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RU-2861618-C2 - TRIAZINE DERIVATIVES AND THEIR USE IN TREATMENT OF CANCER

RU2861618C2RU 2861618 C2RU2861618 C2RU 2861618C2RU-2861618-C2

Abstract

FIELD: pharmaceutics. SUBSTANCE: invention relates to a novel compound of formula Ib or a pharmaceutically acceptable salt thereof, which have NLRP3 inhibitory activity. In formula Ib, R 1 and R 5 together with the atoms to which they are attached form either a 4-6 membered heterocyclic ring containing one O heteroatom, or R 1 and R 5 together with the atoms to which they are attached form a 3-6 membered cycloalkyl ring; R 2 represents H; R 3 represents methyl; Z represents -NH-; R 4 represents a piperidine ring substituted with C1-4alkyl. The invention also relates to specific compounds corresponding to formula Ib, a pharmaceutical composition containing them, their use and a method for inhibiting NLRP3 using them. EFFECT: treatment or prevention of a disease, disorder or condition responsive to NLRP3 inhibition. 8 cl, 1 dwg, 2 tbl, 34 ex

Inventors

  • BUSH, Lea Oreli
  • GUBA, Volfgang
  • ESHKE, Georg
  • MESH, Shtefani Katarina
  • PATINI-ADAM, Anzhelik
  • SHNIDER, Kristian
  • STEJNER, Sandra
  • TOSSTORFF, Andreas Mikhel

Dates

Publication Date
20260506
Application Date
20220602
Priority Date
20210604

Claims (13)

  1. 1. Compound of formula Ib
  2. where R 1 and R 5 and the atoms to which they are bonded form either a 4- to 6-membered heterocyclic ring containing one O heteroatom, or R 1 and R 5 and the atoms to which they are bonded form a 3- to 6-membered cycloalkyl ring;
  3. R 2 is H;
  4. R 3 is methyl;
  5. Z represents -NH-;
  6. R 4 is a piperidine ring substituted with C 1-4 alkyl;
  7. and its pharmaceutically acceptable salt.
  8. 2. The compound 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol or a pharmaceutically acceptable salt thereof.
  9. 3. The compound 3-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol or a pharmaceutically acceptable salt thereof.
  10. 4. The compound 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]indan-4-ol or a pharmaceutically acceptable salt thereof.
  11. 5. A pharmaceutical composition having inhibitory activity against NLRP3, containing an effective amount of a compound according to any one of claims 1-4 and a therapeutically inert carrier.
  12. 6. The use of a compound according to any one of claims 1 to 4 for the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition responds to inhibition of NLRP3.
  13. 7. A method for inhibiting NLRP3, comprising administering an effective amount of a compound according to any one of claims 1-4 for inhibiting NLRP3.

Description

AREA OF TECHNOLOGY The present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular to compounds that modulate NLRP3 inhibition. The present invention provides new compounds of formula 1b Where R 1 is H, halogen, alkyl, haloalkyl, haloalkoxy, or nitrile; R 5 is H; or R 1 and R 5 and the atoms to which they are bonded form either a 4- to 6-membered heterocyclic ring containing one O heteroatom optionally substituted with one or two substituents independently selected from halogen or alkyl, or R 1 and R 5 and the atoms to which they are bonded form a 3- to 6-membered cycloalkyl ring optionally substituted with one or two substituents independently selected from halogen or alkyl; R 2 is H, halogen, alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halogen or haloalkoxy; R 3 is H, alkyl, haloalkyl or cycloalkyl optionally substituted with halogen; Z represents -O-, -NH-, or -NHCH 2 -; R 4 is a heterocyclic ring optionally substituted with 1-2 substituents independently selected from halogen, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO 2 H, or cycloalkyl optionally substituted with halogen; or R 4 is cycloalkyl optionally substituted with 1-3 substituents independently selected from alkyl, halogen, haloalkyl and OH; and pharmaceutically acceptable salts. Furthermore, the present invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers. LEVEL OF TECHNOLOGY The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammasome, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndromes (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes mellitus, Alzheimer's disease, and atherosclerosis. NLRP3 is an intracellular signaling molecule that senses many pathogenic, environmental, and host factors. Upon activation, NLRP3 binds to the apoptosis-associated regulatory protein speck-like (ASC), which contains the activation and recruitment domain of caspases. ASC then polymerizes to form a large aggregate known as ASC-speck. The polymerized ASC, in turn, interacts with the cysteine protease caspase-1 to form a complex called the inflammasome. This leads to the activation of caspase-1, which cleaves the precursor forms of the proinflammatory cytokines IL-1β and IL-18 (referred to as pro-IL-1β and pro-IL-18, respectively), thereby activating these cytokines. Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis. ASC-speck can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 and trigger apoptotic cell death. Caspase-1 cleaves pro-IL-1β and pro-IL-18 to their active forms, which are secreted from the cell. Active caspase-1 also cleaves gasdermin D, inducing pyroptosis. By controlling the pyroptotic cell death pathway, caspase-1 also mediates the release of alarmin molecules such as IL-33 and high-mobility group protein 1 (HMGB1). Caspase-1 also cleaves intracellular IL- 1R2 , leading to its degradation and the release of IL-1α. In human cells, caspase-1 can also control the processing and secretion of IL-37. A number of other caspase-1 substrates, such as cytoskeletal components and the glycolytic pathway, can contribute to caspase-1-dependent inflammation. NLRP3-dependent ASC-speck are released into the extracellular environment where they can activate caspase-1, induce the processing of caspase-1 substrates, and propagate inflammation. Active cytokines produced by NLRP3 inflammasome activation are important inflammatory drivers and interact with other cytokine pathways to shape the immune response to infection and injury. For example, IL-1β signaling induces the secretion of the proinflammatory cytokines IL-6 and TNF. IL-1β and IL-18 interact with IL-23 to induce IL-17 production by memory CD4 Th17 cells and γδ T cells in the absence of T cell receptor engagement. IL-18 and IL-12 also act synergistically to induce IFN-γ production by memory T cells and NK cells, which drive the Th1 response. The inherited disorders CAPS Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID) are caused by gain-of-function mutations in NLRP3, thus identifying NLRP3 as a critical component of the inflammatory process. NLRP3 is also implicated in the pathogenesis of a number of complex diseases, including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout. The role of NLRP3 in diseases of the central nervous system is becoming increasingly known, and NLRP3 has also been shown to influence lung diseases. Furthermore, NLRP3 plays a role in the development of liver and kidney diseases, as well as aging. Many of these associations were identified using Nlrp3 -/- mice, but specific activation of NLR