WO2018161922A1 - Composé ayant une activité inhibitrice de prmt5, préparation pour composé et applications associées - Google Patents

Composé ayant une activité inhibitrice de prmt5, préparation pour composé et applications associées Download PDF

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WO2018161922A1
WO2018161922A1 PCT/CN2018/078308 CN2018078308W WO2018161922A1 WO 2018161922 A1 WO2018161922 A1 WO 2018161922A1 CN 2018078308 W CN2018078308 W CN 2018078308W WO 2018161922 A1 WO2018161922 A1 WO 2018161922A1
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group
alkyl
compound
pyridine
substituted
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PCT/CN2018/078308
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Chinese (zh)
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段文虎
罗成
邵敬伟
朱孔凯
张元元
丁宏
蒋华良
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中国科学院上海药物研究所
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Publication of WO2018161922A1 publication Critical patent/WO2018161922A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and in particular to a compound having PRMT5 inhibitory activity and its preparation and use.
  • the arginine methylation involved in the protein arginine methyltransferase (PRMTs) family is a post-translational modification that is widely present in the nucleus and cytoplasm, with S-adenosyl-methionine as the methyl group. Methylation of the nitrogen atom of the arginine side chain of the modified protein produces S-adenosyl homocysteine and methylarginine.
  • the substrate for PRMTs is a protein rich in glycine and arginine domains. A total of 10 PRMTs have been found in mammals, 8 of which are biologically active.
  • type I PRMT catalyzes the formation of monomethylarginine and asymmetric dimethylarginine
  • type II PRMT catalyzes the formation of MMA and symmetry.
  • PRMT5 belongs to type II PRMT.
  • PRMT5 can methylate different proteins involved in the regulation of physiological processes.
  • PRMT5 can affect gene transcription through methylation of histones and transcription elongation factors; it can methylate the tumor suppressor gene p53 to change the activation state of p53.
  • PRMT5 and its molecular chaperone protein MEP50 can form macromolecular complexes with various proteins, which can catalyze multiple substrates in cytoplasm and nucleus such as Sm protein, nucleolar protein, p53, histone H2A, H3 and H4, SPT5 and MBD2. Protein methylation, therefore, PRMT5 plays a key role in RNA processing, chromatin remodeling, and regulation of gene expression.
  • PRMT5 regulates MAPK/ERK signaling pathway by methylation of RAF protein, regulates ribosome biosynthesis by methylation of ribosomal protein S10, and plays an important role in cell survival by regulating eIF4E expression and P53 translation. In embryonic stem cells, the differentiation gene is inhibited by methylating H2A in the cytosol. Recent studies have found that PRMT5 and MEP50 are important components of the Grg4 complex and are essential for their regulation of transcriptional repression. PRMT5 is capable of inhibiting the tumor suppressor function of programmed cell death protein 4 (PDCD4). The methyltransferase activity of PRMT5 can be regulated by phosphorylation of MEP50 or PRMT5 itself.
  • PDCD4 programmed cell death protein 4
  • Cyclin D1/CDK4 phosphorylates Thr5 on MEP50, activating methyltransferase activity of PRMT5 and prolonging the survival of tumor cells.
  • the tumorigenic mutations on Jak2 (V617F, K539L) phosphorylate tyrosine at positions 297, 304 and 306 on PRMT5, which disrupts the binding of PRMT5 to MEP50 and down-regulates the methylation activity of histone substrates.
  • PRMT5 is a promising target for tumor therapy.
  • X is selected from the group consisting of NR 3 and CHR 3 ;
  • Y is selected from the group consisting of O, NR 4 , CHR 4 ;
  • Z is selected from the group consisting of NR 4 and CHR 4 ;
  • Ring A is selected from the group consisting of substituted or unsubstituted 5-membered heteroaryl rings containing 1-2 heteroatoms selected from N, O, S, substituted or unsubstituted, containing 1-2 selected from N, O, a 6-membered heteroaryl ring, a substituted or unsubstituted phenyl group of a hetero atom of S; wherein, when ring A is a phenyl group, at least one of Y and Z is NR 4 ; and the substitution means is selected from the group consisting of Substituted by one or more substituents: halogen, C 1 -C 3 alkyl;
  • R 1 and R 2 may be the same or different and are each independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl;
  • R 3 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl
  • R 4 is selected from the group consisting of hydrogen, R 5 , V 1 -R 5 ;
  • V 1 is selected from the group consisting of CO, CS, CHR 6 , SO 2 , NH, CH 2 CO, COCH 2 , COCH 2 CH 2 , CH 2 CHR 6 , CHR 6 CH 2 , CONH, NHCO, OCO, COO, CH 2 CH 2 O, CH 2 CH 2 CHR 6 , CH 2 CH 2 CO;
  • R 5 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted, and 1-3 selected from N, O and S. a 4-10 membered cycloheteroalkyl group of a hetero atom, a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-10 membered heterocyclic group containing 1-3 hetero atoms selected from N, O and S.
  • An aryl group wherein said substitution is substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, C1-C6 alkyl, halo C1-C6 alkyl, 4-10 membered cycloheteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkane containing from 1 to 3 heteroatoms selected from N, O and S Oxyl, C1-C6 alkanoyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) (C1-C6 alkyl), -NH(C3-C8 cycloalkyl), -NH( C3-C8 cycloheteroalkyl), -CO (C1-C6 alkyl), -CONH 2 , -CONH (C1-C6 alkyl),
  • R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl.
  • p, X, Y, Z, R 1 , R 2 and R 4 are as defined above;
  • Ring A is selected from the group consisting of substituted or unsubstituted 5-membered heteroaryl rings containing 1-2 heteroatoms selected from N, O, S, substituted or unsubstituted, containing 1-2 selected from N, O, a 6-membered heteroaryl ring, a substituted or unsubstituted phenyl group of a hetero atom of S; wherein, when ring A is a phenyl group, at least one of Y and Z is NR 4 ; and the substitution means is selected from the group consisting of Substituted by one or more substituents: halogen, C 1 -C 3 alkyl;
  • V 1 is selected from the group consisting of CO, CS, CHR 6 , SO 2 , NH, CH 2 CO, COCH 2 , COCH 2 CH 2 , CH 2 CHR 6 , CHR 6 CH 2 , CONH, NHCO, OCO, COO, CH 2 CH 2 O, CH 2 CH 2 CHR 6 , CH 2 CH 2 CO;
  • R 5 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted, and 1-3 selected from N, O and S. a 4-10 membered cycloheteroalkyl group of a hetero atom, a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-10 membered heterocyclic group containing 1-3 hetero atoms selected from N, O and S.
  • An aryl group wherein said substitution is substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, C1-C4 alkyl, halo C1-C4 alkyl, 4-8 membered cycloheteroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, halogenated C1-C4 alkane containing from 1 to 3 heteroatoms selected from N, O and S An oxy group, a C1-C4 alkanoyl group, -NH(C1-C4 alkyl group), -N(C1-C4 alkyl group) (C1-C4 alkyl group), -CO(C1-C4 alkyl group), -CONH 2 , -CONH (C1-C4 alkyl), -CON (C1-C4 alkyl) (C1-C4 alkyl), -CO(
  • R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl.
  • the compound is a compound selected from the group consisting of the formula (II) or the formula (III):
  • p, X, Y, Z, R 1 , R 2 and ring A are as defined above.
  • Ring A is selected from the group consisting of substituted or unsubstituted thiophenes, furans, pyrroles, thiazoles, phenyl groups; wherein said substitution preferably means substitution by a methyl group.
  • R 1 and R 2 may be the same or different and are each independently selected from the group consisting of hydrogen and methyl.
  • V 1 is selected from the group consisting of CO, CHR 6 , SO 2 , NH, CH 2 CO, CH 2 CHR 6 , OCO, COO, CH 2 CH 2 CHR 6 , CH 2 CH 2 CO.
  • the "5-10 membered aryl" is selected from the group consisting of phenyl, naphthyl.
  • the "5-10 membered heteroaryl group” is a 5-9 membered heteroaryl group having 1-2 hetero atoms selected from N, S.
  • the "halo" means that the hydrogen on the group is replaced by a halogen, preferably the halogen is selected from the group consisting of F, Cl, Br, I.
  • R 5 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, allyl, 2-methoxyethyl, tert-butoxycarbonyl, cyclobutyl, cyclopentane , cyclohexane, 4-methylcyclohexyl, cycloheptyl, phenyl, p-methylphenyl, p-methoxyphenyl, p-chlorophenyl, p-fluorophenyl, p-acetylphenyl , p-aminophenyl, p-nitrophenyl, p-cyanophenyl, p-trifluoromethylphenyl, N,N-dimethylaminophenyl, pyridyl, thienyl, furyl, benzothienyl , tetrahydropyranyl, tetrahydropiperidinyl and 2-naph
  • the compound of formula (I) is selected from the specific compounds listed in Table 1.
  • any of p, X, Y, Z, ring A, R 1 , R 2 , R 3 , R 4 , V 1 , R 5 , R 6 As defined in the specific compounds shown in Table 1.
  • a pharmaceutical composition comprising:
  • the pharmaceutical composition is selected from the group consisting of an injection, a sachet, a tablet, a pill, a powder, or a granule.
  • a compound of the first aspect of the invention and a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvent thereof
  • a pharmaceutical composition according to the second aspect of the present invention for the preparation of a medicament for preventing and/or treating a cancer-related disease, preferably an arginine methyltransferase inhibitor, more preferably a PRMT5 inhibitor Agent.
  • the cancer-related disease is selected from the group consisting of breast cancer, lung cancer, bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, multiple myeloma AML, liver cancer, melanoma, head and neck cancer. , thyroid cancer, renal cell carcinoma, glioblastoma, and testicular cancer.
  • an arginine methyltransferase enzyme activity inhibitor comprising an inhibitory effective amount of one or more compounds of the first aspect of the invention, and a stereo Isomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates or solvates.
  • a pharmaceutical composition for treating a cancer or an arginine methyltransferase enzymatic activity-related disease comprising a therapeutically effective amount of the first aspect of the invention
  • One or more compounds, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, as active ingredients are included in a pharmaceutical composition.
  • the condensation agent used in the condensation reaction is 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride/1-hydroxybenzotriazole.
  • the deprotecting agent used in the deprotection reaction is trifluoroacetic acid.
  • the compound (5) is obtained by reductive amination, nucleophilic substitution, or condensation reaction to give the compound (I).
  • a method for inhibiting arginine methyltransferase in vitro comprising the steps of: the compound of the first aspect of the invention, and the stereoisomer thereof, geometric isomerism a body, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate or a solvate or a pharmaceutical composition according to the second aspect of the invention, in contact with an arginine methyltransferase, thereby inhibiting arginine A Base transferase.
  • a method of preventing and/or treating a cancer-related disease comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of the compound of the first aspect of the invention, and a stereo thereof Isomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate or the pharmaceutical composition of the second aspect of the invention.
  • the present inventors designed and synthesized a series of novel compounds by studying the structure and relationship between the crystal structure of PRMT5 and other PRMT5 inhibitors, and screening these compounds at the molecular and cellular levels. These compounds can significantly inhibit the activity of PRMT5 enzyme at the molecular level, and the cell level also significantly inhibits the proliferation of various cancer cells caused by PRMT5 mutation. On this basis, the inventors completed the present invention.
  • halogen refers to F, Cl, Br, and I, and more preferably, the halogen atom is selected from the group consisting of F, Cl, and Br.
  • C1-C6 alkyl refers to a straight or branched alkyl group comprising from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl. , tert-butyl, or the like.
  • Boc refers to t-butoxycarbonyl, ie
  • C1-C6 alkoxy includes a straight or branched alkoxy group of 1 to 6 carbon atoms.
  • alkyl includes saturated or unsaturated, straight-chain, branched, cyclic all-alkylene groups of 1 to 6 carbon atoms or 1 to 3 carbon atoms thereof by oxygen, An alkyl group substituted with a hetero atom such as nitrogen or sulfur, and an aralkyl group bonded through one or more carbon atoms. Further, the alkyl group is unsubstituted or substituted.
  • aryl includes fused or non-fused aryl groups, usually containing from 5 to 10 carbon atoms, and representative aryl groups include phenyl, naphthyl, or oxygen, nitrogen, sulfur, etc. Aromatic group of atoms.
  • cycloheteroalkyl and “heterocycloalkyl” are used interchangeably and refer to a cycloalkyl group containing from 1 to 3 heteroatoms selected from N, O and S.
  • the present invention provides a compound represented by the following formula (I), and a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;
  • the compound is selected from the compounds listed in Table 1.
  • the preparation of the pharmaceutically acceptable salt of the compound of the present invention can be carried out by direct salt formation reaction with an inorganic or organic acid using the free base of the compound.
  • the inorganic or organic acid may be selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, picric acid, citric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonate. Acid and p-toluenesulfonic acid and the like.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • the preparation process of the compounds of the present invention is as follows, wherein the starting materials and reagents used are commercially available unless otherwise specified.
  • the invention also provides a pharmaceutical composition comprising:
  • compositions may be prepared in a variety of forms depending on the route of administration.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 1000 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable other compounds, such as anti-cancer drugs.
  • the methods of treatment of the invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 50 to 1000 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the present invention has the following main advantages:
  • the compound has a novel structure; compared with the prior patent, the representative compound EPZ015666, the compounds of the present invention have stronger inhibitory activity at the enzyme level and the cell level.
  • Step 3 Preparation of tert-butyl-4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
  • Step 6 Preparation of tert-butyl 2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-6,7-tetrahydro[ 3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (I-1)
  • the 1-tert-butoxycarbonylpiperidone is replaced with cyclohexanone, and the remaining starting materials, reagents and preparation methods are the same as those in the first step of Example 1, to obtain a colorless oil of 2-chlorocyclohexane-1-enecarboxaldehyde. .
  • Step 2 Preparation of ethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid ethyl ester
  • Step 3 Preparation of ethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid
  • Step 4 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrobenzo[b] Thiophene-2-carboxamide (I-3)
  • Step 2 Preparation of ethyl-6,7-dihydro-4H-thieno[3,2-b]furan-2-carboxylic acid ethyl ester
  • Step 3 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6,7-dihydro-4-hydro-thieno[3 ,2-c]pyran-2-carboxamide (I-4)
  • Step 2 Preparation of ethyl 4,5,6,7-tetrahydrofuro[3,2-c]pyridine-2-carboxylate
  • Step 3 Preparation of ethyl 5-methyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine-2-carboxylate
  • Step 5 N-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-4,5,6,7-tetrahydrofuran[ 3,2-c]pyridine-2-carboxamide (I-5)
  • Step 1 Preparation of ethyl 5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate
  • Step 2 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-4,5,6,7-tetrahydro -1H-pyrrolo[3,2-c]pyridine-2-carboxamide (I-6)
  • Step 1 Preparation of 3-fluoro-4-pyridinecarboxaldehyde and 3-fluoro-2-pyridinecarboxaldehyde
  • Step 2 Preparation of ethyl thieno[2,3-c]pyridine-2-carboxylate and ethyl thieno[3,2-b]pyridine-2-carboxylate
  • Step 3 Preparation of ethyl 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate
  • Step 5 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-methyl-4,5,6,7-tetrahydro Thieno[2,3-c]pyridine-2-carboxamide (I-7)
  • Step 1 Preparation of ethyl 6-methyl-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylate
  • Step 3 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-methyl-4,5,6,7-tetrahydro Thieno[3,2-b]pyridine-2-carboxamide (I-8)
  • Step 1 Preparation of methyl 4,5-bis(chloromethyl)thiophene-2-carboxylate
  • Step 4 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-5,6-dihydro-4-hydrogen Thieno[2,3-c]pyrrole-2-carboxamide (I-9)
  • Step 2 Preparation of (4-mercaptopyridin-3-yl)carbamic acid tert-butyl ester
  • Step 6 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-4,5,6,7-tetrahydro Thiazolo[4,5-c]pyridine-2-carboxamide (I-10)
  • Step 1 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(1-tert-butoxycarbonylpiperidin-4-yl )-4,5,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide
  • Step 2 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(piperidin-4-yl)-4,5, 6,7-tetrahydro[3,2-c]pyridine-2-carboxamide
  • Step 1 Preparation of ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
  • Step 2 Preparation of ethyl 5-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
  • Step 4 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-phenyl-4,5,6,7-tetrahydro [3,2-c]pyridine-2-carboxamide (I-24)
  • Example 34 The acetyl chloride was replaced with phenyl chloroformate, and the remaining materials, reagents and preparation methods were the same as those in Example 34 to obtain a white powder.
  • Step 3 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-cyclobutylaminobenzoyl)-4, 5,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide (I-48)
  • Step 1 Step 1: Preparation of tert-butyl(4-chloro-3-formylcyclohex-3-en-1-yl)carbamic acid
  • the 1-tert-butoxycarbonylpiperidone is replaced by 4-N-Boc-aminocyclohexanone, and the remaining starting materials, reagents and preparation methods are the same as in Step 3 of Example 1, to obtain a colorless oil tert-butyl ( 4-Chloro-3-formylcyclohex-3-en-1-yl)carbamic acid was used without further purification.
  • Step 2 Preparation of ethyl 5-((tert-butoxycarbonyl)amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-2carboxylate
  • Step 3 Preparation of ethyl 5-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate
  • Step 4 Preparation of ethyl 5-(cyclohexylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate
  • Step 5 Preparation of 5-(cyclohexylamino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)
  • Step 3 Preparation of ethyl 3,5-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
  • Step 4 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,5-dimethyl-4,5,6,7 - Tetrahydro[3,2-c]pyridine-2-carboxamide (I-54)
  • Step 3 Preparation of (S)-tert-butyl 2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-6,7 - tetrahydro[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester
  • Step 4 Preparation of (S)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrothiophene And [3,2-c]pyridine-2-carboxamide
  • Step 5 Preparation of (S)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-benzenesulfonyl-4,5,6 ,7-tetrahydro[3,2-c]pyridine-2-carboxamide
  • Step 3 Preparation of (R)-tert-butyl 2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-6,7 - tetrahydro[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester
  • Step 4 Preparation of (R)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,5,6,7-tetrahydrothiophene And [3,2-c]pyridine-2-carboxamide
  • Step 5 Preparation of (R)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-benzenesulfonyl-4,5,6 ,7-tetrahydro[3,2-c]pyridine-2-carboxamide
  • Step 1 Preparation of ethyl 5-benzyl-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
  • Step 2 Preparation of ethyl 3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
  • Step 2 Preparation of 5-(4-(dimethylamino)benzoyl)-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid ester
  • Step 3 Preparation of 5-(4-(dimethylamino)benzoyl)-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid
  • Step 4 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-chlorobenzoyl)-3-methyl -4,5,6,7-tetrahydro[3,2-c]pyridine-2-carboxamide
  • Step 4 Preparation of methyl 2-(4-(dimethylamino)benzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate
  • Step 5 Preparation of 2-(4-(dimethylamino)benzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid
  • Step 6 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-(dimethylamino)benzoyl) -1,2,3,4-tetrahydroisoquinoline-6-carboxamide
  • Step 1 Preparation of methyl 2-(4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate
  • Step 3 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-methoxybenzoyl)-1, 2,3,4-tetrahydroisoquinoline-6-carboxamide
  • Step 1 Preparation of methyl 2-(4-bromobenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate
  • Step 3 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-(4-bromobenzoyl)-1,2,3, 4-tetrahydroisoquinoline-6-carboxamide
  • Step 1 Preparation of ((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)-3,4-dihydroisoquinoline-2 ( 1H)-tert-butyl formate
  • Step 2 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1,2,3,4-tetrahydroisoquinoline-7 -formamide
  • Step 3 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-(dimethylamino)benzoyl) -1,2,3,4-tetrahydroisoquinoline-7-carboxamide
  • Step 3 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(4-(dimethylamino)benzoyl) Isoindane-5-carboxamide
  • Step 2 Preparation of ethyl 5-benzyl-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
  • Step 2 Preparation of ethyl 7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
  • Step 3 Preparation of 5-(4-(dimethylamino)benzoyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2 -ethyl formate
  • Step 4 Preparation of 5-(4-(dimethylamino)benzoyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2 -formic acid
  • Step 5 Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-(4-(dimethylamino)benzoyl) -7,7-Dimethyl-4,5,6,7-pheno[3,2-c]pyridine-2-carboxamide
  • the enzymatic activity of the compound was tested by a radioisotope method.
  • the experimental methods are as follows: 1. Prepare 1x assay buffer (modified Tris-HCl buffer); 2. Dilute the compound to the desired concentration in a 96-well plate; 3. Prepare the protein solution, also use 1x assay buffer; Add the substrate to 1x assay buffer to prepare the substrate solution; 5. Add [3H]-SAM to 1x assay buffer to prepare [ 3 H]-SAM solution; 6. Add SAM to 1x assay buffer Prepare a cold SAM solution; 7. Pipette 10 L of protein solution into a 96-well plate containing the compound; 8. Incubate for 15 minutes at room temperature; 9. Add 10 L of substrate solution to each well; 10. To each well The reaction was initiated by the addition of 10 L of [ 3 H]-SAM solution; 11.
  • EPZ015666 is as follows:
  • the series of compounds having strong PRMT5 inhibitory activity values 50 between the IC 0.0085-2.7 ⁇ M, EPZ015666 positive control IC 50 value of 0.047 ⁇ M, the visible portion of the active compounds of the present invention is stronger than the Positive control compounds, such as I-55 (0.027 ⁇ M), I-76 (0.011 ⁇ M), I-80 (0.0085 ⁇ M), and the like. .
  • the culture medium used for cell culture of MCL (Maver-1, Z138, Jeko-1) is RPMI 1640 + 10% fetal bovine serum, and in order to prevent bacterial contamination, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin were added to the culture solution. .
  • the cells were cultured at 37 ° C under 5% CO 2 saturated humidity, and the cells used in the experiment were in the logarithmic growth phase.
  • the concentration of MCL cells was adjusted to 1 ⁇ 10 5 /mL and inoculated into 24-well culture plates at a volume of 1 mL per well.
  • the control group and the experimental group were established, and the control group was added with DMSO.
  • the experimental group was added with PRMT5 active small molecule compound and the final concentration was 0.
  • the three detection time points were 4, 8 and 12 days respectively.
  • the cells were cultured at 37 ° C in a 5% CO 2 incubator at various time points, and the amount of viable cells was measured using CellTiter-Glo reagent.
  • the concentration of the compound of the present invention showed significant dose- and time-dependent inhibition of proliferation after 4, 8 and 12 days of treatment of MCL cells in the range of 0-100 ⁇ mol/L, and the IC 50 was 0.02 to 22 ⁇ M. between, have strong cytostatic activity; active compound wherein the portion of the compound is significantly stronger than the positive EPZ015666, such as I-62 on the proliferation of cells 12 days Maver-1 inhibition IC 50 of 0.02 M, was stronger than EPZ015666 (IC 50 of 0.10 ⁇ M), I-39 on the proliferation of cells 12 days Jeko-1 inhibition IC 50 of 0.58 ⁇ M, significantly stronger than EPZ015666 (IC 50 of 1.04 ⁇ M).
  • 1640 medium (Gibco, Life Technologies, 22400-089) containing 10% fetal bovine serum (Gibco, Life Technologies, 10099-141) and 1% antibiotic (penicillin and streptomycin, Life Technologies, 10378016) at 37 °C
  • Acute mononuclear leukemia cell line MV4-11 (ATCC, CRL-9591) was cultured under 5% CO 2 saturated humidity conditions, and the cells were in logarithmic growth phase.
  • the cell density of MV4-11 was adjusted to 1 ⁇ 10 5 /mL, gently pipetted and inoculated into a 24-well cell culture plate, and the volume of the medium was 1 mL per well, and placed in an incubator for 6 hours.
  • a control group and an experimental group were established, and a control group was added with DMSO.
  • the experimental group was added with a PRMT5 active small molecule compound to a final concentration of 0.015 to 100 ⁇ M, and the final concentration of DMSO was maintained at 0.1%.
  • the three detection time points were 4, 8 and 12 days respectively.
  • the cells were cultured at 37 ° C and 5% CO 2 incubator at various time points.
  • the DMSO control cells were recounted, adjusted to the initial seeding density, and passaged into new culture plates to ensure that the DMSO control cells were in the right phase. Within the number of growth cycles.
  • the cells were further cultured and re-added to the compound at the initial dose; while well-suspended 40 ⁇ L of the cell suspension was transferred to a 384-well plate, and 40 uL of CellTiter-Glo reagent (Promega, G7572) was added to each well to allow Mix well and react, incubate for 10 minutes at room temperature in a shaker, then let stand for 10 minutes.
  • the detection was carried out at a wavelength of 400 to 700 nm using a Multilabel reader (EnVision, PerkinElmer), and the whole process was protected from light. Detection data analysis software by GraphPad Prism 5.0, 50 fit values calculated IC.

Abstract

La présente invention concerne un composé ayant une activité inhibitrice de PRMT5, une préparation pour le composé et des applications associées. Particulièrement, le composé de la présente invention possède une structure telle que représentée par la formule I, dans laquelle les définitions des groupes et des substituants sont telles que présentées dans la description. L'invention concerne également un procédé de préparation du composé et ses utilisations dans la prévention et/ou le traitement de maladies liées au cancer. Le composé de l'invention présente une activité inhibitrice élevée de l'arginine N-méthyltransférase 5 et peut donc être utilisé dans la préparation d'une série de médicaments pour le traitement de maladies liées à l'activité de l'arginine N-méthyltransférase 5.
PCT/CN2018/078308 2017-03-09 2018-03-07 Composé ayant une activité inhibitrice de prmt5, préparation pour composé et applications associées WO2018161922A1 (fr)

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CN112125886A (zh) * 2019-06-24 2020-12-25 南京圣和药物研发有限公司 作为prmt5抑制剂的三环类化合物及其应用
CN112778275A (zh) * 2019-11-11 2021-05-11 石药集团中奇制药技术（石家庄）有限公司 金刚烷基prmt5抑制剂及其应用
CN113045543A (zh) * 2019-12-26 2021-06-29 石药集团中奇制药技术（石家庄）有限公司 一种prmt5抑制剂及其应用
WO2022048631A1 (fr) * 2020-09-04 2022-03-10 上海翊石医药科技有限公司 Composé ayant une activité antitumorale et son utilisation

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CN110698377A (zh) * 2019-10-25 2020-01-17 西安工程大学 一类基于单个苯环的荧光小分子探针及其合成方法
WO2021088992A1 (fr) * 2019-11-07 2021-05-14 江苏先声药业有限公司 Composé spiro tétrahydroisoquinoléine en tant qu'inhibiteur de prmt5
CN110950841A (zh) * 2019-11-22 2020-04-03 济南大学 一类新型***类化合物的合成及应用
KR20220123229A (ko) * 2019-12-17 2022-09-06 머크 샤프 앤드 돔 엘엘씨 Prmt5 억제제
WO2022063094A1 (fr) * 2020-09-22 2022-03-31 南京明德新药研发有限公司 Dérivé de tétrahydroisoquinoléine et son utilisation
JP2024517495A (ja) 2021-05-13 2024-04-22 イノブストーン セラピューティクス リミテッド 抗腫瘍活性を有する化合物及びその使用
CN115124534B (zh) * 2021-11-23 2023-09-15 中山大学 非核苷酸类prmt5小分子抑制剂、制备方法及用途
WO2024032572A1 (fr) * 2022-08-09 2024-02-15 上海湃隆生物科技有限公司 Nouvel inhibiteur de prmt5 et son utilisation

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CN112125886A (zh) * 2019-06-24 2020-12-25 南京圣和药物研发有限公司 作为prmt5抑制剂的三环类化合物及其应用
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CN112778275A (zh) * 2019-11-11 2021-05-11 石药集团中奇制药技术（石家庄）有限公司 金刚烷基prmt5抑制剂及其应用
CN112778275B (zh) * 2019-11-11 2023-05-12 石药集团中奇制药技术（石家庄）有限公司 金刚烷基prmt5抑制剂及其应用
CN113045543A (zh) * 2019-12-26 2021-06-29 石药集团中奇制药技术（石家庄）有限公司 一种prmt5抑制剂及其应用
CN113045543B (zh) * 2019-12-26 2023-05-12 石药集团中奇制药技术（石家庄）有限公司 一种prmt5抑制剂及其应用
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