EP4658640A1 - Pyridin-2(1h)-ones and pyrimidin-4(3h)-ones as nlrp3 inhibitors - Google Patents

Pyridin-2(1h)-ones and pyrimidin-4(3h)-ones as nlrp3 inhibitors

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Publication number
EP4658640A1
EP4658640A1 EP24702715.4A EP24702715A EP4658640A1 EP 4658640 A1 EP4658640 A1 EP 4658640A1 EP 24702715 A EP24702715 A EP 24702715A EP 4658640 A1 EP4658640 A1 EP 4658640A1
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EP
European Patent Office
Prior art keywords
3alkyl
hydrogen
mmol
methyl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24702715.4A
Other languages
German (de)
French (fr)
Inventor
Oscar MAMMOLITI
Soufyan JERHAOUI
Laura PEREZ BENITO
Santiago CAÑELLAS ROMAN
Daniel Oehlrich
Marion Laurence Christiane PRIERI
Michael Eric MURATORE
Pavel RYABCHUK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
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Publication of EP4658640A1 publication Critical patent/EP4658640A1/en
Pending legal-status Critical Current

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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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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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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

Provided are compounds for use as inhibitors of the NLRP3 inflammasone pathway, wherein such compounds are as defined by compounds of formula (I) and wherein the radicals R1 to R5 and L are defined in the description, and where the compounds may be useful as medicaments, for instance for use in the treatment of a disease or disorder that is associated with NLRP3 inflammasome activity.

Description

PYRIDIN-2(1H)-ONES AND PYRIMIDIN-4(3H)-ONES AS NLRP3 INHIBITORS
TECHNICAL FIELD
Described herein are pyridine-2(lH)-ones and pyrimidin-4(3H)-ones that are useful as inhibitors of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. Also described herein are 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.
BACKGROUND
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). To date, it was shown that inflammasomes can be formed by nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and Pyrin- and HIN200-domain-containing proteins (n and Lamkanfi M. Immunity, 2019 Jun 18;50(6): 1352-1364). 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)). Additionally, 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).
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). Upon recognition of PAMP or DAMP, NLRP3 aggregates with the adaptor protein, apoptosis-associated speck-like protein (ASC), and with the protease caspase- 1 to form a functional inflammasome. 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. Alternatively, 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. Nat Rev Gastroenterol Hepatol, 2015 Jul;12(7):387- 400) and inflammatory bowel diseases (eg. Crohn’s disease, ulcerative colitis) (Zhen Y and Zhang H. Front Immunol, 2019 Feb 28; 10:276). Also, inflammatory joint disorders (e.g. gout, pseudogout (chondrocalcinosis), arthropathy, osteoarthritis, and rheumatoid arthritis (Vande Walle L et al., Nature, 2014 Aug 7;512(7512):69-73) were linked to NLRP3. Additionally, kidney related diseases (hyperoxaluria (Knauf et al., Kidney Int, 2013 Nov;84(5):895-901), lupus nephritis, 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. Reports link onset and progression of neuroinflammation-related disorders (e.g. brain infection, acute injury, multiple sclerosis, Alzheimer's disease) and neurodegenerative diseases (Parkinsons disease) to NLRP3 inflammasome activation (Sarkar et al., NPJ Parkinsons Dis, 2017 Oct 17;3:30). In addition, 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 (Ridker et al., CANTOS Trial Group. N Engl J Med, 2017 Sep 21;377(12): 1119-1131; and Toldo S and Abbate A. Nat Rev Cardiol, 2018 Apr; 15 (4): 203 -214) have recently been associated to NLRP3. Also, skin associated diseases were described (e.g. wound healing and scar formation; inflammatory skin diseases, eg. acne, hidradenitis suppurativa (Kelly et al., Br J Dermatol, 2015 Dec;173(6)). In addition, respiratory conditions have been associated with NLRP3 inflammasome activity (e.g. asthma, sarcoidosis, Severe Acute Respiratory Syndrome (SARS) (Nieto-Torres et al., Virology, 2015 Nov;485:330-9)), silicosis, pneumonia, but also age-related macular degeneration (Doyle et al., Nat Med, 2012 May;18(5):791-8). Several cancer related diseases/disorders were described linked to NLRP3 (e.g. myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MOS), myelofibrosis, lung cancer, colon cancer (Ridker et al., Lancet, 2017 Oct 21;390(10105): 1833-1842; Derangere et al., Cell Death Differ. 2014 Dec;21(12): 1914-24; Basiorka et al., Lancet Haematol, 2018 Sep;5(9): e393-e402, Zhang et al., Hum Immunol, 2018 Jan;79(l):57-62).
Several patent applications describe NLRP3 inhibitors, with recent ones including for instance WO-2020/234715, WO-2021/193897, WO-2022/135567, US-11,319,319.
There is a need for inhibitors of the NLRP3 inflammasome pathway for example to study neurodegenerative disorders such as Alzheimer’s Disease.
SUMMARY
Described herein are compounds which inhibit the NLRP3 inflammasome pathway. In some embodiments, provided herein are compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein
A is N or CR3;
L is a direct bond or a bivalent radical (CH2)n wherein n is 1, 2 or 3; and
R1 is Cs-ecycloalkyl or heterocyclyl each optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of Ci-salkyl, haloCi-salkyl, Ci-3alkyloxy, halogen, amino, hydroxy, cyano, oxo, C(=O)-Ci-3alkyl, CHFCH2OH, CH2OCH3, and CH2S(O)2CH3; wherein heterocyclyl is a non-aromatic monocyclic or bicyclic group in which at least one and up to four of the atoms in the ring system are N, O, S, S(=O) or S(=O)2 and in which the total number of atoms in the ring system is between 3 and 20; and wherein the bicyclic group is fused, bridged or spiro; or L-R1 is CH2C(=O)-OH, CH2C(=O)-NR6R7, CH2CH2OH, CH2CH2CH2OH or CH2CF2CH2OH; wherein NR6R7 is NH(Ci-3alkyl) or N(Ci-3alkyl)2, or
NR6R7 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;
R2 is hydrogen, Ci-3alkyl, or halogen;
R3 is hydrogen, halo, Ci-3alkyl, Ci-3haloalkyl, Cs-ecycloalkyl, aryl; and
R4 and R5 are each independently hydrogen or Ci-3alkyl. In another aspect, there are provided compounds for use as a medicament. In another aspect, there are provided pharmaceutical compositions comprising a therapeutically effective amount of a compound provided herein.
In a further aspect, there are provided compounds and pharmaceutical 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.
In another aspect, there is provided the use of 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.
In another aspect, there is provided a method of treating a disease or disorder mediated by the NLRP3 inflammasome pathway, for example neurodegenerative disorders such as Alzheimer’s Disease. In a further aspect there is provided a method of inhibiting the NLRP3 inflammasome activity in a subject (in need thereof), the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound as provided herein.
DETAILED DESCRIPTION
Described herein are compounds which inhibit the NLRP3 inflammasome pathway. In a first embodiment, provided herein are compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein
A is N or CR3;
L is a direct bond or a bivalent radical (CFLjn wherein n is 1, 2 or 3; and
R1 is Cs-ecycloalkyl or heterocyclyl each optionally substituted with 1, 2 or 3 substituents selected from Ci-salkyl, haloCi-salkyl, Ci-3alkyloxy, halogen, amino, hydroxy, cyano, oxo, C(=O)-Ci-3alkyl, CHFCH2OH, CH2OCH3, and CH2S(O)2CH3; wherein heterocyclyl is a non-aromatic monocyclic or bicyclic group in which at least one and up to four of the atoms in the ring system are N, O, S, S(=O) or S(=O)2 and in which the total number of atoms in the ring system is between 3 and 20; and wherein the bicyclic group is fused, bridged or spiro; or L-R1 is CH2C(=O)-OH, CH2C(=O)-NR6R7, CH2CH2OH, CH2CH2CH2OH or CH2CF2CH2OH; wherein NR6R7 is NH(Ci-3alkyl) or N(Ci-3alkyl)2, or
NR6R7 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; R2 is hydrogen, Ci-3alkyl, or halogen;
R3 is hydrogen, halo, Ci-3alkyl, Ci-3haloalkyl, Cs-ecycloalkyl, aryl; and
R4 and R5 are each independently hydrogen or Ci-3alkyl.
In a second embodiment
A is CR3;
L is a direct bond or a bivalent radical (CH2)n wherein n is 1; and
R1 is Cs-ecycloalkyl or heterocyclyl each optionally substituted with 1, 2 or 3 substituents selected from Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, halogen, amino, hydroxy, cyano, oxo, C(=O)-Ci-3alkyl, CHFCH2OH, CH2OCH3, and CH2S(O)2CH3; wherein heterocyclyl is a non-aromatic monocyclic or bicyclic group in which at least one and up to four of the atoms in the ring system are N, O, S, S(=O) or S(=O)2 and in which the total number of atoms in the ring system is between 3 and 20; and wherein the bicyclic group is fused, bridged or spiro; or L-R1 is CH2C(=O)-OH, CH2C(=O)-NR6R7, CH2CH2OH, CH2CH2CH2OH or CH2CF2CH2OH; wherein NR6R7 is NH(Ci-3alkyl) or N(Ci-3alkyl)2, or
NR6R7 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;
R2 is hydrogen, methyl, ethyl or chloro;
R3 is hydrogen, chloro, bromo, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, phenyl; and
R4 and R5 are each independently hydrogen or methyl.
In a third embodiment
A is CR3;
L is a direct bond or a bivalent radical (CH2)n wherein n is 1; and
R1 is Cs-ecycloalkyl or heterocyclyl each optionally substituted with 1, 2 or 3 substituents selected from Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, halogen, amino, hydroxy, cyano, oxo, C(=O)-Ci-3alkyl, CHFCH2OH, CH2OCH3, and CH2S(O)2CH3; wherein heterocyclyl is a non-aromatic monocyclic or bicyclic group in which at least one and up to four of the atoms in the ring system are N, O, S, S(=O) or S(=O)2 and in which the total number of atoms in the ring system is between 3 and 20; and wherein the bicyclic group is fused, bridged or spiro; or L-R1 is CH2C(=O)-OH, CH2C(=O)-NR6R7, CH2CH2OH, CH2CH2CH2OH or CH2CF2CH2OH; wherein NR6R7 is NH(Ci-3alkyl) or N(Ci-3alkyl)2, or
NR6R7 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; R2, R4 and R5 are each hydrogen, or one of R2 and R4 is methyl and R5 is hydrogen.
In a fourth embodiment
A is N;
L is a direct bond or a bivalent radical (CH2)n wherein n is 1; and
R1 is Cs-ecycloalkyl or heterocyclyl each optionally substituted with 1, 2 or 3 substituents selected from Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, halogen, amino, hydroxy, cyano, oxo, C(=O)-Ci-3alkyl, CHFCH2OH, CH2OCH3, and CH2S(O)2CH3; wherein heterocyclyl is a non-aromatic monocyclic or bicyclic group in which at least one and up to four of the atoms in the ring system are N, O, S, S(=O) or S(=O)2 and in which the total number of atoms in the ring system is between 3 and 20; and wherein the bicyclic group is fused, bridged or spiro; or L-R1 is CH2C(=O)-OH, CH2C(=O)-NR6R7, CH2CH2OH, CH2CH2CH2OH or CH2CF2CH2OH; wherein NR6R7 is NH(Ci-3alkyl) or N(Ci-3alkyl)2, or
NR6R7 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;
R2 is hydrogen, methyl, ethyl or chloro;
R3 is hydrogen, chloro, bromo, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, phenyl; and
R4 and R5 are each independently hydrogen or methyl.
In a fifth embodiment
A is N;
L is a direct bond or a bivalent radical (CH2)n wherein n is 1; and
R1 is Cs-ecycloalkyl or heterocyclyl each optionally substituted with 1, 2 or 3 substituents selected from Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, halogen, amino, hydroxy, cyano, oxo, C(=O)-Ci-3alkyl, CHFCH2OH, CH2OCH3, and CH2S(O)2CH3; wherein heterocyclyl is a non-aromatic monocyclic or bicyclic group in which at least one and up to four of the atoms in the ring system are N, O, S, S(=O) or S(=O)2 and in which the total number of atoms in the ring system is between 3 and 20; and wherein the bicyclic group is fused, bridged or spiro; or L-R1 is CH2C(=O)-OH, CH2C(=O)-NR6R7, CH2CH2OH, CH2CH2CH2OH or CH2CF2CH2OH; wherein NR6R7 is NH(Ci-3alkyl) or N(Ci-3alkyl)2, or
NR6R7 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;
R2, R4 and R5 are each hydrogen, or one of R2 and R4 is methyl and R5 is hydrogen.
In a sixth embodiment
A is N or CH; when L is a direct bond, then R1 is cyclohexyl, 2-hydroxycyclohexyl, 4-hydroxycyclohexyl, tetrahydropyran-4-yl, 3 -hydroxytetrahydropyran-4-yl, wherein R10 is hydrogen or methyl and R11 is hydrogen or fluoro; when L is CH2, then R1 is herein NR6R7 is N(CH3)2, pyrrolidinyl, or morpholinyl;
R2 is H or CH3 ;
R3 is hydrogen, methyl, trifluoromethyl, chloro or CF3 ;
R4 is hydrogen or methyl;
R5 is hydrogen.
In a further embodiment, A is N or CR3; L is a direct bond or a bivalent radical (CH2)n wherein n is 1 or 2; and
R1 is Cs-ecycloalkyl or heterocyclyl each optionally substituted with 1, 2 or 3 substituents each independently selected from Ci-salkyl, haloCi-salkyl, Ci-3alkyloxy, halogen, hydroxy, oxo, C(=O)-Ci-3alkyl, CH2CH2OH, CHFCH2OH, CH2OCH3, and CH2S(O)2CH3; wherein heterocyclyl is a non-aromatic monocyclic or bicyclic group in which at least one and up to four of the atoms in the ring system are N, O, S, S(=0) or S(=0)2 and in which the total number of atoms in the ring system is between 3 and 20; and wherein the bicyclic group is fused, bridged or spiro; or L-R1 is CH2C(=0)-0H, CH2C(=O)-NR6R7, CH2CH2OH, CH2CH2CH2OH or CH2CF2CH2OH; wherein NR6R7 is NH(Ci-3alkyl) or N(Ci-3alkyl)2, or
NR6R7 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;
R2 is hydrogen, Ci-3alkyl, or halogen;
R3 is hydrogen, halo, Ci-3alkyl, Ci-3haloalkyl, Cs-ecycloalkyl, phenyl; and R4 and R5 are each independently hydrogen or Ci-3alkyl.
Compounds of particular interest are
(7?)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-l-(piperidin-3-yl)pyridin-2(lJ7)-one hydrochloride,
(R)-3-(2 -hydroxy-6-m ethyl -4-(trifluoromethyl)phenyl)-l-(l-methylpiperi din-3 -yl)pyridin- 2(lH)-one, and (7?)-5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-3-(l-methylpiperi din-3 -yl)pyrimidin- 4(3H)-one.
Pharmaceutically-acceptable 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. In certain embodiments, 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. Alternatively 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.
In the structures shown herein, where the 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.
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. Thus, when a compound of formula (I) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer.
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.
Also provided herein are 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 2H, 3H, nC, 13C, 14C , 13N, 15O, 17O, 18O, and 18F. Tritiated (3H) and carbon-14 (14C) 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 15O, 13N, nC and 18F 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.
Unless otherwise specified, 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 (where q is the upper limit of the range) 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. In particular, 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.
The term “halo”, when used herein, preferably includes fluoro, chloro, bromo and iodo.
Ci-q alkoxy groups (where q is the upper limit of the range) refers to the radical of formula -ORa, where Ra 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. one, of the hydrogen atoms is replaced with -OH). Similarly, 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.
Heterocyclyl, as referred to herein, unless otherwise indicated, is a non-aromatic monocyclic or bicyclic group in which at least one and up to four of the atoms in the ring system are N, O, S, S(=O) or S(=O)2 and in which the total number of atoms in the ring system is between 3 and 20; and wherein the bicyclic group is fused, bridged or spiro. 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 names of the compounds were generated according to the nomenclature rules agreed upon by the Chemical Abstracts Service (CAS) using Advanced Chemical Development, Inc., software (ACD/Name product version 10.01; Build 15494, 1 Dec 2006) or according to the nomenclature rules agreed upon by the International Union of Pure and Applied Chemistry (IUPAC) using Advanced Chemical Development, Inc., software (ACD/Name product version 10.01.0.14105, October 2006). In case of tautomeric forms, the name of the depicted tautomeric form of the structure was generated.
The instant compounds can generally be prepared by a succession of steps, each of which is known to the skilled person. In particular, 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 the compounds 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).
PREPARATION OF THE COMPOUNDS
The compounds can generally be prepared by a succession of steps, each of which is known to the skilled person. In particular, 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). In an aspect of the disclosure, there is provided a process for the preparation of compounds of the disclosure, where reference here is made to compounds of Formula (I) as defined herein.
Final compounds according to Formula (la), where A is CH, R4 and R5 are H and where R20 can be deprotected under suitable acid conditions or under catalytic hydrogenation, or where R20 is H, can be prepared:
By deprotecting an intermediate of Formula (II) in the presence of a suitable acidic reagent such as, for example, trifluoroacetic acid or hydrochloric acid, in a suitable solvent such as di chloromethane or 1,4-di oxane, at a suitable temperature such as, room temperature;
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;
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;
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.
Final compounds according to Formula (lb), where A is CH and L is CH2, and where R20 can be deprotected under suitable acid conditions or under catalytic hydrogenation, or where
R20 is H, can be prepared:
By deprotecting an intermediate of Formula (IX) in the presence of a suitable acidic reagent such as trifluoroacetic acid or hydrochloric acid, in a suitable solvent such as di chloromethane or 1,4-di oxane, at a suitable temperature for example at room temperature;
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;
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;
Alternatively, 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.
Alternatively, Intermediates according to Formula (IX), where A is CH and L is CH2, and where R20 can be deprotected under suitable acid conditions or under catalytic hydrogenation, or where R20 is H, can be prepared:
By reacting an Intermediate of Formula (XII) 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;
Alternatively, 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.
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.
Final compounds according to Formula (Ic), where A is CR3, L is a direct bond and R4 and R5 are H, and where R20 can be deprotected under suitable acid conditions or under catalytic hydrogenation, or where R20 is H, can be prepared:
By deprotecting an intermediate of Formula (XIII) in the presence of a suitable acidic reagent such as trifluoroacetic acid or hydrochloric acid, in a suitable solvent such as di chloromethane or 1,4-di oxane, at a suitable temperature for example at room temperature;
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;
Alternatively, 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;
Alternatively, the skilled chemist will understand that any type of functionalization of an Intermediate of Formula (XIV) is possible, provided functional group compatibility with R1, R2 and PG;
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;
Alternatively, Intermediates of Formula (XIV), with X=I, can be prepared by halogen exchange on an Intermediate of Formula (XIII), with X=Br, using a suitable reagent such as, for example, sodium iodide, in the presence of a suitable catalyst such as copper (I) iodide, in the presence of a suitable ligand such as trans-N,N’- dimethylcyclohexane-l,2-diamine, in a suitable solvent such as 1,4-di oxane, at a suitable temperature for example at 120 °C.
Final compounds according to Formula (Id), where A is N, L is CH2 or a direct bond and R5 is H, and where R20 can be deprotected under suitable acid conditions or under catalytic hydrogenation, or where R20 is H, can be prepared:
By deprotecting an intermediate of Formula (XV) in the presence of a suitable acidic reagent such as trifluoroacetic acid or hydrochloric acid, in a suitable solvent such as di chloromethane or 1,4-di oxane, at a suitable temperature for example, room temperature;
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;
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.
Final compounds according to Formula (le), where A is N, L is CH2 and R5 is H, and where R20 can be deprotected under suitable acid conditions or under catalytic hydrogenation, or where R20 is H, can be prepared:
By deprotecting an intermediate of Formula (XVIII) in the presence of a suitable acidic reagent such as trifluoroacetic acid or hydrochloric acid, in a suitable solvent such as dichloromethane or 1,4-di oxane, at a suitable temperature for example at room temperature;
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;
Alternatively, 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.
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.
Boronate intermediates according to Formula (XXI), where R20 can be deprotected under suitable acid conditions or under catalytic hydrogenation to yield (X), and where R21 is typically BPin or OH, can be prepared:
By reacting an intermediate of Formula (XXII) with an appropriate source of boron such as, for example, 4,4,5,5-Tetramethyl[l,3,2]dioxaborolane, in the presence of a suitable catalyst such as palladium(II) acetate, with a suitable ligand such as CyJohnPhos, in the presence of a suitable base such as triethylamine, in a suitable solvent such as 1,4-di oxane, at a suitable temperature for example at 100 °C;
Alternatively, 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;
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;
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.
The skilled chemist will understand that, in the case that R1, R2 or R3 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. 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. PHARMACOLOGY
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.
PHARMACEUTICAL COMPOSITIONS AND COMBINATIONS
In an embodiment, further described herein are 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. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions, 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. These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally or by parenteral injection. For example, in preparing the compositions in oral dosage form, 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. For parenteral compositions, 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. Also included are 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.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein 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. Examples of such 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.
As used herein, term "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.
As used herein, 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).
The term "subject" as used herein, 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.
The term "therapeutically effective amount" as used herein, 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. In one non-limiting embodiment, the term "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. In another non-limiting embodiment, the term "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.
As used herein, the term "inhibit", "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. Specifically, 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.
As used herein, the term "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.
As used herein, the term "treat", "treating" or "treatment" of any disease or disorder 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.
As used herein, 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.
As used herein, a subject is "in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
In an embodiment, there is provided a compound, according to any one of the embodiments described herein, for use as a medicament.
In an embodiment, there is provided a compound, 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 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.
In an embodiment, there is provided the use of compounds 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): 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.
In an embodiment, there is provided the use of compounds as provided herein, according to any one of the embodiments described herein (and/or pharmaceutical compositions comprising such compounds, according to any one of the embodiment described herein), in the manufacture of a medicament for: the treatment of a disease or disorder associated with NLRP3 activity (including inflammasome activity); 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; and/or inhibiting NLRP3 inflammasome activity (including in a subject in need thereof).
In an embodiment, there is provided 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). In a further embodiment, there is provided a method of inhibiting the NLRP3 inflammasome activity in a subject (in need thereof), the method 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.
For instance, 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. Specifically, the instant compounds may also have advantages over prior art compounds when compared in the tests outlined hereinafter. EXPERIMENTAL PART
Several methods for preparing the Compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively can be synthesized by a skilled person by using published methods.
Table 1 : Abbreviations
Preparation of intermediates
For intermediates that were used in a next reaction step as a crude or as a partially purified intermediate, in some cases no mol amounts are mentioned for such intermediate in the next reaction step or alternatively estimated mol amounts or theoretical mol amounts for such intermediate in the next reaction step are indicated in the reaction protocols described below.
2-iodo-5-(trifluoromethyl)phenoI [CAS 102771-00-6] Inti
Sodium hydride [CAS 7646-69-7] (2.47 g, 61.69 mmol) was suspended in anhydrous toluene (92 mL) at 0 °C under nitrogen atmosphere. Then 3 -trifluoromethylphenol [CAS 98-17-9] (3.8 mL, 30.84 mmol) was added dropwise. The mixture was stirred at 0 °C for 30 min. Then iodine [7553-56-2] (7.83 g, 30.84 mmol) was added portionwise and the mixture was stirred from 0 °C to rt for 3 h. The mixture was acidified at 0 °C with 37% HC1 sol. in water until pH reached 4-5, then was extracted with EtOAc and washed twice with brine. The organic layer was separated, dried (MgSCL), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 80 g; EtOAc in heptane 0/100 to 10/90). The desired fractions were collected and concentrated in vacuo to yield Intermediate 1 (6.5 g, yield 72 %) as a colourless oil. l-iodo-2-(methoxymethoxy)-4-(trifluoromethyl)benzene Int2
Intermediate 1 (6.5 g, 22.6 mmol) and K2CO3 [CAS 584-08-7] (5.3 g, 38.4 mmol) were dissolved in anhydrous DMF (95 mL). The reaction mixture was stirred at rt for 30 minutes. Then chloromethyl methyl ether [CAS 107-30-2] (2.4 mL, 29.3 mmol) was added dropwise and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were combined, dried (MgSCL), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica 80 g; heptane 100%). The desired fractions were collected and concentrated in vacuo to yield the Intermediate 2 (5.5 g, yield 72%) as a colorless oil.
2-(2-(methoxymethoxy)-4-(trifluoromethyI)phenyI)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane Int3
Isopropyl magnesium chloride (2 M in THF) [CAS 1068-55-9] (7.2 mL, 14.46 mmol) was added dropwise to a stirred solution of Intermediate 2 (4 g, 12.05 mmol) in anhydrous THF (96 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 2 h. Afterwards, 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane [CAS 61676-62-8] (3.7 mL, 18.07 mmol) was added dropwise to the mixture. The reaction mixture was slowly warmed up to rt and stirred for 18 h. The reaction was quenched with NH4C1 (saturated in water) and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 80 g; EtOAc in heptane 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield Intermediate 3 (2.6 g, yield 63 %) as a colorless oil.
3-methyl-5-(trifluoromethyI)phenol [CAS 934180-46-8] Int4 Lithium hydroxide hydrate (2.8 g, 65.24 mmol) was added to a stirred solution of Tris(dibenzylideneacetone)dipalladium(0) [CAS 51364-51-3] (616 mg, 0.652 mmol) and BippyPhos [CAS 894086-00-1] (681 mg, 1.31 mmol) in 50 mL of 1,4-dioxane and 5 ml of distilled water (previously bubbled with nitrogen for 5 min). The mixture was stirred at rt for 5 min, then 3-bromo-5-methylbenzotrifluoride [CAS 86845-28-5] (5.25 g, 21.74 mmol) was added. The reaction mixture was stirred at 100 °C for 16 h. The mixture was filtered over a pad of celite and was washed with AcOEt. The filtrate was washed with HC1 (2 M in water). The organic layer was separated, dried (MgSC ), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 120g; AcOEt in heptane 0/100 to 2/98). The desired fractions were collected and concentrated in vacuo to yield Intermediate 4 (3.4 g, yield 80%) as a yellow oil.
2-iodo-3-methyl-5-(trifluoromethyl)phenoI Int5
Sodium hydride (60% dispersion in mineral oil, 1.59 g, 39.7 mmol) was added to a stirred solution of Intermediate 4 (3.4 g, 19.9 mmol) in 60 mL of anhydrous toluene at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min. Then iodine (5.05 g, 19.87 mmol) was added portionwise and the mixture was stirred from 0 °C for 3 h. The mixture was acidified at 0 °C with cone. HC1 until pH 4-5, then was extracted with EtOAc and washed twice with brine. The organic layer was separated, dried (MgSCU), filtered and the solvents evaporated in vacuo to yield Intermediate 5 (6.5 g, yield 74%) as a brown oil which was used as such without further purification.
2-iodo-l-(methoxymethoxy)-3-methyI-5-(trifluoromethyI)benzene Int6
Intermediate 5 (9.05 g, 29.96 mmol) was dissolved in DCM (300 mL) and cooled to 0 °C. To this solution was added 7V,7V-diisopropylethylamine [CAS 7087-68-5] (6.34 mL, 35.96 mmol) followed by dropwise addition of chloromethyl methyl ether [CAS 107-30-2] (2.8 mL, 35.96 mmol). This was allowed to gradually warm to rt and react for 16 h. The mixture was concentrated and the residue was purified by flash column chromatography (Load in silica 120g; DCM in heptane from 0/100 to 3/97). The desired fractions were collected and concentrated in vacuo to yield Intermediate 6 (7.39 g, yield 71%) as a yellowish oil.
2-(2-(methoxymethoxy)-6-methyI-4-(trifluoromethyI)phenyI)-4,4,5,5-tetramethyI-l,3,2- dioxaborolane Int7
Intermediate 6 (7.4 g, 21.34 mmol) was added dropwise to a stirred solution of palladium(II) acetate [CAS 3375-31-3] (489 mg, 2.13 mmol), CyJohnPhos [CAS 247940-06-3] (787 mg, 0.57 mmol) and triethylamine (15 mL, 106.72 mmol) and anhydrous 1,4-dioxane (92 mL) (previously bubbled with nitrogen for 5 min) in a sealed tube. The mixture was stirred at rt for 5 min, then 4,4,5,5-tetramethyl[l,3,2]dioxaborolane [CAS 25015-63-8] (16 mL, 106.72 mmol) was added. The reaction mixture was stirred at 100 °C for 16 h. The mixture was filtered over a pad of celite and was washed with EtOAc. The filtrate was washed with sat. aqueous NH4CI. The organic layer was separated, dried (MgSCU), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 120g; EtOAc in heptane 0/100 to 1/99). The desired fractions were collected and concentrated in vacuo to yield Intermediate 7 (6.87 g, yield 90%) as an orange solid.
2-(2-chloro-6-(methoxymethoxy)-4-(trifluoromethyI)phenyI)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane Int8
Intermediate 8 was prepared by a similar sequence as Intermediate 7, using 3-bromo-5- chlorobenzotrifluoride as starting material. The following part relates to the synthesis of Intermediates Intl4-1 to Intl4-6. Example: Synthesis of tert-butyl (7?)-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-2- oxopyri din- l(2H)-yl)piperi dine- 1 -carboxylate Intl4-1
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. Then, 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
Lithium hydroxide [1310-65-2] (2.5 g, 104.39 mmol) was added to a stirred solution of Intermediate 9-1 (25.89 g, 76.965 mmol) in 100 mL of THF, 100 mL of water and 20 mL of MeOH. The resulting mixture was stirred 8 h at room temperature. IM HC1 sol. was added until pH reached ca 2-3. Then, EtOAc was added. The organic layer was separated, and the aqueous layer was back extracted with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4 anhydrous, filtered off and evaporated under reduced pressure to yield Intermediate 10-1 (24.4 g, yield 96 %) as a yellow powder.
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. Upon cooling to room temperature, the mixture was partitioned between EtOAc and saturated NaHCOs solution. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with brine, dried with Na2SO4 anhydrous, filtered off and evaporated under reduced pressure. The excess benzyl alcohol was removed by azeotropic evaporation with water. The crude was purified by flash column chromatography on silica gel with Hept/EtOAc (9: 1 to 65:35) to afford Intermediate 11-1 (23.5 g, yield 75 %) as a pale-yellow solid. Step 4: Synthesis of tert-butyl (A)-3-(3-amino-2-oxopyridin-l(2J7)-yl)piperidine-l- carb oxy late Inti 2-1
10 mol% Pd/C (2 g, 1.879 mmol) was added to a solution of Intermediate 11-1 (23.5 g, 54.971 mmol) in 400 mL of EtOH under nitrogen atmosphere. Three vacuum/hydrogen cycles were performed and the vessel was stirred under hydrogen atmosphere for 1 h at room temperature. Upon completion, the mixture was filtered through a celite pad and washed with EtOH under nitrogen atmosphere. The filtrate was evaporated under reduced pressure to yield Intermediate 12-1 (15.7 g, yield 97 %) as a white solid.
Step 5: Synthesis of tert-butyl (R)-3 -(3 -iodo-2-oxopyri din- l(2J7)-yl)piperi dine- 1 -carboxylate
In a EasyMax reactor, a solution of sodium nitrite [7632-00-0] (4 g, 57.975 mmol) in 20 mL of water was added slowly to a stirred suspension of Intermediate 12-1 (15 g, 51.131 mmol) in 150 mL of HC1 (IM sol. in water) at 0 °C. The resulting mixture was stirred 5 min at this temperature before being slowly poored in an OptiMax reactor charged with sodium iodide [7681-82-5] (28 g, 186.799 mmol) in 300 mL of EtOAc at -10 °C, while maintaining the temperature below - 5 °C. The mixture was then stirred 10 min at 0 °C. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with saturated Na2S20s solution, brine, dried with anhydrous MgSO4, filtered off and evaporated under reduced pressure. The crude was purified by flash column chromatography on silica gel with HeptZEtOAc (1 :0 to 3:2) to afford Intermediate 13-1 (10.63 g, yield 51%) as an off-white solid.
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. Then, tetrakis(triphenylphosphine)palladium [14221-01-3] (600 mg, 0.519 mmol) was added and the previous mixture was heated at 100 °C for 5 h. Then, the mixture was poured out in water and extracted two times with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4 anhydrous, filtered off and evaporated under reduced pressure. The crude was purified by flash column chromatography on silica gel with Hept/EtOAc (1 :0 to 7:3) to afford Intermediate 14-1 (8.45 g, yield 81 %) as a pale- yellow solid.
Intermediates Intl4-2 to Intl4-6 highlighted in Table 1, were prepared according to an analogous procedure as for Intl4-1, following steps 1 to 6 as previously described.
Int16
Example: Synthesis of tert-butyl 3-((3-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-oxopyridin- l(2H)-yl)methyl)pyrrolidine-l -carboxylate Intl6-1
Step 1 : Synthesis of tert-butyl 3-(((3-bromopyridin-2-yl)oxy)methyl)pyrrolidine-l- carboxylate) Inti 5-1
Tert-butyl 3 -(bromomethyl)pyrrolidine-l -carboxylate [305329-97-9] (380 mg, 1.439 mmol) was added to a pre-stirred (ca 10 min) mixture of 3-bromo-2 -hydroxypyridine [13466-43-8] (200 mg, 1.149 mmol) and CS2CO3 (380 mg, 1.166 mmol) in 5 mL of anhydrous DMF at room temperature. After stirring for 16 h, EtOAc and brine were added. The organic layer was separated, washed with water (x3), dried (Na2SC>4 anhydrous), filtered off and evaporated under reduced pressure. The crude was purified by column chromatography on silica gel with Hept/EtOAc (1 :0 to 6:4) to afford Intermediate 15-1 (257 mg, yield 63%) as a clear oil. A more apolar fraction, tert-butyl 3-(((3-bromopyridin-2-yl)oxy)methyl)pyrrolidine-l- carboxylate) (62 mg, yield 15%), was isolated as a clear oil.
Step 2: Synthesis of tert-butyl 3-((3-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-oxopyridin- l(2J7)-yl)methyl)pyrrolidine-l -carboxylate Intl6-1
Intermediate 15-1 (230 mg, 0.644 mmol), (2 -hydroxy -4-(trifluoromethyl)phenyl)boronic acid [1072951-50-8] (150 mg, 0.728 mmol) and ISfeCCh (200 mg, 1.887 mmol) were dissolved in 9 mL of dioxane and 1 mL of water in a vial that was degassed with nitrogen for 5 min. Then, Pd(PPhs)4 [14221-01-3] (75 mg, 0.065 mmol) was added and the resulting mixture was stirred at 100 °C for 1 h. Upon cooling to room temperature, water and EtOAc were added. The organic layer was separated, washed with brine, dried (ISfeSCU anhydrous), filtered off and evaporated under reduced pressure. The crude was purified by column chromatography on silica gel with Heptane/EtOAc (1 :0 to 2:3) to Intermediate 16-1 (228 mg, yield 81%) as a white solid.
Intermediates Intl6-2 to Intl6-6, highlighted in Table 2, were prepared according to an analogous procedure as for Intl6-1, following steps 1 and 2 as previously described.
The following part relates to the synthesis of Intermediates 17 to 25. tert-butyl 3-(5-bromo-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-oxopyridin-l(2jEZ)- yl)piperidine-l-carboxylate Intl7
A solution of NBS [CAS 128-08-5] (670 mg, 3.76 mmol) in DMF, dry (5 mL) was added dropwise over a 5 min period to a stirring solution of Intermediate 14-1 (1.5 g, 3.42 mmol) in 35 mL of dry DMF and the mixture was stirred at rt for 2 h. The RM was poured out in water, extracted twice with EtOAc and then the combined organic layers were washed with brine, dried on MgSCU, filtered and evaporated. The residue was purified on column chromatography with silica gel using EtOAc in Heptane, from 0 to 80 %. The purest fractions were evaporated, yielding Intermediate 17 (1.1 g, yield 62%) as a white foam. tert-butyl 3-(5-chloro-3-(2-hydroxy-4-(trifliioromethyl)pheiiyl)-2-oxopyridin-l(2//)- yl)piperidine-l-carboxylate Intl8
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. tert-butyl 3-(5-iodo-3-(2-hydroxy-4-(trifluoromethyl)pheiiyl)-2-oxopyridin-l(2//)- yl)piperidine-l-carboxylate Intl9
A mixture of Intermediate 17 (318 mg, 0.61 mmol), sodium iodide (184.27 mg, 1.23 mmol), trans-A,A'-dimethylcyclohexane-l,2-diamine (26.23 mg, 0.18 mmol) and Cui (35.12 mg, 0.18 mmol) in 10 mL of anhydrous 1,4-di oxane was heated at 120 °C for 5 h. The mixture was poured out in sat. aqueous bicarbonate solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried on MgSO4 and evaporated under reduced pressure. The residue was purified on a column with silica gel, eluent: EtOAc in Heptane, from 0 to 60 %. The purest fractions were evaporated, yielding Intermediate 19 (306 mg, yield 88 %) as a white foam. tert-butyl 3-(5-phenyl-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-oxopyridin-l(2H)- yl)piperidine-l-carboxylate Int20
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. The residue was purified on a column with silica gel, eluent : EtOAc in Heptane, from 0 to 70 %. The pure fractions were evaporated, yielding Intermediate 20 (206 mg, assumed quant, yield) as a white foam. tert-butyl 3-(5-methyl-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-oxopyridin-l(2EZ)- yl)piperidine-l-carboxylate Int21
Intermediate 17 (200 mg, 0.39 mmol) and 2 mL of anhydrous were placed in a dry tube. The solution was degassed with nitrogen. bis(tri-tert-butyiphosphine)palladium(0) (19.76 mg, 0.039 mmol) was added and then methylzinc chloride (240 pL, 2 M sol. In THF, 0.48 mmol) was added. The tube was sealed and stirred for 2 h at rt. The mixture was quenched by addition of water then aqueous saturated NH4CI, poured onto brine and extracted three times with EtOAc. The combined organic extracts were dried over Na2SO4, filtered off, concentrated and the residue purified by FCC on Biotage (Sfar 50 g, 100 mL/min, Hept/EtOAc 7:3 to 0: 1 over 20 CV. The purest fractions were evaporated, yielding Intermediate 21 (168 mg, yield 96%) as a white foam. tert-butyl 3-(5-cycloprop-3-(2-hydroxy-4-(tnfluoromethyl)phenyl)-2-oxopyndin-l(2/ )- yl)piperidine- l-carboxylate Int22
Intermediate 22 was obtained by analogy with Intermediate 21, using cyclopropylzinc bromide as coupling partner. tert-butyl 3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-oxo-5-(prop-l-en-2-yl)pyridin-
1 (2//)-yI)piperidine- l-carboxylate Int23
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. The combined organic layers were washed with brine, dried on MgSCL, filtered off and evaporated under reduced pressure. The residue was purified on a column with silica gel, eluent : EtOAc in Heptane, from 0 to 70 %. The purest fractions were evaporated, yielding Intermediate 23 (200 mg, yield 86%) as a white foam. tert-butyl 3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-isopropyl-2-oxopyridin-l(2Z7)- yl)piperidine-l-carboxylate Int24
In a 250 mL hydrogenation flask, 10% Pd/C (ca 50 mg) was added to a solution of Intermediate 23 (200 mg, 0.42 mmol) in 10 mL of MeOH. The reaction was purged three times (hydrogen/vacuum) and placed under hydrogen atmosphere. The reaction was stirred 4 h at rt. The mixture was filtered over Decalite, washing thoroughly with MeOH (ca 100 mL), the solvent was concentrated under reduced pressure at 50 °C to afford Intermediate 24 (195 mg, yield 97%) as a white foam which was used without further purification for the next step. tert-butyl 3-(3-(2-hydroxy-4-(trifluoromethyI)phenyI)-2-oxo-5-(trifluoromethyl)pyridin- 1 (2jF7)-yl)piper idine- l-carboxylate Int25
A solution of Intermediate 19 (100 mg, 0.18 mmol) in DMF, dry 1.93 ml was flushed with nitrogen for a few minutes. Then copper(I) iodide (51 mg, 0.27 mmol) was added followed by methyl 2,2-difluoro-2-(fluorosulfonyl)acetate [CAS 680-15-9] (51 mg, 0.27 mmol) and the reaction was heated at 100 °C in a sealed tube for 1 h. The RM was cooled, filtered, taken in water, extracted with EtOAc, washed with brine, filtered off and evaporated, yielding Intermediate 25 (150 mg) as a sticky yellow oil which was used without further purification for the next step.
The following part relates to the synthesis of Intermediates Int27-1 to Int27-84.
Example 1: Synthesis of tert-butyl 3-(5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6- oxopyrimidin-l(6H)-yl)piperidine-l -carboxylate Int27-1 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. The combined organic layers were dried with anhydrous MgSO4, filtered and solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 40g; EtOAc in heptane from: 0/100 to 40/60 gradient elution). The desired fractions were collected and concentrated in vacuo to yield Intermediate 26-1 (322 mg, yield 45%) as a white foamy solid.
Step 2: Synthesis of tert-butyl 3-(5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6- oxopyrimidin-l(6H)-yl)piperidine-l -carboxylate Int27-1
Cesium carbonate [534-17-8] (863 mg, 2.62 mmol) and Pd(dppf)C12.DCM [95464-05-4] (99 mg, 0.12 mmol) were added sequentially to a stirred solution of Intermediate 26-1 (427 mg, 1.19 mmol) and Intermediate 3 (594 mg, 1.79 mmol) in 1.4-dioxane (6.2 mL) and water (1.1 mL) (previously bubbled with nitrogen for 5 min) at rt under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled down to rt, diluted with saturated NaHCCh aqueous solution and extracted with EtOAc three times. The combined organic layers were dried with anhydrous MgSCU, filtered and solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 40 g;
EtOAc in heptane from 0/100 to 80/20 gradient elution). The desired fractions were collected and concentrated in vacuo to yield Intermediate 27-1 (513 mg, yield 88%) as a beige foamy solid. Example 2: Synthesis of tert-butyl 3-((5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6- oxopyrimidin-l(6H)-yl)methyl)piperidine-l -carboxylate Int27-2
Step L : Synthesis of 5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)pyrimidin-4(3H)-one
Int26-2
5-bromopyrimidin-4-ol [19808-30-1] (3 g, 17.14 mmol), Intermediate 3 (6 g, 18.07 mmol) and sodium carbonate [497-19-8] (3.6 g, 33.97 mmol) were suspended in 60 mL of 1,4- di oxane and 10 mL of water, and the resulting mixture was degassed 5 min with nitrogen. Then, Pd(PPhs)4 [14221-01-3] (500 mg, 0.433 mmol) was added and the vial was heated at 120 °C overnight. IM HC1 sol. and EtOAc were added. The organic layer was separated, washed with brine (x2), dried (Na2SO4), filtered off and evaporated under reduced pressure.
The crude was purified by column chromatography on silica gel with DCM/MeOH (1 :0 to 95:5) to afford Intermediate 26-2 (4.8 g, yield 89%) as a pale yellow solid.
Step 2’ : Synthesis of tert-butyl 3-((5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6- oxopyrimidin-l(6H)-yl)methyl)piperidine-l -carboxylate Int27-2
(S)-tert-butyl 3 -(brom omethyl)piperi dine- 1 -carboxylate [158406-99-6] (200 mg, 0.719 mmol) was added to a stirred mixture of Int26-2 (150 mg, 0.475 mmol) and K2CO3 (100 mg, 0.724 mmol) in 5 mL of anhydrous DMF and the resulting mixture was stirred at 50 °C over 2 days. Then, the mixture was diluted with water and EtOAc. The organic layer was separated, washed with brine (x3), dried (MgSCU), filtered off and evaporated under reduced pressure. The crude was purified by column chromatography on silica gel with Hept/EtOAc (1 :0 to 1 :1) to afford Intermediate 27-2 (180 mg, yield 76%) as a clear oil. Intermediates Int27-3 to Int27-84, highlighted in Table 2, were prepared according to an analogous procedure as for Int27-1 (respect. Int27-2), following Steps 1 and 2 (respect. Steps 1’ and 2’) as previously described. The following part relates to the synthesis of Intermediate 30. tert-butyl (R)-3-(5-bromo-4-methyl-6-oxopyrimidin-l(6H)-yl)piperidine-l- carboxylate Int28
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. NaHCO3 aqueous solution and extracted with EtOAc (x3). The combined organic layers were dried (MgSO4), filtered and solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 25 g; EtOAc in heptane 0/100 to 30/70). The desired fractions were collected and concentrated in vacuo to yield Intermediate 28 (596 mg, yield 77%) as a white foam solid. tert-butyl (R)-3-(5-(2-(methoxymethoxy)-4-(trifluoromethyI)phenyl)-4-methyl-6- oxopyrimidin-l(6H)-yl)piperidine-l-carboxylate Int29
Cesium carbonate [534-17-8] (1.16 g, 3.52 mmol) and [l,l'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) dichloromethane [95464-05-4] (0.13 g, 0.16 mmol) were added sequentially to a stirred solution of Intermediate 28 (0.59 g, 1.60 mmol) and Intermediate 3 (0.69 g, 2.08 mmol) in 1.4-dioxane (8.3 mL) and water (1.5 mL) (previously bubbled with nitrogen for 5 min) at rt under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled down to rt, diluted with sat. NaHCCL aqueous solution and extracted with EtOAc (x3). The combined organic layers were dried (MgSO4), filtered and solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 40 g; EtOAc in heptane 0/100 to 60/40). The desired fractions were collected and concentrated in vacuo to yield Intermediate 29 (598 mg, yield 71%) as an oil. tert-butyl (R)-3-(5-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4- methyl-6-oxopyrimidin-l(6H)-yI)piperidme-l-carboxyIate Int30
Tetrakis(triphenylphosphine)palladium (0) [14221-01-3] (42.2 mg, 0.04 mmol, 0.05 eq.) was added to a stirred suspension of Intermediate 28 (269 mg, 0.72 mmol), Intermediate 7 (287.7 mg, 0.83 mmol) and sodium carbonate [497-19-8] (232.1 mg, 2.17 mmol) in 1,4-dioxane (2.7 mL) and water (0.5 mL) (previously bubbled with nitrogen for 5 min). The reaction mixture was stirred at 120 °C for 16 h. 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.
The following part relates to the synthesis of Intermediate 41. tert-butyl (R)-3-(3-benzoyIthioureido)piperidine-l-carboxylate Int31
Tert-butyl 3 -aminopiperidine- 1 -carboxylate [184637-48-7] (5.00 g, 24.96 mmol) was added dropwise at a cooled solution of benzoyl isothiocyanate [622-78-6] (3.1 mL, 22.70 mmol) in Dichloromethane [75-09-2] (68 mL) at 0°C. The reaction mixture was allowed to reach room temperature and stirred for Ih. Solvent was evaporated in vacuo to afford Int31 (9.4 g, 21.98 mmol; yield: 97%) as a pale orange foam. The crude product was used in the next step without further purification. tert-butyl (R)-3-thioureidopiperidine-l-carboxylate Int32
An aqueous solution of Potassium carbonate [584-08-7] (6.08 g, 43.96 mmol) in water (44 mL) was added over a solution of Int31 (9.4 g, 21.98 mmol) in Ethanol [64-17-5] (44 mL) at room temperature. The reaction mixture was stirred at 100°C for 4h. The organic solvent was concentrated and the resulting mixture was diluted with water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The residue was adsorbed in celite and purified by flash column chromatography (silica 80 g, DCM:MeOH (9: 1) in DCM, 0/100 to 15/85). The desired fractions were collected and concentrated in vacuo to yield Int32 (5.15 g; yield: 86%) as a white foam. tert-butyl (R)-3-(3-((dimethylamino)methylene)thioureido)piperidine-l- carboxylate Int33
1,1 -dimethoxy -N,N-dimethylmethanamine [4637-24-5] (3.5 mL, 26.71 mmol) was added to a stirred solution of Int32 (5.15 g, 19.86 mmol) in DCM (62 mL) and was left stirring for 3h. Then, solvent was evaporated in vacuo to yield Int33 (6.19 g; yield: 98%) as a white sticky foam. The product was used in the next step without further purification. tert-butyl (R)-3-(((((dimethylamino)methyIene)amino)(methylthio) methylene)amino)piperidine-l-carboxylate Int34
Methyl iodide [74-88-4] (1.58 mL, 24.61 mmol) was added over a stirred solution of Int32 (6.19 g, 19.68 mmol) in THF (65 mL), and the reaction mixture was left stirring for 16h at room temperature. Solvent was removed under reduced pressure and the residue was washed with diethyl ether. The solvent was decanted and the crude was concentrated in vacuo to yield Int34 (8.42 g; yield: 91%) as a yellowish foam. methyl 2-(2-hydroxy-4-(trifluoromethyI)phenyI)acetate Int35
K2CO3 [584-08-7] (3.18 g, 22.80 mmol) was added to a solution of methyl 2-hydroxy- 4-(trifluoromethyl)benzeneacetate [CAS 936328-30-2] (2.67 g, 11.40 mmol) in acetone (67 mL) at rt. Then benzyl bromide [100-39-0] (2.6 mL, 14.82 mmol) was added dropwise. After the addition was complete, the reaction was heated at 65°C 5 h. The reaction was monitored by TLC. Remove the solid by vacuum filtration, wash the filter cake with acetone. The combined filtrate was concentrated and purified by flash column chromatography (Silica 40g, EtOAc in heptane 0/100 to 18/82). The desired fractions were collected and concentrated in vacuo to yield Int35 (3.27 g; yield: 87%) as a white solid. methyl 2-(2-(benzyIoxy)-4-(trifluoromethyI)phenyl)acetate Int36
Sodium hydroxide (IM in water) [1310-73-2] (15 mL) was added to a stirred suspension of Int35 (3.27 g, 10.08 mmol) in methanol (30 mL). The mixture was stirred at rt for 16h. MeOH was evaporated in vacuo and HC1 6N was added to the mixture until pH= 3. A white solid appeared, was filtered off and washed with water and DCM. The solid was diluted with DCM/MeOH (8:2), then was dried (MgSCU). The filtrate was extracted with water and DCM/MeOH (8:2). The organic layer was separated, dried (MgSOzi), filtered and was combined with the previously obtained solution. Then solvents were evaporated in vacuo to yield Int36 (3.2 g; yield: 97%) as a white solid. Product was used in the next reaction step without further purification.
2-(2-(benzyloxy)-4-(trifluoromethyl)phenyI)acetyl chloride Int37 Oxalyl chloride [79-37-8] (0.36 mL, 4.19 mmol) was added dropwise to a stirred solution of Int36 (1.0 g, 3.23 mmol) and DMF anhydrous [68-12-2] (26 pL, 0.34 mmol) in DCM anhydrous (12.5 mL) at 0 °C under nitrogen atmosphere. The white suspension was stirred at 0 °C for 10 min, then was stirred at rt for 2 h. Solvent was evaporated in vacuo to yield Int37 (1.05 g; yield: 94%) as a yellow solid. Product was used in the next reaction step without further purification. tert-butyl (R)-3-(5-(2-(benzyIoxy)-4-(trifluoromethyI)pheiiyI)-2-(methyIthio)-6- oxopyrimidin-l(6H)-yl)piperidine-l-carboxylate Int38
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. The crude was purified by flash column chromatography (silica 80 g, EtOAc in heptane 0/100 to 15/85). The desired fractions were collected and concentrated in vacuo to yield Int38 (693 mg, yield: 45%) as a white foam. tert-butyl (R)-3-(5-(2-(benzyloxy)-4-(trifluoromethyl)phenyI)-2-methyl-6- oxopyrimidin-l(6H)-yI)piperidine-l-carboxylate Int39
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. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (silica 12 g, EtOAc in heptane 0/100 to 33/67). The desired fractions were collected and concentrated in vacuo to give a yellowish foam. The foam was purified by reverse phase (Phenom enex Gemini Cl 8 3 Ox 100mm 5pm Column; from 49% [65mM NH4OAc + ACN (90: 10)] - 51% MeCN to 6% [65mM NH4OAc + ACN (90: 10)] - 94% MeCN). The desired fractions were collected and extracted with EtOAc (x3). The combined organic layers were dried (MgSO4), filtered and solvents evaporated in vacuo to yield Int39 (127 mg; yield: 34%) as a white foam. tert-butyl (R)-3-(5-(2-hydroxy-4-(trifluoromethyI)phenyI)-2-methyI-6- oxopyrimidin-l(6H)-yI)piperidine-l-carboxylate Int40
10% Palladium on carbon [7440-05-3] (38 mg, 0.04 mmol) was added to a stirred solution of Int39 (127 mg, 0.23 mmol) in Methanol (3.4 mL) at 0 °C under nitrogen atomosphere. Then, nitrogen atmosphere was replaced by hydrogen [1333-74-0] (1 atm, balloon) and the reaction mixture was stirred at rt for 3h. The mixture was filtered off over a pad of celite and washed with DCM/MeOH (4: 1). Solvents were evaporated in vacuo to yield Int40 (95 mg; yield: 88%) as a white solid.
(R)-5-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-methyI-3-(lI4-piperidin-3- yl)pyrimidin-4(3H)-one trifluoroacetate Int41
In a 10 mL round flask, TFA (1.2 mL, 15.55 mmol) was added dropwise to a stirred solution of Intermediate 40 (95 mg, 0.21 mmol) in anhydrous DCM (1.2 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at rt for 1 h. Solvent was evaporated in vacuo to afford Intermediate 41 (97 mg, yield 98%) as a yellow sticky solid, which was used in the next reaction step without further purification.
Preparation of final compounds
Generally, the preparation of the final compounds was done using racemic mixture separated via preparative SFC. Absolute configurations were attributed by synthesizing the enantiopure compounds starting from enantiopure intermediates. (!?)-3-(2-hydroxy-4-(trifluoromethyI)phenyI)-l-(piperidin-3-yI)pyridin-2(lH)-one hydrochloride 1
4M HC1 sol. in dioxane (130 mL, 520 mmol) was added to a stirred solution of Intermediate 14-1 (7.6 g, 17.334 mmol) in 20 mL of anhydrous 1,4-dioxane and the resulting mixture was stirred at room temperature for 1 h. Volatiles were removed under reduced pressure. The crude was co-evaporated with toluene (x2). The product was triturated with diethyl ether, filtered off, washed with diethyl ether, and dried in vacuo to yield Compound 1 (6.14 g, yield 94%) as a white solid. Alternatively, a basic work-up as well as a purification by SFC or RP followed by collection and evaporation of the desired fractions, can afford the nor-piperidine as a free base.
The following compounds were prepared by analogy with Compound 1 :
(l?)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-l-(l-methylpiperidin-3-yl)pyridin-
2(lH)-one (compound 48) Formaldehyde solution [50-00-0] (62 pL, 0.84 mmol) was added to a stirred solution of Compound 1 (220 mg, 0.56 mmol) and triethylamine [121-44-8] (155 pL, 1.12 mmol) in 5 mL of MeOH at rt. The mixture was stirred for 5 min and then, sodium cyanoborohydride [25895-60-7] (52.56 mg, 0.84 mmol) was added and the mixture was stirred at rt for 30 min. The mixture was diluted with NaHCO3 (saturated in water) and extracted with EtOAc. The organic layer was separated, dried (MgSO4) and filtered. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica 25 g; DCM:MeOH (9: 1) in DCM 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to yield Compound 48 (80 mg, yield 40 %) as a white solid.
The following compounds were made by analogy with Compound 48:
Analytical and biological data
Example A - Analytical data
5 LCMS
The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below).
10 Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time. . .) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.
15 Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+ (protonated molecule) and/or [M-H]' (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4]+, [M+HCOO]', etc. . .). For molecules with multiple isotopic patterns (Br, Cl), the
20 reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used. Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass Selective Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “DAD” Diode Array Detector, ”HSS” High Strength silica.
LCMS data for all final compounds are depicted below.
NMR
1 H NMR spectra were recorded on Bruker Avance III and Avance NEO spectrometers.
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) is brought into association with 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.
Example C - Biological Examples
The activity of a compound according to the present invention can be assessed by in vitro methods. A compound the 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.
PBMC assay
Peripheral venous blood was collected from healthy individuals and human peripheral blood mononuclear cells (PBMCs) were isolated from blood by 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 were added at a density of 7.5 x io4 cells per well and incubated for 30 min in a 5% CO2 incubator at 37 °C. 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).
The IC50 values (for IL-ip) and EC50 values (TNFa) were obtained on compounds of the invention/examples, and are depicted in the following table.
Example D - Efflux ratio
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. We report an apparent permeability (A to B (+Inh)) coefficient and efflux ratio.
Example F - In vivo LPS experiments
Animals were treated with NLRP3 inhibitors prior to LPS administration to evaluate the effect of NLRP3 inhibitors on inflammasome activation by measuring ILip. To exclude an effect on NF-kB signaling induced by LPS, 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. The control groups, wild type and NLRP3 knockout mice, received vehicle PO. Nlrpr3 knockout mice were included as a negative control, i.e., to define endogenous levels of ILip in these experiments. Each treatment group included 8 animals. In certain experiments, however, the Nlrp3 knockout group included less animals (usually n = 4). Four hours after LPS injection, 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. Plates were read using a SpectraMax Plus 384 Microplate Reader (Molecular Devices, San Jose, CA, USA) or the MSD reader (Meso Scale reader sector S600) for the Quantikine and MSD assays respectively. Data were further analyzed in Excel and GraphPad Prism, including statistical analysis (one-way ANOVA). Concentrations in plasma were determined according to the procedures described in the pharmacokinetic section. Free concentrations were determined by multiplying the plasma concentration by the free fraction in plasma (free concentration = plasma concentration x fu,p). The free fraction in plasma is defined as follows: fu,p = PPB (% free)/100.
Compound 1
Compound 8
Example G - Further Testing
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.
Metabolic stability test in liver microsomes and hepatocytes
The metabolic stability of a test compound is tested by using liver microsomes (0.5 mg/ml protein) from human and preclinical species incubated up to 60 minutes at 37°C with 1 pM test compound.
The in vitro metabolic half-life (ti/2 ) is calculated using the slope of the log- linear regression from the percentage parent compound remaining versus time relationship (K), ti/2 = - ln(2)/ K.
The in vitro intrinsic clearance (Clint) (ml/min/mg microsomal protein) is calculated using the following formula: 0.693
Clint -
1-1/2
Where: Vine = incubation volume,
Wmic prot,inc weight of microsomal protein in the incubation.
The metabolic stability of a test compound is tested using liver hepatocytes (1 milj cells) from human and preclinical species incubated up to 120 minutes at 37°C with 1 pM test compound.
The in vitro metabolic half-life (ti/2) is calculated using the slope of the log-linear regression from the percentage parent compound remaining versus time relationship (K), ti/2 = - ln(2)/ K.
The in vitro intrinsic clearance (Clint) (pl/min/million cells) is calculated using the following formula:
0.693 Vinc
Clint ~ - X - X 1000 ti/2 # cellsinc
Where: Vine = incubation volume,
# cellS/nC = number of cells (xlO6) in the incubation
Pharmacokinetics
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.

Claims

Claims
1 A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein
A is N or CR3;
L is a direct bond or a bivalent radical (CH2)n wherein n is 1, 2 or 3; and
R1 is Cs-ecycloalkyl or heterocyclyl each optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of Ci-salkyl, haloCi-salkyl, Ci-3alkyloxy, halogen, amino, hydroxy, cyano, oxo, C(=O)-Ci-3alkyl, CH2CH2OH, CHFCH2OH, CH2OCH3, and CH2S(O)2CH3; wherein heterocyclyl is a non-aromatic monocyclic or bicyclic group in which at least one and up to four of the atoms in the ring system are N, O, S, S(=O) or S(=O)2 and in which the total number of atoms in the ring system is between 3 and 20; and wherein the bicyclic group is fused, bridged or spiro; or L-R1 is CH2C(=O)-OH, CH2C(=O)-NR6R7, CH2CH2OH, CH2CH2CH2OH or CH2CF2CH2OH; wherein NR6R7 is NH(Ci-3alkyl) or N(Ci-3alkyl)2, or
NR6R7 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;
R2 is hydrogen, Ci-3alkyl, or halogen;
R3 is hydrogen, halo, Ci-3alkyl, Ci-3haloalkyl, Cs-ecycloalkyl, aryl; and R4 and R5 are each independently hydrogen or Ci-3alkyl.
2 The compound of claim 1 wherein
A is CR3;
L is a direct bond or a bivalent radical (CH2)n wherein n is 1; and
R1 is Cs-ecycloalkyl or heterocyclyl each optionally substituted with 1, 2 or 3 substituents selected from Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, halogen, amino, hydroxy, cyano, oxo, C(=O)-Ci-3alkyl, CHFCH2OH, CH2OCH3, and CH2S(O)2CH3; wherein heterocyclyl is a non-aromatic monocyclic or bicyclic group in which at least one and up to four of the atoms in the ring system are N, O, S, S(=O) or S(=O)2 and in which the total number of atoms in the ring system is between 3 and 20; and wherein the bicyclic group is fused, bridged or spiro; or L-R1 is CH2C(=O)-OH, CH2C(=O)-NR6R7, CH2CH2OH, CH2CH2CH2OH or CH2CF2CH2OH; wherein NR6R7 is NH(Ci-3alkyl) or N(Ci-3alkyl)2, or
NR6R7 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; R2 is hydrogen, methyl, ethyl or chloro;
R3 is hydrogen, chloro, bromo, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, phenyl; and
R4 and R5 are each independently hydrogen or methyl.
3 The compound of claim 1 wherein
A is CR3;
L is a direct bond or a bivalent radical (CH2)n wherein n is 1; and
R1 is Cs-ecycloalkyl or heterocyclyl each optionally substituted with 1, 2 or 3 substituents selected from Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, halogen, amino, hydroxy, cyano, oxo, C(=O)-Ci-3alkyl, CHFCH2OH, CH2OCH3, and CH2S(O)2CH3; wherein heterocyclyl is a non-aromatic monocyclic or bicyclic group in which at least one and up to four of the atoms in the ring system are N, O, S, S(=O) or S(=O)2 and in which the total number of atoms in the ring system is between 3 and 20; and wherein the bicyclic group is fused, bridged or spiro; or L-R1 is CH2C(=O)-OH, CH2C(=O)-NR6R7, CH2CH2OH, CH2CH2CH2OH or CH2CF2CH2OH; wherein NR6R7 is NH(Ci-3alkyl) or N(Ci-3alkyl)2, or
NR6R7 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;
R2, R4 and R5 are each hydrogen, or one of R2 and R4 is methyl and R5 is hydrogen.
4 The compound of claim 1 wherein
A is N;
L is a direct bond or a bivalent radical (CH2)n wherein n is 1; and
R1 is Cs-ecycloalkyl or heterocyclyl each optionally substituted with 1, 2 or 3 substituents selected from Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, halogen, amino, hydroxy, cyano, oxo, C(=O)-Ci-3alkyl, CHFCH2OH, CH2OCH3, and CH2S(O)2CH3; wherein heterocyclyl is a non-aromatic monocyclic or bicyclic group in which at least one and up to four of the atoms in the ring system are N, O, S, S(=O) or S(=O)2 and in which the total number of atoms in the ring system is between 3 and 20; and wherein the bicyclic group is fused, bridged or spiro; or L-R1 is CH2C(=O)-OH, CH2C(=O)-NR6R7, CH2CH2OH, CH2CH2CH2OH or CH2CF2CH2OH; wherein NR6R7 is NH(Ci-3alkyl) or N(Ci-3alkyl)2, or
NR6R7 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;
R2 is hydrogen, methyl, ethyl or chloro;
R3 is hydrogen, chloro, bromo, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, phenyl; and
R4 and R5 are each independently hydrogen or methyl.
5 The compound of claim 1 wherein
A is N;
L is a direct bond or a bivalent radical (CH2)n wherein n is 1; and
R1 is Cs-ecycloalkyl or heterocyclyl each optionally substituted with 1, 2 or 3 substituents selected from Ci-3alkyl, haloCi-salkyl, Ci-3alkyloxy, halogen, amino, hydroxy, cyano, oxo, C(=O)-Ci-3alkyl, CHFCH2OH, CH2OCH3, and CH2S(O)2CH3; wherein heterocyclyl is a non-aromatic monocyclic or bicyclic group in which at least one and up to four of the atoms in the ring system are N, O, S, S(=O) or S(=O)2 and in which the total number of atoms in the ring system is between 3 and 20; and wherein the bicyclic group is fused, bridged or spiro; or L-R1 is CH2C(=O)-OH, CH2C(=O)-NR6R7, CH2CH2OH, CH2CH2CH2OH or CH2CF2CH2OH; wherein NR6R7 is NH(Ci-3alkyl) or N(Ci-3alkyl)2, or
NR6R7 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;
R2, R4 and R5 are each hydrogen, or one of R2 and R4 is methyl and R5 is hydrogen.
6 The compound of claim 1 wherein
A is N or CH; when L is a direct bond, then R1 is cyclohexyl, 2-hydroxcyclohexyl, 4- hydroxy cyclohexyl, tetrahydropyran-4-yl, 3 -hydroxytetrahydropyran-4-yl, wherein R10 is hydrogen or methyl and R11 is hydrogen or fluoro; when L is CH2, then R1 is herein NR6R7 is N(CH3)2, pyrrolidinyl, or morpholinyl;
R2 is H or CH3 ;
R3 is hydrogen, methyl, trifluoromethyl, chloro or CF3 ;
R4 is hydrogen or methyl;
R5 is hydrogen.
7 The compound of claim 1 selected from
(7?)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-l-(piperidin-3-yl)pyridin-2(17/)-one hydrochloride,
(R)-3 -(2-hy droxy-6-m ethyl -4-(trifluoromethyl)phenyl)- 1 -( 1 -methylpiperi din-3 - yl)pyridin-2(lH)-one, and
(J?)-5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-3-(l -methylpiperi din-3 - yl)pyrimidin-4(3H)-one.
8 A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in any one of claims 1 to 7 and a pharmaceutically acceptable carrier.
9 A process for preparing a pharmaceutical composition as defined in claim 8, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as defined in any one of claims 1 to 7.
EP24702715.4A 2023-01-31 2024-01-26 Pyridin-2(1h)-ones and pyrimidin-4(3h)-ones as nlrp3 inhibitors Pending EP4658640A1 (en)

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US12331048B2 (en) 2022-10-31 2025-06-17 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
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