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EP-4735429-A1 - TRIAZINE DERIVATIVES AS NLRP3 INHIBITORS

EP4735429A1EP 4735429 A1EP4735429 A1EP 4735429A1EP-4735429-A1

Abstract

The invention relates to novel compounds having the general formula (I) wherein A, R 1 , R 2 and n are as described herein, composition including the compounds and methods of using the compounds.

Inventors

  • BON, David
  • TOSSTORFF, Andreas Michael
  • BOUCHE, Lea Aurelie
  • GUBA, WOLFGANG
  • HARGRAVE, Emma
  • JAESCHKE, Georg Stefan
  • JOHNSTON, Heather Jennifer
  • MESCH, Stefanie Katharina
  • SCHNIDER, CHRISTIAN
  • STEINER, SANDRA

Assignees

  • F. Hoffmann-La Roche AG

Dates

Publication Date
20260506
Application Date
20240627

Claims (16)

  1. 1. A compound of formula I wherein, A is — O~ or CH2; R 1 is hydroxyalkyl or acetyl; R 2 is alkyl; n is 0 or 1; wherein if n is 0 then A is CH2. and pharmaceutically acceptable salts thereof.
  2. 2. A compound according to claim 1, wherein R 1 is hydroxyalkyl.
  3. 3. A compound according to claim 1 to 2, wherein R 2 is methyl.
  4. 4. A compound according to any one of claims 1 to 3, selected from 3-(4-Hydroxy-2,3-dihydrobenzofuran-5-yl)-6-[[(3A)-l-(2-hydroxyethyl)-3- piperidyl]amino]-4-methyl-l,2,4-triazin-5-one; 6-[[(3A)-l-(2-Hydroxyethyl)-3-piperidyl]amino]-3-(4-hydroxyindan-5-yl)-4-methyl- l,2,4-triazin-5-one; and pharmaceutically acceptable salts thereof.
  5. 5. A compound according to any one of claims 1 to 3, selected from 3-(4-hydroxyindan-5-yl)-6-[[(3R)-l-(3-hydroxypropyl)-3-piperidyl]amino]-4-methyl- l,2,4-triazin-5-one; 3-(2-hydroxy-3-bicyclo[4.2.0]octa-l(6),2,4-trienyl)-6-[[(3R)-l-(2-hydroxyethyl)-3- piperidyl]amino]-4-methyl-l,2,4-triazin-5-one; and pharmaceutically acceptable salts thereof.
  6. 6. A compound according to claim 1, wherein the compound is 6-[[(3R)-l-Acetyl-3- piperidyl]amino]-3-(4-hydroxyindan-5-yl)-4-methyl-l,2,4-triazin-5-one, or a pharmaceutically acceptable salts thereof.
  7. 7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and a therapeutically inert carrier.
  8. 8. A compound according to any one of claims 1 to 6 for use as a therapeutically active substance.
  9. 9. A compound according to any one of claims 1 to 6 for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.
  10. 10. A compound according to any one of claims 1 to 6 for the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.
  11. 11. The use of a compound according to any one of claims 1 to 6 for the treatment or prophylaxis of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.
  12. 12. The use of a compound according to any one of claims 1 to 6 in the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.
  13. 13. The use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.
  14. 14. A method of inhibiting NLRP3, which method comprises administering an effective amount of a compound as claimed in any one of claims 1 to 6 to inhibit NLRP3.
  15. 15. A method for the treatment or prophylaxis of a disease, disorder or condition, which method comprises administering an effective amount of a compound according to any one of claims 1 to 6 wherein the disease, disorder or condition is selected from Asthma or COPD.
  16. 16. The invention as hereinbefore described.

Description

TRIAZINE DERIVATIVES AS NLRP3 INHIBITORS Field of the Invention 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 novel compounds of formula I wherein, A is — O~ or CH2; R1 is hydroxyalkyl or acetyl; R2 is alkyl; n is 0 or 1; wherein if n is 0 then A is CH2. and pharmaceutically acceptable salts thereof. Furthermore, the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers. Background of the Invention The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activity is pathogenic in inherited disorders such as cryopyrin-associated periodic syndromes (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer’s disease and atherosclerosis. NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC then polymerises to form a large aggregate known as an ASC speck. Polymerised ASC in turn interacts with the cysteine protease caspase- 1 to form a complex termed the inflammasome. This results in the activation of caspase- 1, which cleaves the precursor forms of the proinflammatory cytokines IL- ip and IL- 18 (termed pro-IL-ip and pro-IL-18 respectively) to thereby activate these cytokines. Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis. The ASC speck can also recruit and activate caspase-8, which can process pro-IL-ip and pro-IL-18 and trigger apoptotic cell death. Caspase- 1 cleaves pro-IL-ip and pro-IL-18 to their active forms, which are secreted from the cell. Active caspase-1 also cleaves gasdermin-D to trigger pyroptosis. Through its control of the pyroptotic cell death pathway, caspase- 1 also mediates the release of alarmin molecules such as IL-33 and high mobility group box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL- 1R2 resulting in its degradation and allowing the release of IL-la. In human cells caspase-1 may also control the processing and secretion of IL-37. A number of other caspase-1 substrates such as components of the cytoskeleton and glycolysis pathway may contribute to caspase-1- dependent inflammation. NLRP3 -dependent ASC specks are released into the extracellular environment where they can activate caspase-1, induce processing of caspase-1 substrates and propagate inflammation. Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to shape the immune response to infection and injury. For example, IL-ip signalling induces the secretion of the pro-inflammatory cytokines IL-6 and TNF. IL-ip and IL- 18 synergise with IL-23 to induce IL- 17 production by memory CD4 Th 17 cells and by y5 T cells in the absence of T cell receptor engagement. IL- 18 and IL-12 also synergise to induce IFN-y production from memory T cells and NK cells driving a Thl response. The inherited CAPS diseases 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 defining NLRP3 as a critical component of the inflammatory process. NLRP3 has also been implicated in the pathogenesis of a number of complex diseases, notably including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout. A role for NLRP3 in diseases of the central nervous system is emerging, and lung diseases have also been shown to be influenced by NLRP3. NLRP3 has also been suggested to have a role in a number of central nervous system conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis (Walsh et al., Nature Reviews, 15: 84-97, 2014, and Dempsey et al. Brain. Behav. Immun. 201761 : 306-316). NLRP3 has also been shown to play a role in a number of lung diseases including chronic obstructive pulmonary disorder (COPD), asthma (including steroid- resistant asthma), asbestosis, and silicosis (De Nardo et al., Am. J. Pathol., 184: 42-54, 2014 and Kim et al. Am J Respir Crit Care Med. 2017 196(3): 283-97). Furthermore, NLRP3 has a role in the development of liver disease, kidney disease and aging. Many of these associations were defined using Nlrp3~ ~ mice, but there have also been insights into the specific activation of NLRP3 in these diseases. In type 2 diabetes mellitus (T2D), the deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-ip signalling, resulting in cell death and inflammation. Several small molecules have been shown