WO2025256460A1 - Dérivés polycycliques contenant de la dihydropyrimidine-2,4(1h, 3h)-dione et composition pharmaceutique associée, leur procédé de préparation et leur utilisation - Google Patents

Dérivés polycycliques contenant de la dihydropyrimidine-2,4(1h, 3h)-dione et composition pharmaceutique associée, leur procédé de préparation et leur utilisation

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Publication number
WO2025256460A1
WO2025256460A1 PCT/CN2025/099373 CN2025099373W WO2025256460A1 WO 2025256460 A1 WO2025256460 A1 WO 2025256460A1 CN 2025099373 W CN2025099373 W CN 2025099373W WO 2025256460 A1 WO2025256460 A1 WO 2025256460A1
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WO
WIPO (PCT)
Prior art keywords
compound
methyl
pharmaceutically acceptable
solvate
stereoisomer
Prior art date
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Pending
Application number
PCT/CN2025/099373
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English (en)
Inventor
Liqiang Fu
Zude QI
Xuemei JIN
Adrian Contreras
Chin-Chun Lu
Yifeng Xia
Gang Lu
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.)
Linkcure Therapeutics
Original Assignee
Linkcure Therapeutics
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Publication date
Application filed by Linkcure Therapeutics filed Critical Linkcure Therapeutics
Publication of WO2025256460A1 publication Critical patent/WO2025256460A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to medicinal chemistry, in particular, dihydropyrimidine-2, 4 (1H, 3H) -dione-containing polycyclic compounds, or pharmaceutically acceptable salts thereof, and compositions thereof which are effective to reduce or modulate widely interspaced zinc finger motifs (WIZ) protein expression levels and/or induce fetal hemoglobin (HbF) expression, and also relates to methods of their preparation and their use in treatment of subjects in need.
  • WIZ widely interspaced zinc finger motifs
  • HbF fetal hemoglobin
  • Sickle cell disease is caused by the formation of a pathological sickle hemoglobin tetramer consisting of two ⁇ -globin chains and two abnormal ⁇ -globin chains (HbS) , in which the glutamic acid residue at position 6 is replaced by valine owing to a single base change, from adenine to thymine, in the ⁇ -globin gene (HBB) (Rees DC et al., Lancet 2010, 376: 2018-2031) .
  • HBB ⁇ -globin gene
  • the G9a methyltransferase is known to regulate HbF production by repressing the transcription of fetal ⁇ -globin genes (Krivega, et al. Blood, 2015) . WIZ was reported to retain histone H3 lysine 9 methyltransferases G9a and GLP on chromatin to direct the deposition of H3K9me1 and H3K9me2, resulting in gene repression (Bian C et al., Elife 2015, 4: e05606) thereby, potentially contributing to the silencing of ⁇ -globin genes.
  • WIZ is a known neosubstrate of several CRBN-based molecular glue degraders including immunomodulatory (IMiD) drugs and CC-122 (Yu HH et al., bioRxiv 2019 (doi: https: //doi. org/10.1101/595389) ; Hagner PR et al., Blood. 2015, 126: 779-789) .
  • IMD immunomodulatory
  • CC-122 Yu HH et al., bioRxiv 2019 (doi: https: //doi. org/10.1101/595389) ; Hagner PR et al., Blood. 2015, 126: 779-789) .
  • Recruitment of WIZ to the Cul4/DDB1/RBX1/CRBN E3 ligase complex by these compounds results in ubiquitination and subsequent proteasomal degradation of WIZ via a mechanism commonly shared among IMiD substrates (Sievers, Q. L. et al. Science 2018, 362, ea
  • the object of the present invention is to provide a new class of compounds which can reduce/modulate WIZ protein expression levels.
  • the compound is selected from:
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • composition comprising a compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is a tablet, a capsule, a granule, a syrup, a suspension, a solution, a dispersion, a slowed release preparation for oral or non-oral administration, an intravenous injection preparation, a subcutaneous injection preparation, an inhalation preparation, a transdermal preparation, a rectal or vaginal suppository.
  • the pharmaceutical composition is an oral preparation.
  • the third aspect it provides a use of a compound of any one of the first aspect of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder that is affected by the degradation of WIZ protein.
  • it provides a compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder affected by reactivating or increasing fetal hemoglobin expression in a subject in need thereof.
  • the fourth aspect provides a method of inhibiting, reducing, or eliminating the activity of WIZ protein or WIZ protein expression in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the first aspect of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • a disease or disorder includes sickle cell anemia, and beta-thalassemia.
  • the salt of the compound in the present invention may be formed which is also within the scope of the present invention. Unless otherwise stated, the compound in the present invention is understood to include its salt.
  • the term "salt” as used herein refers to a salt formed in the form of acid or base from inorganic or organic acid and base. Further, when the compound in the present invention contains a base fragment which includes, but is not limited to pyridine or imidazole, when contains an acid segment which includes, but is not limited to carboxylic acid.
  • the zwitter-ion that may form “inner salt” is included within the range of the term “salt” .
  • compositions of the present invention may form a salt, for example, compound I is reacted with a certain amount (such as an equivalent amount) of an acid or base, and precipitated in a medium, or freeze-dried in aqueous solution.
  • the compounds in the present invention containing base fragments which include but are not limited to amines or pyridine or imidazole rings, may form salt with organic or inorganic acid.
  • Typical acids that form salts include acetate (e.g., acetate or trihalogenated acetic acid, e.g., trifluoroacetic acid) , adipate, alginate, ascorbate, aspartate, benzoate, benzene sulfonate, disulfate, borate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentane propionate, diethylene glycolate, lauryl sulfate, ethanesulphonate, fumarate, gluceptate, glycerophosphate, hemisulphate, enanthate, caproate, hydrochloride, hydrobromide, hydriodate, isethionate (e.g., 2-hydroxy-ethesulfon
  • Some compounds of the invention may contain acidic fragments including, but not limited to carboxylic acid may form salts with various organic or inorganic bases.
  • Salts formed by typical bases includes ammonium salt, alkali metal salt (such as sodium, lithium and potassium salts) , alkaline earth metal salt (such as calcium and magnesium salts) , and salts formed by organic bases (e.g., organic amines) , such as benzathine, dicyclohexylamine, hydrabamine (salt formed with N, N-bis (dehydroabietyl) ethylenediamine) , N-methyl-D-glucanamine, N-methyl-D-glucoamide, tert-butyllamine, and the salts formed with amino acids such as arginine, lysine, etc.
  • alkali metal salt such as sodium, lithium and potassium salts
  • alkaline earth metal salt such as calcium and magnesium salts
  • organic bases e.g., organic amines
  • organic bases e
  • Basic nitrogen-containing groups can form quaternary ammonium salts with halides, such as small molecular alkyl halides (e.g., chlorides, bromides and iodides of methyl, ethyl, propyl and butyl) , dialkyl sulfates (such as dimethyl, diethyl, dibutyl, and dipentyl sulfates) , long chain halides (e.g., chlorides, bromides and iodides of decyl, dodecyl, tetradecyl, and tetradecyl) , aralkyl halides (such as bromides of benzyl and phenyl) , etc.
  • halides such as small molecular alkyl halides (e.g., chlorides, bromides and iodides of methyl, ethyl, propyl and butyl) , dialkyl sulfates
  • prodrug and solvate of the compound in the present invention are also included within the scope of the present invention.
  • prodrug herein refers to a compound resulting from the chemical transformation of a metabolic or chemical process to produce a compound, salt, or solvate in the present invention for the treatment of an associated disease.
  • the compounds of the invention include solvates such as hydrates.
  • Compound, salt or solvate in the present invention may be present in tautomeric forms such as amide and imino ether. All of these tautomers are part of the present invention.
  • Stereoisomers of all compounds e.g., those asymmetric carbon atoms that may be present due to various substitutions
  • the independent stereoisomer in the present invention may not coexist with other isomers (e.g., as a pure or substantially pure optical isomer with special activity) , or may be a mixture (e.g., racemate) , or a mixture formed with all other stereoisomers or a part thereof.
  • the chiral center of the present invention has two configurations of S or R, which is defined by International Union of Pure and Applied Chemistry (IUPAC) founded in 1974.
  • racemization form can be solved by physical methods, such as fractional crystallization, or separation crystallization by derivation into diastereomers, or separation by chiral column chromatography.
  • Individual optical isomer can be obtained from racemate by appropriate methods, including but not limited to conventional methods, such as recrystallization after salting with optically active acids.
  • stereocenter When a stereocenter is designated as “*R” or “*S” , it means that the absolute stereochemistry for such a stereocenter is undetermined (even if the bonds are drawn stereo specifically) although it is in a substantially single steric configuration.
  • “*R” can be absolute R configuration, or absolute S configuration.
  • “*S” can be absolute R configuration, or absolute S configuration.
  • “*R” or “*S” is assigned randomly for such molecules.
  • a stereocenter designated as “*R” can be in a single steric configuration same as or different from that of another stereocenter designated as “*S” .
  • a stereocenter designated as “*R” can be in a single steric configuration same as or different from that of another stereocenter designated as “*R” .
  • a stereocenter designated as “*S” can be in a single steric configuration same as or different from that of another stereocenter designated as “*S” .
  • Weight content of compound in the present invention obtained by preparation, separation and purification in turn is equal to or greater than 90%, such as equal to or greater than 95%, equal to or greater than 99% ( “very pure” compound) , and listed in the description of the text.
  • “very pure” compound of the present invention is also part of the present invention.
  • All configuration isomers of the compound of the present invention are within the scope, whether in mixture, pure or very pure form.
  • the definition of the compound of the present invention comprises cis (Z) and trans (E) olefin isomers, and cis and trans isomers of carbocyclic and heterocyclic.
  • Some compounds of the present invention may exist in specific geometric or stereoisomer forms.
  • the present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) type isomers, (L) type isomers, racemic mixtures and other mixtures.
  • asymmetric carbon atom can represent substituent, such as alkyl. All isomers and mixtures thereof are included in the present invention.
  • mixtures of isomers may contain a variety ratio of isomers.
  • mixtures with only two isomers may have the following combinations: 50: 50, 60: 40, 70: 30, 80: 20, 90: 10, 95: 5, 96: 4, 97: 3, 98: 2, 99: 1, or 100: 0, all ratios of the isomers are within the scope of the present invention.
  • Similar ratio and the ratio of mixtures of more complex isomers, which are readily understood by general skill of the art are also within the scope of the invention.
  • the present invention also includes the isotope labeled compound, which is equivalent to the original compound herein. However, in fact, the substitution of one or more atoms by an atom with a different atomic weight or mass number usually occurs.
  • Examples of compound isotopes that may be listed in the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl, respectively.
  • isotope-labeled compounds in the present invention such as the radioactive isotopes of 3 H and 14 C, are also included and are useful in experiments on the tissue distribution of drugs and substrates. Tritium ( 3 H) and Carbon-14 ( 14 C) , which are relatively easy to prepare and detect. In addition, heavier isotope substitutions such as deuterium, i.e. 2 H, have advantages in certain therapies due to their good metabolic stability, such as increased half-life or reduced dosage in vivo, and thus may be preferred in certain situations. Isotope-labeled compounds can be prepared by conventional methods through replacing readily available isotope-labeled reagents with non-isotopic reagents that can be prepared using the disclosed scheme shown in the Example.
  • the synthesis of the compound of the invention can be prepared by asymmetric synthesis, or derivatized with chiral auxiliary reagent, separating the resulting diastereomeric mixture and removing the chiral adjunct to obtain a pure enantiomer.
  • a molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group
  • a diastereomer can be formed with a salt of suitable optically active acids or bases, which can be separated by conventional means, such as crystallization or chromatography, to obtain a pure enantiomer.
  • the compound in the present invention may be substituted with any number of substituents or functional groups to extend its scope.
  • the general formula that includes substituents in the compound of the present invention means the substitution of a specified structural substituent for a hydrogen radical.
  • each location of the substituents can be the same or different.
  • stable herein refers to a stable compound which is sufficient for maintaining the integrity of the compound structure within a sufficiently long time, preferably in a sufficiently long time, which is hereby used for the above purposes.
  • the preparation method of the compound of the present invention is more specifically described below, but these specific methods do not constitute any limitation of the invention.
  • the compound of the invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such a combination may be easily performed by a skilled person in the art to which the invention belongs.
  • compositions of the present invention are used to prevent and /or treat a disease or disorder that is affected by the degradation of WIZ protein, such as sickle cell disease, beta-thalassemia, anemia, or related hemoglobinopathy.
  • the compounds of the present invention may be used in combination with other drugs known to treat or improve similar conditions.
  • the original administration for the drug can remain unchanged, while compound of the present invention may be administered simultaneously or subsequently.
  • Pharmaceutical composition containing one or more known drugs and the compound of the present invention may be preferred when administered in combination with one or more other drugs.
  • the drug combination also includes administering the compound of the present invention and other one or more known drugs at overlapping time. When the compound of the present invention is combined with other one or more drugs, the dose of the compound or known drug may be lower than that of their individual use.
  • the dosage forms of the pharmaceutical composition of the present invention include (but are not limited to) : injection, tablet, capsule, aerosol, suppository, pellicle, pill, liniment for external use, controlled release or sustained-release or nano formulation.
  • the pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient or carrier with safe and effective amount.
  • safe and effective amount refers to the amount of compound is sufficient to significantly improve the condition, not to produce severe side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound /dosage of the present invention, and preferably contains 1-1000 mg of the compound /dosage of the present invention.
  • "one dosage" is a capsule or a pill.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances, which are suitable for human use, and must be sufficiently pure and of sufficiently low toxicity. "Compatible” herein refers to the ability of each component of a composition can be mixed with the compound of the present invention and can be mixed with each other without appreciably reducing the efficacy of the compound.
  • pharmaceutically acceptable carrier include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc, solid lubricant (such as stearic acid, magnesium stearate) , calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc. ) , polyol (such as propylene glycol, glycerol, mannitol, sorbitol, etc. ) , emulsifier (such as ) , wetting agent (such as lauryl sodium sulfate) , colorant, flavoring, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • solid lubricant such as stearic acid, magnesium stearate
  • calcium sulfate such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerol, mannitol, sorbitol, etc.
  • emulsifier such as )
  • wetting agent such as lauryl sodium
  • administration mode for the compound or pharmaceutical compositions of the present invention
  • representative administration mode includes (but is not limited to) : oral, intratumorally, rectal, parenteral (intravenous, intramuscular or subcutaneous) , and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compounds are mixed with at least one conventional inert excipient (or carrier) , such as sodium citrate or dicalcium phosphate, or mixed with any of the following components: (a) fillers or compatibilizer, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and arabic gum; (c) humectant, such as, glycerol; (d) disintegrating agent, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain composite silicates, and sodium carbonate; (e) dissolution-retarding agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as
  • the solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared by using coating and shell materials, such as enteric coatings and any other materials known in the art. They can contain an opaque agent.
  • the release of the active compounds or compounds in the compositions can be released in a delayed mode in a given portion of the digestive tract.
  • the embedding components include polymers and waxes. If necessary, the active compounds and one or more above excipients can form microcapsules.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage forms may contain any conventional inert diluents known in the art such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butanediol, dimethyl formamide, as well as oil, in particular, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or the combination thereof.
  • composition may also contain additives such as wetting agents, emulsifiers, suspending agent, sweetener, flavoring agents and perfume.
  • additives such as wetting agents, emulsifiers, suspending agent, sweetener, flavoring agents and perfume.
  • the suspension may contain suspending agent, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, methanol aluminum and agar, or the combination thereof.
  • suspending agent for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, methanol aluminum and agar, or the combination thereof.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders which can be re-dissolved into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and any suitable mixtures thereof.
  • the dosage forms for topical administration of compounds of the invention include ointments, powders, patches, aerosol, and inhalants.
  • the active ingredients are mixed with physiologically acceptable carriers and any preservatives, buffers, or propellant if necessary, under sterile conditions.
  • Compounds of the present invention can be administrated alone, or in combination with any other pharmaceutically acceptable compounds.
  • a safe and effective amount of compound of the present invention is administered to a mammal (such as human) in need thereof, wherein the dose of administration is a pharmaceutically effective dose.
  • the daily dose is usually 1-2000 mg, preferably 50-1000mg.
  • the particular dose should also depend on various factors, such as the route of administration, patient health status, which are well within the skills of an experienced physician.
  • the present invention also provides a preparation method of pharmaceutical composition comprising the step of mixing a pharmaceutically acceptable carrier with the compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof of the present invention.
  • the main advantages of the present invention include:
  • the compounds described in the present invention are effective to reduce or modulate widely interspaced zinc finger motifs (WIZ) protein expression levels and/or induce fetal hemoglobin (HbF) expression.
  • WIZ widely interspaced zinc finger motifs
  • HbF fetal hemoglobin
  • the compounds described in the present invention possess a low clearance rate, good oral exposure, and high oral bioavailability.
  • ACN means acetonitrile
  • AcOH means acetic acid
  • Boc means tert-butyloxycarbonyl
  • Bn means benzyl
  • BINAP means 1.1'-binaphthyl-2.2'-diphemyl phosphine
  • calcd. means calculated
  • Cbz means benzyloxycarbonyl
  • col. means column, conc.
  • DCM dichloromethane
  • DIEA or DIPEA means N,N-diisopropylethyl amine
  • DIBAL Diisobutylaluminium hydride
  • DMF means dimethylformamide
  • DMP means Dess-Martin periodinane
  • DMSO means dimethyl sulphoxide
  • Dppf means 1, 1'-Bis (diphenylphosphino) ferrocene
  • Et 3 N means triethylamine
  • EtOAc or EA means ethyl acetate
  • ee means enantiomeric excess
  • ESI means electrospray ionization
  • FA means formic acid
  • HNMR means 1 H NMR
  • HCl means hydrochloric acid
  • HPLC means high performance liquid chromatography
  • LC-MS or LCMS means liquid chromatography-mass spectrometry
  • LAH means lithium aluminum hydride
  • NIS means N-iodosuccinimide
  • Prep-HPLC means preparative
  • PCC means pyridinium chlorochromate
  • Pd 2 (dba) 3 means tris (dibenzylideneacetone) dipalladium (0)
  • Pd (OAc) 2 means Palladium acetate
  • t R or Rt mean retention time, (s) or (s) mean solid, sat.
  • TEA means saturated
  • THF means tetrahydrofuran
  • TFA means trifluoroacetic acid
  • T or Temp mean temperature
  • Tf 2 O means trifluoromethanesulfonic anhydride
  • TfOH means trifluoromethanesulfonic
  • K 2 CO 3 means potassium carbonate
  • RuPhos Pd G3 means RuPhos-G3-Palladacycle
  • Methanesulfonato 2-dicyclohexylphosphino-2', 6'-di-isopropoxy-1, 1'-biphenyl) (2'-amino-1, 1'-bi phenyl-2-yl) palladium (II)
  • XPhos Pd G2 means Chloro (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1, 1'-biphenyl) [2- (2'-amino
  • Step 1 Synthesis of methyl 4- (2-methylpyrimidin-5-yl) cyclohex-3-ene-1-carboxylate
  • Step 2 Synthesis of methyl 4- (2-methylpyrimidin-5-yl) cyclohexane-1-carboxylate
  • Step 4 Synthesis of 4- (2-methylpyrimidin-5-yl) cyclohexane-1-carbaldehyde
  • Step 1 Synthesis of methyl 4- (pyrimidin-2-yl) cyclohex-3-ene-1-carboxylate
  • Step 2 Synthesis of methyl 4- (pyrimidin-2-yl) cyclohexane-1-carboxylate
  • Step 3 Synthesis of 4- (pyrimidin-2-yl) cyclohexane-1-carbaldehyde
  • HT-1080 cell line ATCC, Cat#CCL-121
  • WIZ, and IKZF1 HiBiT assays HT-1080 cells were engineered to stably overexpress GSPT ⁇ (1-138) /G575N mutant, and HiBiT tagged WIZ, and IKZF1 respectively.
  • HT-1080 cells were engineered to stably overexpress GSPT ⁇ (1-138) /G575N mutant, CRBN and HiBiT tagged CK1 ⁇ , and GSPT1 respectively.
  • Cells were cultured in DMEM medium supplemented with 10%heat-inactivated FBS, 1X sodium pyruvate, 1X non-essential amino acids, 1X glutamine, 100 U/ml penicillin, and 100 ug/mL streptomycin.
  • HiBiT degradation assay about 10,000 engineered HT-1080 cells in 35 ⁇ l culture medium were seeded into 384-well plates (Cat#3764, Corning) , pre-spotted with test compounds using the Echo 650 liquid handler (Beckman) .
  • the half-log dose-response-curve (DRC) typically has 10 points with the highest concentration at 10 ⁇ M, and the lowest concentration at 0.316 nM.
  • Assay plates were incubated at 37 °C with 5%CO 2 for 20 hrs.
  • Target protein degradation was then assessed using the Nano-Glo HiBiT Lytic Detection Reagent according to the manufacturer’s instructions. Luminescence was measured on a Pherastar microplate reader (BMG Labtech) .
  • A Y min (lowest target protein level normalized to DMSO control in response to compound treatment, as determined by curve fit)
  • y target protein level normalized to DMSO control
  • D max represented the maximum percentage of target protein degradation that could be achieved by a compound at its highest treatment concentration.
  • the results of compounds described in the present invention are shown in Table 1 and 2.
  • the compounds of the present invention have significantly improved degradation activity towards WIZ protein compared to Reference 1.
  • the compounds of the present invention have lower degradation activity towards CK1 ⁇ , GSPT1, and IKZF1 compared to Reference 1, demonstrating a better selectivity and lower toxicity.
  • Microsome working solutions 54 ⁇ L was transferred to a Blank60 plate, followed by the addition of 6 ⁇ L NADPH cofactor and 180 ⁇ L of stop solution into each well.
  • Compound working solution 5 ⁇ L was added to the 'incubation' plates (T60 and NCF60) containing microsomes.
  • NADPH working solution 44 ⁇ L was added, followed by a 60 min incubation at 37°C.
  • Example 4 The pharmacokinetic study after single intravenous and oral administration in SD rat
  • Sample collection and preparation After intravenous injection or oral administration of test compounds, blood samples were collected and collection time was recorded. After collection, the blood sample was immediately transferred into a labeled centrifuge tube containing K2-EDTA, followed by centrifugation and plasma collection. The plasma was then transferred into a pre-cooled centrifuge tube, quickly frozen on dry ice, and stored in an ultra-low temperature refrigerator at -70 ⁇ 10°C until the LC-MS/MS analysis was performed.
  • Pharmacokinetic data analysis The pharmacokinetic software was used to process the plasma drug concentration data of the compound in a non-compartmental model.
  • the peak concentration (C max ) , peak time (T max ) and quantifiable end time can be directly obtained from the plasma concentration-time diagram.
  • the log-linear trapezoidal method was used to calculate the following pharmacokinetic parameters: half-life (T 1/2 ) , apparent volume of distribution (V ss ) and clearance (Cl) , and the area under the time-plasma concentration curve (AUC 0-last ) from the 0 point to the end point.

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Abstract

La présente invention concerne des composés polycycliques contenant de la dihydropyrimidine-2,4(1H, 3H)-dione, ou des sels pharmaceutiquement acceptables de ceux-ci, et des compositions de ceux-ci qui sont efficaces pour réduire ou moduler des niveaux d'expression de protéine à motifs de doigts de zinc (WIZ) largement espacés et/ou induire l'expression de l'hémoglobine foetale (HbF), et concerne également des procédés pour leur préparation et leur utilisation pour le traitement de sujets en ayant besoin.
PCT/CN2025/099373 2023-06-15 2025-06-05 Dérivés polycycliques contenant de la dihydropyrimidine-2,4(1h, 3h)-dione et composition pharmaceutique associée, leur procédé de préparation et leur utilisation Pending WO2025256460A1 (fr)

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CN114401960A (zh) * 2019-09-16 2022-04-26 诺华股份有限公司 胶降解剂及其使用方法
CN114828959A (zh) * 2019-12-18 2022-07-29 诺华股份有限公司 3-(5-甲氧基-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮衍生物及其用途
WO2022268229A1 (fr) * 2021-06-25 2022-12-29 和径医药科技（上海）有限公司 Inhibiteur de protéine ou agent de dégradation, composition pharmaceutique le contenant et utilisation pharmaceutique
CN116802182A (zh) * 2021-03-15 2023-09-22 诺华股份有限公司 吡唑并吡啶衍生物及其用途
CN116940571A (zh) * 2021-03-15 2023-10-24 诺华股份有限公司 苯并异噁唑衍生物及其用途

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WO2022195355A1 (fr) * 2021-03-15 2022-09-22 Novartis Ag Dérivés de benzisoxazole et leurs utilisations
US20240368121A1 (en) * 2021-08-20 2024-11-07 Biotheryx, Inc. Estrogen receptor degraders, pharmaceutical compositions thereof, and their therapeutic applications

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114401960A (zh) * 2019-09-16 2022-04-26 诺华股份有限公司 胶降解剂及其使用方法
CN114828959A (zh) * 2019-12-18 2022-07-29 诺华股份有限公司 3-(5-甲氧基-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮衍生物及其用途
CN116802182A (zh) * 2021-03-15 2023-09-22 诺华股份有限公司 吡唑并吡啶衍生物及其用途
CN116940571A (zh) * 2021-03-15 2023-10-24 诺华股份有限公司 苯并异噁唑衍生物及其用途
WO2022268229A1 (fr) * 2021-06-25 2022-12-29 和径医药科技（上海）有限公司 Inhibiteur de protéine ou agent de dégradation, composition pharmaceutique le contenant et utilisation pharmaceutique

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