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WO2024160693A1 - Pyridin-2(1h)-ones et pyrimidin-4(3h)-ones utiles en tant qu'inhibiteurs de nlrp3 - Google Patents

Pyridin-2(1h)-ones et pyrimidin-4(3h)-ones utiles en tant qu'inhibiteurs de nlrp3 Download PDF

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WO2024160693A1
WO2024160693A1 PCT/EP2024/051982 EP2024051982W WO2024160693A1 WO 2024160693 A1 WO2024160693 A1 WO 2024160693A1 EP 2024051982 W EP2024051982 W EP 2024051982W WO 2024160693 A1 WO2024160693 A1 WO 2024160693A1
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3alkyl
hydrogen
mmol
methyl
compound
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Inventor
Oscar MAMMOLITI
Soufyan JERHAOUI
Laura PEREZ BENITO
Santiago CAÑELLAS ROMAN
Daniel Oehlrich
Marion Laurence Christiane PRIERI
Michael Eric MURATORE
Pavel RYABCHUK
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Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
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Priority to CN202480023481.XA priority Critical patent/CN121001996A/zh
Priority to EP24702715.4A priority patent/EP4658640A1/fr
Priority to KR1020257028705A priority patent/KR20250152069A/ko
Priority to AU2024215094A priority patent/AU2024215094A1/en
Publication of WO2024160693A1 publication Critical patent/WO2024160693A1/fr
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Definitions

  • pyridine-2(lH)-ones and pyrimidin-4(3H)-ones that are useful as inhibitors of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway.
  • processes for the preparation of said compounds, pharmaceutical compositions comprising said compounds, methods of using said compounds in the treatment of various diseases and disorders mediated by the NLRP3 inflammasome pathway are also described herein.
  • Inflammasomes considered as central signalling hubs of the innate immune system, are multi-protein complexes that are assembled upon activation of a specific set of intracellular pattern recognition receptors (PRRs) by a wide variety of pathogen- or danger- associated molecular patterns (PAMPs or DAMPs).
  • PRRs pattern recognition receptors
  • PAMPs or DAMPs pathogen- or danger- associated molecular patterns
  • the NLRP3 inflammasome is assembled upon detection of environmental crystals, pollutants, host-derived DAMPs and protein aggregates (Tartey S and Kanneganti TD. Immunology, 2019 Apr; 156(4): 329-338).
  • Clinically relevant DAMPs that engage NLRP3 include uric acid and cholesterol crystals that cause gout and atherosclerosis, amyloid-P fibrils that are neurotoxic in Alzheimer’s disease and asbestos particles that cause mesothelioma (Kelley et al., IntJMol Sci, 2019 Jul 6;20(13)).
  • NLRP3 is activated by infectious agents such as Vibrio cholerae,' fungal pathogens such as Aspergillus fumigatus and Candida albicans,' adenoviruses, influenza A virus and SARS-CoV-2 (Tartey and Kanneganti, 2019; Fung et al. Emerg Microbes Infect, 2020 Mar 14;9(l):558-570).
  • infectious agents such as Vibrio cholerae,' fungal pathogens such as Aspergillus fumigatus and Candida albicans,' adenoviruses, influenza A virus and SARS-CoV-2 (Tartey and Kanneganti, 2019; Fung et al. Emerg Microbes Infect, 2020 Mar 14;9(l):558-570).
  • NLRP3 activation mechanism Although the precise NLRP3 activation mechanism remains unclear, for human monocytes, it has been suggested that a one-step activation is sufficient while in mice a two- step mechanism is in place. Given the multitude in triggers, the NLRP3 inflammasome requires add-on regulation at both transcriptional and post-transcriptional level (Yang Y et al., Cell Death Dis, 2019 Feb 12; 10(2): 128).
  • the NLRP3 protein consists of an N-terminal pyrin domain, followed by a nucleotide- binding site domain (NBD) and a leucine-rich repeat (LRR) motif on C-terminal end (Sharif et al., Nature, 2019 Jun; 570(7761):338-343).
  • NBD nucleotide- binding site domain
  • LRR leucine-rich repeat
  • NLRP3 aggregates with the adaptor protein, apoptosis-associated speck-like protein (ASC), and with the protease caspase- 1 to form a functional inflammasome.
  • ASC apoptosis-associated speck-like protein
  • procaspase- 1 Upon activation, procaspase- 1 undergoes autoproteolysis and consequently cleaves gasdermin D (Gsdmd) to produce the N- terminal Gsdmd molecule that will ultimately lead to pore-formation in the plasma membrane and a lytic form of cell death called pyroptosis.
  • Gsdmd gasdermin D
  • caspase-1 cleaves the pro- inflammatory cytokines pro-IL-ip and pro-IL-18 to allow release of its biological active form by pyroptosis (Kelley et al., 2019).
  • Dysregulation of the NLRP3 inflammasome or its downstream mediators are associated with numerous pathologies ranging from immune/inflammatory diseases, auto- immune/auto-inflammatory diseases (Cryopyrin-associated Periodic Syndrome (Miyamae T. Paediatr Drugs, 2012 Apr 1 ; 14(2): 109-17); sickle cell disease; systemic lupus erythematosus (SLE)) to hepatic disorders (e.g. non-alcoholic steatohepatitis (NASH), chronic liver disease, viral hepatitis, alcoholic steatohepatitis, non-alcoholic fatty acid liver disease, and alcoholic liver disease) (Szabo G and Petrasek J.
  • NASH non-alcoholic steatohepatitis
  • NASH non-alcoholic steatohepatitis
  • chronic liver disease viral hepatitis
  • viral hepatitis alcoholic steatohepatitis
  • non-alcoholic fatty acid liver disease non-alcoholic fatty acid liver disease
  • kidney related diseases hypertensive nephropathy (Krishnan et al., Br J Pharmacol, 2016 Feb;173(4):752-65), hemodialysis related inflammation and diabetic nephropathy which is a kidney -related complication of diabetes (Type 1, Type 2 and mellitus diabetes), also called diabetic kidney disease (Shahzad et al., Kidney Int, 2015 Jan;87(l):74-84) are associated to NLRP3 inflammasome activation.
  • cardiovascular or metabolic disorders e.g. cardiovascular risk reduction (CvRR), atherosclerosis, type I and type II diabetes and related complications (e.g. nephropathy, retinopathy), peripheral artery disease (PAD), acute heart failure and hypertension.
  • myeloproliferative neoplasms myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MOS), myelofibrosis, lung cancer, colon cancer
  • MOS myelodysplastic syndromes
  • lung cancer colon cancer
  • Described herein are compounds which inhibit the NLRP3 inflammasome pathway.
  • A is N or CR 3 ;
  • L is a direct bond or a bivalent radical (CH2) n wherein n is 1, 2 or 3;
  • NR 6 R 7 is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, each optionally substituted with 1 or 2 independently selected Ci-3alkyl groups;
  • R 2 is hydrogen, Ci-3alkyl, or halogen
  • R 3 is hydrogen, halo, Ci-3alkyl, Ci-3haloalkyl, Cs-ecycloalkyl, aryl;
  • R 4 and R 5 are each independently hydrogen or Ci-3alkyl.
  • compounds for use as a medicament there are provided pharmaceutical compositions comprising a therapeutically effective amount of a compound provided herein.
  • compositions comprising such compounds for use in the treatment of a disease or disorder mediated by the NLRP3 inflammasome pathway, for example neurodegenerative disorders such as Alzheimer’s Disease.
  • the instant compounds in the manufacture of a medicament for the treatment of a disease or disorder mediated by the NLRP3 inflammasome pathway, for example neurodegenerative disorders such as Alzheimer’s Disease.
  • a method of treating a disease or disorder mediated by the NLRP3 inflammasome pathway for example neurodegenerative disorders such as Alzheimer’s Disease.
  • Described herein are compounds which inhibit the NLRP3 inflammasome pathway.
  • A is N or CR 3 ;
  • L is a direct bond or a bivalent radical (CFLjn wherein n is 1, 2 or 3;
  • NR 6 R 7 is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, each optionally substituted with 1 or 2 Ci-3alkyl groups;
  • R 2 is hydrogen, Ci-3alkyl, or halogen;
  • R 3 is hydrogen, halo, Ci-3alkyl, Ci-3haloalkyl, Cs-ecycloalkyl, aryl;
  • R 4 and R 5 are each independently hydrogen or Ci-3alkyl.
  • A is CR 3 ;
  • L is a direct bond or a bivalent radical (CH2) n wherein n is 1;
  • NR 6 R 7 is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or
  • R 2 is hydrogen, methyl, ethyl or chloro
  • R 3 is hydrogen, chloro, bromo, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, phenyl;
  • R 4 and R 5 are each independently hydrogen or methyl.
  • A is CR 3 ;
  • L is a direct bond or a bivalent radical (CH2) n wherein n is 1;
  • NR 6 R 7 is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, each optionally substituted with 1 or 2 Ci-3alkyl groups; R 2 , R 4 and R 5 are each hydrogen, or one of R 2 and R 4 is methyl and R 5 is hydrogen.
  • A is N;
  • L is a direct bond or a bivalent radical (CH 2 ) n wherein n is 1;
  • NR 6 R 7 is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or
  • R 2 is hydrogen, methyl, ethyl or chloro
  • R 3 is hydrogen, chloro, bromo, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, phenyl;
  • R 4 and R 5 are each independently hydrogen or methyl.
  • A is N;
  • L is a direct bond or a bivalent radical (CH 2 ) n wherein n is 1;
  • NR 6 R 7 is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or
  • R 2 , R 4 and R 5 are each hydrogen, or one of R 2 and R 4 is methyl and R 5 is hydrogen.
  • A is N or CH; when L is a direct bond, then R 1 is cyclohexyl, 2-hydroxycyclohexyl, 4-hydroxycyclohexyl, tetrahydropyran-4-yl, 3 -hydroxytetrahydropyran-4-yl, wherein R 10 is hydrogen or methyl and R 11 is hydrogen or fluoro; when L is CH2, then R 1 is herein NR 6 R 7 is N(CH 3 ) 2 , pyrrolidinyl, or morpholinyl;
  • R 2 is H or CH 3 ;
  • R 3 is hydrogen, methyl, trifluoromethyl, chloro or CF 3 ;
  • R 4 is hydrogen or methyl
  • R 5 is hydrogen
  • A is N or CR 3 ;
  • L is a direct bond or a bivalent radical (CH2) n wherein n is 1 or 2;
  • NR 6 R 7 is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, each optionally substituted with 1 or 2 independently selected Ci-3alkyl groups;
  • R 2 is hydrogen, Ci-3alkyl, or halogen
  • R 3 is hydrogen, halo, Ci-3alkyl, Ci-3haloalkyl, Cs-ecycloalkyl, phenyl; and R 4 and R 5 are each independently hydrogen or Ci-3alkyl.
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound as provided herein with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counterion of a compound provided herein in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.
  • the instant compounds may contain double bonds and may thus exist as E (entgegeri) and Z (ziisammeri) geometric isomers about each individual double bond.
  • Compounds as provided herein may contain one or more asymmetric carbon atoms and may therefore exhibit enantiomerism or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired isomers may be made by reaction of an appropriate enantiomeric starting material under conditions which will not cause racemisation or epimerisation, or by reaction of an appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by resolution, including dynamic resolution, for example salt formation with a homochiral acid followed by separation of the diastereomeric salts by conventional means such as crystallization, or by reaction with an appropriate chiral reagent or chiral catalyst.
  • resolution including dynamic resolution, for example salt formation with a homochiral acid followed by separation of the diastereomeric salts by conventional means such as crystallization, or by reaction with an appropriate chiral reagent or chiral catalyst.
  • stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated. Where stereochemistry is specified by a solid or dashed wedge representing a particular configuration, then that stereoisomer is so specified and defined. Absolute configurations are specified according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate polarized light.
  • stereoisomer When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other isomers.
  • a compound of formula (I) is for instance specified as (R)
  • the instant compounds may occur as atropisomers.
  • Atropisomers or atropoisomers are stereoisomers which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance.
  • the compounds may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • isotopically-labelled compounds wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature).
  • exemplary isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine, such as 2 H, 3 H, n C, 13 C, 14 C , 13 N, 15 O, 17 O, 18 O, and 18 F.
  • Tritiated ( 3 H) and carbon-14 ( 14 C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium may afford therapeutic advantages resulting from greater metabolic stability.
  • Isotopes such as 15 O, 13 N, n C and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labelled compounds can generally be prepared by following procedures analogous to those disclosed in the Examples hereinafter.
  • Ci- q alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or be branched-chain.
  • Cs-q cycloalkyl refers to an alkyl group that is cyclic, for instance cycloalkyl groups may be monocyclic or, if there are sufficient atoms, bicyclic. In an embodiment, such cycloalkyl groups are monocyclic.
  • the Cs- q cycloalkyl is a C3-6 cycloalkyl, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Substituents may be attached at any point on the cycloalkyl group.
  • halo when used herein, preferably includes fluoro, chloro, bromo and iodo.
  • Ci-q alkoxy groups refers to the radical of formula -OR a , where R a is a Ci- q alkyl group as defined herein.
  • HaloCi-q alkyl (where q is the upper limit of the range) groups refer to Ci- q alkyl groups, as defined herein, where such group is substituted by one or more halo.
  • HydroxyCi-q alkyl (where q is the upper limit of the range) refers to Ci- q alkyl groups, as defined herein, where such group is substituted by one or more (e.g. one) hydroxy (-OH) groups (or one or more, e.g.
  • haloCi-q alkoxy and hydroxyCi- q alkoxy represent corresponding -OCi- q alkyl groups that are substituted by one or more halo, or, substituted by one or more (e.g. one) hydroxy, respectively.
  • Examples of monocyclic heterocyclyl substituents include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, azepanyl, 1,4-oxazepanyl, tetrahydropyranyl, tetrahydrofuranyl, thietane, oxathiane, tetrahydrothiophene, tetrahydrothiopyran (the latter optionally substituted with at least oxo, to form 1,4-oxathiane 4,4-dioxide, thietane 1,1 -di oxide, tetrahydrothiophene 1,1 -di oxide, tetrahydro-2H-thiopyran 1,1, -di oxide).
  • Examples of bicyclic heterocyclyl substituents include for example, those depicted hereinbelow:
  • the instant compounds can generally be prepared by a succession of steps, each of which is known to the skilled person.
  • the compounds can be prepared according to the following synthesis methods.
  • the compounds of Formula (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures.
  • the racemic compounds of Formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkalination.
  • An alternative manner of separating the enantiomeric forms of the compounds of Formula (I) involves liquid chromatography using a chiral stationary phase or a chiral supercritical fluid chromatography (SFC). Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • the compounds can generally be prepared by a succession of steps, each of which is known to the skilled person.
  • the compounds can be prepared according to the following synthesis methods.
  • the compounds of Formula (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures.
  • the racemic compounds of Formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkalination.
  • An alternative manner of separating the enantiomeric forms of the compounds of Formula (I) involves liquid chromatography using a chiral stationary phase or a chiral supercritical fluid chromatography (SFC).
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • the absolute configuration of compounds of the invention reported herein was determined by analysis of the racemic mixture by supercritical fluid chromatography (SFC) followed by SFC comparison of the separate enantiomer(s) which were obtained by asymmetric synthesis, followed by vibrational circular dichroism (VCD) analysis of the particular enantiomer(s).
  • SFC supercritical fluid chromatography
  • VCD vibrational circular dichroism
  • Intermediates of Formula (II) can be prepared by reaction of an Intermediate of Formula (III) with an appropriate boronic acid or boronic ester Intermediate of Formula (XX) or (XXI) via Suzuki coupling in the presence of a suitable palladium catalyst such as tetrakis triphenylphosphine palladium, in the presence of a suitable base such as, for example, sodium carbonate, in a suitable solvent such as a mixture of 1,4-di oxane and water, at a suitable temperature, for example, at 100 °C;
  • a suitable palladium catalyst such as tetrakis triphenylphosphine palladium
  • a suitable base such as, for example, sodium carbonate
  • a suitable solvent such as a mixture of 1,4-di oxane and water
  • Intermediates of Formula (III) can be prepared by Sandmeyer type reaction in an Intermediate of Formula (IV) using the appropriate conditions such as, for example, sodium nitrite, sodium iodide and hydrochloride acid, in a suitable solvent such as a mixture of ethyl acetate and water, at a suitable temperature for example, at 0 °C;
  • Intermediates of Formula (IV) can be prepared by deprotection of an Intermediate of Formula (V) with a suitable catalyst such as Pd/C, in a suitable solvent such as ethanol, at a suitable temperature for example at room temperature;
  • Intermediates of Formula (V) can be prepared by Curtius rearrangement type reaction in an Intermediate of Formula (VI) using the appropriate conditions such as diphenylphosphoryl azide, benzyl alcohol and triethylamine, in an suitable solvent such as toluene, at a suitable temperature for example at 80 °C;
  • Intermediates of Formula (VI) can be prepared by saponification of an Intermediate of Formula (VII) with a suitable base such as lithium hydroxide, in a suitable solvent or mixture of solvent such as THF, methanol and water, at a suitable temperature for example at 50 °C;
  • a suitable base such as lithium hydroxide
  • a suitable solvent or mixture of solvent such as THF, methanol and water
  • Intermediates of Formula (VII) can be prepared by reacting methyl 2-oxo-2H-pyran-3- carboxylate (VIII) with a suitable amine reagent with a suitable coupling agent such as EDC.HC1, with a suitable base such as 4-dimethylaminopyridine, in a suitable solvent such as DMF, at a suitable temperature for example at room temperature.
  • R 20 is H, can be prepared:
  • Intermediates of Formula (IX) can be prepared by reacting an Intermediate of Formula (X) with an appropriate boronic acid or boronic ester Intermediate of Formula (XX) or (XXI) via Suzuki coupling in the presence of a suitable palladium catalyst such as tetrakis triphenylphosphine palladium, in the presence of a suitable base such as sodium carbonate, in a suitable solvent such as a mixture of 1,4-di oxane and water, at a suitable temperature for example at 100 °C;
  • a suitable palladium catalyst such as tetrakis triphenylphosphine palladium
  • a suitable base such as sodium carbonate
  • a suitable solvent such as a mixture of 1,4-di oxane and water
  • Intermediates of Formula (X) can be prepared by alkylation of an Intermediate of Formula (XI) with a suitable alkylating agent in the presence of a suitable base such as potassium carbonate, in a suitable solvent such as acetonitrile or dimethyl formamide, at a suitable temperature for example at 80 °C;
  • a suitable base such as potassium carbonate
  • a suitable solvent such as acetonitrile or dimethyl formamide
  • Intermediates of Formula (X) can be prepared by Mitsunobu-type reaction of an Intermediate of Formula (XI) with a suitable primary alcohol in the presence of a suitable coupling agent such as Tsunoda reagent or triphenylphosphine combined with diethyl azodi carb oxy late, in a suitable solvent such as toluene or THF, at a suitable temperature for example between room temperature and 100 °C.
  • a suitable coupling agent such as Tsunoda reagent or triphenylphosphine combined with diethyl azodi carb oxy late
  • Intermediates of Formula (IX) can be prepared by Mitsunobu-type reaction of an Intermediate of Formula (XII) with a suitable primary alcohol in the presence of a suitable coupling agent such as Tsunoda reagent or triphenylphosphine combined with diethyl azodicarboxylate, in a suitable solvent such as toluene or THF, at a suitable temperature for example between room temperature and 100 °C.
  • a suitable coupling agent such as Tsunoda reagent or triphenylphosphine combined with diethyl azodicarboxylate
  • Intermediates of Formula (XII) can be prepared by reacting an Intermediate of Formula (XI) with an appropriate boronic acid or boronic ester Intermediate of Formula (XX) or (XXI) via Suzuki coupling in the presence of a suitable palladium catalyst such as, tetrakis triphenylphosphine palladium, in the presence of a suitable base such as sodium carbonate, in a suitable solvent such as, a mixture of 1,4-di oxane and water, at a suitable temperature for example at 100 °C.
  • a suitable palladium catalyst such as, tetrakis triphenylphosphine palladium
  • a suitable base such as sodium carbonate
  • a suitable solvent such as, a mixture of 1,4-di oxane and water
  • Intermediates of Formula (XIII) can be prepared by reacting an Intermediate of Formula (XIV) with an appropriate boronic acid or boronic ester Intermediate of Formula (XX) or (XXI) via Suzuki coupling in the presence of a suitable palladium catalyst such as tetrakis triphenylphosphine palladium, in the presence of a suitable base such as sodium carbonate, in a suitable solvent such as a mixture of 1,4-di oxane and water, at a suitable temperature for example at 100 °C;
  • a suitable palladium catalyst such as tetrakis triphenylphosphine palladium
  • a suitable base such as sodium carbonate
  • a suitable solvent such as a mixture of 1,4-di oxane and water
  • Intermediates of Formula (XIII) can be prepared by reacting an Intermediate of Formula (XIV) with a suitable organozinc reagent in the presence of a suitable palladium catalyst such as cataCXium Pd G4 or bis(tri-tert- butylphosphine)palladium(O), in a suitable solvent such as THF, at a suitable temperature for example at 50 °C;
  • a suitable palladium catalyst such as cataCXium Pd G4 or bis(tri-tert- butylphosphine)palladium(O)
  • Intermediates of Formula (XIV) can be prepared by halogenation of an Intermediate of Formula (II) using a suitable halogenating agent such as N-bromosuccinimide or N-chlorosuccinimide, in a suitable solvent such as dimethyl formamide, at a suitable temperature for example between 0 °C and room temperature;
  • a suitable halogenating agent such as N-bromosuccinimide or N-chlorosuccinimide
  • a suitable reagent such as, for example, sodium iodide
  • a suitable catalyst such as copper (I) iodide
  • a suitable ligand such as trans-N,N’- dimethylcyclohexane-l,2-diamine
  • a suitable solvent such as 1,4-di oxane
  • Intermediates of Formula (XV) can be prepared by reacting an Intermediate of Formula (XVI) with an appropriate boronic acid or boronic ester Intermediate of Formula (XX) or (XXI) via Suzuki coupling in the presence of a suitable palladium catalyst such as tetrakis triphenylphosphine palladium, in the presence of a suitable base such as sodium carbonate, in a suitable solvent such as a mixture of 1,4-di oxane and water, at a suitable temperature, for example at 100 °C;
  • a suitable palladium catalyst such as tetrakis triphenylphosphine palladium
  • a suitable base such as sodium carbonate
  • a suitable solvent such as a mixture of 1,4-di oxane and water
  • Intermediates of Formula (XVI) can be prepared by reacting 5-bromopyrimidin- 4(3H)-one (XVII) with a suitable amine in the presence of a suitable coupling agent such as HATU, with a suitable base such as DBU, in a suitable solvent such as acetonitrile, at a suitable temperature for example between rt and50 °C.
  • a suitable coupling agent such as HATU
  • a suitable base such as DBU
  • a suitable solvent such as acetonitrile
  • Intermediates of Formula (XVIII) can be prepared by reacting an Intermediate of Formula (XIX) with a suitable alkylating agent in the presence of a suitable base such as, potassium carbonate, in a suitable solvent such as acetonitrile or dimethyl formamide, at a suitable temperature for example at 80 °C;
  • a suitable base such as, potassium carbonate
  • a suitable solvent such as acetonitrile or dimethyl formamide
  • Intermediates of Formula (XVIII) can be prepared by Mitsunobu-type reaction of an Intermediate of Formula (XIX) with a suitable primary alcohol in the presence of a suitable coupling agent such as Tsunoda reagent or triphenylphosphine combined with diethyl azodi carb oxy late, in a suitable solvent such as toluene or THF, at a suitable temperature for example between room temperature and 100 °C.
  • a suitable coupling agent such as Tsunoda reagent or triphenylphosphine combined with diethyl azodi carb oxy late
  • Intermediates of Formula (XIX) can be prepared by reacting 5-bromopyrimidin- 4(3H)-one (XVII) with an appropriate boronic acid or boronic ester Intermediate of Formula (XX) or (XXI) via Suzuki coupling in the presence of a suitable palladium catalyst such as, tetrakis triphenylphosphine palladium, in the presence of a suitable base such as sodium carbonate, in a suitable solvent such as a mixture of 1,4-di oxane and water, at a suitable temperature for example at 100 °C.
  • a suitable palladium catalyst such as, tetrakis triphenylphosphine palladium
  • a suitable base such as sodium carbonate
  • a suitable solvent such as a mixture of 1,4-di oxane and water
  • they can be prepared by reacting an intermediate of Formula (XXII) with an appropriate source of boron such as, for example, 2-Isopropoxy-4,4,5,5- tetramethyl-l,3,2-dioxaborolane, in the presence of a suitable reagent such as isopropyl magnesium chloride, in a suitable solvent such as THF, at a suitable temperature for example between -78 °C and 0 °C;
  • an appropriate source of boron such as, for example, 2-Isopropoxy-4,4,5,5- tetramethyl-l,3,2-dioxaborolane
  • Intermediates of Formula (XXII) can be prepared by protection of an Intermediate of Formula (XXIII) with a suitable protecting group such as chloromethyl methyl ether or benzyl chloride, with a suitable base such as potassium carbonate, in a suitable solvent such as DMF, at a suitable temperature for example between rt and 50 °C;
  • a suitable protecting group such as chloromethyl methyl ether or benzyl chloride
  • a suitable base such as potassium carbonate
  • Intermediates of Formula (XXIII) can be prepared by reacting an Intermediate of Formula (XXIV) with iodine in the presence of a suitable base such as sodium hydride, in a suitable solvent such as toluene, at a suitable temperature for example at 0 °C.
  • a suitable base such as sodium hydride
  • a suitable solvent such as toluene
  • R 1 , R 2 or R 3 contain a protecting group such as, for example, Boc, deprotection of intermediates of Formula (II) or analogues will afford the deprotected compound of Formula (la) or analogues.
  • a protecting group such as, for example, Boc
  • deprotection of intermediates of Formula (II) or analogues will afford the deprotected compound of Formula (la) or analogues.
  • Further functionalization of those nor-compounds is possible using, for example, an aldehyde coupling partner in the presence of a reductive agent such as, for example, sodium triacetoxyborohydride, in a suitable solvent such as, for example, methanol or dichloromethane, at a suitable temperature such as, for example, 0 °C.
  • the instant compounds are brain-penetrant and may be useful in central nervous system diseases such as Parkinson’s disease, Alzheimer’s disease, dementia, motor neuron disease, Huntington’s disease, traumatic brain injury, multiple sclerosis and amyotrophic lateral sclerosis.
  • central nervous system diseases such as Parkinson’s disease, Alzheimer’s disease, dementia, motor neuron disease, Huntington’s disease, traumatic brain injury, multiple sclerosis and amyotrophic lateral sclerosis.
  • compositions comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as provided herein.
  • the compounds may be formulated into various pharmaceutical forms for administration purposes.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • an effective amount of the particular compound, optionally in salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally or by parenteral injection.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
  • the pharmaceutical composition may additionally contain various other ingredients known in the art, for example, a lubricant, stabilising agent, buffering agent, emulsifying agent, viscosity-regulating agent, surfactant, preservative, flavouring or colorant.
  • a lubricant for example, a lubricant, stabilising agent, buffering agent, emulsifying agent, viscosity-regulating agent, surfactant, preservative, flavouring or colorant.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • the daily dosage of the compound will, of course, vary with the compound employed, the mode of administration, the treatment desired and the mycobacterial disease indicated. However, in general, satisfactory results will be obtained when the compound is administered at a daily dosage not exceeding 1 gram, e.g. in the range from 10 to 50 mg/kg body weight.
  • pharmaceutical composition refers to a compound as provided herein or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.
  • the term "pharmaceutically acceptable carrier” refers to a substance useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegration agents, lubricants, wetting agents, sweetening agents, flavoring agents, dyes, and combinations thereof, as would be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).
  • subject refers to an animal, preferably a mammal, most preferably a human, for example who is or has been the object of treatment, observation or experiment.
  • terapéuticaally effective amount means that amount of compound that elicits a biological or medicinal response in a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • a therapeutically effective amount refers to the amount of the compound that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and/or ameliorate a condition, or a disorder or a disease (i) mediated by NLRP3, or (ii) associated with NLRP3 activity, or (iii) characterised by activity (normal or abnormal) of NLRP3; or (2) reduce or inhibit the activity ofNLRP3; or (3) reduce or inhibit the expression of NLRP3.
  • a therapeutically effective amount refers to the amount of the compound that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reduce or inhibit the activity of NLRP3; or at least partially reduce or inhibit the expression of NLRP3.
  • inhibiting NLRP3 or inhibiting NLRP3 inflammasome pathway comprises reducing the ability ofNLRP3 or NLRP3 inflammasome pathway to induce the production of IL-1 and/or IL-18. This can be achieved by mechanisms including, but not limited to, inactivating, destabilizing, and/or altering distribution of NLRP3.
  • NLRP3 is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and anti-sense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous NLRP molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.
  • treat refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.
  • the term “prevent”, “preventing” or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.
  • a subject is "in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • a compound for use as a medicament.
  • a compound for use in the treatment of a disease or disorder associated with NLRP3 activity (including inflammasome activity); in the treatment of a disease or disorder in which the NLRP3 signalling contributes to the pathology, and/or symptoms, and/or progression, of said disease/disorder; in inhibiting NLRP3 inflammasome activity (including in a subject in need thereof); and/or as an NLRP3 inhibitor.
  • NLRP3 activity including inflammasome activity
  • NLRP3 signalling contributes to the pathology, and/or symptoms, and/or progression, of said disease/disorder
  • inhibiting NLRP3 inflammasome activity including in a subject in need thereof.
  • a method of treating a disease or disorder in which the NLRP3 signalling contributes to the pathology, and/or symptoms, and/or progression, of said disease/disorder comprising administering a therapeutically effective amount of a compound as provided herein, according to any one of the embodiments described herein (and/or pharmaceutical compositions comprising such compound, according to any one of the embodiment described herein), for instance to a subject (in need thereof).
  • a method of inhibiting the NLRP3 inflammasome activity in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound as provided herein, according to any one of the embodiments described herein (and/or pharmaceutical compositions comprising such compound, according to any one of the embodiment described herein).
  • the instant compounds may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise.
  • a better pharmacokinetic profile e.g. higher oral bioavailability and/or lower clearance
  • the instant compounds may have the advantage that they have a good or an improved thermodynamic solubility (e.g. compared to compounds known in the prior art; and for instance as determined by a known method and/or a method described herein).
  • the instant compounds may have the advantage that they will block pyroptosis, as well as the release of pro-inflammatory cytokines (e.g. IL-10) from the cell.
  • the instant compounds may also have the advantage that they avoid side-effects, for instance as compared to compounds of the prior art, which may be due to selectivity of NLRP3 inhibition.
  • Compounds as provided herein may also have the advantage that they have good or improved in vivo pharmacokinetics and oral bioavailability. They may also have the advantage that they have good or improved in vivo efficacy.
  • the instant compounds may also have advantages over prior art compounds when compared in the tests outlined hereinafter. EXPERIMENTAL PART
  • Step 1 Synthesis of methyl ( ?)-l-(l-(tert-butoxycarbonyl)piperidin-3-yl)-2-oxo-l,2- dihydropyridine-3 -carboxylate Int9-1
  • Methyl 2-oxo-27/-pyran-3 -carboxylate [25991-27-9] 25 g, 154 mmol was added to a stirred solution of l-Boc-3 -aminopiperidine [184637-48-7] (32 g, 159.8 mmol, 1 eq.) in 250 mL of anhydrous DMF at 0 °C and the reaction mixture was stirred at 0 °C for 3 h.
  • N-(3- dimethylaminopropyl)-A'-ethylcarbodiimide hydrochloride (40 g, 208.7 mmol, 1.3 eq.) and DMAP (5 g, 40.93 mmol, 0.27 eq.) were added and the mixture was allowed to warm to room temperature and stirred overnight. Water and EtOAc were added. The organic layer was separated, washed with brine (x3), dried with ISfeSCU anhydrous, filtered off and evaporated under reduced pressure. The crude was purified by column chromatography on silica gel with Hept/EtOAc (7:3 to 1 :4) to afford Intermediate 9-1 (25.9 g, yield 50 %) as a brownish oil.
  • Step 2 Synthesis of (A)-l-(l-(tert-butoxycarbonyl)piperidin-3-yl)-2-oxo-l,2-dihydropyridine- 3-carboxylic acid Intl0-l
  • Step 3 tert-butyl (A)-3-(3-(((benzyloxy)carbonyl)amino)-2-oxopyridin-l(2J7)-yl)piperidine-l- carb oxy late Inti 1-1
  • DPPA [26386-88-9] (18 mL, 1.227 g/mL, 80.253 mmol) was added to a stirred mixture of Intermediate 10-1 (24 g, 72.962 mmol) and triethylamine (30 mL, 0.72 g/mL, 213.46 mmol) in 350 mL of anhydrous toluene. The resulting mixture was stirred 6 h at 60 °C, then cooled to room temperature. Benzyl alcohol [100-51-6] (20 mL, 1.045 g/mL, 193.268 mmol) was added and the mixture was further heated at 80 °C for 2 h.
  • Step 5 Synthesis of tert-butyl (R)-3 -(3 -iodo-2-oxopyri din- l(2J7)-yl)piperi dine- 1 -carboxylate
  • Step 6 Synthesis of tert-butyl (A)-3 -(3 -(2 -hydroxy -4-(trifluoromethyl)phenyl)-2-oxopyri din- l(2J7)-yl)piperidine-l -carboxylate Intl4-1
  • Intermediate 13-1 (9 g, 22.264 mmol), 2-hydroxy-4-trifluoromethylphenylboronic acid [1072951-50-8] (5 g, 24.28 mmol) and Na2COs (7 g, 66.045 mmol) were suspended in 100 mL of 1,4-di oxane and 20 mL of water in a pressure vessel, and the mixture was degassed for 15 min with nitrogen.
  • Step 1 Synthesis of tert-butyl 3-(((3-bromopyridin-2-yl)oxy)methyl)pyrrolidine-l- carboxylate) Inti 5-1
  • Step 2 Synthesis of tert-butyl 3-((3-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-oxopyridin- l(2J7)-yl)methyl)pyrrolidine-l -carboxylate Intl6-1
  • NCS (79.19 mg, 0.59 mmol) was added portionwise over a 5 min period to a stirring solution of Intermediate 14-1 (200 mg, 0.46 mmol) in 5 mL of anhydrous DMF. The mixture was stirred at 50 °C for 6 h. The RM was poured out in water, extracted twice with EtOAc an dthen the combined organic layers were washed with brine, dried on MgSC , filtered off and evaporated. The residue was purified on a column with silica gel, eluent EtOAc in Heptane, from 0 to 70%. The purest fractions were evaporated to yield Intermediate 18 (200 mg, yield 93%) as a white foam.
  • Tetrakis(triphenylphosphine)palladium (0) 45 mg, 0.039 mmol was added to a stirred suspension of Intermediate 17 (200 mg, 0.39 mmol), phenylboronic acid (64 mg, 0.52 mmol) and Na2CO3 (124 mg, 1.16 mmol) in 10 mL of 1,4-dioxane and 2.5 mL of water (previously bubbled with nitrogen for 5 min) in a sealed tube.
  • the reaction mixture was stirred at 110 °C for 2 h.
  • the RM was cooled, poured out in water, extracted with EtOAc twice. The combined organic layers were washed with brine, dried on MgSO4, filtered off and evaporated under reduced pressure.
  • Tetrakis(triphenylphosphine)palladium (0) (56 mg, 0.048 mmol) was added to a stirred suspension of Intermediate 17 (250 mg, 0.48 mmol) , 4,4,5,5-tetrametyl-2-(prop-l-en-2-yl)- 1,3,2-dioxaborolane (121.81 mg, 0.72 mmol) and Na?CO3 (155 mg, 1.45 mmol) in 1 mL of 1,4-di oxane and 2.5 mL of water (previously bubbled with nitrogen for 5 min) in a sealed tube. The reaction mixture was stirred at 110 °C for 2 h. The RM was cooled, poured out in water, extracted with EtOAc twice.
  • Example 1 Synthesis of tert-butyl 3-(5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6- oxopyrimidin-l(6H)-yl)piperidine-l -carboxylate
  • Step 1 Synthesis of tert-butyl 3-(5-bromo-6-oxopyrimidin-l(6H)-yl)piperidine-l-carboxylate
  • HATU [148893-10-1] (1.01 g, 2.57 mmol) and DBU [6674-22-2] (392 pL, 2.57 mmol) were added sequentially to a stirred suspension of 5-bromopyrimidin-4-ol [19808-30-1] (528 mg, 2.37 mmol) and l-boc-3 -aminopiperidine [184637-48-7] (400 mg, 1.98 mmol) in acetonitrile anhydrous (9.5 mL) at rt under nitrogen atmosphere. The resulting clear yellow solution was stirred at 50 °C for 16 h. The reaction mixture was cooled down to room temperature, diluted with saturated NaHCCE aqueous solution and extracted with EtOAc three times.
  • Step 2 Synthesis of tert-butyl 3-(5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6- oxopyrimidin-l(6H)-yl)piperidine-l -carboxylate Int27-1
  • Step L Synthesis of 5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)pyrimidin-4(3H)-one
  • Step 2 Synthesis of tert-butyl 3-((5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6- oxopyrimidin-l(6H)-yl)methyl)piperidine-l -carboxylate Int27-2
  • HATU [148893-10-1] (1.01 g, 2.57 mmol) and DBU [6674-22-2] (0.4 ml, 2.57 mmol) were added sequentially to a stirred suspension of 5-bromo-6-methylpyrimidin-4-ol [3438-52-6] (563 mg, 2.37 mmol) and (R)-(-)-3-Amino-l-Boc-piperidine [188111-79- 7] (400 mg, 1.98 mmol) in acetonitrile anhydrous (9.5 mL) at rt under nitrogen atmosphere. The resulting clear yellow solution was stirred at 50 °C for 16 h. The reaction mixture was cooled down to rt, diluted with sat.
  • the reaction was recharged with tetrakis(triphenylphosphine)palladium (0) [14221-01-3] (42.2 mg, 0.04 mmol, 0.05 eq.) and more Intermediate 7 (150.1 mg, 0.43 mmol).
  • the reaction mixture was stirred at 120 °C for 16 h.
  • the mixture was diluted with sat. aqueous NaHCCh and extracted with EtOAc.
  • the organic layer was separated, dried (MgSCh), filtered and the solvents evaporated in vacuo.
  • the crude product was purified by flash column chromatography (silica 12g; EtOAc in heptane 0/100 to 70/30). The desired fractions were collected and concentrated in vacuo to yield Intermediate 30 (213 mg, yield 57%) as a beige solid.
  • VILL_sjimenez_445 1 (1.05 g, 3.19 mmol) diluted in DCM anhydrous (5 mL) was added dropwise to a stirred mixture of Int37 (1.21 g, 2.66 mmol) and triethylamine [121-44-8] (0.93 mL, 6.65 mmol) in DCM anhydrous (10 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at rt for 16 h. Then was diluted with sat. NaHCO3 aqueous solution (30 mL) and extracted with EtOAc (x3). The combined organic layers were dried (MgSCL), filtered and solvents evaporated in vacuo.
  • Tetrakis(triphenylphosphine)palladium (0) [14221-01-3] (119 mg, 0.102 mmol) was added to a stirred suspension of Int38 (390 mg, 0.68 mmol), Trimethylboroxine [823- 96-1] (303 pL, 2.17 mmol) and CuTC [68986-76-5] (395 mg, 2.033 mmol) in THF anhydrous (11 mL) (previously bubbled with nitrogen for 5 min) at rt under nitrogen atmosphere in a glass sealed tube. The mixture was stirred at 85 °C for 16 h.
  • HPLC High-Performance Liquid Chromatography
  • MS Mass Spectrometer
  • SQL Single Quadrupole Detector
  • MSD Mass Selective Detector
  • RT room temperature
  • BEH bridged ethylsiloxane/silica hybrid
  • DAD Diode Array Detector
  • HSS High Strength silica
  • CDCh was used as solvent, unless otherwise mentioned.
  • the chemical shifts are expressed in ppm relative to tetramethylsilane.
  • Example B Pharmaceutical Compositions
  • a compound of the invention for instance, a compound of the examples
  • a pharmaceutically acceptable carrier thereby providing a pharmaceutical composition comprising such active compound.
  • a therapeutically effective amount of a compound of the invention e.g. a compound of the examples
  • is intimately mixed with a pharmaceutically acceptable carrier in a process for preparing a pharmaceutical composition.
  • a compound according to the present invention exhibits valuable pharmacological properties, e.g. properties susceptible to inhibit NLRP3 activity, for instance as indicated the following test, and are therefore indicated for therapy related to NLRP3 inflammasome activity.
  • PBMCs peripheral blood mononuclear cells
  • Ficoll- Histopaque Sigma-Aldrich, A0561 density gradient centrifugation. After isolation, PBMCs were stored in liquid nitrogen for later use. Upon thawing, PBMC cell viability was determined in growth medium (RPMI media supplemented with 10% fetal bovine serum, 1% Pen-Strep and 1% L-glutamine). Compounds were spotted in a 1 :3 serial dilution in DMSO and diluted to the final concentration in 30 pl medium in 96 well plates (Falcon, 353072).
  • PBMCs peripheral blood mononuclear cells
  • LPS stimulation was performed by addition of 100 ng/ml LPS (final concentration, Invivogen, tlrl-smlps) for 6 hrs followed by collection of cellular supernatants and the analysis of IL-ip (pM) and TNFa cytokines levels (pM) via MSD technology according to manufacturers’ guidelines (MSD, K151A0H).
  • IC50 values for IL-ip
  • EC50 values for IL-ip
  • TNFa EC50 values
  • the objective of this assay is to measure the permeability and efflux of test compounds, using MDCK cells transfected with the P-glycoprotein (MDR1). Two control compounds are screened alongside the test compounds, propranolol (highly permeable) and prazosin (a substrate for P-glycoprotein).
  • MDCK cells are an epithelial cell line of canine kidney origin. These cells can be stably transfected to express active P-glycoprotein (MDR1-MDCK) and are ideal for studying drug efflux due to P-gp.
  • Test compound is added to either the apical or basolateral side of a confluent monolayer of MDR1-MDCK cells and permeability in the apical to basolateral (A-B) and basolateral to apical (B-A) direction is measured by monitoring the appearance of the test compound on the opposite side of the membrane using LCMS/MS.
  • Efflux ratios (B-A permeability over A-B permeability) are calculated to determine if the test compound is subject to P-gp efflux.
  • mice were treated with NLRP3 inhibitors prior to LPS administration to evaluate the effect of NLRP3 inhibitors on inflammasome activation by measuring ILip.
  • IL6 and TNFa were measured as well.
  • Compounds were administered via oral gavage (PO) 30 minutes before intraperitoneal LPS injection (10 mg/kg) injection (Escherichia coli 0111 :B4; L4130, Sigma- Aldrich). Three doses were tested for each compound.
  • Nlrpr3 knockout mice were included as a negative control, i.e., to define endogenous levels of ILip in these experiments.
  • animals were sacrificed by decapitation and plasma samples were collected for bioanalysis and cytokine (ILip, IL6 and TNFa) analysis using ELISA (ILip, Quantikine MLBOOC, R&D Systems Minneapolis, Canada) and MSD (IL6 and TNFa, V-Plex K15048D MSD, Meso Scale Diagnostics, Maryland, USA). Plasma samples were diluted 1/20 for ILip and TNFa measurements and further diluted to 1/60 for the analysis of IL6.
  • One or more compound(s) may be tested in a number of other assays to evaluate, amongst other properties, permeability, stability (including metabolic stability and blood stability) and solubility.
  • liver microsomes 0.5 mg/ml protein
  • preclinical species incubated up to 60 minutes at 37°C with 1 pM test compound.
  • liver hepatocytes (1 milj cells) from human and preclinical species incubated up to 120 minutes at 37°C with 1 pM test compound.
  • # cellS/n C number of cells (xlO 6 ) in the incubation
  • the compound of interest is spiked at a certain concentration in plasma or blood from the agreed preclinical species; then after incubating to predetermined times and conditions (37°C, 0°C (ice) or room temperature) the concentration of the test compound in the blood or plasma matrix can then be determined with LCMS/MS.

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Abstract

L'invention concerne des composés destinés à être utilisés en tant qu'inhibiteurs de la voie de l'inflammasone NLRP3, de tels composés étant tels que définis par les composés de formule (I) et les radicaux R1 à R5 et L étant définis dans la description, et ces composés pouvant être utiles en tant que médicaments, par exemple pour une utilisation dans le traitement d'une maladie ou d'un trouble qui est associé à l'activité de l'inflammasome NLRP3.
PCT/EP2024/051982 2023-01-31 2024-01-26 Pyridin-2(1h)-ones et pyrimidin-4(3h)-ones utiles en tant qu'inhibiteurs de nlrp3 Ceased WO2024160693A1 (fr)

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EP24702715.4A EP4658640A1 (fr) 2023-01-31 2024-01-26 Pyridin-2(1h)-ones et pyrimidin-4(3h)-ones utiles en tant qu'inhibiteurs de nlrp3
KR1020257028705A KR20250152069A (ko) 2023-01-31 2024-01-26 Nlrp3 억제제로서의 피리딘-2(1h)-온 및 피리미딘-4(3h)-온
AU2024215094A AU2024215094A1 (en) 2023-01-31 2024-01-26 Pyridin-2(1h)-ones and pyrimidin-4(3h)-ones as nlrp3 inhibitors

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US12312351B2 (en) 2022-10-31 2025-05-27 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
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US12281112B2 (en) 2021-04-07 2025-04-22 Ventus Therapeutics U.S., Inc. Compounds for inhibiting NLRP3 and uses thereof
US12312350B2 (en) 2021-04-07 2025-05-27 Ventus Therapeutics U.S., Inc. Compounds for inhibiting NLRP3 and uses thereof
US12410167B2 (en) 2021-04-07 2025-09-09 Ventus Therapeutics U.S., Inc. Pyridazine compounds for inhibiting NLRP3
US12441728B2 (en) 2021-04-07 2025-10-14 Ventus Therapeutics U.S., Inc. Pyridazine compounds for inhibiting NLRP3
US12195460B2 (en) 2022-03-25 2025-01-14 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
US12312351B2 (en) 2022-10-31 2025-05-27 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
US12331048B2 (en) 2022-10-31 2025-06-17 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
US12398136B2 (en) 2022-10-31 2025-08-26 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
WO2025153532A1 (fr) 2024-01-16 2025-07-24 NodThera Limited Polythérapies faisant intervenir des inhibiteurs de nlrp3 et des agonistes de glp-1

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