RBR E3 ubiquitin ligases: new structures, new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) titled “Roles of F-box proteins in cancer.” UPP plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation. The pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman's syndrome, and Liddle syndrome), in immune surveillance/viral pathogenesis, and in the pathology of muscle wasting. Many diseases are associated with an abnormal UPP and negatively affect cell cycle and division, the cellular response to stress and to extracellular modulators, morphogenesis of neuronal networks, modulation of cell surface receptors, ion channels, the secretory pathway, DNA repair and biogenesis of organelles. Aberrations in the process have recently been implicated in the pathogenesis of several diseases, both inherited and acquired. These diseases fall into two major groups: (a) those that result from loss of function with the resultant stabilization of certain proteins, and (b) those that result from gain of function, i.e. abnormal or accelerated degradation of the protein target. The UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome-dependent degradation. Bifnctional compounds composed of a target protein-binding ligand and an E3 ubiquitin ligase ligand, induced proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression. Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(1):40-46). An ongoing need exists in the art for effective treatments for disease, especially diseases and discorders mediated by pro-inflammatory molecules such as TNFα, IL-1, and IL-6. As such, small molecule therapeutic agents that leverage E3 ligase mediated protein degradation to pro-inflammatory associated proteins such as mitogen-activated protein kinase-activated protein kinase-2 (MAPKAP kinase-2 or MK2) hold promise as therapeutic agents. Accordingly, there remains a need to find compounds that are MK2 degraders useful as therapeutic agents. SUMMARY OF THE INVENTION The present application relates novel bifunctional compounds, which function to recruit MK2 proteins to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof. In particular, the present disclosure provides bifunctional compounds, which find utility as modulators of ta