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CN-121991057-A - IRAK4 targeted degradation compound and application thereof

CN121991057ACN 121991057 ACN121991057 ACN 121991057ACN-121991057-A

Abstract

The present disclosure relates to IRAK4 degrading agent compounds, in particular, compounds of formula (I) or pharmaceutically acceptable salts thereof, having the substituents and structural features described herein. The application also describes a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the use of said compound or a pharmaceutically acceptable salt thereof in medicine.

Inventors

  • GU PENG
  • LIANG QIANQIAN
  • WANG MENGYU
  • ZHOU MINYUN
  • WANG XIN
  • ZHAO XIAOFENG
  • TANG FENG

Assignees

  • 江苏先声药业有限公司

Dates

Publication Date
20260508
Application Date
20251031
Priority Date
20241101

Claims (12)

  1. 1. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, Wherein: R 1 is selected from pyridonyl substituted with one or more R a or pyrazolopyrimidinyl optionally substituted with one or more R b ; R 3 is selected from H, deuterium, halogen, CN, NO 2 、OH、NH 2 、C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl, said OH, NH 2 、C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl optionally substituted with one or more R c ; R a is selected from halogen, CN, =o, OH, NH 2 、C 3 -C 8 saturated or partially saturated carbocyclyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl, said OH, NH 2 、C 3 -C 8 membered saturated or partially saturated carbocyclyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl being optionally substituted with one or more R 1a ; R b is selected from halogen, OH, NH 2 、C 1 -C 4 alkyl, C 3 -C 8 saturated or partially saturated carbocyclyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl, said NH 2 、C 1 -C 4 alkyl, C 3 -C 8 saturated or partially saturated carbocyclyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl optionally substituted with one or more R 1a ; R 1a 、R c is independently selected from deuterium, halogen, CN, =o, OH, NH 2 、C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-8 membered heterocyclyl, said OH, NH 2 、C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-8 membered heterocyclyl being optionally substituted with one or more R d ; R d is selected from deuterium, halogen, OH, NH 2 、＝O、C 1 -C 3 alkyl, C 1 -C 3 alkoxy, CN, COOH, C (O) (C 1 -C 3 alkyl), CONH 2 、C(O)O(C 1 -C 3 alkyl), C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl; The Linker is a connecting unit, and has the structure of Wherein the method comprises the steps of Representative and A linked bond; X 1 、X 2 、X 3 is independently selected from the group consisting of bond, -O-, -N (R 10 ) -, -C (O) -or C 1 -C 6 alkylene, R 10 is H or C 1 -C 6 alkyl; Het 1 、Het 2 is independently selected from a bond, a C 3 -C 8 cycloalkylene group or a 4-8 membered heterocyclylene group, said C 3 -C 8 cycloalkylene group or 4-8 membered heterocyclylene group optionally substituted with halogen or C 1 -C 6 alkyl; DIM is With the proviso that the compound of formula (I) does not include the following compounds or pharmaceutically acceptable salts thereof:
  2. 2. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is selected from the group consisting of substituted with one or more R a Or optionally substituted with one or more R b Or R 1 is substituted with one or more R a Or R 1 is optionally substituted with one or more R b
  3. 3. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R a is selected from CN, =o, OH, NH 2 、C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl, the OH, NH 2 、C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl being optionally substituted with one or more R 1a , or R a is selected from CN, =o or cyclopropyl, the cyclopropyl being optionally substituted with one or more R 1a , or R a is cyclopropyl optionally substituted with one or more R 1a , or R a is
  4. 4. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R b is selected from halogen, OH, NH 2 、C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl, the OH, NH 2 、C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl being optionally substituted by one or more R 1a , or R b is selected from halogen, OH, NH 2 or C 1 -C 4 alkyl, the OH, NH 2 or C 1 -C 4 alkyl being optionally substituted by one or more R 1a , or R b is selected from C 1 -C 4 alkyl, or R b is methyl.
  5. 5. The compound of formula (I), stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein R 3 is selected from H, deuterium, halogen, CN, OH, or C 1 -C 4 alkyl, optionally substituted with one or more R c , or R 3 is selected from H or OH optionally substituted with one R c , or R 3 is OH optionally substituted with one R c , or R 3 is isopropoxy.
  6. 6. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 1a 、R c is independently selected from halogen, CN, =o, OH, NH 2 or C 1 -C 6 alkyl, the OH, NH 2 or C 1 -C 6 alkyl being optionally substituted by one or more R d , or R 1a 、R c is independently selected from halogen or C 1 -C 6 alkyl optionally substituted by one or more R d , or R 1a is selected from methyl or halogen such as F, or R c is selected from C 1 -C 6 alkyl, or R c is isopropyl.
  7. 7. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6, wherein the Linker structure is Wherein the method comprises the steps of Representative and And a connected key.
  8. 8. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein X 1 、X 2 、X 3 is independently selected from the group consisting of a bond, -C (O) -or C 1 -C 3 alkylene, or X 1 、X 2 、X 3 is independently selected from the group consisting of a bond, -C (O) -or methylene; Or X 1 is selected from the group consisting of a bond, -C (O) -or methylene, or X 2 、X 3 is a bond.
  9. 9. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein Het 1 、Het 2 is selected independently from the others from the group consisting of C 3 -C 6 cycloalkylene or 4-7 membered heterocyclylene optionally substituted with halo or C 1 -C 6 alkyl, or Het 1 、Het 2 is selected independently from the others from the group consisting of piperazinyl, piperidinyl, or azetidinyl optionally substituted with halo or C 1 -C 6 alkyl, or Het 1 、Het 2 is selected independently from the group consisting of piperidinyl or azetidinyl, or Het 1 、Het 2 is selected independently from the others from the group consisting of Or Het 1 is Or Het 2 is
  10. 10. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein the compound has a structure selected from one of:
  11. 11. a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 10, and a pharmaceutically acceptable adjuvant.
  12. 12. Use of a compound according to any one of claims 1-10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11 for the manufacture of a medicament for the prevention or treatment of an IRAK4 mediated disease, preferably wherein the IRAK4 mediated disease is selected from a tumor, an inflammatory disease, a neurodegenerative disease or an autoimmune disease.

Description

IRAK4 targeted degradation compound and application thereof Cross Reference to Related Applications The present application claims priority and benefit from the following inventive patent applications, the entire contents of which are hereby incorporated by reference herein in their entirety: 202411552536.4 Chinese patent application submitted to the national intellectual property agency on 1 st 11 th 2024. Technical Field The present disclosure relates to compounds or pharmaceutically acceptable salts thereof as IRAK4 degrading agents, methods of preparing the same, pharmaceutical compositions containing the same, and uses of the same in preventing or treating diseases or conditions mediated by IRAK 4. Background Interleukin-1 receptor kinase 4 (IRAK 4) is a serine/threonine protein kinase, a core regulator in the innate immune response, and plays an important role in activating the immune system. IL-1 receptor and Toll-like receptor bind to their ligands and are activated, followed by recruitment of intracellular myeloid differentiation factor MyD88, myD88 recruits IRAK4 further via its N-terminal death domain, IRAK4 autophosphorylation followed by recruitment and activation of IRAK1 and IRAK2 to form a MyD88-IRAK4-IRAK1/2 complex, signaling downstream to E3 ubiquitin ligase TNF receptor-related factor (TRAF 6), activation of serine/threonine kinase TAK1, further activation of NF-. Kappa.B and MAPK signaling pathways, leading to release of various inflammatory cytokines and proliferation-related factors. Studies have shown that IRAK4 overactivation is associated with a variety of autoimmune diseases, such as atopic dermatitis, hidradenitis suppurativa, rheumatoid arthritis, etc. Whereas IRAK4 deficiency is non-lethal to individuals and, after adulthood, the risk of bacterial infection is reduced, unlike healthy humans. Furthermore, IRAK 4's scaffold function may also modulate downstream signaling pathways and is independent of its kinase function. Studies indicate that mouse macrophages with deleted IRAK4 kinase function can still be induced to activate NF- κb signaling pathway, and that IRAK4 kinase inhibitors cannot block IRAK 4-mediated NF- κb signaling pathway in human monocytes, suggesting that this may be related to insufficient efficacy of the IRAK4 kinase inhibitors in clinical studies. The protein degradation targeting chimeric body (Proteolysis TARGETING CHIMERA, PROTAC) is a bifunctional molecule, one end of the targeting chimeric body is a small molecule inhibitor for identifying target protein, and through a Linker (Linker), the other end of the targeting chimeric body is an E3 ubiquitin ligase ligand capable of identifying E3 ubiquitin ligase, so that a ternary complex is formed, and after ubiquitination of the target protein, the target protein is degraded in vivo through an ubiquitin-proteasome pathway. Traditional IRAK4 small molecule inhibitors can only block the kinase activity of IRAK4, but IRAK4 PROTAC can degrade intracellular IRAK4, so as to simultaneously block the kinase activity of IRAK4 and the biological activity of the scaffold function, and more effectively inhibit IRAK 4-mediated release of downstream inflammatory factors. Thus, there is a need to develop novel IRAK4 PROTAC medicaments for the treatment of IRAK4 related diseases or conditions. Disclosure of Invention The present disclosure relates to a compound of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof: Wherein: R 1 is selected from pyridonyl substituted with one or more R a or pyrazolopyrimidinyl optionally substituted with one or more R b; R 3 is selected from H, deuterium, halogen, CN, NO 2、OH、NH2、C1-C6 alkyl, or C 3-C6 cycloalkyl, said OH, NH 2、C1-C6 alkyl, or C 3-C6 cycloalkyl optionally substituted with one or more R c; R a is selected from halogen, CN, =o, OH, NH 2、C3-C8 saturated or partially saturated carbocyclyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl, said OH, NH 2、C3-C8 membered saturated or partially saturated carbocyclyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl being optionally substituted with one or more R 1a; R b is selected from halogen, OH, NH 2、C1-C4 alkyl, C 3-C8 saturated or partially saturated carbocyclyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl, said NH 2、C1-C4 alkyl, C 3-C8 saturated or partially saturated carbocyclyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl optionally substituted with one or more R 1a; R 1a、Rc is independently selected from deuterium, halogen, CN, =o, OH, NH 2、C1-C6 alkyl, C 3-C6 cycloalkyl or 4-8 membered heterocyclyl, said OH, NH 2、C1-C6 alkyl, C 3-C6 cycloalkyl or 4-8 membered heterocyclyl being optionally substituted with one or more R d; R d is selected from deuterium, halogen, OH, NH 2、＝O、C1-C3 alkyl, C 1-C3 alkoxy, CN, COOH, C (O) (C 1-C3 alkyl), CONH 2、C(O)O(C1-C3 alkyl), C 3-C6 cycloalkyl or 4-6 membered heterocyclyl; The Linker is a connecting