WO2024099992A1 - Dérivés de triazinone utilisés en tant qu'inhibiteurs de nlrp3 - Google Patents

Dérivés de triazinone utilisés en tant qu'inhibiteurs de nlrp3 Download PDF

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Publication number
WO2024099992A1
WO2024099992A1 PCT/EP2023/080895 EP2023080895W WO2024099992A1 WO 2024099992 A1 WO2024099992 A1 WO 2024099992A1 EP 2023080895 W EP2023080895 W EP 2023080895W WO 2024099992 A1 WO2024099992 A1 WO 2024099992A1
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Prior art keywords
methyl
pyrrolo
pyridin
hexahydro
triazin
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PCT/EP2023/080895
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English (en)
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Lea Aurelie BOUCHE
Wolfgang Guba
Georg Jaeschke
Stefanie Katharina MESCH
Jonathan Martin SHANNON
Sandra Steiner
Andreas Michael TOSSTORFF
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F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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Publication of WO2024099992A1 publication Critical patent/WO2024099992A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • 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,
  • R 1 is H, alkyl, alkoxy, -CN, halo, haloalkyl, haloalkoxy, acetyl or SFe;
  • R 5 is H; or R 1 and R 5 , and the atoms to which they are bonded, form either an 4-6 membered heterocycle ring comprising a single O heteroatom optionally substituted with one or two substituents independently selected from halo or alkyl, or R 1 and R 5 , and the atoms to which they are bonded, form a 4-6 membered cycloalkyl ring optionally substituted with 1 to 2 substituents independently selected from halo or alkyl;
  • R 2 is H, halo or alkyl and R 3 is H or alkyl, wherein only one of R 2 and R 3 can be H;
  • R 4 is oxetane, alkyl, or -(CH2) n -R 6 wherein R 6 is hydroxy or methoxy and n is greater than 1; and pharmaceutically acceptable salts thereof.
  • the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers.
  • NLR NOD-like receptor
  • NLRP3 pyrin domain-containing protein 3
  • 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.
  • ASC caspase activation and recruitment domain
  • 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.
  • 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 y6 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.
  • NLRP3 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.
  • 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).
  • Parkinson's disease PD
  • AD Alzheimer's disease
  • dementia Huntington's disease
  • cerebral malaria brain injury from pneumococcal meningitis
  • 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 Nlrpi- ⁇ 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.
  • COPD chronic obstructive pulmonary disorder
  • asthma including steroid-resistant asthma
  • asbestosis asbestosis
  • silicosis
  • Glyburide inhibits IL-ip production at micromolar concentrations in response to the activation of NLRP3 but not NLRC4 or NLRP1.
  • Other previously characterised weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-P-nitrostyrene and dimethyl sulfoxide (DMSO), although these agents have limited potency and are nonspecific.
  • NLRP3-related diseases include biologic agents that target IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-ip antibody canakinumab and the soluble decoy IL-1 receptor rilonacept. These approaches have proven successful in the treatment of CAPS, and these biologic agents have been used in clinical trials for other IL-ip-associated diseases.
  • the present invention provides novel compounds of formula I wherein,
  • R 1 is H, alkyl, alkoxy, -CN, halo, haloalkyl, haloalkoxy, acetyl or SFe;
  • R 5 is H; or R 1 and R 5 , and the atoms to which they are bonded, form either an 4-6 membered heterocycle ring comprising a single O heteroatom optionally substituted with one or two substituents independently selected from halo or alkyl, or R 1 and R 5 , and the atoms to which they are bonded, form a 4-6 membered cycloalkyl ring optionally substituted with 1 to 2 substituents independently selected from halo or alkyl;
  • R 2 is H, halo or alkyl and R 3 is H or alkyl, wherein only one of R 2 and R 3 can be H;
  • R 4 is oxetane, alkyl, or -(CH2) n -R 6 wherein R 6 is hydroxy or methoxy and n is greater than 1; and pharmaceutically acceptable salts thereof.
  • alkyl denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms. In some embodiments, if not otherwise described, alkyl comprises 1 to 6 carbon atoms (Ci-6-alkyl), or 1 to 4 carbon atoms (Ci-4-alkyl).
  • Ci-6-alkyl examples include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl. Particular alkyl group is methyl.
  • alkoxy denotes a group of the formula -O-R’, wherein R’ is a Ci-6-alkyl group.
  • Ci-6-alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.
  • cycloalkyl denotes monocyclic or polycyclic saturated or partially unsaturated, non-aromatic hydrocarbon. In some embodiments, unless otherwise described, cycloalkyl comprises 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and octahydropentalenyl, and the like. Particular example is cyclobutyl. Another particular example is cyclopentyl.
  • halogen halide and halo are used interchangeably herein and denote fluoro, chloro, bromo or iodo. Particular halogens are fluoro and chloro. Preferred halogen is fluoro.
  • haloalkyl denotes a Ci-6-alkyl group wherein at least one of the hydrogen atoms of the Ci-6-alkyl group has been replaced by the same or different halogen atoms.
  • Example of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl. Particular example is tri fluoromethyl.
  • haloalkoxy denotes a Ci-6-alkoxy group wherein at least one of the hydrogen atoms of the Ci-6-alkoxy group has been replaced by the same or different halogen atoms.
  • haloalkoxy are difluoromethoxy, trifluoromethoxy, difluoroethoxy and trifluoroethoxy. Particular examples are difluoromethoxy and trifluromethoxy.
  • heterocycle ring denotes a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 4 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
  • Examples for monocyclic saturated heterocycle rings are azetidinyl, diazepanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, and piperazinyl.
  • Examples of polycyclic saturated heterocycle rings are azaspiroheptanyl, diazaspiroheptanyl.
  • azaspirooctanyl diazospirooctanyl, diazaspirononanyl, oxaazaspirooctanyl, and oxadiazaspirononanyl.
  • a heterocycle ring is a saturated furanyl ring.
  • hydroxy denotes a -OH group.
  • salts refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
  • the salts are formed with inorganic acids such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, particularly hydrochloric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein.
  • salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts.
  • Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins.
  • the compound of formula I can also be present in the form of zwitterions.
  • Particularly preferred pharmaceutically acceptable salts of compounds of formula I are the salts formed with formic acid and the salts formed with hydrochloric acid yielding a hydrochloride, dihydrochloride or trihydrochloride salt.
  • the abbreviation uM means microMolar and is equivalent to the symbol pM.
  • the abbreviation uL means microliter and is equivalent to the symbol pL.
  • the abbreviation ug means microgram and is equivalent to the symbol pg.
  • the compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • the asymmetric carbon atom can be of the "R” or "S” configuration.
  • an embodiment of the present invention provides compounds according to formula I as described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula I as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula I as described herein.
  • An embodiment of the present invention provides compounds according to formula I as described herein, where R 1 is H, alkyl, alkoxy, halo, haloalkyl, or haloalkoxy;
  • An embodiment of the present invention provides compounds according to formula I as described herein, wherein R 1 is haloalkyl or haloalkoxy.
  • An embodiment of the present invention provides compounds according to formula I as described herein, wherein R 2 is H and R 3 is alkyl.
  • An embodiment of the present invention provides compounds according to formula I as described herein, wherein R 4 is alkyl or -(CH2) n -R 6 wherein R 6 is hydroxy and n is 2.
  • An embodiment of the present invention provides compounds according to formula I as described herein, wherein R 4 is alkyl.
  • An embodiment of the present invention provides compounds according to formula I as described herein, wherein R 1 and R 5 , with the atoms to which they are attached, form a 4-to-5 membered cycloalkyl or a 5-membered heterocycle comprising a single O heteroatom.
  • An embodiment of the present invention provides compounds according to formula I as described herein, wherein
  • R 1 is haloalkyl or haloalkoxy
  • R 5 is H; or R 1 and R 5 , with the atoms to which they are attached, form a 4-to-5 membered cycloalkyl or a 5-membered heterocycle comprising a single O heteroatom;
  • R 2 is H
  • R 3 is alkyl
  • R 4 is alkyl or -(CH2) n -R 6 wherein R 6 is hydroxy and n is 2. and pharmaceutically acceptable salts thereof.
  • An embodiment of the present invention provides compounds according to formula I as described herein, wherein
  • R 1 is haloalkyl or haloalkoxy
  • R 5 is H; or R 1 and R 5 , with the atoms to which they are attached, form a 4-to-5 membered cycloalkyl or a 5-membered heterocycle comprising a single O heteroatom;
  • R 2 is H
  • R 3 is alkyl
  • R 4 is alkyl; and pharmaceutically acceptable salts thereof.
  • Another preferred examples of compounds of formula I as described herein is 6- [(3aS,7aR)-6-Methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-l-yl]-3-(4- hydroxyindan-5-yl)-4-methyl-l,2,4-triazin-5-one, or a pharmaceutically acceptable salt thereof.
  • the compound of formula I may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8.
  • a compound of formula I is formulated in an acetate buffer, at pH 5.
  • the compound of formula I is sterile.
  • the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
  • compositions are formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing
  • the compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical formulations Lactose, com starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.
  • Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
  • Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
  • Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
  • Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
  • Suitable adjuvants for topical ocular formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.
  • the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • the formulation can contain 0.001% to 15% by weight of medicament and the required dose, which can be between 0.1 and 25 mg in can be administered either by single dose per day or per week, or by multiple doses (2 to 4) per day, or by multiple doses per week It will, however, be clear that the upper or lower limit given herein can be exceeded when this is shown to be indicated.
  • An embodiment of the present invention is a compound according to formula I as described herein for use as a therapeutically active substance.
  • An embodiment of the present invention is a compound according to formula I as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.
  • An embodiment of the present invention is a compound according to formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.
  • NLRP3 inhibition refers to the complete or partial reduction in the level of activity of NLRP3 and includes, for example, the inhibition of active NLRP3 and/or the inhibition of activation of NLRP3.
  • the disease, disorder or condition is selected from:
  • the disease, disorder or condition is selected from:
  • the disease, disorder or condition is inflammation.
  • inflammation examples include inflammatory responses occurring in connection with, or as a result of: (i) a skin condition such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopical dermatitis, contact dermatitis, allergic contact dermatitis, seborrhoetic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythemas, or alopecia;
  • a skin condition such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopical dermatitis, contact dermatitis, allergic contact dermatitis, seborrhoetic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythemas, or alopecia;
  • a joint condition such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still’s disease, relapsing polychondritis, rheumatoid arthritisjuvenile chronic arthritis, gout, or a seronegative spondyloarthropathy (e.g. ankylosing spondylitis, psoriatic arthritis or Reiter’s disease);
  • a muscular condition such as polymyositis or myasthenia gravis
  • a gastrointestinal tract condition such as inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), colitis, gastric ulcer, Coeliac disease, proctitis, pancreatitis, eosinopilic gastro-enteritis, mastocytosis, antiphospholipid syndrome, or a food-related allergy which may have effects remote from the gut (e.g., migraine, rhinitis or eczema);
  • a respiratory system condition such as chronic obstructive pulmonary disease (COPD), asthma (including eosinophilic, bronchial, allergic, intrinsic, extrinsic or dust asthma, and particularly chronic or inveterate asthma, such as late asthma and airways hyper-responsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, rhinitis caseosa, hypertrophic rhinitis, rhinitis pumlenta, rhinitis sicca, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis e.g.
  • COPD chronic obstructive pulmonary disease
  • asthma including eosinophilic, bronchial, allergic, intrinsic, extrinsic or dust asthma, and particularly chronic or inveterate asthma, such as late asthma and airways hyper-responsiveness
  • bronchitis
  • hay fever, and vasomotor rhinitis sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer’s lung, silicosis, asbestosis, volcanic ash induced inflammation, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia;
  • IPF idiopathic pulmonary fibrosis
  • sarcoidosis farmer’s lung, silicosis, asbestosis, volcanic ash induced inflammation, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia
  • vascular condition such as atherosclerosis, Behcet’s disease, vasculitides, or Wegener’s granulomatosis;
  • an autoimmune condition such as systemic lupus erythematosus, Sjogren’s syndrome, systemic sclerosis, Hashimoto’s thyroiditis, type I diabetes, idiopathic thrombocytopenia purpura, or Graves disease;
  • an ocular condition such as uveitis, allergic conjunctivitis, or vernal conjunctivitis;
  • a nervous condition such as multiple sclerosis or encephalomyelitis
  • x an infection or infection-related condition, such as Acquired Immunodeficiency Syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, mycobacterium tuberculosis (including mycobacterium tuberculosis and HIV co-infection), mycobacterium avium intracellulare, pneumocystis carinii pneumonia, orchitis/epidydimitis, legionella, Lyme disease, influenza A, Epstein-Barr virus infection, viral encephalitis/aseptic meningitis, or pelvic inflammatory disease;
  • AIDS Acquired Immunodeficiency Syndrome
  • acute or chronic bacterial infection such as acute or
  • a renal condition such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerular nephritis, obesity related glomerulopathy, acute renal failure, acute kidney injury, uremia, nephritic syndrome, kidney fibrosis including chronic crystal nephropathy, or renal hypertension;
  • xiii a condition of, or involving, the immune system, such as hyper IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft versus host disease;
  • a hepatic condition such as chronic active hepatitis, non-alcoholic steatohepatitis (NASH), alcohol-induced hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, liver fibrosis, or liver failure;
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • AFLD alcoholic fatty liver disease
  • ASH alcoholic steatohepatitis
  • primary biliary cirrhosis fulminant hepatitis
  • liver fibrosis or liver failure
  • xvii radiation exposure
  • xviii a metabolic disease such as type 2 diabetes (T2D), atherosclerosis, obesity, gout or pseudo-gout; and/or
  • (xix) pain such as inflammatory hyperalgesia, pelvic pain, allodynia, neuropathic pain, or cancer-induced bone pain.
  • An embodiment of the present invention is a compound according to formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from:
  • An embodiment of the present invention is the use of a compound according to formula I as described herein in the treatment or prophylaxis of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.
  • An embodiment of the present invention is the use of a compound according to formula I as described herein in the treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease.
  • An embodiment of the present invention is the use a compound according to formula I as described herein for use in the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.
  • An embodiment of the present invention is a compound according to formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease.
  • An embodiment of the present invention is a compound according to formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.
  • An embodiment of the present invention is the use of a compound according to formula I as described herein for preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease.
  • An embodiment of the present invention is the use of a compound according to formula I as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.
  • An embodiment of the present invention is a method of treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease, which method comprises administering an effective amount of a compound according to formula I as described herein.
  • An embodiment of the present invention is a method of treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD, which method comprises administering an effective amount of a compound according to formula I as described herein.
  • An embodiment of the present invention relates to a method of inhibiting NLRP3, which method comprises administering an effective amount of a compound according to formula I as described herein. Also an embodiment of the present invention are compounds of formula I as described herein, when manufactured according to any one of the described processes.
  • An embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to formula I as described herein and a therapeutically inert carrier.
  • THP-1 cells (ATCC # TIB-202) were grown in RPMI containing L-glutamine (Gibco #11835) supplemented with ImM sodium pyruvate (Sigma # S8636) and penicillin (lOOunits/ml) / streptomycin (O.lmg/ml) (Sigma # P4333) in 10% Fetal Bovine Serum (FBS) (Sigma # F0804). The cells were routinely passaged and grown to confluency ( ⁇ 10 6 cells/ml). On the day of the experiment, THP-1 cells were harvested and resuspended into RPMI medium (without FBS). The cells were then counted and viability (>90%) checked by Trypan blue (Sigma # T8154).
  • IC50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)
  • IL-ip was measured according to the manufacturer protocol (Perkin Elmer- AlphaLisa IL-1 Kit AL220F-5000)
  • the CHO crelox hERG cell line (ATCC reference Nr. PTA-6812, female Chinese hamster cells) was generated and validated at Roche. Ready-to-use frozen instant CHO-hERG cells were cryopreserved at Evotec (Germany) and used directly in the experiments.
  • the extracellular solution contains (in mM): NaCl 150; KC1 4; CaCh 1; MgCh 1; HEPES 10; pH 7.2-7.4 with NaOH, osmolarity 290-330 mOsm.
  • the hERG test is performed using automated patch clamp system SynchroPatch® 384 (Nanion Technologies GmbH, Germany). K+ currents are measured with the patch-voltage- clamp technique in the whole-cell configuration at 35-37°C.
  • Cells were held at a resting voltage of -80 mV and they were stimulated by a voltage pattern shown in Figure 1 (pulse pattern used to elicit outward K + current at 35-37°C) to activate hERG channels and conduct outward IKhERG current, at a stimulation frequency of 0.1 Hz (6 bpm)
  • the general assay uses transfected LLC-PK1 cells (porcine kidney epithelial cells) overexpressing human or mouse P-gp, cultured on 96 well semi-permeable filter membrane plates, where they form a polarized monolayer with tight junctions, and act as a barrier between the apical and basolateral compartment.
  • P-gp is expressed in the apical-facing membrane of the monolayer.
  • the tightness of the cell monolayer and functional activity of P-gp are confirmed by addition of a cell-impermeable marker, Lucifer yellow, and a reference P-gp substrate, edoxaban, respectively.
  • PAMPA Parallel Artificial Membrane Permeability Assay
  • the PAMPA assay mimics the transcellular absorption conditions using an artificial phospholipid membrane. This assay determines a permeability value that can be used for compound optimization and ranking purposes as well as input parameters for in silico models to predict intestinal absorption.
  • the donor concentration is measured at t-start (reference) and compared with the donor and acceptor concentration after a certain time (t-end) to calculate the extent of passage of the compound through the membrane.
  • Incubations of test compounds at 1 pM in microsomes (0.5 mg/mL) plus cofactor NADPH are performed in 96 well plates at 37°C on a TEC AN (Tecan Group Ltd, Switzerland) automated liquid handling system. After a 10 minutes pre-incubation step of the test compound with the microsomes, the enzymatic reaction is started by the addition of cofactors. At 1, 3, 6, 9, 15, 25, 35 and 45 minutes, aliquots of the incubations are removed and quenched with 1 :3 (v/v) acetonitrile containing internal standard. Samples are then cooled and centrifuged before analysis of the supernatant by LC-MS/MS 2.
  • Table 1 NLRP3 inhibitory activity
  • Table 2 hERG inhibition assay
  • the pure enantiomers or diastereomers can be obtained by methods described herein or by methods known to those skilled in the art, such as e.g. chiral chromatography or crystallization.
  • Step A 2-[(4-Methoxyphenyl)methyl]-4-methyl-6-(6-methyl-3, 3 a, 4,5,7, 7a-hexahydro-2//- pyrrolo[2,3 -c]pyridin- 1 -yl)- 1 ,2,4-triazine-3 ,5-dione
  • Step B 4-Methyl-6-(6-methyl-3, 3a, 4,5,7, 7a-hexahydro-2J/-pyrrolo[2,3-c]pyri din-l-yl)-2J/-l, 2,4- triazine-3, 5-dione
  • 2-[(4-methoxyphenyl)methyl]-4-methyl-6-(6-methyl-3, 3a, 4,5,7, 7a-hexahydro- 2J/-pyrrolo[2,3-c]pyridin-l-yl)-l, 2, 4-triazine-3, 5-dione (step A) (603 mg, 1.56 mmol, 1.0 eq) in DCM (3 mL) and MeCN (1.5 mL) was added trifluoromethanesulfonic acid (360 pL, 4.07 mmol, 2.6 eq).
  • Step C 3-Chloro-4-methyl -6-(6-methyl-3, 3a, 4,5,7, 7a-hexahydro-2J/-pyrrolo[2,3-c]pyri din-1 -yl)- l,2,4-triazin-5-one
  • step B Aforementioned 4-methyl-6-(6-methyl-3, 3a, 4,5,7, 7a-hexahydro-2J/-pyrrolo[2,3-c]pyri din-l-yl)- 2J/-1, 2, 4-triazine-3, 5-dione (step B) (503 mg, 1.90 mmol, 1.0 eq) was added to a stirred solution of phosphorus oxychloride (5.0 mL, 53.6 mmol, 28.3 eq) and the reaction was heated to 100 °C for 16 h. The reaction was diluted with further phosphorus oxychloride (5.0 mL, 53.6 mmol, 28.3 eq) and heated to 100 °C for an additional 24 h.
  • Step A 1 -Bromo-4-(difluoromethoxy)-2-methoxy-benzene
  • Step B 2-[4-(Difluoromethoxy)-2-methoxy-phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane
  • step A A solution of l-bromo-4-(difluoromethoxy)-2-methoxy-benzene (step A) (2.05 g, 8.10 mmol, 1.0 eq), bis(pinacolato)diboron (2.67 g, 10.5 mmol, 1.3 eq), Potassium acetate (2.67 g, 27.2 mmol, 3.35 eq), Xphos (82.0 mg, 0.17 mmol, 0.02 eq) and Xphos Pd G3 (410.0 mg, 0.48 mmol, 0.06 eq) in isopropyl acetate (50 mL) was heated to 90 °C under a nitrogen atmosphere and stirred at this temperature for 16.
  • Step B 5-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol
  • reaction was cooled degassed and additional saturated aqueous sodium carbonate (250 pL, 2.67 mmol, 3.67 eq) and xphos Pd g3 (35.0 mg, 0.04 mmol, 0.06 eq) was added and the reaction was heated at 80 °C and stirred for a further 18 h.
  • the reaction mixture was concentrated and loaded onto some celite then added to a plug of celite and rinsed with EtOAc (100 mL).
  • At-column dilution pump gives 2 mL min' 1 Methanol over the entire method, which is included in the following MeCN percentages.
  • the clean fractions were combined and evaporated to afford the title compound (86 mg, 29%) as a light-yellow solid.
  • Example 1 (80.6 mg) was dissolved in MeOH (3 mL), filtered and was then separated by chiral SFC on a Waters prep 100 with a PDA and a QDA detectors, 40 °C, 120 bar.
  • the column was a Lux® 5 pM Amylose- 1, LC Column 250 x 21.2 mm, AXIATM Packed (Phenomenex®); flow rate 65 mL/ min of 30 % ethanol (0.4 % triethylamine), 70 % CO2.
  • the clean fractions were pooled, rinsed with methanol and concentrated to dryness using a rotary evaporator. The residues were redissolved in methanol, transferred into final vials and evaporated on a Biotage VI 0.
  • Enantiomer 1 A 6- 1 (3a.S.7a/?)-6-M et hy 1-3.3a.4.5.7.7a-hexa hyd ro-2//-pyrrolo [2 ,3-c] pyridin- l-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-l,2,4-triazin-5-one
  • Enantiomer IB 6-
  • At-column dilution pump gives 2 mL min' 1 Methanol over the entire method, which is included in the following MeCN percentages.
  • the clean fractions were evaporated in a Genevac and then dissolved in MeOH (5 mL) with sonication, filtered and was then separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210 - 400 nm, 40 °C, 120 bar.
  • the column was a Phenomenex Lux Al 10X250 mm, 5pm, flow rate 15 mL/min at 60% MeOH (0.2% DEA), 40% CO2.
  • the clean fractions were pooled, rinsed with methanol and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in methanol, transferred into final vials and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30 °C/5 mbar over the weekend to afford Enantiomer 2A (13.9 mg, 4.74%) and 2B (14.2 mg, 5%) both as a light brown freeze-dried solid for which the stereochemistry was arbitrarily assigned.
  • Enantiomer 2A 6-
  • Enantiomer 2B 6- [(3a/?,7a5)-6-Methyl-3,3a,4,5,7,7 a-hexa hy d ro-2//-py r rolo [2 ,3-c] pyridin- l-yl]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-l,2,4-triazin-5-one
  • Step A 3-[4-(Difluoromethoxy)-2-methoxy-phenyl]-4-methyl-6-(6-methyl-3,3a,4,5,7,7a- hexahydro-2Z7-pyrrolo[2,3-c]pyridin-l-yl)-l,2,4-triazin-5-one
  • Step B 3-[4-(Difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-6-(6-methyl-3,3a,4,5,7,7a- hexahydro-2J/-pyrrolo[2,3-c]pyridin-l-yl)-l,2,4-triazin-5-one
  • step A (296 mg, 0.7 mmol, 1.0 eq), potassium carbonate (292 mg, 2.11 mmol, 3.01 eq) and NMP (3 m ) were placed in a microwave vial, sonicated and sealed, benzenethiol (76.0 pL, 0.74 mmol, 1.06 eq) was added and the reaction mixture irradiated in a biotage microwave for 65 mins at 120 °C.
  • reaction mixture was filtered and then added directly onto a basic RP column (Cis, 43 g cartridge, 10-100%, eluting at 35% to give, after concentration to dryness, to afford the title compound in 2 fractions: the first (114 mg, 39% yield) as a light brown solid. A second fraction was also obtained (100 mg, 34% yield) as a white solid.
  • Example 3 (190.1 mg) was dissolved to 19 mg/mL in DCM/DMSO/MeOH with sonication, filtered and was then separated by chiral SFC on a Sepiatec with UV detection by DAD at 220 nm, 40 °C, 120 bar.
  • the column was Chiralpak IG 10X250mm, 5um, flow rate 20mL/ min at 30% MeOH (0.5% DEA), 70% CO2.
  • the clean fractions were pooled, rinsed with methanol and concentrated to dryness using a rocket evaporator at 40 °C. The residues were re-dissolved in methanol transferred into final vials and evaporated on a Biotage VI 0.
  • Enantiomer 3A 6-
  • Enantiomer 3B 6- [(3aR,7aS)-6-Methyl-3,3a,4,5,7,7 a-hexa hy d ro-2//-py r rolo [2 ,3-c] pyridin- l-yl]-3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-l,2,4-triazin-5-one
  • the reaction mixture was cooled to r.t., sparged and additional xphos Pd g3 (11.0 mg, 0.01 mmol, 0.03 eq) was added and heated at 80 °C for an additional 2 h.
  • the sample was cooled to r.t., sparged, additional saturated aqueous sodium carbonate (250 pL,), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (51.0 mg, 0.25 mmol, 0.5 eq) and xphos Pd g3 (11.0 mg, 0.01 mmol, 0.03 eq) were added and the reaction was heated at 80 °C for a further 2 h.
  • At- column dilution pump gives 2 mL min-1 Methanol over the entire method, which is included in the following MeCN percentages.
  • Gradient information 0.0-0.5 min, 10% MeCN; 0.5-5.5 min, ramped from 10% MeCN to 40% MeCN; 5.5 -5.6 min, ramped from 40% MeCN to 100% MeCN; 5.6-8.5 min, held at 100% MeCN.
  • the clean fractions were evaporated in a Genevac and then the residue was dissolved in MeOH (2 mL) with sonication, filtered and was then separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210 - 400 nm, 40 °C, 120 bar.
  • the column was IG 10X250mm, 5pm, flow rate 15mL/ min at 20% EtOH (0.5% DEA), 80% CO2.
  • the clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in methanol transferred into final vials and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30 °C/5 mbar over the weekend to afford Enantiomer 4A (15.9 mg, 8% yield) and 4B (17.1 mg, 8% yield) both as a light brown freeze-dried solid for which the stereochemistry was arbitrarily assigned.
  • Enantiomer 4 A 6- [(3aR,7aS)-6-Methyl-3,3a,4,5,7,7 a-hexa hy d ro-2//-py r rolo [2 ,3-c] pyridin- l-yl]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-l,2,4-triazin-5-one
  • Enantiomer 4B 6-[(3aS,7aR)-6-Methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin- l-yl]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-l,2,4-triazin-5-one
  • the reaction mixture was allowed to cool to rt and was concentrated in vacuo.
  • the crude material was purified by column chromatography on silica gel (24 g cartridge, 0-10% (0.7 M NH3)MeOH/DCM), then by RP chromatography on Cis (4 g cartridge, 0-20% MeCN/lhO (0.1% Formic acid)) to afford an off white solid (17.7 mg).
  • the white solid was dissolved in MeOH (1 mL) with sonication, filtered and was then separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210 - 400 nm, 40 °C, 120 bar.
  • the column was Al 10X250 mm, 5 pm, flow rate 15mL/ min at 40% MeOH (neutral) 60% CO2.
  • the clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator.
  • the residues were re-dissolved in methanol transferred into final vials and evaporated on a Biotage V10.
  • the samples were then further dried in a vacuum oven at 30 °C/5 mbar over the weekend to afford Enantiomer 5A (5.8 mg, 3%) and 5B (5.3 mg, 3%) both as off-white solids for which the stereochemistry was arbitrarily assigned.
  • Enantiomer 5 A 6- [ ( 3 a.S', 7 al?)-6-Methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo [2 ,3- c] pyridin- l-yl]-3-(2-hydroxy-3-bicyclo[4.2.0]octa-l,3,5-trienyl)-4-methyl-l,2,4-triazin-5-one 'l l NMR
  • Enantiomer 5B 6- [(3al?, 7 aA)-6-Methyl-3,3a,4,5,7,7 a-hexa hy d ro-2//-py r rolo [2 ,3- c] pyridin- l-yl]-3-(2-hydroxy-3-bicyclo[4.2.0]octa-l,3,5-trienyl)-4-methyl-l,2,4-triazin-5-one 'l l NMR (500 MHz, DMSO) 8 7.07 (d, 1H), 6.63 (d, 1H), 4.80 - 4.56 (m, 1H), 3.85 - 3.68 (m, 1H), 3.68 - 3.57 (m, 1H), 3.14 (s, 3H), 3.11 - 3.01 (m, 4H), 2.90 (dd, 1H), 2.48 - 2.42 (m, 1H), 2.34 - 2.25 (m, 1H), 2.14 (s, 3H),
  • Example 6 (71.5 mg) was dissolved in MeOH, filtered and was then separated by chiral SFC on a Waters prep 100 with a PDA and a QDa detectors, 40 °C, 120 bar.
  • the column was a Lux Amylose-1, 5 pM, 21 mm X 250 mm; flow rate 65 mL/min of 65 % MeOH (0.5% DEA), 35% CO2.
  • the clean fractions were pooled, rinsed with methanol and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in methanol, transferred into final vials and evaporated on a Biotage V10.
  • Enantiomer 6A and Enantiomer 6B were then further dried in a vacuum oven at 30 °C/ 5 mbar overnight to afford Enantiomer 6A and Enantiomer 6B as yellowish glass.
  • the samples were then co-evaporated with MeCN, followed by MeOH, to remove trace DEA and dried in a desiccator to give Enantiomer 6A (31.6 mg, 11% yield) and Enantiomer 6B (23.7 mg, 8% yield) both as off-white solids for which the stereochemistry was arbitrarily assigned.
  • Enantiomer 6A 6-[(3aS, 7al?)-6-Methyl-3, 3a, 4,5,7, 7a-hexahydro-2//-pyrrolo
  • Enantiomer 6B 6-[(3aR, 7a5)-6-Methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin- l-yl]-3-(4-hydroxyindan-5-yl)-4-methyl-l,2,4-triazin-5-one
  • Step A /c/7-Butyl pyrrolo[2,3-c]pyridine-l -carboxylate
  • Step B /crt-Butyl 2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridine-l-carboxylate
  • the reaction mixture was diluted with a mixture of chloroform: iPrOH (9:1, 100 mL) and 2M NaOH added until a pH of 8-9 was achieved (-100 mL).
  • the separated aqueous layer was further extracted with the solvent mix (2 x 100 mL).
  • the combined extracts were dried (TsfeSCU), filtered and concentrated to provide the title compound (20.6 g, 91% yield) as a viscous yellow oil.
  • LCMS m/z 171.5 [M-tBu+H] + , ESI pos.
  • Step C tert- Butyl 6-benzyl-3,3a,4,5,7,7a-hexahydro-2J/-pyrrolo[2,3-c]pyridine-l-carboxylate
  • tert-butyl 2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridine-l- carboxylate 9.2 g, 34.55 mmol, 1.0 eq
  • potassium carbonate (10.6 g, 76.6 mmol, 2.22 eq)
  • MeCN 150 mL
  • benzyl bromide 4.3 mL, 36.2 mmol, 1.05 eq
  • Step D 6-Benzyl-l,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3-c]pyridine; dihydrochloride salt tert-butyl 6-benzyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-l-carboxylate (827.0 mg, 2.61 mmol, 1.0 eq) was dissolved in DCM (10 mL) and 4M hydrochloric acid in dioxane (2.6 mL, 10.4 mmol, 3.98 eq) was added drop wise. The reaction mixture was stirred at rt for -16 h.
  • Step E 6-(6-Benzyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-l-yl)-2-[(4- methoxyphenyl)methyl]-4-methyl-l, 2, 4-triazine-3, 5-dione
  • Step F 6-(6-Benzyl -3, 3a, 4,5,7, 7a-hexahydro-2J7-pyrrolo[2,3-c]pyridin-l-yl)-4-methyl -277-1,2, 4- triazine-3, 5-dione
  • Trifluorom ethanesulfonic acid 320.0 uL, 3.62 mmol, 2.52 eq
  • 6-(6-benzyl-3,3a,4,5,7,7a-hexahydro-277-pyrrolo[2,3-c]pyridin-l-yl)-2-[(4- methoxyphenyl)methyl]-4-methyl- 1, 2, 4-triazine-3, 5-dione 697.0 mg, 1.43 mmol, 1.0 eq
  • DCM 8 mL
  • MeCN 4 mL
  • the reaction was diluted with H2O (100 mL) and DCM (100 mL) and transferred to a separating funnel.
  • the separated organic layer was further extracted with IM Aq HC1 (100 mL).
  • the aqueous layers were combined in a vigorously stirring conical flask, cooled to 0 °C and basified with sodium phosphate tribasic until a pH of -8-9 was achieved.
  • the mixture was again transferred to a separating funnel and diluted with DCM (200 mL).
  • the separated aqueous layer was further extracted with DCM (2 x 100 mL) and the combined organic layers were dried with MgSCU and concentrated in vacuo to provide the title compound (420.0 mg, 84% yield) as an off-white solid.
  • Step G 6-(6-Benzyl-3, 3a, 4,5,7, 7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-l-yl)-3 -chi oro-4-methyl- l,2,4-triazin-5-one
  • Phosphorus oxychloride (5.0 mL, 53.64 mmol, 43.6 eq) was added to 6-(6-benzyl-3,3a,4,5,7,7a- hexahydro-2H-pyrrolo[2,3-c]pyridin-l-yl)-4-methyl-2J/-l, 2, 4-triazine-3, 5-dione (420.0 mg, 1.23 mmol, 1.0 eq) and the solution was stirred at 105 °C. The resulting brown opaque solution was vigorous stirred for 3 days.
  • Step H 6-(6-Benzyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-l-yl)-3-[2-benzyloxy-4- (trifluoromethoxy)phenyl]-4-methyl-l,2,4-triazin-5-one
  • XPhos Pd G3 (75.0 mg, 0.09 mmol, 0.11 eq) was added and the reaction mixture was heated at 85 °C for 3 h. The reaction was cooled to rt, filtered through celite and concentrated in vacuo. The reaction was diluted with EtOAc (100 mL) and IM aq HC1 (100 mL) and transferred to a separating funnel. The separated organic layer was further extracted with IM aq HC1 (100 mL). The aqueous layers were combined in a vigorously stirring conical flask, cooled to 0 °C and basified with NaOH until a pH of ⁇ 8-9 was achieved.
  • Step I 6-(2,3,3a,4,5,6,7,7a-Octahydropyrrolo[2,3-c]pyridin-l-yl)-3-[2-hydroxy-4-
  • Pd/C (Type 39) (190.0 mg, 0.18 mmol, 0.25 eq) and Pd/C (Type 87) (380.0 mg, 0.18 mmol, 0.25 eq) were added to a stirred solution of 6-(6-benzyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3- c]pyridin-l-yl)-3-[2-benzyloxy-4-(trifluoromethoxy)phenyl]-4-methyl-l,2,4-triazin-5-one (423.0 mg, 0.71 mmol, 1.0 eq) in 1,4-Dioxane (7 mL).
  • the hydrogenation vessel was placed under an atmosphere of hydrogen gas (2 bar) at 50 °C and vigorously stirred for 4 h.
  • the reaction was filtered through a plug of celite, rinsing with dioxane then MeOH, and concentrated to dryness to give the title compound (246.0 mg, 80% yield) as a light-yellow solid.
  • Step J 6-[6-(2-Hydroxyethyl)-3,3a,4,5,7,7a-hexahydro-2J/-pyrrolo[2,3-c]pyridin-l-yl]-3-[2- hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-l,2,4-triazin-5-one
  • the reaction mixture was transferred to a separating funnel and diluted with EtOAc (25 mL) and IM aq HC1 (25 mL). The separated organic layer was further extracted with IM aq HC1 (25 mL). The combined aqueous layers were washed with EtOAc (25 mL). The aqueous layer was basified with sat aq NaHCOs until a pH of ⁇ 8 was achieved and then extracted with DCM (3 x 25 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to provide the crude product.
  • Example 7 (24 mg) was dissolved to 8 mg/mL in 2 mL MeOH and 1 mL DCM with sonication and heating, filtered and was then separated by chiral SFC on a Waters Prep 100 with a PDA and a QDA detector, 40 °C, 120 bar.
  • the column was a ChiralpaK IC, 21 x 250 mm, 5 pm, flow rate 65mL/ min at 30% MeOH (0.3% DEA), 70% CO2.
  • the clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator.
  • Example 7A 1.3 mg, 2 % yield
  • Example 7B 5.2 mg, 9% yield
  • Example 7A 6-[(3aS, 7i//?)-6-(2-Hydroxyethyl)-3.3a.4.5.7.7a-hexahydro-2//-pyrrolo
  • Example 7B 6-[(3aR, 7i/.S)-6-(2-Hydroxyethyl)-3.3a.4.5.7.7a-hexahydro-2//-pyrrolo
  • a compound of formula I can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:
  • a compound of formula I can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

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Abstract

L'invention concerne de nouveaux composés de formule générale (I) dans laquelle R1, R2, R3, R4 et R5 sont tels que décrits dans la description, une composition comprenant les composés et des procédés d'utilisation des composés.
PCT/EP2023/080895 2022-11-09 2023-11-07 Dérivés de triazinone utilisés en tant qu'inhibiteurs de nlrp3 WO2024099992A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020234715A1 (fr) * 2019-05-17 2020-11-26 Novartis Ag Inhibiteurs d'inflammasome nlrp3
WO2021219784A1 (fr) * 2020-04-30 2021-11-04 Janssen Pharmaceutica Nv Nouveaux composés de triazinoindole

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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