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WO2025092739A1 - Dérivé de dihydrobenzofurane, son procédé de préparation et son utilisation - Google Patents

Dérivé de dihydrobenzofurane, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2025092739A1
WO2025092739A1 PCT/CN2024/128182 CN2024128182W WO2025092739A1 WO 2025092739 A1 WO2025092739 A1 WO 2025092739A1 CN 2024128182 W CN2024128182 W CN 2024128182W WO 2025092739 A1 WO2025092739 A1 WO 2025092739A1
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alkyl
compound
formula
mmol
heteroatoms selected
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Chinese (zh)
Inventor
蒋青云
周少青
李佩峰
刘宁姝
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S Infinity Pharmaceuticals Co Ltd
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S Infinity Pharmaceuticals Co Ltd
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    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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

Definitions

  • the present invention relates to the field of biomedicine, and in particular to a dihydrobenzofuran derivative, a preparation method and use thereof.
  • TTP can continuously degrade the mRNA of proinflammatory cytokines such as TNF ⁇ , IL-6, IL-1 ⁇ , etc., resulting in the inhibition of the expression level of inflammatory factors.
  • proinflammatory cytokines such as TNF ⁇ , IL-6, IL-1 ⁇ , etc.
  • MK2 is activated by phosphorylation. After activation, MK2 can phosphorylate the AU-rich element binding protein TTP, resulting in its reduced stability, which ultimately causes the increase of mRNA expression of these proinflammatory cytokines, protein expression, and promotes inflammation.
  • the purpose of the present invention is to provide a novel p38-MK2 inhibitor compound, a preparation method and use thereof.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotope thereof,
  • each R 1 , each R 2 , each R 3 and each R 4 are independently selected from H, halogen, OH, CN, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocyclyl having 1 or 2 heteroatoms selected from O, N and S, wherein said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocyclyl having 1 or 2 heteroatoms selected from O, N and S are independently optionally substituted by 1, 2 or 3 Ra ;
  • R 7 , R 8 are each independently selected from H, halogen, OH, -NR 9 R 10 , -NHCO C 1-3 alkyl, CN, C 1-6 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 4-10 membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, N and S, phenyl and 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S, wherein said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 heteroatoms selected from O, N and S, phenyl and 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S are independently optionally substituted with 1, 2 or 3 R b ;
  • R 9 and R 10 are independently selected from H and -C 1-3 alkyl, wherein said -C 1-3 alkyl is optionally substituted with 1, 2 or 3 R d ;
  • R and R together with the N atom to which they are commonly attached form a 4-10 membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, N and S, and at least one heteroatom is N; or a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S, and at least one heteroatom is N, wherein the 4-6 membered heterocyclyl having 1 or 2 heteroatoms selected from O, N and S or the 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S are independently optionally substituted by 1, 2 or 3 Re ;
  • X is selected from O, S, Se and NR 11 ;
  • R 11 is selected from H, C 1-3 alkyl-C(O)- and C 1-3 alkyl;
  • z is selected from 1, 2, 3 and 4;
  • n, p and q are independently selected from 0, 1, 2 and 3;
  • Each Ra , each Rb , each Rc , each Rd and each Re are independently selected from halogen, OH, CN, C1-3 alkyl, C1-3 halo C 1-3 alkyl, -O-halogenated C 1-3 alkyl, and -O-C 1-3 alkyl.
  • the compound has the structure of formula (I-1):
  • the compound of formula (I) is a compound having formula (IIa), (IIb) or (IIc):
  • R 5 and R 6 are selected from H and deuterium.
  • R7 and R8 are independently selected from H, OH, NH2 , -NHCH3 , -N( CH3 ) 2 , -NHCOCH3, CH3 , CH2CH3 , CH2CH2CH3 , CH (CH3) 2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl and pyridyl, wherein -NHCH3, -N(CH3)2 , -NHCOCH3 , CH3 ,
  • R 7 is selected from H, C 1-3 alkyl
  • R 8 is selected from OH, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCOCH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and pyrazolyl, and the -NHCH 3 , -N(CH 3 ) 2 , -NHCOCH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhex
  • R 7 Selected from H, C 1-3 alkyl
  • R 8 is selected from OH, NH 2 ,
  • the compound of formula I is selected from the group consisting of:
  • m, n, p, q, z, R1 , R2 , R3 , R4 , R5 , R6 , R7 and R8 are optionally independently the corresponding groups in compounds E001-E060.
  • m, n, p, q, z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are optionally independently the corresponding groups in the following specific compounds.
  • the compound is selected from the group consisting of:
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound as described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotope thereof, and a pharmaceutically acceptable carrier.
  • the third aspect of the present invention provides the use of the compound as described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotope thereof, or the pharmaceutical composition as described in the second aspect of the present invention in the preparation of a medicament for preventing or treating (p38/MK2-related) diseases, preferably, the disease is selected from autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, atherosclerosis, diabetes, fibrotic diseases, metabolic disorders, cancer (such as lymphoma) and neoplasia, preferably chronic inflammatory disorders and acute inflammatory disorders; preferably rheumatoid arthritis, osteoarthritis, spondyloarthritis, inflammatory bowel disease, psoriasis, lupus erythema.
  • the disease is selected from autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, atherosclerosis, diabetes, fibrotic diseases, metabolic disorders, cancer (such as lympho
  • the term “comprising” or “including (comprising)” may be open, semi-closed and closed. In other words, the term also includes “consisting essentially of” or “consisting of”.
  • substituents When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left.
  • -CH2O- includes -OCH2- .
  • Cu-v indicates that the following group has from u to v carbon atoms.
  • C 1-6 alkyl means that the alkyl group has 1 to 6 carbon atoms.
  • Cu-v includes all positive integers of C atoms between u and v, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 carbon atoms.
  • Alkyl refers to a non-branched or branched saturated hydrocarbon chain. Alkyl used herein or as part of other groups thereof has 1 to 6 carbon atoms (i.e., C1-6 alkyl), 1 to 4 carbon atoms (i.e., C1-4 alkyl), 1 to 3 carbon atoms (i.e., C1-3 alkyl).
  • alkyl examples include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
  • Any non-aromatic ring containing at least one heteroatom is considered to be a heterocyclic group, regardless of the connection (i.e., it can be connected to the rest of the molecule by carbon atoms or heteroatoms (such as N atoms)).
  • Aryl refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or polycyclic (e.g., bicyclic or tricyclic) (including fused systems).
  • the aryl used herein has 6 to 10 ring carbon atoms (i.e., C6-10 aryl). Examples of aryl include phenyl, naphthyl, fluorenyl, and anthracenyl. However, aryl does not include heteroaryl defined below or overlaps with heteroaryl defined below in any way. If one or more aryl is fused with heteroaryl, the resulting ring system is heteroaryl. If one or more aryl is fused with heterocyclic radical, the resulting ring system is heterocyclic radical.
  • Heteroaryl refers to an aromatic group having a monocyclic ring, multiple rings or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl includes 5 to 10 ring atoms (i.e., 5-10 heteroaryl), or 5 to 6 ring atoms (i.e., 5-6 heteroaryl); wherein, 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom may be included, and the ring heteroatoms are independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl examples include pyrimidinyl, purinyl, pyridinyl, pyridazinyl, benzothiazolyl and pyrazolyl.
  • fused heteroaromatic rings include, but are not limited to, benzo[d]thiazolyl, quinolyl, isoquinolyl, benzo[b]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaromatic group may be attached via any ring of the fused system.
  • heteroaromatic group Any aromatic ring having single or multiple fused rings containing at least one heteroatom is considered a heteroaromatic group, regardless of attachment to the rest of the molecule (i.e., via any of the fused rings).
  • Heteroaromatic groups do not include or overlap with aryl groups as defined above.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • one or more may refer to one or more, 1, 2, 3, 4, 5 or 6.
  • EtOH refers to ethanol.
  • F refers to formic acid.
  • MeCN refers to acetonitrile.
  • MeLi refers to methyllithium.
  • MeOH refers to methanol.
  • NaBH(OAc) 3 refers to sodium triacetoxyborohydride.
  • NCS N-chlorosuccinimide.
  • LiHMDS lithium bistrimethylsilylamide.
  • PE refers to petroleum ether.
  • TFA trifluoroacetic acid.
  • THF tetrahydrofuran.
  • substituted means that any one or more hydrogen atoms on the designated atom or group are replaced by a moiety other than hydrogen, provided that the normal valence of the designated atom is not exceeded. Unless otherwise specified, “substituted” may refer to one or more hydrogen atoms on the group being replaced by a group selected from the group consisting of halogen, OH, CN, C 1-3 alkyl, C 1-3 haloalkyl, -OC 1-3 alkyl, -O-halogenated C 1-3 alkyl, and -OC 1-3 alkyl.
  • the present invention provides a compound of formula I:
  • the compounds of the present invention are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or similar groups.
  • “Pharmaceutically acceptable salts” include, for example, salts formed with inorganic acids or with organic acids.
  • free bases can be obtained by alkalizing acid salt solutions.
  • addition salts, specifically pharmaceutically acceptable addition salts can be produced according to conventional procedures for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and treating the solution with an acid.
  • Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids.
  • Inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic 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 prepared from inorganic and organic bases.
  • salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dienylamines (i.e., HN(alkenyl)2), trialenylamines (i.e., N(alkenyl)3), substituted alkeny
  • Suitable amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., isolated enantiomers) are all intended to be included within the scope of the present invention.
  • compounds provided herein have defined stereochemistry (expressed as R or S, or indicated by dashed or wedge-shaped bonds)
  • those compounds will be understood by those skilled in the art to be substantially free of other isomers (e.g., at least 80%, 90%, 95%, 98%, 99% and up to 100% free of other isomers).
  • any general formula or structure given in the present application is also intended to represent the non-labeled form of the compound and the isotope-labeled form.
  • Isotope-labeled compounds have the structure described by the general formula given in the present application, except that one or more atoms are replaced by the atom with the atomic mass or mass number selected.
  • the example of the isotope that can be incorporated into the compounds of the present invention includes the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, but not limited to 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl and 125I.
  • the present invention includes multiple isotope-labeled compounds of the present invention, for example, those radioactive isotopes such as 3H, 13C and 14C are incorporated into the compound therein.
  • isotopically labeled compounds are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as nuclear magnetic resonance imaging (NMR), positron emission tomography (PET), or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays or in radiotherapy of patients.
  • NMR nuclear magnetic resonance imaging
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • the present disclosure also includes "deuterated compounds of Formula I in which 1 to n (where n is the number of hydrogens in the molecule) hydrogens attached to carbon atoms are replaced by deuterium.
  • deuterated compounds of Formula I exhibit enhanced resistance to metabolism and are therefore useful for increasing the half-life of any compound of Formula I (when administered to a mammal, particularly a human).
  • Such compounds are synthesized by methods known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.
  • Deuterium-labeled or substituted therapeutic compounds of the present invention can have improved DMPK (drug metabolism and pharmacokinetics) properties, which are related to distribution, metabolism and excretion (ADME). Substitution using heavier isotopes (e.g., deuterium) can provide some therapeutic advantages based on greater metabolic stability, such as increased half-life in vivo, reduced dosage requirements and/or improved therapeutic index. 18F-labeled compounds can be used for PET or SPECT studies.
  • Isotope-labeled compounds of the present invention and prodrugs thereof are generally prepared by utilizing the synthetic routes described below or the steps described in the embodiments and preparations, wherein non-isotope-labeled reagents are replaced with conveniently available isotope-labeled reagents. It is understood that deuterium in the present application can be regarded as a substituent of a compound of formula I.
  • the concentration of such heavier isotopes can be defined by an isotopic enrichment factor.
  • any atom that is not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is specifically designated as "H” or "hydrogen”, it is understood that the position is a hydrogen with its natural abundance isotopic composition. Therefore, in the compounds of the present invention, any atom that is specifically designated as deuterium (D) is meant to represent deuterium.
  • Prodrugs and solvates of the compounds of the present invention are also within the scope of the invention.
  • the term "prodrug” herein refers to a compound that undergoes chemical transformation by metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when treating a related disease.
  • the compounds of the present invention include solvates, such as hydrates.
  • solvate refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.
  • hydrate refers to a complex formed by coordination of the compound of the present invention with water, such as a monohydrate.
  • prodrugs of the compounds described herein are provided.
  • Prodrug refers to any compound that produces a drug substance or active ingredient due to a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, photolysis, and/or a metabolic chemical reaction when administered to a biological system. Prodrugs are therefore covalently modified analogs or latent forms of therapeutically active compounds.
  • Non-limiting examples of prodrugs include ester moieties, quaternary ammonium moieties, ethylene glycol moieties, and the like.
  • the present invention provides a pharmaceutical composition, which comprises the compound of formula I, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotope substituted product thereof; and a pharmaceutically acceptable carrier.
  • the compounds of the present invention can selectively bind to and inhibit the p38 ⁇ -MK2 complex, thereby inhibiting diseases related to/mediated by the p38-MK2 pathway, especially autoimmune diseases, chronic inflammatory diseases, acute inflammatory diseases, autoinflammatory diseases, atherosclerosis, diabetes, fibrotic diseases, metabolic diseases, cancer and tumor formation, etc.
  • diseases related to/mediated by the p38-MK2 pathway especially autoimmune diseases, chronic inflammatory diseases, acute inflammatory diseases, autoinflammatory diseases, atherosclerosis, diabetes, fibrotic diseases, metabolic diseases, cancer and tumor formation, etc.
  • the disease is rheumatoid arthritis, spondyloarthritis, inflammatory bowel disease, psoriasis, lupus erythema, etc. More preferably, it is relapsed, refractory, and poorly responsive to existing therapies.
  • the compounds of general formula (I) can be used in combination with other drugs known to treat or improve similar symptoms.
  • Other drugs may include one or more anti-inflammatory drugs, anti-atherosclerotic drugs, immunosuppressive drugs, immunomodulatory drugs, cytostatic drugs, angiogenesis inhibitors, kinase inhibitors, cytokine blockers and inhibitors of cell adhesion molecules.
  • “Pharmaceutically acceptable excipients” and “pharmaceutically acceptable carriers” refer to substances that aid in the formulation and/or administration of active agents and/or absorption by individuals, and can be included in the compositions of the present disclosure without causing significant adverse toxicological effects on the individual.
  • Non-limiting examples of pharmaceutically acceptable carriers and excipients include water, NaCl, physiological saline solutions, lactated Ringer's solution, conventional sucrose, conventional glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, straight-chain starch or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and pigments, etc.
  • Such preparations can be sterilized and, if necessary, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, and/or aromatic substances, etc. that do not react harmfully with the compounds provided herein or interfere with the activity of the compounds provided herein.
  • adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, and/or aromatic substances, etc.
  • compositions of the present invention may be in solid or liquid form.
  • the medicament containing the active ingredient of the present invention can be in a suitable oral dosage form, such as tablets, tablets, lozenges, water-soluble or oily suspensions, dispersed latex powders or granules, emulsions, hard or soft capsules or syrups or elixirs.
  • Oral medicaments can be prepared according to the known process methods of the manufacturers of pharmaceutical ingredients, and these compositions may include one or more of the following agents, such as sweeteners, flavoring agents, colorants and protective agents, so as to provide elegant and delicious pharmaceutical preparations. Tablets contain active ingredients mixed with non-toxic pharmaceutically acceptable excipients, which are suitable for the production of tablets.
  • excipients examples include inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating, disintegrants, such as corn starch or alginic acid; binders, such as starch, gelatin or gum arabic, and lubricants, such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or coated to delay degradation and absorption in the gastrointestinal tract, thereby maintaining activity over a longer period of time.
  • the active compound can be administered to the subject by any suitable route, including orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally or via an implanted cartridge.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the composition is administered orally, intraarticularly or intravenously.
  • compositions of the invention suitable for administration will typically be discrete units in solid form, such as tablets, capsules, powders, granules, patches, suppositories, pills, pastes, or in liquid form, such as liquid preparations, injectable or infusible solutions or suspensions.
  • the precise amount of the compound that provides a therapeutically effective amount to an individual will depend on the mode of administration, the type and severity of the disease and/or condition, and the characteristics of the individual, such as general health, age, sex, weight, and tolerance to drugs. One of ordinary skill in the art will be able to determine the appropriate dosage based on these and other factors. When administered in combination with other therapeutic agents, a "therapeutically effective amount" of any other therapeutic agent will depend on the type of drug used.
  • compositions should be formulated so that a dosage of 0.01-100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • the compositions of the invention provide a dosage of 0.01 mg to 50 mg. In other embodiments, a dosage of 0.1 mg-25 mg or 5 mg-40 mg is provided.
  • subjects to whom the pharmaceutical composition or therapeutic agent of the present invention can be administered include mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.).
  • mammals eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.
  • the present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotope substituted product thereof, thereby forming a pharmaceutical composition.
  • the present invention also provides a treatment method, which comprises the steps of administering to a subject in need of treatment a compound of the general formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotope thereof, or administering the pharmaceutical composition of the present invention, for selectively inhibiting the p38-MK2 pathway, or treating a disease related to the p38-MK2 pathway (such as inflammation).
  • a treatment method which comprises the steps of administering to a subject in need of treatment a compound of the general formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotope thereof, or administering the pharmaceutical composition of the present invention, for selectively inhibiting the p38-MK2 pathway, or treating a disease related to the p38-MK2 pathway (such as inflammation).
  • the compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.
  • the present invention provides a class of p38-MK2 inhibitors with novel structures.
  • the compounds of the present invention have excellent p38-MK2 inhibitory activity and can specifically inhibit the p38-MK2 pathway, thereby preventing or/treating related diseases.
  • the compounds of the present invention have lower adverse reactions (such as headache and dizziness) and are more suitable for oral administration.
  • the compounds of the present invention have good pharmacokinetic (such as longer half-life and higher bioavailability) and pharmacodynamic properties, as well as excellent drugability, and are very suitable for preparing drugs for preventing or/treating p38-MK2-mediated diseases or conditions.
  • 1,4-dioxane (2 mL) was added to the reaction bottle containing compound E006a (40 mg, 0.15 mmol) and diboronic acid pinacol ester (75 mg, 0.30 mmol) and stirred to dissolve. Then Pd(dppf)Cl 2 (11 mg, 0.015 mmol) and potassium acetate (43.6 mg, 0.44 mmol) were added in sequence and stirred at 95°C for 3 hours. After the reaction was completed, ice water (10 mL) was added to the reaction solution to quench the reaction, and EA (10 mL ⁇ 3) was used for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product E006b was obtained, which was used directly in the next step. MS m/z (ESI): 318 [M+H] + .
  • 1,4-dioxane/water (5:1, 3 mL) was added to the reaction bottle containing crude compound E006b and I001 (68 mg, 0.15 mmol) and stirred to dissolve, and then Pd(dppf)Cl 2 (11 mg, 0.015 mmol) and sodium carbonate (32 mg, 0.30 mmol) were added in sequence and stirred at 90° C. for 2 hours. After the reaction was completed, the reaction solution was directly spin-dried.
  • Test Example 1 Determination of the inhibitory effect of the compounds of the present invention on p38 ⁇ /MK2 enzyme activity
  • the compounds were distributed into a 384-well plate by Echo 650 (LABCYTE), and 2.5 ⁇ L pp-p38 (Thermo, PR5049C), 5 ⁇ L MK2 (Thermo, PV3316) and 2.5 ⁇ L ATP were added to each well of the 384-well reaction plate. After incubation at room temperature for 1 hour, 3 volumes of 8M urea were added to each well to terminate the reaction. The reaction product of each well was then transferred to a 96-well nickel-plated plate (Thermo Scientific, 15142), and the amount of phosphorylated MK2 in each well was detected by ELISA. The fluorescence value was read at a wavelength of 325 nm (Ex)/420 nm (Em) on Ensight (Perkin Elmer). The intensity of the fluorescence value is proportional to the amount of phosphorylated MK2.
  • Test Example 2 Determination of the inhibitory effect of the compounds of the present invention on the expression level of TNF ⁇ in human monocytes
  • TPCS human monocytes
  • the cells were then stimulated with 50pg/mL of LPS (Sigma), excluding the outer columns of the plate for unstimulated cell control wells.
  • the cells were incubated at 37°C for another 4 hours, and then the cells were centrifuged to take 15 ⁇ L of cell supernatant and analyzed for TNF ⁇ content using the ELISA human TNF ⁇ detection system (R&D).
  • the pharmacokinetic characteristics of rodents after intravenous and oral administration of the compound were tested by standard protocols.
  • the candidate compound was formulated into a clear solution and administered to mice by single intravenous injection (IV) and single oral administration (PO).
  • the solvent was 5% DMSO + 10% Solutol + 85% ddH 2 O.
  • the animals in the oral administration group were fasted overnight (10-14 hours) before administration.
  • Whole blood samples were collected within 24 hours after administration (oral: 0.25, 0.5, 1, 2, 4, 6, 8, 24h, intravenous injection: 0.083, 0.25, 0.5, 1, 2, 4, 8, 24h), respectively.
  • the blood was collected by submandibular vein or other appropriate methods.
  • LC-MS/MS is used to quantitatively analyze blood drug concentrations and calculate pharmacokinetic parameters such as peak concentration (C max ), distribution volume (Vd ss ), clearance rate (CI), half-life (T 1/2 ), area under the concentration-time curve (AUC 0-last ), bioavailability (F), etc.

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Abstract

La présente invention concerne un dérivé de dihydrobenzofurane, son procédé de préparation et son utilisation. Plus particulièrement, l'invention concerne un composé de formule (I), ou un sel pharmaceutiquement acceptable de celui-ci, un stéréoisomère de celui-ci, ou un composé à substitution isotopique de celui-ci. Le composé de formule (I) de la présente invention présente une excellente activité inhibitrice vis-à-vis d'un complexe p38a/MK2. Par conséquent, la présente invention concerne également l'utilisation du composé de formule (I) dans la préparation d'un médicament pour la prévention ou le traitement de maladies associées à p38a/MK2.
PCT/CN2024/128182 2023-10-30 2024-10-29 Dérivé de dihydrobenzofurane, son procédé de préparation et son utilisation Pending WO2025092739A1 (fr)

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CN103391718A (zh) * 2010-12-06 2013-11-13 汇合生命科学股份有限公司 取代的吡啶酮-吡啶基化合物
CN105263326A (zh) * 2013-06-07 2016-01-20 汇合生命科学股份有限公司 甲基/氟-吡啶基-甲氧基取代的吡啶酮-吡啶基化合物及氟-嘧啶基-甲氧基取代的吡啶酮-吡啶基化合物
CN115636814A (zh) * 2022-02-28 2023-01-24 瑞石生物医药有限公司 一种嘧啶衍生物及其用途
WO2023125707A1 (fr) * 2021-12-29 2023-07-06 上海美悦生物科技发展有限公司 Régulateur de la voie p38 mapk/mk2, composition de celui-ci, son procédé de préparation et son utilisation
CN118344289A (zh) * 2023-01-13 2024-07-16 上海美悦生物科技发展有限公司 苯基取代的杂芳基类化合物及其药物组合物、制备方法和用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130274272A1 (en) * 2010-12-06 2013-10-17 Confluence Life Sciences Inc. Methyl/difluorophenyl-methoxy substituted pyridinone-pyridinyl compounds, methyl-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds, and methyl-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds
CN103391718A (zh) * 2010-12-06 2013-11-13 汇合生命科学股份有限公司 取代的吡啶酮-吡啶基化合物
CN105263326A (zh) * 2013-06-07 2016-01-20 汇合生命科学股份有限公司 甲基/氟-吡啶基-甲氧基取代的吡啶酮-吡啶基化合物及氟-嘧啶基-甲氧基取代的吡啶酮-吡啶基化合物
WO2023125707A1 (fr) * 2021-12-29 2023-07-06 上海美悦生物科技发展有限公司 Régulateur de la voie p38 mapk/mk2, composition de celui-ci, son procédé de préparation et son utilisation
CN115636814A (zh) * 2022-02-28 2023-01-24 瑞石生物医药有限公司 一种嘧啶衍生物及其用途
CN118344289A (zh) * 2023-01-13 2024-07-16 上海美悦生物科技发展有限公司 苯基取代的杂芳基类化合物及其药物组合物、制备方法和用途

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