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WO2025125811A1 - Composés hétérocycliques et leur utilisation pour le traitement de troubles neurologiques - Google Patents

Composés hétérocycliques et leur utilisation pour le traitement de troubles neurologiques Download PDF

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WO2025125811A1
WO2025125811A1 PCT/GB2024/053100 GB2024053100W WO2025125811A1 WO 2025125811 A1 WO2025125811 A1 WO 2025125811A1 GB 2024053100 W GB2024053100 W GB 2024053100W WO 2025125811 A1 WO2025125811 A1 WO 2025125811A1
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Alleyn Thomas Plowright
Thomas Pfeiffer
Emil MÄRCHER-RØRSTED
Edward Joseph DUCKWORTH
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Ontrack Therapeutics Ltd
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Ontrack Therapeutics Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel synthetic compounds related to naturally occurring flavonoids such as 7,8-dihydroxyflavone (7,8-DHF).
  • the invention further relates to the method of synthesis, the use of these compounds as research tools and their use as pharmaceuticals.
  • Flavonoids are a large class of plant secondary metabolites, and they are also common polyphenols in the human diet. Studies have shown that flavonoids have various pharmacological activities, such as anti-tumor, anti-inflammatory, and antioxidant properties.
  • the flavonoid, 7,8-dihydroxyflavone (7,8-DHF) is a naturally occurring flavone found in Godmania aesculifolio, Tridax procumbens and Primula helleri leaves. It is known to act as a potent and selective agonist of tropomyosin receptor kinase B (TrkB), which is the main signaling receptor of neurotrophin brain-derived neurotrophic factor (BDNF).
  • TrkB tropomyosin receptor kinase B
  • 7,8-DHF has been shown to have therapeutic efficacy in several animal models including depression, Alzheimer’s disease, cognitive deficits in schizophrenia, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral ischemia, fragile X syndrome and Rett syndrome.
  • a derivative of 7,8-DHF, 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8- d]imidazol-8- yl)benzonitrile, also known as CF3CN has been shown to be useful in the treatment of various diseases and conditions including neurodegenerative diseases and movement disorders.
  • the present invention relates to novel synthetic flavonoid compounds.
  • Compounds were tested in a primary neuronal culture functional assay to determine whether they were able to promote neuronal survival upon insult.
  • 3333 is a single or double bond
  • Ri is selected from the group consisting of: Cl, F, Br, H, OH, O-alkyl (C1-C6), O-fluoroalkyl (C1- C6), alkyl (C1-C6), fluoroalkyl(C1-C6), NH 2 , NH-alkyl(C1-C6) N-alkyh (C1-C6), cycloalkyl (C3- C6), fluorocycloalkyl (C3-C6), CH2-cycloalkyl (C3-C6), and CHF-cycloalkyl (C3-C6).
  • R 2 is selected from the group consisting of: alkyl (C1-C6), fluoroalkyl (C1-C6), Cl, F, I, Br, H, OH, O-alkyl (C1-C6), SMe, CN, cycloalkyl (C3-C6), and fluorocycloalkyl (C3-C6).
  • R4 is selected from the group consisting of: semi-saturated or saturated cycloalkyls including bridged bicyclic or spirocyclic ring systems, unsaturated, semi-saturated or saturated heterocycloalkyls including bridged bicyclic or spirocyclic ring systems, or aryls, including but not limited to benzene, pyridine, pyrimidine, pyridazine, piperidine, or pyrrolidine.
  • R 4 is an aryl, monocyclic cycloalkyl or monocyclic heterocycloalkyl
  • the monocyclic ring may carry a 2, 3 or 4 position substituent from the list: H, CN, F, Cl, Br, OH, alkyl(C1-C6), fluoroalkyl (C1-C6), N-alkyl 2 (C1-C6), NH-alkyl (C1-C6), NH-cycloalkyl (C3-C6) N-cycloalkyl (C3-C6), alkyl (C1-C6)-NH 2 , alkyl (C1-C6)-OH , CH 2 -N-Cycloalkyl (C3-C6), CH 2 - heterocycloalkyl(C1-C6), CH 2 N-Alkyl 2 (C1-C6), CH 2 NH-Alkyl (C1-C6), CH 2 N-cycloalkyl, and CH 2 N-flu
  • Rs is selected from the group consisting of: alkyl (C1-C6), fluoroalkyl (C1-C6), Cl, F, I, Br, H, OH, OMe, SMe, CN, cycloalkyl (C3-C6), and fluorocycloalkyl (C3-C6).
  • X is independently selected from the group consisting of: N or C.
  • Y is independently selected from the group consisting of: O, N, C, and S.
  • 3333 is a single or double bond
  • Ri and R2 are independently selected from the group consisting of: OH, OMe, O-alkyl(C1-C6), O-fluoro alkyl(C1-C6), OiPr, SMe, SFs, alkyl(C1-C6), fluoro alkyl(C1-C6), pyrazole, methyl pyrazole, oxazole, imidazole, thiazole, triazole oxadiazole, and thiadiazole; where the heterocycles can be substituted with alkyl(C1-C3).
  • R3 is selected from the group consisting of: alkyl(C1-C6), fluoro alkyl(C1-C6), Cl, F, I, Br, CN, H O-alkyl (C1-C6).
  • R4 is selected from the group consisting of: semi-saturated or saturated cycloalkyls including bridged bicyclic or spirocyclic ring systems, unsaturated, semi-saturated or saturated heterocycloalkyls including bridged bicyclic or spirocyclic ring systems, or aryls, including but not limited to benzene, pyridine, pyrimidine, pyridazine or piperidine.
  • R 4 is an aryl, monocyclic cycloalkyl or monocyclic heterocycloalkyl
  • the monocyclic ring may carry a 2, 3 or 4 position substituent from the list: H, CN, F, Cl, Br, OH, alkyl(C1-C6), fluoroalkyl (C1-C6), N-alkyh (C1-C6), NH-alkyl (C1-C6), NH-cycloalkyl (C3-C6) N-cycloalkyl (C3-C6), alkyl (C1-C6)-NH 2 , alkyl (C1-C6)-OH , CH 2 -N-Cycloalkyl (C3-C6), CH 2 -heterocycloalkyl(C1-C6), CH 2 N-Alkyl 2 (C1-C6), CH 2 NH-Alkyl (C1-C6), CH 2 N-cycloalkyl, and CH 2 N-
  • Rs is selected from the group consisting of: alkyl (C1-C6), fluoroalkyl (C1-C6), Cl, F, I, Br, H, OH, OMe, SMe, CN cycloalkyl (C3-C6), and fluorocycloalkyl (C3-C6).
  • the compound of the invention with respect to either Formula I, Formula II or Formula III is defined by any one of the compounds numbered 1 to 50 in Table 1.
  • a compound of Formula I, Formula II, or Formula III or a pharmaceutical composition comprising the compound of Formula I, Formula II, or Formula III, for use as a medicament.
  • a method of treatment comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula I, Formula II, or Formula III.
  • Alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups.
  • An alkyl group may contain from one to twelve carbon atoms (e.g., C1-12 alkyl), such as one to eight carbon atoms (C1-8 alkyl) or one to six carbon atoms (C1-6 alkyl).
  • the cycloalkyl group is bicyclic or spirocyclic. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e. having a bond in common with) to the cycloalkyl ring, e.g. benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like.
  • a cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, and cyclohexadienyl.
  • Examples of polycyclic cycloalkyl groups include, but are not limited to, nonane and adamantane.
  • Spirocyclic cycloalkyl groups include, but are not limited to spiro-, heptane, octane, nonane, decane and undecane.
  • heterocycloalkyl employed alone or in combination with other terms, refers to both aromatic and non-aromatic rings or ring systems, which may optionally contain one or more carbon-carbon double bonds as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus, and which has 3 - 12 total ring members. Any heterocycloalkyl ring member may be further mono-, or di-, alkylated (C1-C6) if allowed by rules for carbon valency. Included within the term “heterocycloalkyl” are monocyclic 3-, 4-, 5-, 6-, and 7-, membered heterocycloalkyl groups.
  • Heterocycloalkyl groups can include bicyclic (e.g. having two fused or bridged rings) or spirocyclic (e.g. having two ring systems fused by a single shared carbon atom) ring systems containing 3-12 total ring members.
  • the heterocycloalkyl group is a monocyclic group having 1 , 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
  • the heterocycloalkyl group is a poly-, or spirocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
  • Ring- forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfido group or other oxidized linkage (e.g. C (O), S (O), C (S) or S (0)2, N- oxide etc.) or a nitrogen atom can be quaternized. Where a heteroatom is selected to be a nitrogen, this heteroatom may be further functionalized to the corresponding N-alkyl(C1-C6), N- fluoroalkyl (C1-C6) or N-C0-Alkyl(C1-C6).
  • the heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom.
  • the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e. having a bond in common with) to the heterocycloalkyl ring, e.g. benzo or thienyl derivatives of piperidine, morpholine, azepine, etc.
  • a heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • Examples of monocyclic heterocycloalkyl groups include, but are not limited to oxirane, aziridine, azetidine, pyrrolidine, piperidine, piperizine, pyridine, pyrimidine, pyridazine, pyrazole, pyrrole, imidazole, morpholine, dioxane, pyran, furan, thiophene, thoiazole, and oxazole in any variation of saturation.
  • Examples of polycyclic heterocycloalkyl groups include, but are not limited to, quinoline, isoquinoline, indole, benzofuran, benzimidazole, chromane, chromene, and coumarine.
  • spirocyclic heterocycloalkyls include, but are not limited to, 1-oxa-8- azaspiro[4.5]decane, 2,2-dimethyl-1-oxa-8-azaspiro[4.5]decane, 1,1-dimethyl-2-oxa-8- azaspiro[4.5]decane 3-oxa-9-azaspiro[5.5]undecane, 2,6-diazaspiro[3.4]octan-5-one
  • alkenyl refers to substituted or unsubstituted hydrocarbon groups, including straightchain or branched-chain alkenyl groups containing at least one double bond.
  • An alkenyl group may contain from two to twelve carbon atoms (e.g., C2-12 alkenyl).
  • Exemplary alkenyl groups include ethenyl (j.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1, 4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more substituents such as those substituents described herein.
  • Alkynyl refers to substituted or unsubstituted hydrocarbon groups, including straightchain or branched-chain alkynyl groups containing at least one triple bond.
  • An alkynyl group may contain from two to twelve carbon atoms (e.g., C2-12 alkynyl).
  • Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents such as those substituents described herein.
  • Aryl refers to an all carbon monocyclic or fused-ring polycyclic (i.e. , rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi electron system. Examples, without limitation, of aryl groups are phenyl, napthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted.
  • Esters refers to a functional group -COO and may also be referred to as an “ester link”. Esters are formed by the condensation reaction between an alcohol and a carboxylic acid.
  • halo or, alternatively, “halogen” means fluoro or fluorine, chloro or chlorine, bromo or bromine and iodo or iodine.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocycle, an aralkyl, a carbocycle, a heterocycle,
  • substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to a “heteroaryl” group or moiety implicitly includes both substituted and unsubstituted variants. [0029] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.
  • “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.
  • Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • the compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • hydrogen has three naturally occurring isotopes, denoted 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant isotope of hydrogen in nature.
  • Enriching deuterium may afford certain therapeutic advantages, such as increased in vivo halflife and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
  • Isotopically enriched compounds may be prepared by conventional techniques well known to those skilled in the art.
  • “Isomers” are different compounds that have the same molecular formula. “Regioisomers” are isomers that differ only in the attachment point of a single functional group. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a “racemic” mixture. The term “( ⁇ )” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.
  • the absolute stereochemistry is specified according to the Cahn-lngold-Prelog R-S system.
  • the stereochemistry at each chiral carbon can be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques.
  • the optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.
  • Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well.
  • Isolation and purification of the chemical entities and intermediates described herein can be affected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.
  • certain small molecules described herein include, but are not limited to, when possible, their isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation.
  • the single enantiomers or diastereomers, /.e., optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers.
  • Racemates or mixtures of diastereomers can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high- pressure liquid chromatography (HPLC) column.
  • HPLC high- pressure liquid chromatography
  • a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and/or trituration.
  • certain small molecules include Z- and E- forms (or cis- and trans- forms) of certain small molecules with carbon-carbon double bonds or carbon-nitrogen double bonds.
  • the term “certain small molecule” is intended to include all tautomeric forms of the certain small molecule.
  • salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • 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, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, 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, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • 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, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • treatment refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including but not limited to a therapeutic benefit and/or a prophylactic benefit.
  • a therapeutic benefit can include, for example, the eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit can include, for example, the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • Modifying tropoflavin compounds can significantly change their chemical and biological properties.
  • Such chemical functional groups can include a polar moiety, a monosaccharide, disaccharide, a carbohydrate, an amino acid, an acyl group, a diacid group, and other chemical moieties.
  • the addition of such modifying functional groups can significantly alter the resulting biological activity or tissue targeting.
  • modifications have major impacts on downstream formulations, preparations, pharmacokinetics, pharmacodynamics, and ultimate end uses.
  • R 2 is selected from the group consisting of: alkyl (C1-C6), fluoroalkyl (C1-C6), Cl, F, I, Br, H, OH, O-alkyl (C1-C6), SMe, ON, cycloalkyl (C3-C6), and fluorocycloalkyl (C3-C6);
  • R 3 if present when Y is selected from N or C is selected from the group consisting of: H, alkyl(C1-C6), fluoroalkyl(C1-C6); cycloalkyl (C3-C6), alkyl (C1-C6)-OH, alkyl-(C1-C6)-OMe, alkyl-(C1-C6)-cycloalkyl (C3-C6) and deutereoalkyl (C1-C6).;
  • R4 is selected from the group consisting of: semi-saturated or saturated cycloalkyls including bridged bicyclic or spirocyclic ring systems, unsaturated, semi-saturated or saturated heterocycloalkyls including bridged bicyclic or spirocyclic ring systems, or aryls, including but not limited to benzene, pyridine, pyrimidine, pyridazine, piperidine, or pyrrolidine.
  • R 4 is an aryl, monocyclic cycloalkyl or monocyclic heterocycloalkyl
  • the monocyclic ring may carry a 2, 3 or 4 position substituent from the list: H, CN, F, Cl, Br, OH, alkyl(C1-C6), acyl, fluoroalkyl (C1-C6), N-alkyl 2 (C1-C6), NH-alkyl (C1-C6), NH-cycloalkyl (C3-C6) N-cycloalkyl (C3-C6), alkyl (C1-C6)-NH 2 , alkyl (C1-C6)-OH , CH 2 -N-Cycloalkyl (C3-C6), CH 2 - heterocycloalkyl(C1-C6), CH 2 N-Alkyl 2 (C1-C6), CH 2 NH-Alkyl (C1-C6), CH 2 N-cycloalkyl, and CH
  • R 5 is selected from the group consisting of: alkyl (C1-C6), fluoroalkyl (C1-C6), Cl, F, I, Br, H, OH, OMe, SMe, CN, cycloalkyl (C3-C6), and fluorocycloalkyl (C3-C6);
  • X is independently selected from the group consisting of: N or C;
  • Y is independently selected from the group consisting of: O, N, C, and S.
  • the present disclosure provides a compound of Formula III or a salt thereof:
  • 7333 is a single or double bond
  • Ri and R 2 are independently selected from the group consisting of: OH, OMe, O-alkyl(C1-C6), O-fluoro alkyl(C1-C6), OiPr, SMe, SF5, alkyl(C1-C6), fluoro alkyl(C1-C6), pyrazole, methyl pyrazole, oxazole, imidazole, thiazole, triazole oxadiazole, and thiadiazole; where the heterocycles can be substituted with alkyl(C1-C3).
  • R3 is selected from the group consisting of: alkyl(C1-C6), fluoro alkyl(C1-C6), Cl, F, I, Br, CN, H O-alkyl (C1-C6).
  • R4 is selected from the group consisting of: semi-saturated or saturated cycloalkyls including bridged bicyclic or spirocyclic ring systems, unsaturated, semi-saturated or saturated heterocycloalkyls including bridged bicyclic or spirocyclic ring systems, or aryls, including but not limited to benzene, pyridine, pyrimidine, pyridazine or piperidine.
  • R 4 is an aryl, monocyclic cycloalkyl or monocyclic heterocycloalkyl
  • the monocyclic ring may carry a 2, 3 or 4 position substituent from the list: H, CN, F, Cl, Br, OH, alkyl(C1-C6), fluoroalkyl (C1-C6), N-alkyh (C1-C6), NH-alkyl (C1-C6), NH-cycloalkyl (C3-C6) N-cycloalkyl (C3-C6), alkyl (C1-C6)-NH 2 , alkyl (C1-C6)-OH , CH 2 -N-Cycloalkyl (C3-C6), CH 2 -heterocycloalkyl(C1-C6), CH 2 N-Alkyl 2 (C1-C6), CH 2 NH-Alkyl (C1-C6), CH 2 N-cycloalkyl, and CH 2 N-
  • Rs is selected from the group consisting of: alkyl (C1-C6), fluoroalkyl (C1-C6), Cl, F, I, Br, H, OH, OMe, SMe, CN cycloalkyl (C3-C6), and fluorocycloalkyl (C3-C6).
  • provided herein is one or more pharmaceutically acceptable salts of a compound selected from Table 1.
  • a pharmaceutical composition may comprise: (i) a compound of Formula I, Formula II or Formula III, as detailed in Table 1, or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and/or diluent.
  • suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.
  • suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. Sterile phosphate-buffered saline is one example of a pharmaceutically acceptable carrier.
  • Formulations can further include one or more excipients, preservatives, solubilizers, buffering agents, albumin to prevent protein loss on vial surfaces, etc.
  • compositions comprising a compound of Formula (I) or Formula (II), as detailed in Table 1 or a pharmaceutically acceptable salt thereof, may also contain one or more additional ingredients including, but not limited to, a mucoadhesive compound, a buffering agent, a plasticizing agent, a stabilizing agent, a taste-masking agent, a flavoring agent, a coloring agent, an antiseptic, an inert filler agent, a preservative, and combinations thereof.
  • the formulations may comprise one or more solubilizing agents that increase the solubility of active compounds in the formulation. Suitable solubilizing agents include, for example, complexing agents, surfactants, and the like.
  • Suitable complexing agents include unsubstituted cyclodextrins (such as alpha-cyclodextrin, beta-cyclodextrin) and substituted cyclodextrins, (such as hydroxypropyl beta-cyclodextrin, sulfobutylether-beta- cyclodextrin).
  • Suitable surfactants include polyoxyethylene sorbitan monolaurate (for example, Tween 20), polyoxyethylene sorbitans monooleate (for example, Tween 80), polyethylene glycol (15)-hydroxystearate (for example, Kolliphor® HS 15), PEG-35 castor oil (for example, Kolliphor® EL) and PEG-60 hydrogenated castor oil (for example, Cremophor® RH 60).
  • the formulations comprise one or more buffer agents that maintain the pH of the IV solution within a pharmaceutically acceptable range.
  • the buffer maintains the pH of the IV solution between about 5 and 9.
  • the buffer maintains the pH of the IV solution at about 7.4.
  • Suitable buffers include, for example, citrates, lactate, acetate, maleate, phosphates, and the like.
  • the formulations comprise one or more density modifiers that are used to control the density of the IV formulation. Suitable density modifiers include, for example, dextrose.
  • the formulations comprise one or more isotonicity modifiers that provide a formulation that is iso- osmotic with tissue to prevent pain and irritation when the formulation is administered.
  • Suitable isotonicity modifiers include, for example, electrolytes, monosaccharides, and disaccharides.
  • isotonicity modifiers include glycerin, dextrose, potassium chloride, and sodium chloride.
  • the formulations comprise one or more viscosity enhancers. Suitable viscosity enhancers include, for example, povidone, hydroxyethylcellulose, polyvinyl alcohol, and carbomer (such as, acrylic acid homopolymers and acrylic acid copolymers).
  • the formulations comprise one or more preservatives that increase the stability of active compounds in the formulation and/or provide antimicrobial activity.
  • Suitable preservatives include, for example, antimicrobial agents and antioxidants.
  • antimicrobial agents include benzyl alcohol, methyl paraben, propyl paraben, phenol, cresol, methyl paraben, chlorbutanol, sodium metabisulphite, sodium bisulphite, benzethonium chloride, and benzalkonium chloride.
  • antioxidants include sodium bisulphite and other sulfurous acid salts, ascorbic acid, salts of ethylenediaminetetraacetic acid (including sodium), alpha tocopherol, butylated hydroxyl hydroxytoluene, and butylated hydroxyanisole.
  • a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), as detailed in Table 1 , or a pharmaceutically acceptable salt thereof; may be formulated in a dosage form selected from the group consisting of: an oral unit dosage form, an intravenous unit dosage form, an intranasal unit dosage form, a suppository unit dosage form, an intradermal unit dosage form, an intramuscular unit dosage form, an intraperitoneal unit dosage form, a subcutaneous unit dosage form, an epidural unit dosage form, a sublingual unit dosage form, a liquid, a lozenge, a fast disintegrating tablet, a lyophilized preparation, a film, a spray (including a nasal spray, an oral spray, or a topical spray), or a mucoadhesive.
  • a dosage form selected from the group consisting of: an oral unit dosage form, an intravenous unit dosage form, an intranasal unit dosage form, a suppository unit dosage form, an intradermal unit dosage form, an intra
  • the oral unit dosage form may be selected from the group consisting of: tablets, pills, pellets, capsules, powders, lozenges, granules, solutions, suspensions, emulsions, syrups, elixirs, sustained-release formulations, aerosols, and sprays.
  • the modified mesembrine alkaloid is formulated as a liquid, a lozenge, a fast-disintegrating tablet, a lyophilized preparation, a film, a spray, or a mucoadhesive.
  • the compounds of Formula (I) or Formula (II), as detailed in Table 1, or a pharmaceutically acceptable salt thereof can be administered to subjects by a variety of administration modes, including, for example, by intramuscular, subcutaneous, intravenous, intra-atrial, intra-articular, parenteral, intranasal, intrapulmonary, transdermal, intrapleural, intrathecal, and oral routes of administration.
  • a compound of Formula (I) or Formula (II), as detailed in Table 1 , or a pharmaceutically acceptable salt thereof can be administered to a subject in a single bolus delivery, via continuous delivery (e.g., continuous transdermal delivery) over an extended time period, or in a repeated administration protocol (e.g., on an hourly, daily, weekly, or monthly basis).
  • a repeated administration protocol e.g., on an hourly, daily, weekly, or monthly basis.
  • Pharmaceutical compositions comprising a compound of Formula (I) or Formula (II), as detailed in Table 1 , or a pharmaceutically acceptable salt thereof can be supplied as a kit comprising a container that comprises the pharmaceutical composition as described herein.
  • novel synthetic flavonoid compounds of the invention may be useful in the treatment or prevention of medical conditions. More specifically the activity of these compounds is likely to enable their use in the treatment or prevention of medical conditions associated with neurodegeneration.
  • Reaction products can be purified by known methods including silica gel chromatography using various organic solvents such as hexane, dichloromethane, ethyl acetate, MeOH and the like, preparative reverse phase high pressure liquid chromatography, or preparative supercritical fluid chromatography.
  • Preparation of compounds can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 44th. Ed., Wiley & Sons, 2006, as well as Jerry March, Advanced Organic Chemistry, 4th edition, John Wiley & Sons, publisher, New York, 1992 which are incorporated herein by reference in their entirety.
  • Example 2 describes the efficacy of these compounds in an in vitro neuronal survival assay.
  • EXAMPLE 1 describes the efficacy of these compounds in an in vitro neuronal survival assay.
  • Organic Solvents and chemical reagents were purchased from commercial sources and used as received unless otherwise stated.
  • NMR Nuclear Magnetic Resonance Spectroscopy
  • Apparatus Waters HCIass; Binary Solvent Pump, SM-FTN, CMA, PDA, QDa Column: Waters ACQUITY UPLC® BEH C18, 1.7 pm, 2.1 x 30 mm at 40 °C
  • Apparatus Agilent 1260; Binary Pump, HiP Sampler, Column Compartment, DAD:, G6150 MS
  • the product was dissolved in a suitable mixture of mobile phases and DMSO to ensure compete solvation.
  • the solution was filtered and injected onto a Waters XBridge BEH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min -1 eluting with a 0.3% Ammonia in water-MeCN gradient over 17.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector.
  • At-column dilution pump gives 2 mL min -1 Methanol over the entire method, which is included in the following MeCN percentages, (Waters system).
  • the product was dissolved in a suitable mixture of mobile phases and DMSO to ensure compete solvation.
  • the solution was filtered and injected onto a Waters X-Select CSH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min -1 eluting with a 0.1% Formic acid in water-MeCN gradient over 17.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector.
  • At-column dilution pump gives 2 mL min -1 methanol over the entire method, which is included in the individually provided MeCN percentages, (Waters system).
  • the product was dissolved in a suitable mixture of mobile phases and DMSO to ensure compete solvation.
  • the solution was filtered and injected onto a Waters XSelect CSH C18, 10pm, 30 X 250 mm prep column, flow rate 42 mL min-1 eluting with a 0.1% Formic Acid in water-MeCN gradient over 18 min. Monitoring UV across all wavelengths. At-column dilution pump gives 5 mL min-1 MeCN for 1.2 min, (Gilson System).
  • the product was dissolved in a suitable mixture of mobile phases and DMSO to ensure compete solvation.
  • the solution was filtered and injected onto a Waters XBridge BEH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1 eluting with a 0.3% Ammonia in water-MeCN gradient over 12.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector.
  • At-column dilution pump gives 2 mL min-1 Methanol over the entire method, which is included in the given MeCN percentages, (Waters system).
  • the product was dissolved in a suitable mixture of mobile phases and DMSO to ensure complete solvation.
  • the solution was filtered and injected onto a on a Waters X-Select CSH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1 eluting with a 0.1% Formic acid in water-MeCN gradient over 12.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector.
  • At-column dilution pump gives 2 mL min-1 Methanol over the entire method, which is included in the given MeCN percentages, (Waters system).
  • the crude product was purified by column chromatography using a gradient of 0-30% THF/[1 :1 DCM/isohexane]) to give 8-bromo-6-chloro-7-methoxy-2-phenyl-4H-chromen-4-one (0.50 g, 1.1 mmol, 90%) as a white solid.
  • At-column dilution pump gives 2 mL min-1 Methanol over the entire method, which is included in the following MeCN percentages.
  • Gradient information 0.0-0.5 min, 5% MeCN; 0.5-10.5 min, ramped from 5% MeCN to 30% MeCN; 10.5-10.6 min, ramped from 30% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN.
  • the clean fractions were evaporated in a Genevac to give 7-hydroxy-8-(1-methyl-1H-pyrazol-5-yl)-2-phenyl-4H-chromen- 4-one (14 mg, 44 pmol, 9.6%) as a white solid.
  • a vial containing 7-(benzyloxy)-8-bromo-4H-chromen-4-one (1.4 g, 1 Eq, 4.2 mmol), 1 ,2,4-triazole (0.85 g, 2.9 Eq, 12 mmol), iodine (1.6 g, 1.5 Eq, 6.3 mmol) and potassium carbonate (2.9 g, 5.0 Eq, 21 mmol) was charged with DMF (20 mL). The mixture was stirred at 80 °C for 2 h. The mixture was cooled to rt, diluted with 10% aq. Na2S20s (20 mL) and water (40 mL), then stirred at rt for 10 min.
  • tripotassium phosphate (1.59 g, 5.00 mL, 3.5 Eq, 7.50 mmol). The mixture was stirred at 95 °C for 2 h. The mixture was diluted with EtOAc (20 mL), washed with brine (10 mL), dried over MgSC , filtered and concentrated.
  • reaction mixture was stirred at rt for 90 min before being diluted with TBME (2 mL) and stirred at rt for 30 min, the solid was collected by filtration, rinsed with TBME (1 mL) and dried to give 2-(2,2- dimethyl-1-oxa-8-azaspiro[4.5]decan-8-yl)-7-hydroxy-8-(1 H-pyrazol-5-yl)-4H-chromen-4-one as the hydrochloride salt (18 mg, 41 pmol, 57%) as a white solid.
  • Method A To a suspension of 7-hydroxy-2-phenyl-4H-chromen-4-one (2.0 g, 1 Eq, 8.4 mmol) in acetic acid (100 mL) was added aq. nitric acid (70%) (5.6 g, 4.0 mL, 70% Wt, 7.5 Eq, 63 mmol). The mixture was stirred at rt for 2 h, then at 40 °C for 1 h, then at 45 °C overnight, then at 50 °C for 90 min. The mixture was stirred at 60 °C for 90 min, UPLC showed 2% conv. to the desired product.
  • the reaction was removed from the heating block and sodium hydride (60 wt% in mineral oil) (767 mg, 60% Wt, 4 Eq, 19.2 mmol) was added portionwise (internal temperature ⁇ 30 °C).
  • the reaction was heated to 40 °C, then ethyl formate (3.55 g, 3.87 mL, 10 Eq, 47.9 mmol) was added in one portion.
  • the reaction was stirred at 40 °C for 18 h.
  • the reaction mixture was poured into ice (250 mL) and then acidified to pH 1 by addition of cone. HCI.
  • the aqueous phase was extracted with DCM (2 x 250 mL) and the combined organic extracts were concentrated in vacuo.
  • Trifluoroacetic acid (5.32 g, 3.60 mL, 20 Eq, 46.7 mmol) was slowly added to 7,8- diamino-4H-chromen-4-one (514 mg, 80% Wt, 1 Eq, 2.33 mmol) while cooling over and ice bath. The mixture was stirred at reflux for 2 h, then concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and the aqueous phase was neutralised with sat. aq. NaHCOs while stirring. The phases were separated and the organic phase was washed with brine (10 mL), dried over MgSCU, filtered and concentrated.
  • MS The product was analysed by LCMS (Method 1): m/z 255.0 (M+H) + (ES+); 253.0 (M-H)' (ES-), at 0.85 min, >99% purity at 260nm +/- 80nm.
  • the reaction mixture was carefully quenched with MeOH ( ⁇ 3 mL) and then concentrated in vacuo to afford the crude product.
  • the crude product was purified by column chromatography using a gradient of 0-10% MeOH in DCM, then 1-10% (0.7 M Ammonia in MeOH) in DCM, to afford 8-(4-(azetidin-1-ylmethyl)phenyl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (57.0 mg, 143 pmol, 52%) as a yellow/orange solid.
  • the product was further purified by preparative HPLC General procedure 4, Method 2.
  • the product was further purified by colomn chromatography using a gradient of 0-100% EtOAc in isohexane to afford tert-butyl 6-(4-(6-oxo-2-(trifluoromethyl)-1,6-dihydrochromeno[7,8-d]imidazol-8-yl)phenyl)- 3,4-dihydropyridine-1(2H)-carboxylate (54.0 mg, 53 pmol, 12 %) as a yellow solid with significant impurities. The product was deemed of sufficient quality for further reaction and was not purified further.
  • MS The product was analysed by LCMS (Method 1): m/z 344.0/346.0 (M+H) + (ES+); 342.0/344.0 (M-H)- (ES-), at 1.75 min, >99% purity at 260nm +/- 80nm.
  • the reaction mixture was diluted with DMSO (10 mL), EtOH (10 mL) and additional sodium dithionite (500 mg, 0.3 eq., 2.87 mmol) was added.
  • the reaction mixture was stirred at 80 °C for 2.5 h.
  • the reaction mixture was poured into a mixture of ice and water (200 mL) and allowed to stand overnight.
  • the resultant precipitate was collected by filtration then washed with water, MeCN and EtOH.
  • the solid was dried in vacuo (40 °C, overnight) to afford 4-(7,8-diamino-4-oxo-4H- chromen-2-yl)benzonitrile (2.778 g, 7.7 mmol, 81 %) as an orange solid.
  • reaction mixture was diluted with water (20 mL) and the resultant precipitate was collected by filtration, washing with water.
  • the solid was dried in vacuo (50 °C, overnight) to afford an inconsequential mixture ( ⁇ 2:1) of regioisomers (484 mg, 1.1 mmol, 92 %) as a tan solid.
  • the product was taken on without separating the isomers.
  • the mixture (402 mg) was dissolved to 50.25 mg/mL in MeOH/DCM (3:1) with sonication, filtered and was then separated by chiral SFC on a Waters Prep 100 with a PDA and QDa detectors, 40 °C, 120 bar.
  • the column was a Phenomenex A1 , 20 x 250mm, 5pm, flow rate 65mL/ min at 50% MeOH (0.2% DEA), 50% CO2.
  • the clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in DCM, transferred into final vials and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30°C 1 5 mbar over the weekend to afford:
  • the reaction mixture was carefully quenched with MeOH ( ⁇ 3 mL) and then concentrated in vacuo to afford the crude product.
  • the crude product was purified by column chromatography on silica gel using a gradient of 0-10% (0.7 M Ammonia in MeOH)/DCM to afford 8-(4-(pyrrolidin-1-ylmethyl)phenyl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (49.0 mg, 0.11 mmol, 70 %) as a tan solid.
  • the reaction mixture was carefully quenched with MeOH ( ⁇ 3 mL) and then concentrated in vacuo to afford the crude product.
  • the crude product was purified by chromatography on silica gel using a gradient of 0-10% (0.7 M Ammonia in MeOH)/DCM to afford 8-(4-(piperidin-1-ylmethyl)phenyl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (38.0 mg, 87 pmol, 43 %) as a yellow solid.
  • the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with brine (5 x 10 mL), dried over MgSCU, filtered and concentrated in vacuo to give a mixture of regioisomers which were dissolved to 15.2 mg/mL in MeOH/DCM (3:2) with sonication. The solution was filtered and regioisomers were separated by chiral SFC on a Waters Prep 15 with a PDA detector, 40 °C, 120 bar. The column was a Chiralpak IG, 10 x 250mm, 5pm, flow rate 15mL/ min at 35% MeOH (0.1% neutral), 65% CO2.
  • DIAD 120 pL, 1.44 Eq, 617 pmol
  • the reaction was cooled to 0 °C and additional DIAD (60 pL, 0.72 Eq, 0.31 mmol) was added dropwise. After 15 min, the reaction was allowed to warm to room temperature and stirred for 4 h.
  • the reaction mixture was dried onto Celite and purified by column chromatography on silica gel using a gradient of 0-10% MeOH/DCM to afford a mixture of regio isomers.
  • the mixture (106 mg) was dissolved to 35.3 mg/mL in THF/MeOH (2:1) with sonication, filtered and was then separated by chiral SFC on a Waters Prep 100 with a PDA and a QDA detector, 40 °C, 120 bar.
  • the column was a Chiralpak IBN, 21 x 250mm, 5pm, flow rate 65mL/ min at 30% MeOH (neutral), 70% CO2.
  • the clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were redissolved in THF/MeOH, transferred into final vials and evaporated on a Biotage V10.
  • the mixture was passed through a phase separator and the aqueous phase was extracted with DCM (2 x 10 mL). The combined organics were washed with sat. aq. NaHCOs (20 mL), 50% brine (20 mL), dried over MgSO4 and concentrated in vacuo to afford the crude product.
  • the crude product was purified by chromatography on silica gel using a gradient of 0-10% (0.7 M Ammonia in MeOH)/DCM to afford 7-amino-2-(1-ethylpiperidin-4-yl)-8-nitro-4H-chromen-4- one (150 mg, 0.45 mmol, 51 %) as a yellow solid.
  • the reaction mixture was concentrated in vacuo and the residue was azeotroped with DCM (2 times) to afford the crude product as a mixture of 7,8-diamino-2-(1-ethylpiperidin-4-yl)-4H-chromen-4- one and (7-amino-2-(1-ethylpiperidin-4-yl)-4-oxo-4H-chromen-8-yl)sulfamic acid.
  • the crude product was dissolved in TFA (2 mL) and stirred at 60 °C for 10 h.
  • the reaction mixture was concentrated in vacuo and azeotroped with DCM (3 times) to afford the crude product.
  • the residue was azeotroped with DCM (2 times) to afford the crude product as a mixture of 7,8-diamino-2- (1-isobutylpiperidin-4-yl)-4H-chromen-4-one and (7-amino-2-(1-isobutylpiperidin-4-yl)-4-oxo-4H- chromen-8-yl)sulfamic acid.
  • the crude product was dissolved in TFA (2 mL) and stirred at 70 °C for 8 h. The reaction mixture was concentrated in vacuo and azeotroped with DCM (3 times) to afford the crude product.
  • the product was purified by chromatography on RP Flash C18 using a gradient of 5-30% MeCN/(0.1% Ammonium Hydroxide in Water) to afford 8-(1 -isobutylpiperidin- 4-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (35.0 mg, 87 pmol, 53 %) as an off- white solid.
  • the reaction mixture was stirred on for 16 h without further heating.
  • the reaction mixture was carefully quenched with 50% sat. aq. NaHCO3 (10 mL).
  • the mixture was passed through a phase separator and the aqueous was extracted with DCM (2 x 10 mL) and chloroform/IPA (3:1) (2 x 25 mL).
  • the combined organics were washed with 50% brine (25 mL), dried over MgSC and concentrated in vacuo.
  • the residue was azeotroped with toluene (3 times) to afford the crude product.
  • the crude product was purified by column chromatography on silica gel using a gradient of 0-10% (0.7 M Ammonia in MeOH)/DCM to afford 7-amino-2-(1-methylpiperidin-4-yl)-
  • the product was purified by column chromatography on RP Flash C18 using a gradient of 5-30% MeCN/(0.1% Ammonium Hydroxide in Water) to afford 8-(1-methylpiperidin-4-yl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (31.0 mg, 84 pmol, 50 %) as an off-white solid.
  • DI PEA 80 pL, 1.7 Eq, 0.46 mmol
  • dibromodifluoromethane 1.2 mL, 47 Eq, 13 mmol
  • 4-(6-oxo-2-(trifluoromethyl)-3,6- dihydrochromeno[7,8-d]imidazol-8-yl)benzonitrile 100 mg, 98% Wt, 1 Eq, 276 pmol
  • DMF 3.0 mL
  • the reaction mixture was filtered through glass fibre filter paper, washing with MeOH, and the filtrate was concentrated in vacuo to afford the crude product.
  • the crude product was purified by column chromatography on silica gel using a gradient of 0-10% MeOH/DCM, then 20% (0.7 M Ammonia in MeOH)/DCM to afford 8-(4- (aminomethyl)phenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (13.0 mg, 35 pmol, 26 %) as a pale yellow solid.
  • reaction mixture was stirred at 0 °C for 15 min and then allowed to warm to rt for 1 h. Additional borane tetra hydrofuran complex (1 M) (450 pL, 1.05 Eq, 450 pmol) was added at 1 h intervals for 7 h and then stirred overnight. The reaction mixture was quenched with aq. HCI (1 M) (10 mL), then extracted with DCM (2 x 10 mL). The combined organics were passed through a phase separator and concentrated in vacuo to afford the crude product.
  • the crude product was purified by column chromatography on silica gel using a gradient of 0-10% MeOH/DCM.
  • the product containing fractions were concentrated in vacuo to afford a mixture of enantiomers.
  • the mixture (30 mg) was dissolved in MeOH (3 ml) with sonication and heating, filtered and then separated by chiral SFC on a Waters Prep 15 with a PDA detector, 40 °C, 120 bar.
  • the column was a ChiralpaK IC, 10 x 250mm, 5pm, flow rate 15mL/ min at 30% MeOH (0.2% Ammonia), 70% CO2.
  • the clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator.
  • Acetyl chloride (34.5 mL, 99% Wt, 1.25 Eq, 480 mmol) was added to a solution of 3,4- difluorophenol (50.0 g, 1 Eq, 384 mmol) in DCM (1.00 L) and triethylamine (67.0 mL, 1.25 Eq, 480 mmol) at 0 °C. The reaction was allowed to warm to rt and stirred overnight. The reaction was filtered and the precipitate washed with DCM (100 mL).
  • nitric acid (69%) (0.7 mL, 15.4 molar, 0.1 Eq, 0.01 mol) was added dropwise in portions (maintaining the internal temperature below 5 °C) and the reaction stirred for a further 10 min.
  • the reaction mixture was poured onto crushed ice (-500 g), diluted with DCM (600 mL) and the stirred until the ice had melted and the solids had dissolved.
  • the organic layer was collected and the aqueous layer extracted with DCM (400 mL). The combined organics were washed with brine (200 mL), dried over MgSC and concentrated in vacuo.
  • the resultant precipitate mixture was cooled over an (ice/water bath) and the solids were collected by filtration and washed with water, to afford the desired product 3-amino-4-fluoro-6- (1-iminoethyl)-2-nitrophenol as a yellow gum.
  • the crude product was sucked dry for 10 min. and then taken onto the next step without further purification assuming quantitative yield.
  • the reaction mixture was heated to 50 °C for 24 h. Additional methyl iodide (20.0 pL, 1.06 Eq, 320 pmol) was added, and the reaction heated for a further 2 h.
  • the reaction mixture was diluted with water (10 mL) and the precipitate was collected by filtration, washing with water, to afford a mixture of products.
  • the mixture (96.7 mg, 90.9%) was dissolved in DMSO (9 mL) with sonication and heating to give a cloudy solution which was filtered, and then separated by chiral SFC on a Waters Prep 100 with a PDA and QDa detectors, 40 °C, 120 bar.
  • the column was a Chiralpak IH, 20 x 250mm, 5pm, flow rate 65mL/ min at 25% MeOH (no modifier), 75% CO2.
  • the clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator.
  • the residues were re-dissolved in dichloromethane, transferred into final vials and evaporated on a Biotage V10.
  • the samples were then further dried in a vacuum oven at 30°C/ 5 mbar overnight to afford: Compound 57
  • the reaction was quenched with MeOH (10 mL), and the reaction mixture was dried onto Celite.
  • the crude product was purified by column chromatography on silica gel using a gradient of 0-20% MeOH/DCM then 0-20% [0.7 M Ammonia in MeOH]/DCM, dried in a desiccator and freeze dried from water/MeCN (5:1). The product was triturated with sat. aq.
  • the reaction mixture was stirred at 60 °C for 1 h and then concentrated in vacuo, to afford the crude product as a mixture of 7,8-diamino-6-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one and (7-amino-6- fluoro-2-(4-methoxyphenyl)-4-oxo-4H-chromen-8-yl) sulfamic acid.
  • TFA 5.00 mL, 52.8 Eq, 64.9 mmol
  • the reaction mixture was stirred at 70 °C for 4 h.
  • the reaction mixture was concentrated in vacuo and the residue was azeotroped with DCM to afford the crude product.
  • the crude product was purified by column chromatography on silica gel using a gradient of 0- 4% MeOH/DCM to afford a mixture of regioisomers.
  • the mixture (51 mg) was dissolved to 3 mg/mL in equal amounts MeOH/THF/DCM with sonication and heat then filtered and separated by chiral SFC on a Waters Prep 15 with a PDA detector, 40 °C, 120 bar.
  • the column was a Chiralpak I H , 10 x 250mm, 5pm, flow rate 15mL/ min at 35% MeOH, 65% CO2.
  • the clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator.
  • the residues were transferred into final vials with methanol and evaporated on a Biotage V10.
  • the samples were then further dried in a vacuum oven at 30 °C/ 5 mbar overnight to afford:
  • reaction mixture was poured into water (150 mL) and the resultant precipitate was collected by filtration, washed with water and EtOH then dried in vacuo to afford 5-(3-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3- oxoprop-1-en-1-yl)picolinonitrile (1.244 g, 3.8 mmol, 38 %) as an orange solid.
  • the reaction mixture was quenched with MeOH ( ⁇ 3 mL) and then concentrated in vacuo to afford the crude product.
  • the crude product was purified by column chromatography on silica gel using a gradient of 0-10% (3:1 , EtOAc/EtOH)/DCM to afford a mixture of regioisomers as a yellow solid.
  • the mixture (39.2 mg) was dissolved to 10 mg/mL in MeOH with sonication, filtered and was then separated by chiral SFC on a Sepiatec with UV detection at 220 nm, 40 °C, 120 bar.
  • the column was a ChiralpaK IH, 10 x 250mm, 5pm, flow rate 20mL/ min at 25% MeOH (neutral), 75% CO2.
  • the clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in methanol, transferred into final vials and evaporated on a Biotage V10 to afford: Compound 73
  • the reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene (2 times) to afford the crude product.
  • the crude product was purified by column chromatography on silica gel using a gradient of 0-50% (3:1 , EtOAc/EtOH)/DCM to afford 5-(2-(difluoromethyl)-4-fluoro-6-oxo-3,6- dihydrochromeno[7,8-d]imidazol-8-yl)picolinonitrile (89.0 mg, 0.25 mmol, 22 %) as a yellow solid.
  • the residue was azeotroped with toluene (2 times) to afford the crude product.
  • the crude product was purified by column chromatography on silica gel using a gradient of n0-10% (3:1 EtOAc/EtOH)/DCM to afford a mixture of regioisomers.
  • the mixture (47 mg) was dissolved in DMF/MeOH (8 mL), filtered and was then separated by chiral SFC on a Waters Prep 100 with a PDA and QDa detectors, 40 °C, 120 bar.
  • the column was a ChiralpaK IB-N, 20 x 250mm, 5pm, flow rate 65mL/ min at 50% MeOH, 50% CO2.
  • the resultant solution was stirred at 50 °C for 3 h then allowed to cool to rt.
  • the reaction mixture was diluted with EtOAc (100 mL) and washed with 50% brine (50 mL).
  • the organic layer was collected and the aqueous layer extracted with EtOAc (50 mL).
  • the combined organics were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo to afford the crude product.
  • the reaction mixture was stirred at 70 °C for 5 h and then concentrated in vacuo. The residue was azeotroped with DCM (3 times) to afford the crude product.
  • the crude product was purified by column chromatography on silica gel using a gradient of 0-50% (3:1 , EtOAc/EtOH)/DCM to afford 4-fluoro-8-(tetrahydro-2H-pyran-4-yl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (65.0 mg, 182 pmol, 68.9 %) as a yellow solid.
  • the column was a ChiralpaK IH, 10 x 250mm, 5pm, flow rate 20 mL/min at 35% MeOH, 65% CO2.
  • the clean fractions were pooled, rinsed with MeOH, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in MeOH, transferred into final vials and evaporated on a Biotage V10 to afford: Compound 84
  • reaction mixture was evaporated to dryness, diluted with EtOAc (100 mL) and washed with 50% brine (50 mL). The organic layer was collected and the aqueous layer extracted with EtOAc (50 mL). The combined organics were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo to afford the crude product.
  • reaction mixture was stirred at 110 °C for 3 h. Additional iodine (1 .76 g, 1 Eq, 6.95 mmol) was added and stirred at 110 °C for 30 min. The reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene (3 times). EtOAc (300 mL) and sat. aq. sodium thiosulfate (200 mL) was added and the mixture was filtered through cotton wool. The organic layer was collected and washed with sat. aq. sodium thiosulfate (150 mL), brine (2 x 100 mL), dried over MgSO4 and concentrated in vacuo to afford the crude product.

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Abstract

La présente invention concerne de nouveaux composés synthétiques de formule (I) et (II) liés à des flavonoïdes d'origine naturelle tels que la 7,8-dihydroxyflavone (7,8-DHF). L'invention concerne en outre le procédé pour les synthétiser, l'utilisation de ces composés en tant qu'outils de recherche et leur utilisation en tant que produits pharmaceutiques.
PCT/GB2024/053100 2023-12-12 2024-12-12 Composés hétérocycliques et leur utilisation pour le traitement de troubles neurologiques Pending WO2025125811A1 (fr)

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GBGB2318964.0A GB202318964D0 (en) 2023-12-12 2023-12-12 Novel compounds and uses thereof
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GB2414004.8 2024-09-24

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2414004A (en) 2004-05-11 2005-11-16 Tna Australia Pty Ltd Slip conveyor having vertical acceleration less than gravity
WO2011033265A1 (fr) * 2009-09-18 2011-03-24 Almac Discovery Limited Composés pharmaceutiques
WO2014018741A1 (fr) * 2012-07-27 2014-01-30 Emory University Dérivés hétérocycliques de flavone, compositions et procédés s'y rapportant
WO2020033604A1 (fr) * 2018-08-07 2020-02-13 Emory University Dérivés hétérocycliques de flavone, compositions et procédés associés
WO2023227882A1 (fr) * 2022-05-24 2023-11-30 Ontrack Therapeutics Limited 4-(6-oxo-2-(trifluorométhyl)-3,6-dihydrochroméno [7,8-d] imidazol-8-yl) benzonitril pour le traitement de maladies et d'états associés à des troubles du mouvement
WO2023227881A1 (fr) * 2022-05-24 2023-11-30 Ontrack Therapeutics Limited Composés destinés à être utilisés dans le traitement de maladies et d'états associés à un dysfonctionnement neurodégénératif
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GB2414004A (en) 2004-05-11 2005-11-16 Tna Australia Pty Ltd Slip conveyor having vertical acceleration less than gravity
WO2011033265A1 (fr) * 2009-09-18 2011-03-24 Almac Discovery Limited Composés pharmaceutiques
WO2014018741A1 (fr) * 2012-07-27 2014-01-30 Emory University Dérivés hétérocycliques de flavone, compositions et procédés s'y rapportant
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