WO2022257875A1 - 嘧啶类化合物、包含其的药物组合物、其制备方法及其用途 - Google Patents

嘧啶类化合物、包含其的药物组合物、其制备方法及其用途 Download PDF

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WO2022257875A1
WO2022257875A1 PCT/CN2022/097105 CN2022097105W WO2022257875A1 WO 2022257875 A1 WO2022257875 A1 WO 2022257875A1 CN 2022097105 W CN2022097105 W CN 2022097105W WO 2022257875 A1 WO2022257875 A1 WO 2022257875A1
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compound
pharmaceutically acceptable
alkyl
polymorph
stereoisomer
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PCT/CN2022/097105
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English (en)
French (fr)
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张寰
景何凤
孟丽娟
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上海日馨医药科技股份有限公司
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Priority to CN202280041466.9A priority Critical patent/CN117545742A/zh
Publication of WO2022257875A1 publication Critical patent/WO2022257875A1/zh

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51Thiamines, e.g. vitamin B1
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32One oxygen, sulfur or nitrogen atom
    • C07D239/42One nitrogen atom

Definitions

  • the present invention relates to a pyrimidine compound, a pharmaceutical composition containing it, a preparation method thereof and an application for treating neurodegenerative diseases.
  • Alzheimer's disease (commonly known as senile dementia, Alzheimer's disease, AD) is a progressive neurodegenerative disease with cognitive and behavioral disorders as the main clinical manifestations. Impairment of recognition ability and rapid decline of memory function.
  • the main pathophysiological features are the deposition of ⁇ -amyloid (A ⁇ ) in the brain to form senile plaques, the hyperphosphorylation of tau protein to form neurofibrillary tangles, the disturbance of brain glucose metabolism, and the loss of neurons/synapses. Due to the long course of the disease and poor self-care ability of patients, it brings serious mental and economic burdens to families and society. However, there is currently no drug that can prevent or delay the development of the disease in the world. The drugs currently on the market for the treatment of AD are only symptomatic drugs, which can only control or improve cognitive and functional symptoms for a period of time, but cannot prevent or delay the progression of the disease.
  • the present invention provides pyrimidine compounds, which can be used to prevent or treat neurodegenerative diseases.
  • the compounds of the present invention also have better physicochemical properties (such as solubility, physical and/or chemical stability), improved pharmacokinetic properties (such as improved bioavailability, suitable half-life and duration of action) , improved safety (lower toxicity (such as reduced cardiotoxicity) and/or fewer side effects), less prone to drug resistance and other superior properties.
  • One aspect of the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein
  • the compound has the structure of formula (I):
  • L and L are each independently selected from direct bonds, C 1-6 alkylene and C 2-6 alkenylene ;
  • R 3 and R 4 are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • R 5 and R 6 are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl; and
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, Solvates, metabolites, isotope-labeled compounds or prodrugs and one or more pharmaceutically acceptable carriers.
  • Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Use of the prodrug or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating neurodegenerative diseases or alleviating the symptoms of neurodegenerative diseases.
  • Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or
  • the prodrug or the pharmaceutical composition of the present invention is used for preventing or treating neurodegenerative diseases or alleviating the symptoms of neurodegenerative diseases.
  • Another aspect of the present invention provides a method of preventing or treating a neurodegenerative disease or alleviating the symptoms of a neurodegenerative disease, said method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable Salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs or pharmaceutical compositions of the invention.
  • Another aspect of the invention provides processes for the preparation of the compounds of the invention.
  • alkylene means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or Butylene.
  • alkyl is defined as a straight or branched chain saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12, eg, 1 to 6 carbon atoms.
  • C 1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl group, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as halogen (in which case the group group is referred to as "haloalkyl”) (eg CF3 , C2F5 , CHF2 , CH2F , CH2CF3 , CH2Cl or -CH2CH2CF3
  • haloalkyl eg CF3 , C2F5 ,
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • alkenylene denotes a divalent hydrocarbon radical containing one or more double bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethenylene, propenylene or Allyl.
  • alkenyl means a linear or branched monovalent hydrocarbon group containing one double bond and having 2-6 carbon atoms (“ C2-6 alkenyl”).
  • the alkenyl is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-butenyl, -hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • a compound of the present invention contains an alkenylene or alkenyl group
  • the compound may exist in pure E (entadel) form, pure Z (zusammen) form, or any mixture thereof.
  • alkynyl denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, eg ethynyl or propynyl.
  • cycloalkylene means ring carbons having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Atoms of saturated (i.e., “cycloalkylene” and “cycloalkyl”) or unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings, which Including but not limited to (ylidene)cyclopropyl (ring), (ylidene)cyclobutyl (ring), ((ylidene)cyclopentyl (ring), ((ylidene)cyclohexyl (ring), (ylidene)cycloheptyl ( (ring), (sub)cyclooctyl (ring), (sub)cyclononyl (ring), (sub)cyclohexenyl (ring), etc.
  • cycloalkyl refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic rings, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[ 3.2.1] octyl or bicyclo [5.2.0] nonyl, decalinyl, etc.), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cyclohepty
  • C 3-6 cycloalkyl refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring ( eg cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) optionally substituted with 1 or more (such as 1 to 3) suitable substituents eg methyl substituted cyclopropyl.
  • a 3-10 membered heterocyclic group is a group with 3-10 carbon atoms and heteroatoms in the ring, such as but not limited to oxiranyl, aziridinyl, azetidinyl ( azetidinyl), oxetanyl (oxetanyl), tetrahydrofuryl, dioxolinyl (dioxolinyl), pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyrrolidinyl pyryl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ -electron system.
  • C 6-14 aryl means an aromatic group containing 6 to 14 carbon atoms, such as phenyl or naphthyl.
  • Aryl is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg, halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • aralkyl preferably denotes an aryl-substituted alkyl group, wherein said aryl and said alkyl are as defined herein.
  • the aryl group may have 6-14 carbon atoms
  • the alkyl group may have 1-6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • heteroaryl refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, In particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms and which contain at least one heteroatom which may be the same or different (the heteroatom is for example oxygen, nitrogen or sulfur), and, in addition May be benzo-fused in each case.
  • heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, Diazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives.
  • halo or halogen group is defined to include F, Cl, Br or I.
  • alkylthio as used herein means an alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom.
  • Representative examples of C 1-6 alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.
  • the nitrogen-containing heterocyclic ring is preferably a saturated nitrogen-containing monocyclic ring.
  • a 3- to 14-membered nitrogen-containing heterocycle is a group having 3-14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to a three-membered nitrogen-containing heterocycle (such as Aziridinyl), four-membered nitrogen-containing heterocycle (such as azetidinyl), five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidinyl ring), pyrrolinyl, pyrrolidonyl, imidazole group, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidinyl ring), morpholinyl, thiomorpholinyl, piperazinyl) , Seven-membered nitrogen-containing heterocycle, etc.
  • substituted means that one or more (e.g., one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is present.
  • the normal valences of the cases and such substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Selected optional substituents are substituted. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected Substituent substitution.
  • each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms have been labeled with the same atomic number but an atomic mass or mass number different from the atomic mass prevailing in nature. or mass number of atomic substitutions.
  • isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. deuterium (D, 2 H), tritium (T, 3 H)); isotopes of carbon (e.g.
  • isotopes of chlorine such as 36 Cl
  • isotopes of fluorine such as 18 F
  • isotopes of iodine such as 123 I and 125 I
  • isotopes of nitrogen such as 13 N and 15 N
  • phosphorus isotopes such as 32 P
  • sulfur isotopes such as 35 S.
  • Certain isotopically-labeled compounds of the invention eg, those incorporating radioactive isotopes
  • are useful in drug and/or substrate tissue distribution studies eg, assays).
  • radioisotopes tritium (ie3H ) and carbon- 14 (ie14C) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron-emitting isotopes such as 11 C, 18 F, 15 O, and 13 N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.
  • Pharmaceutically acceptable solvates of the invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O , acetone-d6 or DMSO - d6.
  • stereoisomer means isomers formed as a result of at least one asymmetric center.
  • compounds with one or more (e.g., one, two, three or four) asymmetric centers which can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereoisomers.
  • Certain individual molecules may also exist as geometric isomers (cis/trans).
  • compounds of the present invention may exist as mixtures of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of this application encompasses all such ratios in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) %) isomers or mixtures thereof.
  • Solid lines can be used in this article solid wedge or imaginary wedge Depicting the carbon-carbon bonds of the compounds of the invention.
  • the use of a solid line to delineate a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, specific enantiomers, racemic mixtures, etc.).
  • the use of solid or dashed wedges to delineate bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, solid and imaginary wedges are used to define relative rather than absolute stereochemistry.
  • the compounds of the present invention are intended to be stereoisomers (which include cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof).
  • the compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof, such as racemic mixtures and pairs of diastereoisomers.
  • the present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.
  • compositions of the present invention may exist in free form for use in therapy, or, where appropriate, as pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which can directly Or indirectly provide a compound of the invention or a metabolite or residue thereof. Therefore, when a "compound of the present invention" is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate/carbonate, bisulfate/sulfate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluoro Phosphate, hydrobromide/bromide, hydroiodide/iodide, maleate, malonate, methylsulfate, naphthylate, nicotinate, nitrate , orotate, oxalate, palmitate and other similar salts.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, meglumine salts, potassium salts, and other similar salts.
  • esters means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (hydrolyzable under physiological conditions to release the free acid or alcohol form of the present invention) compound).
  • the compounds of the invention may also themselves be esters.
  • the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise a polar solvent, such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • a polar solvent such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • metabolites of the compounds of the present invention ie substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic hydrolysis, etc., of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolite thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which themselves may have little or no pharmacological activity when administered into or on the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound which are readily converted in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987( Edited by E.B. Roche, American Pharmaceutical Association).
  • prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as "pro-moiety (for example as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))". Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention which contain protecting groups.
  • protecting groups During any of the preparations of the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming chemically protected forms of the compounds of the invention. This can be achieved by conventional protecting groups, for example, as described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 For those protecting groups, these references are incorporated herein by reference. Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • the term "about” means within ⁇ 10%, preferably within ⁇ 5%, more preferably within ⁇ 2% of the stated numerical value.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or precursor thereof Drug, wherein said compound has the structure of formula (I):
  • L and L are each independently selected from direct bonds, C 1-6 alkylene and C 2-6 alkenylene ;
  • R 3 and R 4 are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • R 5 and R 6 are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl; and
  • R is selected from C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl; preferably, R is cyclobutyl, cyclohexyl , phenyl, thienyl or pyridyl.
  • the present invention provides the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite thereof , isotope-labeled compound or prodrug, wherein L 1 is a direct bond or C 2-6 alkenyl.
  • L 1 is a direct bond or vinylidene.
  • the present invention provides the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite thereof , isotope-labeled compound or prodrug, wherein R 1 is selected from C 3-6 cycloalkyl, C 6-10 aryl and 5-14 membered heteroaryl, which is optionally selected from one or more independently selected from halogen and -O-(C 1-6 alkyl) substituents.
  • R is selected from cyclohexyl, phenyl, and furyl, which is optionally substituted with one or more substituents independently selected from F, Cl , Br, I, and -OCH.
  • the present invention provides the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite thereof , isotope-labeled compound or prodrug, wherein -L 1 -R 1 is selected from
  • the present invention provides the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite thereof , isotope-labeled compound or prodrug, wherein L 2 is a direct bond, C 1-4 alkylene or C 2-4 alkenylene.
  • L is a direct bond, methylene, ethylene, or vinylene.
  • the present invention provides the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite thereof , isotope-labeled compounds or prodrugs, wherein
  • the present invention provides the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite thereof , isotope-labeled compound or prodrug, wherein -L 2 -R 2 is selected from methyl, ethyl, vinyl,
  • the present invention provides the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite thereof , isotope-labeled compound or prodrug, wherein said compound has the structure of formula (II) or formula (III):
  • the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or precursor thereof drug, wherein the compound is
  • the present invention provides methods for the preparation of compounds of formula (I):
  • Hal 1 and Hal 2 are each independently selected from F, Cl, Br and I;
  • the method comprises the steps of:
  • the reaction solvent of step (I) is preferably amide solvent (such as DMF), nitrile solvent (such as acetonitrile), aromatic hydrocarbon solvent (such as toluene or chlorobenzene), ether solvent (such as dioxane), N- Methylpyrrolidone or mixtures thereof.
  • the reaction temperature in step (I) is, for example, 80-150°C, preferably 100-110°C.
  • step (II) is preferably carried out in the presence of a base such as an inorganic base (such as sodium hydroxide) or an organic base.
  • a base such as an inorganic base (such as sodium hydroxide) or an organic base.
  • the reaction solvent of step (II) is preferably water, dichloromethane, THF or a mixture thereof.
  • the reaction temperature of step (II) is preferably 0-50°C, eg 10°C.
  • compositions and methods of treatment are provided.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorphic form thereof compounds, solvates, metabolites, isotope-labeled compounds or prodrugs and one or more pharmaceutically acceptable carriers.
  • the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled
  • a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled
  • the present invention provides a method of preventing or treating a neurodegenerative disease or alleviating the symptoms of a neurodegenerative disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable Accepted salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs or pharmaceutical compositions of the invention.
  • the neurodegenerative disease is selected from Alzheimer's disease, Creutzfeldt-Jakob disease, Huntington's disease, multiple sclerosis, Guillain-Barré syndrome, Parkinson's disease, Logehrig Alzheimer's disease, paralytic dementia and progressive disorders caused by gradual nerve cell death; preferably Alzheimer's disease.
  • “Pharmaceutically acceptable carrier” in the present invention refers to a diluent, adjuvant, excipient or vehicle administered together with a therapeutic agent, and it is suitable for contacting human beings and/or Tissues from other animals without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol etc.
  • the composition if desired, can also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents.
  • Oral formulations can contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the invention may act systemically and/or locally.
  • they may be administered by a suitable route, for example by injection (e.g. intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, transdermal Nasally, transmucosally, topically, in the form of ophthalmic formulations or by inhalation.
  • the pharmaceutical composition of the present invention can be administered in an appropriate dosage form.
  • the dosage forms include but are not limited to tablets, capsules, lozenges, hard lozenges, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions , Injectable solutions, elixirs, syrups.
  • an effective amount refers to the amount of a compound which, when administered, alleviates to some extent one or more symptoms of the condition being treated.
  • Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may comprise single or multiple doses. It is further understood that for any given individual, the specific dosing regimen will be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • the amount of a compound of this invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician.
  • the effective dosage is about 0.0001 to about 50 mg per kg body weight per day, for example about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg human this would amount to about 0.007 mg/day to about 3500 mg/day, eg about 0.7 mg/day to about 700 mg/day.
  • Dosage levels up to the lower limit of the foregoing range may be sufficient in some cases, while in other cases larger doses may still be employed without causing any deleterious side effects, provided that the larger dose is first administered.
  • the dose is divided into several smaller doses to be administered throughout the day.
  • the content or amount of the compound of the present invention in the pharmaceutical composition can be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2mg, 4mg, 10mg, 25mg, etc.
  • treating means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term applies or one or more symptoms of such disorder or condition, or preventing such A disorder or condition or one or more symptoms of such a disorder or condition.
  • “Individual” as used herein includes a human or non-human animal.
  • Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • compositions of the present invention may also comprise one or more additional therapeutic or prophylactic agents.
  • Instrument model Elite P3500, chromatographic column: welch Ultimate XB-C18 (30 ⁇ 250mm, 10 ⁇ m); chromatographic column temperature, 25°C; flow rate: 42mL/min; detection wavelength: 254nm; elution gradient: (0min: 10% A, 90% B; 25min: 90%A, 10%B; 35min: 90%A, 10%B; 38min: 10%A, 90%B; 40min: 10%A, 90%B); mobile phase: A: Methanol, B: 0.05% formic acid aqueous solution.
  • Step 1 Dissolve compound 1a (2.5g, 0.088mol) and 1b (1.3g, 0.088mol) in 25g DMF, stir at 100-110°C for 2 hours, cool to room temperature, add methyl tert-butyl ether ( 50mL), the product was precipitated, filtered, the filter cake was dissolved with 20mL methanol, and then methyl tert-butyl ether (50mL) was added, the product was precipitated, filtered, the filter cake was washed with methyl tert-butyl ether, and vacuum-dried at 40°C to obtain 2.7 g Intermediate 1c.
  • the title compound 2 (pale yellow solid) was prepared by the same synthetic route as in Example 1, except that benzoyl chloride in Step 2 of Example 1 was replaced with o-fluorobenzoyl chloride.
  • the title compound 3 (pale yellow solid) was obtained by the same synthetic route as in Example 1, except that benzoyl chloride in Step 2 of Example 1 was replaced with o-bromobenzoyl chloride.
  • the title compound 4 (pale yellow solid) was obtained by the same synthetic route as in Example 1, except that benzoyl chloride in Step 2 of Example 1 was replaced with o-iodobenzoyl chloride.
  • Step 1 Compound 1a (4.0 g, 0.014 mol) and compound 5b (1.6 g, 0.01 mol) were dissolved in a mixed solution of DMF (8 mL) and acetonitrile (8 mL), and stirred at 110° C. for 3 hours. The reactant was cooled to room temperature, acetonitrile was added, the product was precipitated, filtered, the filter cake was washed with DCM, and dried under vacuum at 40°C to obtain intermediate 5c (2.3 g, off-white solid).
  • Step 2 Add intermediate 5c (1.0g, 0.0027mol) and water (2g) to the reaction flask, adjust the pH value to 10-12 with 30% sodium hydroxide solution, stir for half an hour, add dropwise benzoyl chloride (0.25g , 0.0017mol) THF (2mL) solution, keep the pH value 10-12 and stir for half an hour.
  • the title compound 8 (pale yellow solid) was prepared by the same synthetic route as in Example 1, except that benzoyl chloride in Step 2 of Example 1 was replaced with 8d.
  • Step 1 Dissolve compound 1a (5.6g, 0.02mol) and 9b (3.7g, 0.02mol) in 10mL DMF, heat to 110°C, reflux for three hours; then cool to room temperature, add methyl tert-butyl ether dropwise, The product precipitated out to give the crude product 9c (2.5 g, yellow oil), which was used directly in the next reaction.
  • Step 2 Add the above crude product (2.5g) into 10g of water, stir and dissolve, adjust the pH value to 10-11 with 30% sodium hydroxide solution, add dropwise a tetrahydrofuran solution of benzoyl chloride (0.7g), and keep the pH value as 10-11, reacted for 0.5 hours, the reaction solution was extracted twice with dichloromethane, and then concentrated to dryness to obtain a yellow oily liquid, which was purified by preparative liquid chromatography, and the product was lyophilized to obtain the title compound 9 (0.1g, white solid).
  • the title compound 13 (white solid) was prepared by the same synthetic route as in Example 9, except that benzoyl chloride in Step 2 of Example 9 was replaced by cinnamoyl chloride.
  • Step 1 Add compound 14a (34g, 0.1mol) into 200mL DMF, stir, add DIPEA (26g, 0.2mol) dropwise, cool down to 0°C, react for 0.5 hours, add TBSCl (23g, 0.15mol) dropwise, and keep warm 0-5°C, reacted for 16 hours, added MTBE 500mL, continued to stir for 2 hours, filtered, washed the filter cake with MTBE, and then dried at 40°C to obtain a white solid 14b (30g).
  • Step 1 Add 1a (2.0g, 0.007mol) and 15b (1.0g, 0.006mol) into DMF 5mL, keep stirring at 110°C for 2 hours. The reactant was cooled to room temperature, acetonitrile was added, the product was precipitated, filtered, the filter cake was washed with DCM, and dried under vacuum at 40° C. to obtain intermediate 15c (1.5 g).
  • the title compound 19 (white solid) was obtained by the same synthetic route as in Example 15, except that benzoyl chloride in Step 2 of Example 15 was replaced with furan-2-carbonyl chloride.
  • the title compound 20 (white solid) was obtained by the same synthetic route as in Example 15, except that benzoyl chloride in Step 2 of Example 15 was replaced with cyclohexanoyl chloride.
  • the title compound 21 (white solid) was obtained by the same synthetic route as in Example 15, except that benzoyl chloride in Step 2 of Example 15 was replaced by cinnamoyl chloride.
  • the title compound 23 (white solid) was obtained by the same synthetic route as in Example 22, except that benzoyl chloride in Step 2 of Example 22 was replaced with m-bromobenzoyl chloride.
  • the title compound 24 (white solid) was obtained by the same synthetic route as in Example 22, except that benzoyl chloride in Step 2 of Example 22 was replaced with o-methoxybenzoyl chloride.
  • the title compound 25 (white solid) was prepared by the same synthetic route as in Example 22, except that benzoyl chloride in Step 2 of Example 22 was replaced by cinnamoyl chloride.
  • the title compound 26 (white solid) was obtained by the same synthetic route as in Example 22, except that benzoyl chloride in Step 2 of Example 22 was replaced with furan-2-carbonyl chloride.
  • the title compound 27 (white solid) was prepared by the same synthetic route as in Example 22, except that benzoyl chloride in Step 2 of Example 22 was replaced with cyclohexanoyl chloride.
  • Step 1 Add 1a (1.54g), 30b (1.67g), anhydrous acetonitrile (2g) and anhydrous DMF (6g) to a 100mL single-necked bottle in turn, stir, heat up to 110°C and reflux for 3h, the reaction is complete, and cool After reaching room temperature, add 100 mL of anhydrous acetonitrile, filter, dissolve the filter cake with MEOH/CH 3 CN, and concentrate under reduced pressure to remove the solvent to obtain the product 30c (1.25 g).
  • Step 2 Add 30c (1.25g) and H 2 O (3g) in sequence to a 100mL single-necked bottle, stir to dissolve, add dropwise 30% NaOH to adjust the pH to 10-12, stir for 0.5h, add dropwise 2-methoxy Benzoyl chloride (0.189g), HPLC detection shows that reaction is finished, and 36% HCl is added dropwise to adjust pH to 4-5, adds DCM, leaves standstill after stirring 10min, separates organic phase, and aqueous phase is washed twice with DCM, merges The organic phase was spin-dried, dissolved in MeOH, purified by preparative chromatography, and lyophilized to obtain the title compound 30 (white solid).
  • Step 1 Add 1a (2.1g), 36b (1.0g), acetonitrile (20g) and N,N-dimethylformamide (6g) into a 100mL one-necked bottle, raise the temperature to 100-110°C and stir for 3 hours.
  • the reactant was cooled to room temperature, the product was precipitated, filtered, the filter cake was slurried with 20 mL of acetonitrile, filtered, and the filter cake was vacuum-dried at 40° C. to obtain intermediate 36c.
  • Step 2 Add 36c (2.1g) and water (5.0g) into a 100mL single-necked bottle, add 30% NaOH dropwise to adjust the pH to 11.0, stir for 30 minutes, and retest the pH to be greater than 11.0; add o-fluorobenzoyl chloride/tetrahydrofuran dropwise (0.38g/2mL), added ethyl acetate 5mL, separated, the aqueous phase was extracted twice with 5mL ethyl acetate, the organic phase was combined, dried, dissolved in methanol after spin-dried, and purified by preparative chromatography to obtain the title compound 36. salt (white solid).
  • Step 1 37b (1.8g, 0.0075mol) and 1a (3.2g, 0.0125mol) were dissolved in a mixed solution of DMF (15g) and acetonitrile (5g), and the oil bath was heated to 110°C for 3 hours. The reaction liquid was cooled to room temperature, filtered, the filter cake was washed with acetonitrile, and the filter cake was dried to obtain light grayish yellow solid 37c (2.71g).
  • Step 2 Dissolve 37c (5.56g, 0.0106mol) in water (20mL), stir to dissolve; add dropwise 30% sodium hydroxide solution to the reaction solution, adjust the pH to 10-11, cool down to 10°C in an ice bath, Keep warm for 10 minutes. A tetrahydrofuran (5 mL) solution of o-fluorobenzoyl chloride was added dropwise at 10°C, and the pH was controlled to 10-11 during the dropwise addition.
  • Step 1 Add 1a (1.4g), 38b (0.7g), acetonitrile (2.0g) and N,N-dimethylformamide (6.0g) into a 100mL single-necked bottle, heat up to 100-110°C and stir for 3 hours .
  • the reactant was cooled to room temperature, acetone was added, the product was precipitated, filtered, the filter cake was slurried with 20 mL of acetonitrile, filtered, and the filter cake was vacuum-dried at 40°C to obtain intermediate 38c (3.3 g).
  • Step 2 Add intermediate 38c (3.3g) and water (4.4g) to a 100mL single-necked bottle, add dropwise 30% NaOH to adjust the pH to 11.0, stir for 10 minutes, and retest the pH to be greater than 11.0; add o-fluorobenzoyl chloride dropwise /tetrahydrofuran (0.3g/2mL), add ethyl acetate 5mL, separate liquid, the aqueous phase is extracted twice with 5mL ethyl acetate, combine organic phase, dry, dissolve with methanol after spin-drying, obtain compound 38 by preparative chromatography purification FORMATE (WHITE SOLID).
  • Step 1 Add 39b (1.8g, 0.01mol) and 1a (5.6g, 0.02mol) into 8mL DMF, heat to 110°C, then stir for 2 hours; cool to 0-10°C, add MTBE to precipitate the product, filter, The filter cake was washed with MTBE and dried to give the crude intermediate 39c (5.5 g, yellow solid)
  • Step 1 40b (1.0g, 0.0043mol) was added in 5mL DMF, then 1a (1.6g, 0.0057mol) was added, heated to 110° C. for reflux for 3 hours, then cooled to room temperature, filtered, and the filter cake was washed with acetonitrile and reduced Drying under pressure afforded intermediate 40c (1.7 g, white solid).
  • Step 1 41b (1.8g, 0.0088mol) and 1a (3.2g, 0.0125mol) were dissolved in a mixed solution of DMF (15g) and acetonitrile (5g), and the oil bath was heated to 110°C for 3 hours. The reaction solution was cooled to room temperature, filtered, the filter cake was washed with acetonitrile, and the filter cake was dried to obtain intermediate 41c (2.71 g, light gray-yellow solid).
  • Step 2 Dissolve intermediate 41c (2.71g) in water (20mL), stir to dissolve; add 30% sodium hydroxide solution dropwise to the reaction solution, adjust the pH to 10-11, cool down to 10°C in an ice bath, and keep warm 10 minutes.
  • a tetrahydrofuran (5 mL) solution of o-fluorobenzoyl chloride was added dropwise at 10°C, and the pH was controlled to 10-11 during the dropwise addition.
  • After the dropwise addition keep warm and keep the pH value to continue the reaction for 15 minutes, adjust the pH of the reaction solution to 7-8, extract three times with dichloromethane, dry the dichloromethane layer with anhydrous sodium sulfate, remove the solvent, and purify the crude product by column chromatography .
  • the product purified by column chromatography was dissolved in pure water and lyophilized to obtain the title compound 41 (0.31 g, off-white solid).
  • Step 1 Add 1a (1.54g), 42b (1.67g), anhydrous acetonitrile (2g) and anhydrous DMF (6g) to a 100mL single-necked bottle in sequence, stir, heat up to 110°C and reflux for 3 hours, and the reaction is complete. After cooling to room temperature, 100 mL of anhydrous acetonitrile was added and filtered. The filter cake was dissolved in MeOH/CH 3 CN and concentrated under reduced pressure to remove the solvent to obtain intermediate product 42c (1.25 g).
  • Step 2 In a 100mL single-necked bottle, add 42c (1.25g) and H 2 O (3g) successively, stir to dissolve, add dropwise 30% NaOH to adjust the pH to 10-12, stir for 0.5h, add dropwise benzoyl chloride (0.189 g), HPLC detection, adding DCM, stirring for 10min and standing still, separating the organic phase, washing the aqueous phase twice with DCM, combining the organic phases, spin-dried, dissolved in MeOH, purified by preparative chromatography, and freeze-dried to obtain the title compound 42 (white solid).
  • Step 1 Add acetonitrile, 1a (0.0079mol) and 44b (0.0079mol) to a 100mL single-necked bottle, heat to reflux at 110°C, reflux for 2 hours, solids are precipitated, filter, and the obtained solids are concentrated under reduced pressure to remove the solvent, and then use a small amount of MeOH Dissolved, EA was added, solid precipitated out, filtered, concentrated under reduced pressure to remove solvent to obtain intermediate 44c (2.0 g).
  • Step 2 In a 100mL single-necked bottle, add 2.0g of intermediate 44c and 4.0g of H 2 O at a time, stir to dissolve; add 30% NaOH dropwise for 30min, and control the pH at 10-12; dropwise add 0.20g of benzoyl chloride ( 0.00141mol), reacted for 1 h; adjusted the pH to 4.0, solid precipitated, filtered, and the filter cake was beaten with EA, then MeOH, and dried to obtain the title compound 44 (off-white solid).
  • Step 1 Add 46b (1.4g) and 1a (4.4g) into 10mL DMF, heat to 110°C, and reflux for three hours. Then the reactant was cooled to room temperature, methyl tert-butyl ether was added dropwise, and the product was precipitated to obtain 1.8 g of yellow oil, which was directly used in the next reaction.
  • Step 2 Add the above crude product (1.8g) into 10g of water, stir to dissolve. Adjust the pH to 10-11 with 30% sodium hydroxide solution. The tetrahydrofuran solution of benzoyl chloride was added dropwise, and the pH value was maintained at 10-11 for 0.5 hours. The reaction solution was extracted twice with dichloromethane, and then concentrated to dryness to obtain a yellow oily liquid, which was purified by preparative liquid chromatography, and the product was freeze-dried. The title compound 46 (0.03 g, off-white solid) was obtained.
  • Step 1 Dissolve 2.02g of compound 1a and 2.3g of compound 47b in 6.9g of DMF, heat to 110°C for 4h, add 20mL of acetonitrile after cooling, and stir to precipitate a solid. After filtering, the filter cake was rinsed with acetonitrile, and dried to obtain 3.4 g of crude product.
  • Step 2 Dissolve 3.4g of the crude product in 10g of water and stir to dissolve.
  • Sodium hydroxide solution (30%) was added dropwise to adjust the pH to 10-11. Stabilize the pH at 10-11, lower the temperature in an ice bath and stir for 10 minutes; keep below 10°C and add dropwise a tetrahydrofuran solution of benzoyl chloride, and add sodium hydroxide solution during the dropwise addition to keep the pH at 10-11.
  • the dropwise addition was completed, and the reaction was incubated for 10 minutes.
  • Dichloromethane was added to extract twice, the organic phase was discarded, concentrated to obtain a crude product, purified by preparative HPL, and lyophilized to obtain the title compound 47 (off-white solid).
  • Step 1 Add 1a (2.8g, 0.01mol) and 49b (1.2g, 0.01mol) into a mixed solution of 12mL DMF and 4mL acetonitrile, and react at 110°C for 2h. After cooling, acetonitrile was added to precipitate a solid, which was filtered to obtain about 1.2 g of crude product.
  • Step 2 Add 3g of water to the crude product of step 1, adjust the pH value to 10-12 with 30% sodium hydroxide solution, stir for half an hour, add a solution of benzoyl chloride (0.4g) in tetrahydrofuran (2mL) dropwise, and keep the pH The value is 10-12 and stirred for half an hour.
  • Add 50 mL of dichloromethane for extraction, dry over anhydrous sodium sulfate, and purify by silica gel column chromatography (dichloromethane:methanol 30:1) to obtain 32 mg of a crude product, which is then purified by preparative liquid chromatography and freeze-dried to obtain the title compound 49 (10 mg , yellow solid).
  • Step 2 Add 52b (23.5g) and RaneyNi (24.5g) into 125g of formic acid and 24.5g of water, heat to 60°C, and reflux for three hours.
  • the reactant was filtered, and the filter cake was washed with formic acid. Cool the filtrate to 0°C, add ammonia water dropwise, the product precipitates, and stir for 1 hour; filter, and vacuum-dry the filter cake to obtain 25 g of a light yellow crude product.
  • the crude product was added to 150 mL of methanol, and sodium borohydride (4.8 g, 0.126 mol) was added in batches with a cold water bath to 0° C., and stirred for 3 hours.
  • LC-MS monitoring showed that the reaction was complete.
  • Step 3 Add 52c (6.1g, 0.03mol) and DMAP (6.6g, 0.054mol) into 100mL dichloromethane, cool down to 0°C with a cold water bath, add methanesulfonyl chloride (5.2g, 0.045mol) dropwise, and then Stir for 2 hours. Concentrate under reduced pressure and evaporate the solvent to dryness.
  • Step 4 Add DMF 20mL and 5-(2-methoxyethyl)-4-methylthiazole (4.7g, 0.03mol) to the product of step 3, heat to 110°C and reflux for 3 hours, LC-MS monitoring It indicated that the reaction was complete, cooled to room temperature, added MTBE to precipitate the product, separated the clear night, and concentrated the residue under reduced pressure to obtain an oily liquid 52e (14g), which was directly used in the next reaction without further purification.
  • Step 5 Add the crude product 52e (4.3g, 0.01mol) in step 4 into 30g of water, stir to dissolve, adjust the pH value to 10-11 with 30% sodium hydroxide solution, add dropwise a tetrahydrofuran solution of benzoyl chloride, and maintain the pH value 10-11 was reacted for 0.5 hours, the reaction solution was extracted twice with dichloromethane, and then concentrated to dryness to obtain a yellow oily liquid, which was purified by preparative liquid chromatography, and the product was lyophilized to obtain the title compound 52 (0.06 g, white solid).
  • Step 1 Add 54a (50.0g, 318.5mmol, 1.0eq) and methanol (500mL) into a 500mL single-necked flask, add MeONa (18g, 333.3mmol, 1.05eq) under stirring, stir at room temperature for 0.5 hours, add ethoxy Methylenemalononitrile (38.8g, 318.5mmol, 1.0eq), was stirred at room temperature for 2 hours, filtered, and the filter cake was dried to give 54b (yellow solid, 40g, yield: 63.7%).
  • Step 2 Add 54b (40g, 203mmol, 1.0eq), 30% NaOH (200mL) and methanol (200mL) into a 250mL three-necked flask, raise the temperature to 90°C and stir for 4 hours, cool to room temperature, adjust the pH to 5 with 2M HCl , filtered, and the filter cake was dried to obtain 32 g of a white solid.
  • Step 4 Add 54d (6g, 29.7mmol, 1.0eq) and 33% HBr acetic acid solution (18g) into a 100mL single-necked flask, raise the temperature to 100°C and stir for 2 hours, cool, add acetonitrile, and filter to obtain 54e (yellow solid, 6.5g, yield 82.5%).
  • Step 5 Add 5-(2-methoxyethyl)-4-methylthiazole (2.67g, 17mmol, 1.5eq), 54e (3.0g, 11.4mmol, 1.0eq) and DMF ( 30 mL), heated to 110°C and stirred for 3 hours, cooled, added acetonitrile and stirred and filtered, and the filter cake was dried to obtain 54f (yellow solid, 2.6 g, yield 54%).
  • Step 6 Dissolve 54f (2.6g, 6.4mmol, 1.0eq) in 10g of water, add dropwise 30% sodium hydroxide solution to adjust the pH to 10-12, stir for 1 hour, retest the pH, adjust the pH to 10-12 until Stable and unchanged, keep below 10°C and add benzoyl chloride (0.89g, 6.4mmol, 1.0eq) dropwise, after the addition is complete, keep the reaction for 10 minutes, adjust the pH to 6, add ethyl acetate, separate the liquids, and adjust the pH of the aqueous phase.
  • Step 1 Add 55a (50.0g, 458.7mmol, 1.0eq) and methanol (50mL) into a 500mL single-necked bottle, add 350g of 20% HCl dioxane solution under stirring, and stir at room temperature for 12 hours. Then sodium methoxide (49.5g, 917.4mmol, 2.0eq) was added and stirred for 2 hours, NH 3 methanol solution (100mL) was added, stirred at room temperature for 0.5 hours, concentrated, and the solvent was removed.
  • Step 2 55c (yellow solid) was prepared using the same synthetic route as in Example 52, except that 52b in Step 2 in Example 52 was replaced with 55b.
  • Step 3 to Step 5 Except that 54d in Step 4 in Example 54 was replaced with 55c, the title compound 55 (white solid) was obtained by using the same synthetic steps and methods as Step 4 to Step 6 in Example 54 .
  • the title compound 56 (off-white solid) was prepared by the same synthetic route as in Example 55, except that 55a in Step 1 of Example 55 was replaced by cyclohexanenitrile.
  • Example 55 Except that 55a in Step 1 of Example 55 was replaced by cyclobutyronitrile, the title compound 57 (white solid) was prepared using the same synthetic route as in Example 55
  • the BCA protein concentration determination kit was purchased from Beyond, the A ⁇ 40 and A ⁇ 42 detection kits were purchased from Wako Company, and the cell culture-related reagents were purchased from Gibco Company.
  • HEK293APP/sw overexpression cells were cultured in 48-well plates with DMEM medium (containing 10% FBS, 100 ⁇ g/mL G418 (Geneticin, Geneticin) and double antibody (1 ⁇ Penicillin, Streptomycin). Take 4 mM compound stock solution (the compound was prepared by dissolving in DMEM culture fluid), filtered through a 0.22 ⁇ m sterile filter and stored at -20°C for later use. At 70% cell density, add 40 ⁇ L of the compound test solution to each well, with a final concentration of 400 ⁇ M , and cultured for 24 hours.
  • DMEM medium containing 10% FBS, 100 ⁇ g/mL G418 (Geneticin, Geneticin) and double antibody (1 ⁇ Penicillin, Streptomycin).
  • the compounds of the present invention can significantly reduce the levels of A ⁇ 42 and/or A ⁇ 40.
  • CCK-8 kit is a WST-8 (chemical name 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4- Disulfophenyl)-2H-tetrazole monosodium salt) kit for cell proliferation and toxicity detection.
  • the detection principle is that in the presence of electron coupling reagents, WST-8 can be reduced by dehydrogenase in mitochondria to generate highly water-soluble orange-yellow formazan. The shade of color is directly proportional to the number of viable cells and inversely proportional to cytotoxicity.
  • the OD value was measured by a microplate reader at a wavelength of 450 nm to reflect the level of cell proliferation and toxicity.
  • HEK293-APP cell density grows to 80% to 90%, it is collected by digestion and centrifugation, then the supernatant is removed, 5ml of medium is added and mixed.
  • the compound to be tested was made into 4mM stock solution with DMEM culture solution, filtered through a 0.22 ⁇ m sterile filter and stored at -20°C for later use.
  • Inhibition rate (1-absorbance of test group/absorbance of control group)*100%, and the experimental results are shown in the table below.

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Abstract

本发明涉及式(I)的化合物、包含其的药物组合物、其制备方法及其用于治疗神经退行性疾病的用途。

Description

嘧啶类化合物、包含其的药物组合物、其制备方法及其用途 技术领域
本发明涉及嘧啶类化合物、包含其的药物组合物、其制备方法及其用于治疗神经退行性疾病的用途。
背景技术
阿尔茨海默病(俗称老年性痴呆,Alzheimer’s disease,AD)是一种以认知、行为失常为主要临床表现的进行性神经退行性疾病,是一种最常见的老年期痴呆,主要表现为识别能力障碍与记忆功能的迅速衰减。主要病理生理特征是脑内β-淀粉样蛋白(β-amyloid,Aβ)沉积形成老年斑、tau蛋白过度磷酸化形成神经纤维缠结、脑葡萄糖代谢障碍和神经元/突触丢失。由于病程长、患者生活自理能力差,给家庭、社会带来严重的精神和经济负担。但是,全球范围内目前没有能阻止或延缓疾病发展的药物,目前市场销售的治疗AD的药物仅为对症治疗药物,只能控制或改善认知和功能症状一段时间,不能阻止或延缓病情恶化。
发明内容
本发明提供嘧啶类化合物,其可用于预防或治疗神经退行性疾病。此外,本发明的化合物还具有更好的物理化学性质(例如溶解度、物理和/或化学稳定性)、改善的药物代谢动力学性质(例如改善的生物利用度、合适的半衰期和作用持续时间)、改善的安全性(较低的毒性(例如降低的心脏毒性)和/或较少的副作用)、较不易产生耐药性等更优异的性质。
本发明的一个方面提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中所述化合物具有式(I)的结构:
Figure PCTCN2022097105-appb-000001
其中
R选自H、卤素、羟基、氨基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(=NH)NH 2、-C(=O)R 3、-OC(=O)R 3、-C(=O)OR 3、-OR 3、-SR 3、-S(=O)R 3、-S(=O) 2R 3、-S(=O) 2NR 3R 4、-NR 3R 4、-C(=O)NR 3R 4、-NR 3-C(=O)R 4、-NR 3-C(=O)OR 4、-NR 3-S(=O) 2-R 4、-NR 3-C(=O)-NR 3R 4、-C 1-6亚烷基-NR 3R 4和-O-C 1-6亚烷基-NR 3R 4
L 1和L 2各自独立地选自直接键、C 1-6亚烷基和C 2-6亚烯基;
R 1和R 2各自独立地选自H、卤素、羟基、氧代、氨基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、=N-OR 3、-C(=NH)NH 2、-C(=O)R 3、-OC(=O)R 3、-C(=O)OR 3、-OR 3、-SR 3、-S(=O)R 3、-S(=O) 2R 3、-S(=O) 2NR 3R 4、-NR 3R 4、-C(=O)NR 3R 4、-NR 3-C(=O)R 4、-NR 3-C(=O)OR 4、-NR 3-S(=O) 2-R 4、-NR 3-C(=O)-NR 3R 4、-C 1-6亚烷基-NR 3R 4和-O-C 1-6亚烷基-NR 3R 4
R 3和R 4在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基;
上述烷基、亚烷基、烯基、亚烯基、炔基、环烃基、杂环基、芳基、杂芳基和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代:卤素、羟基、氧代、氨基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、=N-OR 5、-C(=NH)NH 2、-C(=O)R 5、-OC(=O)R 5、-C(=O)OR 5、-OR 5、-SR 5、-S(=O)R 5、-S(=O) 2R 5、-S(=O) 2NR 5R 6、-NR 5R 6、-C(=O)NR 5R 6、-NR 5-C(=O)R 6、-NR 5-C(=O)OR 6、-NR 5-S(=O) 2-R 6、-NR 5-C(=O)-NR 5R 6、-C 1-6亚烷基-NR 5R 6和-O-C 1-6亚烷基-NR 5R 6,所述烷基、烯基、炔基、环烃基、 杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代:卤素、羟基、氧代、氨基、氰基、硝基、C 1-6烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基;
R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基;并且
条件是当-L 2-R 2共同构成C 1-6烷基时,-L 1-R 1不是未取代的苯基;并且
当-L 2-R 2共同构成-(CH 2) 2-OC(=O)-(C 1-7烷基)时,-L 1-R 1不是未取代的苯基和未取代的呋喃基。
本发明的另一方面提供药物组合物,其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药以及一种或多种药学上可接受的载体。
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物在制备用于预防或治疗神经退行性疾病或者减轻神经退行性疾病的症状的药物中的用途。
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物,其用于预防或治疗神经退行性疾病或者减轻神经退行性疾病的症状。
本发明的另一方面提供预防或治疗神经退行性疾病或者减轻神经退行性疾病的症状的方法,所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物。
本发明的另一方面提供本发明的化合物的制备方法。
具体实施方式
定义
除非在下文中另有定义,本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术,包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解,但仍然阐述以下定义以更好地解释本发明。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的,且不排除其它未列举的元素或方法步骤。
如本文中所使用,术语“亚烷基”表示饱和二价烃基,优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基,例如亚甲基、亚乙基、亚丙基或亚丁基。
如本文中所使用,术语“烷基”定义为直链或支链饱和脂肪族烃。在一些实施方案中,烷基具有1至12个,例如1至6个碳原子。例如,如本文中所使用,术语“C 1-6烷基”指1至6个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基),其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CF 3、C 2F 5、CHF 2、CH 2F、CH 2CF 3、CH 2Cl或-CH 2CH 2CF 3等)。术语“C 1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
如本文中所使用,术语“亚烯基”表示包含一个或多个双键的二价烃基,其优选具有2、3、4、5或6个碳原子,例如亚乙烯基、亚丙烯基或亚烯丙基。
如本文中所使用,术语“烯基”意指线性的或支化的单价烃基,其包含一个双键,且具有2-6个碳原子(“C 2-6烯基”)。所述烯基为例如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。
当本发明的化合物含有亚烯基或烯基时,所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。
如本文中所使用,术语“炔基”表示包含一个或多个三键的单价烃基,其优选具有2、3、4、5或6个碳原子,例如乙炔基或丙炔基。
如本文中所使用,术语“亚环烃基”、“环烃基”和“烃环”是指具有例如3-10个(适合地具有3-8个,更适合地具有3-6个)环碳原子的饱和(即,“亚环烷基”和“环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环烃环,其包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基 (环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环己烯基(环)等。
如本文中所使用,术语“环烷基”指饱和或不饱和的非芳族单环或多环(诸如双环)烃环(例如单环,诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基,或双环,包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等),其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如,术语“C 3-6环烷基”指3至6个成环碳原子的饱和或不饱和的非芳族单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基),其任选地被1或多个(诸如1至3个)适合的取代基取代,例如甲基取代的环丙基。
如本文中所使用,术语“杂环基”指饱和或不饱和的一价单环或双环基团,其在环中具有2、3、4、5、6、7、8或9个碳原子和一个或多个(例如一个、两个、三个或四个)选自C(=O)、O、S、S(=O)、S(=O) 2和NR a的含杂原子的基团,其中R a表示氢原子或C 1-6烷基或卤代-C 1-6烷基;所述杂环烷基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地,3-10元杂环基为在环中具有3-10个碳原子及杂原子的基团,例如但不限于环氧乙烷基、氮丙啶基、氮杂环丁烷基(azetidinyl)、氧杂环丁烷基(oxetanyl)、四氢呋喃基、二氧杂环戊烯基(dioxolinyl)、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、吡咯啉基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基或三噻烷基(trithianyl)。
如本文中所使用,术语“芳基”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。例如,如本文中所使用,术语“C 6-14芳基”意指含有6至14个碳原子的芳族基团,诸如苯基或萘基。芳基任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO 2、C 1-6烷基等)取代。
术语“芳烷基”优选表示芳基取代的烷基,其中所述芳基和所述烷基如本文中所定义。通常,所述芳基可具有6-14个碳原子,并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基。
如本文中所使用,术语“杂芳基”指一价单环、双环或三环芳族环系,其具有5、6、8、9、10、11、12、13或14个环原子,特别是1或2或3或4或5或6或9或10个碳原子,且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫),并且,另外在每一种情况下可为苯并稠合的。特别地,杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等,以及它们的苯并衍生物;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等,以及它们的苯并衍生物。
如本文中所使用,术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
如本文中所使用,术语“烷基硫基”意指通过硫原子连接至母体分子部分的如上文所定义的烷基。C 1-6烷基硫基的代表性实例包括但不限于甲硫基、乙硫基、叔丁硫基及己硫基。
如本文中所使用,术语“含氮杂环”指饱和或不饱和的单环或双环基团,其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子,其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C=O、S、S=O和S(=O) 2的环成员;所述含氮杂环通过氮原子与分子的其余部分连接。所述含氮杂环优选为饱和含氮单环。特别地,3至14元含氮杂环为在环中具有3-14个碳原子及杂原子(其中至少一个为氮原子)的基团,其包括但不限于三元含氮杂环(如氮丙啶基)、四元含氮杂环(如氮杂环丁烷基)、五元含氮杂环(如吡咯基、吡咯烷基(吡咯烷环)、吡咯啉基、吡咯烷酮基、咪唑基、咪唑烷基、咪唑啉基、吡唑基、吡唑啉基)、六元含氮杂环(如哌啶基(哌啶环)、吗啉基、硫吗啉基、哌嗪基)、七元含氮杂环等。
术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替,条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
如果取代基被描述为“任选地被取代”,则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代,则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代,则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。
如果取代基被描述为“独立地选自”一组,则各取代基独立于另一者被选择。因此,各取代基可与另一(其他)取代基相同或不同。
如本文中所使用,术语“一个或多个”意指在合理条件下的1个或超过1个,例如2个、3个、4个、5个或10个。
除非指明,否则如本文中所使用,取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时,则这样的取代基可键连至该可取代的环中的任一成环原子。
本发明还包括所有药学上可接受的同位素标记的化合物,其与本发明的化合物相同,除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘(D, 2H)、氚(T, 3H));碳的同位素(例如 11C、 13C及 14C);氯的同位素(例如 36Cl);氟的同位素(例如 18F);碘的同位素(例如 123I及 125I);氮的同位素(例如 13N及 15N);氧的同位素(例如 15O、 17O及 18O);磷的同位素(例如 32P);及硫的同位素(例如 35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即 3H)及碳-14(即 14C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如 11C、 18F、 15O及 13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些,例如,D 2O、丙酮-d 6或DMSO-d 6
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中,其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地,本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解,本申请的范围涵盖所有这样的以任意比例(例如60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%)的异构体或其混合物。
本文中可使用实线
Figure PCTCN2022097105-appb-000002
实楔形
Figure PCTCN2022097105-appb-000003
或虚楔形
Figure PCTCN2022097105-appb-000004
描绘本发明的化合物的碳-碳键。使用实线以描绘键连至不对称碳原子的键欲表明,包括该碳原子处的所有可能的立体异构体(例如,特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明,存在所示的立体异构体。当存在于外消旋混合物中时,使用实及虚楔形以定义相对立体化学,而非绝对立体化学。除非另外指明,否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象,且由其混合物(例如外消旋混合物及非对映异构体对)组成。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物,其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
还应当理解,本发明的某些化合物可以游离形式存在用于治疗,或适当时,以其药学上可接受的衍生物形式存在。在本发明中,药学上可接受的衍生物包括但不限于,药学上可接受的盐、酯、溶剂合物、代谢物或前药,在将它们向需要其的患者给药后,能够直接或间接提供本发明的化合物或其代谢物或残余物。因此,当在本文中提及“本发明的化合物”时,也意在涵盖化合物的上述各种衍生物形式。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。
适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括天冬氨酸盐、苯甲酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、氢溴酸盐/溴化物、氢碘酸盐/碘化物、顺丁烯二酸盐、丙二酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐及其它类似的盐。
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、胆碱盐、二乙胺盐、赖氨酸盐、镁盐、葡甲胺盐、钾盐及其它类似的盐。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
如本文中所使用,术语“酯”意指衍生自本申请中各个通式化合物的酯,其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
本发明的化合物可以溶剂合物(优选水合物)的形式存在,其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂,特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量 比或非化学计量比存在。
在本发明的范围内还包括本发明的化合物的代谢物,即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱脂化、酶解等产生。因此,本发明包括本发明的化合物的代谢物,包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药,其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物,其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”,第14卷,ACS Symposium Series(T.Higuchi及V.Stella)及“Bioreversible Carriers in Drug Design,”Pergamon Press,1987(E.B.Roche编辑,American Pharmaceutical Association)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”,H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中,保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的,由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现,例如,在Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973;和T.W.Greene & P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley & Sons,1991中所述的那些保护基,这些参考文献通过援引加入本文。使用本领域已知的方法,在适当的后续阶段可以移除保护基。
如本文中所使用,术语“约”是指在所述数值的±10%范围内,优选±5%范围内,更优选±2%范围内。
化合物
在一些实施方案中,本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中所述化合物具有式(I)的结构:
Figure PCTCN2022097105-appb-000005
其中
R选自H、卤素、羟基、氨基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(=NH)NH 2、-C(=O)R 3、-OC(=O)R 3、-C(=O)OR 3、-OR 3、-SR 3、-S(=O)R 3、-S(=O) 2R 3、-S(=O) 2NR 3R 4、-NR 3R 4、-C(=O)NR 3R 4、-NR 3-C(=O)R 4、-NR 3-C(=O)OR 4、-NR 3-S(=O) 2-R 4、-NR 3-C(=O)-NR 3R 4、-C 1-6亚烷基-NR 3R 4和-O-C 1-6亚烷基-NR 3R 4
L 1和L 2各自独立地选自直接键、C 1-6亚烷基和C 2-6亚烯基;
R 1和R 2各自独立地选自H、卤素、羟基、氧代、氨基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、=N-OR 3、-C(=NH)NH 2、-C(=O)R 3、-OC(=O)R 3、-C(=O)OR 3、-OR 3、-SR 3、-S(=O)R 3、-S(=O) 2R 3、-S(=O) 2NR 3R 4、-NR 3R 4、-C(=O)NR 3R 4、-NR 3-C(=O)R 4、-NR 3-C(=O)OR 4、-NR 3-S(=O) 2-R 4、-NR 3-C(=O)-NR 3R 4、-C 1-6亚烷基-NR 3R 4和-O-C 1-6亚烷基-NR 3R 4
R 3和R 4在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基;
上述烷基、亚烷基、烯基、亚烯基、炔基、环烃基、杂环基、芳基、杂芳基和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代:卤素、羟基、氧代、氨基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、=N-OR 5、-C(=NH)NH 2、-C(=O)R 5、-OC(=O)R 5、-C(=O)OR 5、-OR 5、-SR 5、-S(=O)R 5、-S(=O) 2R 5、 -S(=O) 2NR 5R 6、-NR 5R 6、-C(=O)NR 5R 6、-NR 5-C(=O)R 6、-NR 5-C(=O)OR 6、-NR 5-S(=O) 2-R 6、-NR 5-C(=O)-NR 5R 6、-C 1-6亚烷基-NR 5R 6和-O-C 1-6亚烷基-NR 5R 6,所述烷基、烯基、炔基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代:卤素、羟基、氧代、氨基、氰基、硝基、C 1-6烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基;
R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基;并且
条件是当-L 2-R 2共同构成C 1-6烷基时,-L 1-R 1不是未取代的苯基;并且
当-L 2-R 2共同构成-(CH 2) 2-OC(=O)-(C 1-7烷基)时,-L 1-R 1不是未取代的苯基和未取代的呋喃基。
在一些实施方案中,R选自C 3-6环烃基、3-10元杂环基、C 6-10芳基和5-14元杂芳基;优选地,R为环丁基、环己基、苯基、噻吩基或吡啶基。
在一些实施方案中,本发明提供所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中L 1为直接键或C 2-6烯基。
在一些实施方案中,L 1为直接键或亚乙烯基。
在一些实施方案中,本发明提供所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中R 1选自C 3-6环烃基、C 6-10芳基和5-14元杂芳基,其任选地被一个或多个独立地选自卤素和-O-(C 1-6烷基)的取代基取代。
在一些实施方案中,R 1选自环己烷基、苯基和呋喃基,其任选地被一个或多个独立地选自F、Cl、Br、I和-OCH 3的取代基取代。
在一些实施方案中,本发明提供所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中-L 1-R 1选自
Figure PCTCN2022097105-appb-000006
在一些实施方案中,本发明提供所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中L 2为直接键、C 1-4亚烷基或C 2-4亚烯基。
在一些实施方案中,L 2为直接键、亚甲基、亚乙基或亚乙烯基。
在一些实施方案中,本发明提供所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中
R 2选自H、卤素、羟基、C 1-6烷基、C 2-6烯基、C 1-6卤代烷基、3-10元杂环基、-C(=O)R 3、-OC(=O)R 3、-OR 3、-SR 3、-NR 3-C(=O)R 4、-NR 3-S(=O) 2-R 4、-NR 3R 4、-C(=O)NR 3R 4和-C(=O)OR 3;其中R 3和R 4各自独立地选自H、C 1-6烷基、3-10元杂环基、C 6-10芳基和C 6-12芳烷基,优选地,R 3和R 4各自独立地选自H、甲基、乙基、吗啉基、苯基(Ph)和苄基(Bn)。
在一些实施方案中,R 2为H、F、Cl、羟基、甲基、乙基、乙烯基、-CH 2CH 2F、-CH 2CH 2Cl、-OC(=O)CH 3、-OC(=O)Ph、-SCH 3、-OCH 3、-OCH 2CH 3、-OBn、-NHC(=O)CH 3、-NHS(=O) 2CH 3、-N(CH 3)Ph、-C(=O)NH 2、-C(=O)NHCH 3、-C(=O)N(CH 3) 2、-C(=O)OH、-C(=O)OCH 2CH 3
Figure PCTCN2022097105-appb-000007
Figure PCTCN2022097105-appb-000008
在一些实施方案中,本发明提供所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中-L 2-R 2选自甲基、乙基、乙烯基、
Figure PCTCN2022097105-appb-000009
Figure PCTCN2022097105-appb-000010
在一些实施方案中,本发明提供所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、 互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中所述化合物具有式(II)或式(III)的结构:
Figure PCTCN2022097105-appb-000011
在一些实施方案中,本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中所述化合物为
Figure PCTCN2022097105-appb-000012
Figure PCTCN2022097105-appb-000013
Figure PCTCN2022097105-appb-000014
Figure PCTCN2022097105-appb-000015
Figure PCTCN2022097105-appb-000016
Figure PCTCN2022097105-appb-000017
Figure PCTCN2022097105-appb-000018
制备方法
在一些实施方案中,本发明提供式(I)的化合物的制备方法:
Figure PCTCN2022097105-appb-000019
其中:
Hal 1和Hal 2各自独立地选自F、Cl、Br和I;
其余各基团如上文所定义;
所述方法包括以下步骤:
步骤(I):使式(I)-a的化合物或其盐与式(I)-b的化合物反应,以得到式(I)-c的化合物。
步骤(I)的反应溶剂优选为酰胺类溶剂(例如DMF)、腈类溶剂(例如乙腈)、芳香烃类溶剂(例如甲苯或氯苯)、醚类溶剂(例如二氧六环)、N-甲基吡咯烷酮或其混合物。步骤(I)的反应温度为例如80-150℃,优选为100~110℃。
步骤(II):使式(I)-c的化合物与式(I)-d的化合物反应,以得到式(I)的化合物。
步骤(II)的反应优选在碱(例如无机碱(如氢氧化钠)或有机碱)的存在下进行。步骤(II)的反应溶剂优选为水、二氯甲烷、THF或其混合物。步骤(II)的反应温度优选为0-50℃,例如10℃。
药物组合物和治疗方法
在一些实施方案中,本发明提供药物组合物,其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药以及一种或多种药学上可接受的载体。
在一些实施方案中,本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物在制备用于预防或治疗神经退行性疾病或者减轻神经退行性疾病的症状的药物中的用途。
在一些实施方案中,本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物,其用于预防或治疗神经退行性疾病或者减轻神经退行性疾病的症状。
在一些实施方案中,本发明提供预防或治疗神经退行性疾病或者减轻神经退行性疾病的症状的方法,所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物。
在一些实施方案中,所述神经退行性疾病选自阿尔茨海默病、克-雅氏病、亨廷顿氏病、多发性硬化、格林-巴利综合征、帕金森病、洛盖赫里格病、由逐渐的神经细胞死亡导致的麻痹性痴呆和进行性失调所引起的疾病;优选为阿尔茨海默病。
本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物,并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体,例如水和油,包括那些石油、动物、植物或合成来源的油,例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时,水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体,特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体,如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。
本发明的药物组合物可以系统地作用和/或局部地作用。为此目的,它们可以适合的途径给药,例如通过注射(如静脉内、动脉内、皮下、腹膜内、肌内注射,包括滴注)或经皮给药;或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
对于这些给药途径,可以适合的剂型给药本发明的药物组合物。
所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂。
如本文中所使用的术语“有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。
可调整给药方案以提供最佳所需响应。例如,可给药单次推注,可随时间给药数个分剂量,或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意,剂量值可随要减轻的病况的类型及严重性而变化,且可包括单次或多次剂量。要进一步理解,对于任何特定个体,具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言,有效剂量在每日每kg体重约0.0001至约50mg,例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言,这会合计为约0.007mg/日至约3500mg/日,例如约0.7mg/日至约700mg/日。在一些情况下,不高于前述范围的下限的剂量水平可以是足够的,而在其它情况下,仍可在不引起任何有害副作用的情况下采用较大剂量,条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。
本发明的化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg,适合地是0.1-500mg,优选0.5-300mg,更优选1-150mg,特别优选1-50mg,例如1.5mg、2mg、4mg、10mg、25mg等。
除非另外说明,否则如本文中所使用,术语“治疗”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展,或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物,例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物,例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、 奶牛、猪等)。
在另种实施方案中,本发明的药物组合物还可以包含一种或多种另外的治疗剂或预防剂。
实施例
为了使本发明的目的和技术方案更加清楚,以下结合实施例对本发明的实施方案进行详细描述。但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,均按照常规条件或者制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市场购买获得的常规产品。
化合物的结构是通过核磁共振( 1H NMR)或质谱(MS)来确定的。NMR的测定是用Bruker AVANCE-500核磁仪或AVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代甲醇(CD 3OD)、氘代水(D 2O)等,内标为四甲基硅烷(TMS),化学位移(δ)以百万分之一(ppm)的单位给出。
MS的测定仪器为安捷伦(ESI)质谱仪(生产商:安捷伦,型号:安捷伦6110)。
制备高效液相色谱分离的方法:
仪器型号:依利特P3500,色谱柱:welch Ultimate XB-C18(30×250mm,10μm);色谱柱温,25℃;流速:42mL/min;检测波长:254nm;洗脱梯度:(0min:10%A,90%B;25min:90%A,10%B;35min:90%A,10%B;38min:10%A,90%B;40min:10%A,90%B);流动相:A:甲醇,B:0.05%甲酸水溶液。
以下实施例中合成的化合物以分子式所表示的化合物为准,化合物名称由ChemBioDraw软件生成。
本发明中的缩写具有以下含义:
缩写 含义
Bn 苄基
DCM 二氯甲烷
DIEA/DIPEA N,N-二异丙基乙胺
DMAP 4-二甲氨基吡啶
DMF N,N-二甲基甲酰胺
EA 乙酸乙酯
HATU O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐
H 2O
LiAlH 4 氢化铝锂
MeOH 甲醇
MeONa 甲醇钠
MTBE 甲基叔丁基醚
NaOH 氢氧化钠
Ph 苯基
TBSCl 叔丁基二甲基氯硅烷
THF 四氢呋喃
实施例1:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-氟戊-2-烯-3-基)硫代苯甲酸酯(化合物1)的合成
Figure PCTCN2022097105-appb-000020
步骤1:将化合物1a(2.5g,0.088mol)和1b(1.3g,0.088mol)溶解在25g DMF中,于100~110℃下搅拌2小时,冷却到室温,加入甲基叔丁基醚(50mL),产物析出,过滤,将滤饼用20mL甲醇溶解,然后加入甲基叔丁基醚(50mL),产物析出,过滤,滤饼用甲基叔丁基醚洗涤,40℃真空干燥得到2.7g中间体1c。
步骤2:将中间体1c(1.7g,0.005mol)溶解在5g水,30%氢氧化钠溶液调节pH值到12,搅拌 半小时,降温至10℃,滴加苯甲酰氯(1d)(0.8g,0.005mol)的THF溶液(5mL),保持pH值10-12搅拌半小时,加入二氯甲烷(50mL)萃取,将有机相通过硅胶柱色谱法(二氯甲烷∶甲醇=10∶1)纯化,40℃下真空浓缩得到标题化合物1(0.3g,类白色固体)。
MS m/z(ESI):389[M+1] +.
1H NMR(500MHz,DMSO-d 6):δ7.87(s,1H),7.83(s,1H),7.76-7.75(dd,2H),7.72-7.69(t,1H),7.56-7.53(t,2H),6.68(br,2H),4.56(t,1H),4.47-4.43(m,3H),2.89(dt,2H),2.19(s,3H),2.18(s,3H).
实施例2:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-氟戊-2-烯-3-基)2-氟硫代苯甲酸酯(化合物2)的合成
Figure PCTCN2022097105-appb-000021
除了将实施例1步骤2中的苯甲酰氯替换为邻氟苯甲酰氯之外,采用与实施例1相同的合成路线,制得标题化合物2(淡黄色固体)。
MS m/z(ESI):407[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ8.42(s,1H),8.35(s,1H),8.24(t,1H),8.16(dd,1H),7.81-7.72(m,2H),6.88(br,2H),5.09-4.98(m,4H),3.44(dt,2H),2.74(s,3H),2.67(s,3H).
实施例3:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-氟戊-2-烯-3-基)2-溴硫代苯甲酸酯(化合物3)的合成
Figure PCTCN2022097105-appb-000022
除了将实施例1步骤2中的苯甲酰氯替换为邻溴苯甲酰氯之外,采用与实施例1相同的合成路线,制得标题化合物3(淡黄色固体)。
MS m/z(ESI):467[M+1] +;469[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.92(s,1H),7.85(s,1H),7.76-7.75(d,1H),7.53-7.49(m,3H),6.76(br,2H),4.60-4.58(t,1H),4.51-4.46(m,3H),2.92(dt,2H),2.22(s,3H),2.19(s,3H).
实施例4:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-氟戊-2-烯-3-基)2-碘硫代苯甲酸酯(化合物4)的合成
Figure PCTCN2022097105-appb-000023
除了将实施例1步骤2中的苯甲酰氯替换为邻碘苯甲酰氯之外,采用与实施例1相同的合成路线,制得标题化合物4(淡黄色固体)。
MS m/z(ESI):515[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.99(d,1H),7.93(s,1H),7.85(s,1H),7.55-7.52(t,1H),7.47(d,1H),7.33(t,1H),6.75(br,2H),4.62(t,1H),4.52(t,1H),4.46(s,2H),2.93(dt,2H),2.22(s,3H),2.18(s,3H).
实施例5:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-氯戊-2-烯-3-基)硫代苯甲酸酯(化合物5)的合成
Figure PCTCN2022097105-appb-000024
步骤1:将化合物1a(4.0g,0.014mol)和化合物5b(1.6g,0.01mol)溶于DMF(8mL)与乙腈(8mL)的混合溶液,保温110℃搅拌3小时。将反应物冷却到室温,加入乙腈,产物析出,过滤,滤饼用DCM洗涤,40℃真空干燥得到中间体5c(2.3g,类白色固体)。
步骤2:向反应瓶中加入中间体5c(1.0g,0.0027mol)和水(2g),30%氢氧化钠溶液调节pH值到10~12,搅拌半小时,滴加苯甲酰氯(0.25g,0.0017mol)的THF(2mL)溶液,保持pH值10~12搅拌半小时。加入二氯甲烷(50mL)萃取,将有机相通过硅胶柱色谱法(二氯甲烷∶甲醇=30∶1)纯化,将所得产品再通过液相制备色谱法纯化,冻干得到标题化合物5(类白色固体)。
MS m/z(ESI):405[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.86(s,1H),7.85(s,1H),7.77(d,2H),7.72(t,1H),7.56(t,2H),6.66(br,2H),4.44(s,2H),3.71(t,2H),2.91(t,2H),2.21(s,3H),2.18(s,3H).
实施例6:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-氟戊-2-烯-3-基)呋喃-2-硫代甲酸酯(化合物6)的合成
Figure PCTCN2022097105-appb-000025
除了将实施例1步骤2中的苯甲酰氯替换为6d之外,采用与实施例1相同的合成路线,制得标题化合物6(淡黄色固体)。
MS m/z(ESI):379[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ8.04(s,1H),7.86(s,1H),7.81(s,1H),7.32(d,1H),6.76(d,1H),6.65(br,2H),4.55(t,1H),4.45-4.41(m,2H),2.85(dt,2H),2.24(s,3H),2.15(s,3H).
实施例7:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-氟戊-2-烯-3-基)环己基硫代甲酸酯(化合物7)的合成
Figure PCTCN2022097105-appb-000026
除了将实施例1步骤2中的苯甲酰氯替换为7d之外,采用与实施例1相同的合成路线,制得标题化合物7(黄色固体)。
MS m/z(ESI):395[M+1] +.
1H NMR(500MHz,DMSO-d 6):δ7.78(s,1H),7.76-7.74(d,1H),6.70(s,2H),4.51-4.48(t,1H),4.37(s,2H),2.78-2.67(m,2H),2.39(s,1H),2.27(s,3H),2.10(s,3H),1.81-1.55(m,6H),1.36-1.14(m,5H).
实施例8:S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-氟戊-2-烯-3-基)(E)-3-苯基丙-2-硫代烯酸酯(化合物8)的合成
Figure PCTCN2022097105-appb-000027
除了将实施例1步骤2中的苯甲酰氯替换为8d之外,采用与实施例1相同的合成路线,制得标题化合物8(淡黄色固体)。
MS m/z(ESI):415[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ8.38(s,1H),8.34(s,1H),8.19(d,2H),8.00-7.93(m,4H),7.22(d,1H),6.81(s,2H),5.07-4.95(m,4H),3.40(dt,2H),2.73(s,3H),2.70(s,3H).
实施例9:(Z)-4-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-3-(苯甲酰基硫基)戊-3-烯-1-基醋酸酯(化合物9)的合成
Figure PCTCN2022097105-appb-000028
步骤1:将化合物1a(5.6g,0.02mol)和9b(3.7g,0.02mol)溶解在10mLDMF中,加热到110℃,回流三小时;然后冷却到室温,滴加甲基叔丁基醚,产物析出,得到粗产物9c(2.5g,黄色油状物),将其直接用于下一步反应。
步骤2:将上述粗产物(2.5g)加入10g水中,搅拌溶解,用30%氢氧化钠溶液调节pH值至10-11,滴加苯甲酰氯(0.7g)的四氢呋喃溶液,保持pH值为10-11,反应0.5小时,反应液用二氯甲烷萃取两次,然后浓缩干,得到黄色油状液体,将其通过制备液相色谱法纯化,产物冻干,得到标题化合物9(0.1g,白色固体)。
MS m/z(ESI):429[M+1] +.
1H NMR(500MHz,DMSO-d 6):δ7.85(s,1H),7.84(s,1H),7.77(d,2H),7.72(t,1H),7.56(t,2H),6.68(br,2H),4.44(s,2H),4.09(t,2H),2.77(t,2H),2.19(s,3H),2.18(s,3H),2.01(s,3H)。
实施例10:(Z)-4-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-3-((3-溴苯甲酰基)硫基)戊-3-烯-1-基醋酸酯(化合物10)的合成
Figure PCTCN2022097105-appb-000029
除了将实施例9步骤2中的苯甲酰氯替换为间溴苯甲酰氯之外,采用与实施例9相同的合成路线,制得标题化合物10(类白色固体)。
MS m/z(ESI):509[M+1] +.
1H NMR(500MHz,CD 3OD)δ7.95(s,1H),7.88-7.87(m,2H),7.84-7.79(m,2H),7.45(t,1H),4.57(br,2H),4.23(t,2H),2.86(t,2H),2.29(s,3H),2.25(s,3H),2.05(s,3H).
实施例11:(Z)-4-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-3-((呋喃-2-羰基)硫基)戊-3-烯-1-基醋酸酯(化合物11)的合成
Figure PCTCN2022097105-appb-000030
除了将实施例9步骤2中的苯甲酰氯替换为呋喃-2-甲酰氯之外,采用与实施例9相同的合成路线,制得标题化合物11(类白色固体)。
MS m/z(ESI):419[M+1] +.
1H NMR(500MHz,DMSO-d 6):δ8.03(s,1H),7.83(s,2H),7.31(dd,1H),6.77(dd,1H),6.64(br,2H),4.41(s,2H),4.07(t,2H),2.73(t,2H),2.23(s,3H),2.15(s,3H),1.99(s,3H)。
实施例12:(Z)-4-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-3-((2-甲氧基苯甲酰基)硫基)戊-3-烯-1-基醋酸酯(化合物12)的合成
Figure PCTCN2022097105-appb-000031
除了将实施例9步骤2中的苯甲酰氯替换为2-甲氧基苯甲酰氯之外,采用与实施例9相同的合成路线,制得标题化合物12(白色固体)。
MS m/z(ESI):459[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.83(s,1H),7.80(s,1H),7.60-7.57(m,2H),7.19(d,1H),7.05(t,1H),6.71(br,2H),4.42(s,2H),4.04(t,2H),3.87(s,3H),2.71(br,2H),2.24(s,3H),2.15(s,3H),2.00(s,3H).
实施例13:(Z)-4-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-3-(肉桂酰基硫基)戊-3-烯-1-基醋酸酯(化合物13)的合成
Figure PCTCN2022097105-appb-000032
除了将实施例9步骤2中的苯甲酰氯替换为肉桂酰氯之外,采用与实施例9相同的合成路线,制得标题化合物13(白色固体)。
MS m/z(ESI):455[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.84(s,1H),7.83(s,1H),7.75(d,2H),7.50-7.44(m,4H),6.88(d,1H),6.70(br,2H),4.42(s,2H),4.08(t,2H),2.72(t,2H),2.23(s,3H),2.14(s,3H),2.01(s,3H).
实施例14:(Z)-4-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-3-(苯甲酰基硫基)戊-3-烯-1-基苯甲酸酯(化合物14)的合成。
Figure PCTCN2022097105-appb-000033
步骤1:将化合物14a(34g,0.1mol)加入200mL DMF中,搅拌,滴加DIPEA(26g,0.2mol),降温到0℃,反应0.5小时,滴加TBSCl(23g,0.15mol),然后保温0-5℃,反应16小时,加入MTBE500mL,继续搅拌2小时,过滤,滤饼用MTBE洗涤,然后40℃烘干得到白色固体14b(30g)。
步骤2:将14b(30g,0.072mol)加入30mL水和60mL四氢呋喃中,搅拌,滴加30%NaOH溶液调节pH=10-11,反应0.5小时,然后在0-5℃,保持pH=10-11滴加苯甲酰氯(31g,0.216mol), 反应1小时,萃取,将有机相通过硅胶柱色谱法(甲醇∶二氯甲烷=1∶20)纯化,得到标题化合物14(0.3g,白色固体)。
MS m/z(ESI):491[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.93(dd,2H),7.85(s,1H),7.79(s,1H),7.74-7.65(m,4H),7.54-7.51(m,4H),6.65(s,2H),4.44-4.37(m,4H),2.92(t,2H),2.19(s,3H),2.13(s,3H)。
实施例15:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-甲氧基戊-2-烯-3-基)硫代苯甲酸酯(化合物15)的合成
Figure PCTCN2022097105-appb-000034
步骤1:将1a(2.0g,0.007mol)和15b(1.0g,0.006mol)加入DMF 5mL中,保温110℃搅拌2小时。将反应物冷却到室温,加入乙腈,产物析出,过滤,滤饼用DCM洗涤,40℃真空干燥得到中间体15c(1.5g)。
步骤2:将15c(1.5g,0.004mol)加入到100mL单口瓶中,加入3g H 2O和30%氢氧化钠溶液调节pH值到12,搅拌半小时,降温到10℃,滴加苯甲酰氯(0.4g,0.0028mol)的THF溶液(4mL),保持pH值10-12搅拌半小时。加入二氯甲烷(50mL)萃取,将有机相通过硅胶柱色谱法(二氯甲烷∶甲醇=20∶1)纯化,40℃下真空浓缩得到标题化合物15(0.3g,类白色固体)。
MS m/z(ESI):401[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.84(s,1H),7.83(s,1H),7.76(d,2H),7.70(t,1H),7.54(t,2H),6.67(br,2H),4.41(s,2H),3.38(t,2H),3.21(s,3H),2.66(t,2H),2.21(s,3H),2.16(s,3H).
实施例16:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-甲氧基戊-2-烯-3-基)硫代苯甲酸酯(化合物15)的盐酸盐的合成
Figure PCTCN2022097105-appb-000035
将如实施例15中制备的化合物15加入乙酸乙酯(10mL)中,在冰盐浴下搅拌至完全溶解,滴加适量盐酸异丙醇溶液,至白色固体析出,过滤,将滤饼在50℃下真空干燥,得到化合物15的盐酸盐(类白色固体)。
MS m/z(ESI):401[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ14.45(br,1H),9.14(br,1H),8.20(s,1H),8.04(br,1H),7.93(s,1H),7.75-7.70(m,3H),7.56(t,2H),4.53(s,2H),3.42(t,2H),3.22(s,3H),2.66(t,2H),2.28(s,3H),2.23(s,3H).
实施例17:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-甲氧基戊-2-烯-3-基)2-甲氧基硫代苯甲酸酯(化合物17)的合成
Figure PCTCN2022097105-appb-000036
除了将实施例15步骤2中的苯甲酰氯替换为邻甲氧基苯甲酰氯之外,采用与实施例15相同的合成路线,得到标题化合物17(白色固体)。
MS m/z(ESI):431[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.82(s,1H),7.80(s,1H),7.60-7.56(m,2H),7.19(d,1H),7.04(t,1H),6.71(s,2H),4.40(s,2H),3.87(s,3H),3.36(t,2H),3.21(s,3H),2.61(br,2H),2.26(s,3H),2.13(s,3H).
实施例18:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-甲氧基戊-2-烯-3-基)3-溴硫代苯甲酸酯(化合物18)的合成
Figure PCTCN2022097105-appb-000037
除了将实施例15步骤2中的苯甲酰氯替换为间溴苯甲酰氯之外,采用与实施例15相同的合成路线,得到标题化合物18(白色固体)。
MS m/z(ESI):481[M+1] +.
1H NMR(500MHz,CDCl3)δ7.93-7.92(m,2H),7.84(s,1H),7.73-7.69(m,2H),7.32(t,1H),5.94(s,2H),3.45(t,2H),3.31(s,3H),2.71(br,2H),2.41(s,3H),2.17(s,3H)
实施例19:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-甲氧基戊-2-烯-3-基)呋喃-2-硫代甲酸酯(化合物19)的合成
Figure PCTCN2022097105-appb-000038
除了将实施例15步骤2中的苯甲酰氯替换为呋喃-2-甲酰氯之外,采用与实施例15相同的合成路线,得到标题化合物19(白色固体)。
MS m/z(ESI):391[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ8.03(s,1H),7.83(s,1H),7.81(s,1H),7.30(d,1H),6.75(d,1H),6.66(br,2H),4.39(s,2H),3.36(t,2H),3.19(s,3H),2.62(t,2H),2.26(s,3H),2.13(s,3H).
实施例20:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-甲氧基戊-2-烯-3-基)环己基硫代甲酸酯(化合物20)的合成
Figure PCTCN2022097105-appb-000039
除了将实施例15步骤2中的苯甲酰氯替换为环己甲酰氯之外,采用与实施例15相同的合成路线,得到标题化合物20(白色固体)。
MS m/z(ESI):407[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.78(s,1H),7.71(s,1H),6.69(br,2H),4.36(s,2H),3.31(t,2H),3.18(s,3H),2.52(t,2H),2.38(br,1H),2.28(s,3H),2.08(s,3H),1.76-1.71(m,2H),1.68-1.62(m,2H),1.57-1.55(m,1H),1.28-1.14(m,5H).
实施例21:S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-甲氧基戊-2-烯-3-基)(E)-3-苯基丙-2-硫代烯酸酯(化合物21)的合成
Figure PCTCN2022097105-appb-000040
除了将实施例15步骤2中的苯甲酰氯替换为肉桂酰氯之外,采用与实施例15相同的合成路线,得到标题化合物21(白色固体)。
MS m/z(ESI):427[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.82(s,1H),7.81(s,1H),7.77-7.71(m,2H),7.49-7.42(m,4H),6.85(d,1H),6.66(s,2H),4.39(s,2H),3.37(t,2H),3.20(s,3H),2.62(t,2H),2.23(s,3H),2.11(s,3H).
实施例22:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-乙氧基戊-2-烯-3-基)硫代苯甲酸酯(化合物22)的合成
Figure PCTCN2022097105-appb-000041
除了将实施例15步骤1中的15b替换为22b之外,采用与实施例15相同的合成路线,制得标题化合物22(类白色固体)。
MS m/z(ESI):415[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.84(s,2H),7.76(d,2H),7.69(t,1H),7.54(t,2H),6.71(d,2H),4.42(s,2H),3.42(t,2H),3.37(q,2H),2.65(t,2H),2.21(s,3H),2.16(s,3H),1.08(t,3H).
实施例23:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-乙氧基戊-2-烯-3-基)3-溴硫代苯甲酸酯(化合物23)的合成
Figure PCTCN2022097105-appb-000042
除了将实施例22步骤2中的苯甲酰氯替换为间溴苯甲酰氯之外,采用与实施例22相同的合成路线,制得标题化合物23(白色固体)。
MS m/z(ESI):495[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.91(dd,1H),7.83(s,1H),7.81(s,1H),7.78(t,1H),7.76(d,1H),7.50(t,1H),6.66(d,2H),4.41(s,2H),3.42(t,2H),3.36(q,2H),2.63(t,2H),2.19(s,3H),2.16(s,3H),1.07(t,3H).
实施例24:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-乙氧基戊-2-烯-3-基)2-甲氧基硫代苯甲酸酯(化合物24)的合成
Figure PCTCN2022097105-appb-000043
除了将实施例22步骤2中的苯甲酰氯替换为邻甲氧基苯甲酰氯之外,采用与实施例22相同的合成路线,制得标题化合物24(白色固体)。
MS m/z(ESI):445[M+1] +.
1H NMR(500MHz,CD 3OD)δ7.92(s,1H),7.83(s,1H),7.66(dd,1H),7.58-7.52(m,1H),7.14(d,1H),7.02(t,1H),4.52(br,2H),3.93(s,3H),3.53(t,2H),3.48(q,2H),2.72(br,2H),2.28(s,3H),2.23(s,3H),1.19(t,3H).
实施例25:S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-乙氧基戊-2-烯-3-基)(E)-3-苯基丙-2-硫代烯酸酯(化合物25)的合成
Figure PCTCN2022097105-appb-000044
除了将实施例22步骤2中的苯甲酰氯替换为肉桂酰氯之外,采用与实施例22相同的合成路线,制得标题化合物25(白色固体)。
MS m/z(ESI):441[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.82(s,2H),7.76(d,2H),7.50-7.44(m,4H),6.86(d,1H),6.68(br,2H),4.40(s,2H),3.41-3.38(m,4H),2.62(t,2H),2.24(s,3H),2.12(s,3H),1.08(t,3H).
实施例26:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-乙氧基戊-2-烯-3-基)呋喃-2-硫代甲酸酯(化合物26)的合成
Figure PCTCN2022097105-appb-000045
除了将实施例22步骤2中的苯甲酰氯替换为呋喃-2-甲酰氯之外,采用与实施例22相同的合成路线,制得标题化合物26(白色固体)。
MS m/z(ESI):405[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ8.03(d,1H),7.82(s,1H),7.82(s,1H),7.81(s,1H),7.30(d,1H),6.75(dd,3H),6.65(br,2H),4.40(s,2H),3.40(t,2H),3.36(q,2H),2.61(t,2H),2.24(s,3H),2.13(s,3H),1.07(t,3H).
实施例27:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-乙氧基戊-2-烯-3-基)环己基硫代甲酸酯(化合物27)的合成
Figure PCTCN2022097105-appb-000046
除了将实施例22步骤2中的苯甲酰氯替换为环己甲酰氯之外,采用与实施例22相同的合成路线,制得标题化合物27(白色固体)。
MS m/z(ESI):421[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.77(s,1H),7.70(s,1H),6.70(br,2H),4.36(s,2H),3.37-3.32(m,4H),2.52(br,2H),2.38(br,1H),2.27(s,3H),2.08(s,3H),1.77-1.71(m,2H),1.68-1.62(m,2H),1.57-1.55(m,1H),1.26-1.21(m,4H),1.14(br,1H),1.07(t,3H).
实施例28:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-乙氧基戊-2-烯-3-基)硫代苯甲酸酯(化合物22)的盐酸盐的合成
Figure PCTCN2022097105-appb-000047
将由实施例22制备的化合物22(0.1g,0.0146mol)加入到乙酸乙酯(3mL)中,搅拌溶清,然后在搅拌下滴加氯化氢的异丙醇溶液,至pH值达到1-2(约滴加0.5mL)。滴加完毕,搅拌30min,40℃下旋转蒸发除去溶剂,得到油状物。向油状物中加入去离子水(50mL),待油状物溶解后冷冻结冰,冻干,得到化合物22的盐酸盐(0.08g,类白色固体)。
MS m/z(ESI):415[M+1] +.
1H NMR(500MHz,DMSO-d 6):δ14.76(s,1H),9.13(s,1H),8.22(s,1H),8.05(s,1H),7.93(s,1H),7.76-7.70(m,3H),7.58-7.54(t,2H),4.55(s,2H),3.48-3.44(t,2H),3.41-3.36(q,2H),2.67-2.64(t,2H),2.29(s,3H),2.23(s,3H),1.08-1.05(t,3H)。
实施例30:(Z)-5-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-4-((2-甲氧基苯甲酰基)硫基)己-4-烯酸(化合物30)的合成
Figure PCTCN2022097105-appb-000048
步骤1:于100mL单口瓶中,依次加入1a(1.54g)、30b(1.67g)、无水乙腈(2g)、无水DMF(6g)搅拌,升温至110℃回流反应3h,反应完全,冷却至室温,加入无水乙腈100mL,过滤,滤饼用MEOH/CH 3CN溶清,减压浓缩除去溶剂,得产物30c(1.25g)。
步骤2:于100mL单口瓶中,依次加入30c(1.25g)、H 2O(3g),搅拌溶清,滴加30%NaOH调节pH至10-12,搅拌0.5h,滴加2-甲氧基苯甲酰氯(0.189g),HPLC检测表明反应完成,滴加36%HCl调节pH至4-5,加入DCM,搅拌10min后静置,分出有机相,水相用DCM洗涤两次,合并有机相,旋干,MeOH溶清,制备色谱法纯化,冻干,得到标题化合物30(白色固体)。
MS m/z(ESI):445[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.82(s,1H),7.79(s,1H),7.58-7.55(m,2H),7.19(d,1H),7.05(t,1H),6.71(br,2H),4.39(s,2H),3.86(s,3H),2.60(t,2H),2.33(t,2H),2.27(s,3H),2.13(s,3H).
实施例31:(Z)-5-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-4-((3-溴苯甲酰基)硫基)己-4-烯酸(化合物31)的合成
Figure PCTCN2022097105-appb-000049
除了将实施例30步骤2中的2-甲氧基苯甲酰氯替换为间溴苯甲酰氯之外,采用与实施例30相同的合成路线,制得标题化合物(类白色固体)。
MS m/z(ESI):493[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.92-7.88(m,1H),7.86(s,1H),7.85(s,1H),7.77(t,1H),7.76-7.72(m,1H),7.50(t,1H),6.77(br,2H),4.40(br,2H),2.64(t,2H),2.37(t,2H),2.18(s,3H),2.17(s,3H).
实施例32:(Z)-5-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-4-(苯甲酰基硫基)己-4-烯酸乙酯(化合物32)的合成
Figure PCTCN2022097105-appb-000050
向100mL单口瓶中,依次加入30c(1.45g)、4.0g H 2O,搅拌溶清;滴加30%NaOH,调节pH至10-12左右,至pH稳定不变为止;控制pH于10-12下滴加苯甲酰氯(0.336g,0.0024mol)/THF,反应10min,加入DCM,搅拌分层,将有机相干燥旋干,制备色谱法纯化制得标题化合物32(白色固体)。
MS m/z(ESI):443[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.84(s,1H),7.83(s,1H),7.76(d,2H),7.70(t,1H),7.56(t,2H),6.68(br,2H),4.41(s,2H),4.06(q,2H),2.69(t,2H),2.46(t,2H),2.20(s,3H),2.18(s,3H),1.18(t,3H).
实施例33:(Z)-5-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-4-((2-甲氧基苯甲酰基)硫基)己-4-烯酸乙酯(化合物33)的合成
Figure PCTCN2022097105-appb-000051
除了将实施例32中的苯甲酰氯替换为2-甲氧基苯甲酰氯之外,采用与实施例32相同的合成路线,制得标题化合物33(白色固体)。
MS m/z(ESI):473[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.80(s,1H),7.78(s,1H),7.58-7.56(m,2H),7.19(d,1H),7.05(t,1H),6.68(s,2H),4.38(s,2H),4.06(t,2H),3.86(s,3H),2.64(t,2H),2.40(t,2H),2.27(s,3H),2.14(s,3H),1.18(t,3H).
实施例34:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-吗啉代戊-2-烯-3-基)硫代苯甲酸酯(化合物34)的合成
Figure PCTCN2022097105-appb-000052
除了将实施例1步骤1中的1b替换为34b之外,采用与实施例1相同的合成路线,得到标题化合物34(白色固体)。
MS m/z(ESI):456[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.85(s,1H),7.84(s,1H),7.76(d,2H),7.71(t,1H),7.56(t,2H),6.67(br,2H),4.42(s,2H),3.54(br,4H),2.57(t,2H),2.38-2.33(m,6H),2.21(s,3H),2.16(s,3H).
实施例35:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-吗啉代戊-2-烯-3-基)2-甲氧基硫代苯甲酸酯(化合物35)的合成
Figure PCTCN2022097105-appb-000053
除了将实施例34步骤2中的苯甲酰氯替换为邻甲氧基苯甲酰氯之外,采用与实施例34相同的合成路线,制得标题化合物35(白色粉末状固体)。
MS m/z(ESI):486[M+1] +.
1H NMR(500MHz,CD 3OD):δ7.93(s,1H),7.84(s,1H),7.65(dd,1H),7.59-7.53(m,1H),7.14(d,1H),7.03(t,1H),4.55(br,2H),3.93(s,3H),3.70(t,4H),2.68(t,2H),2.54-2.44(m,6H),2.28(s,3H),2.24(s,3H)。
实施例36:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(4-苯基哌嗪-1-基)戊-2-烯-3-基)2-氟硫代苯甲酸酯(化合物36)的甲酸盐的合成
Figure PCTCN2022097105-appb-000054
步骤1:于100mL单口瓶中加入1a(2.1g)、36b(1.0g)、乙腈(20g)和N,N-二甲基甲酰胺(6g),升温至100~110℃搅拌3小时。将反应物冷却到室温,产物析出,过滤,滤饼用20mL乙腈打浆,过滤,滤饼40℃真空干燥得到中间体36c。
步骤2:于100mL单口瓶中加入36c(2.1g),水(5.0g),滴加30%NaOH调pH至11.0,搅拌 30分钟,复测pH大于11.0;滴加邻氟苯甲酰氯/四氢呋喃(0.38g/2mL),加入乙酸乙酯5mL,分液,水相用5mL乙酸乙酯萃取两次,合并有机相,干燥,旋干后用甲醇溶解,制备色谱法纯化得到标题化合物36的甲酸盐(白色固体)。
MS m/z(ESI):549[M+1] +.
1H NMR(500MHz,CD 3OD)δ8.29(s,1H),7.97(s,1H),7.90(s,1H),7.74(t,1H),7.65(d,1H),7.34-7.20(m,4H),6.96(d,2H),6.85(t,1H),4.55(br,2H),3.25(t,4H),2.91(t,4H),2.82(s,4H),2.27(s,3H),2.15(s,3H).
实施例37:S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-((2S,6R)-2,6-二甲基吗啉代)戊-2-烯-3-基)2-氟硫代苯甲酸酯(化合物37)的合成
Figure PCTCN2022097105-appb-000055
步骤1:将37b(1.8g,0.0075mol)与1a(3.2g,0.0125mol)溶于DMF(15g)与乙腈(5g)的混合溶液中,油浴加热至110℃反应3小时。反应液冷却至室温,过滤,滤饼用乙腈洗涤,将滤饼烘干得到浅灰黄色固体37c(2.71g)。
步骤2:将37c(5.56g,0.0106mol)溶解在水中(20mL),搅拌溶解;向反应液中滴加30%的氢氧化钠溶液,调节pH至10~11,冰浴降温至10℃,保温10分钟。10℃下滴加邻氟苯甲酰氯的四氢呋喃(5mL)溶液,在滴加过程中控制pH至10~11。滴加完毕,保温并保持pH值继续反应15分钟,调节反应液pH至7~8,用二氯甲烷萃取三次,二氯甲烷层用无水硫酸钠干燥,除去溶剂,将粗品通过柱色谱法纯化。柱色谱法纯化后的产品用纯净水溶解,冻干得到目标化合物37(0.055g,类白色固体)。
MS m/z(ESI):502[M+1] +.
1H NMR(500MHz,DMSO-d 6):δ7.80(s,2H),7.70-7.60(m,2H),7.36-7.30(m,2H),6.65(br,2H),4.39(s,2H),3.53-3.42(m,2H),2.67(d,2H),2.52(d,2H),2.32(t,2H),2.16(s,3H),2.12(s,3H),1.58(t,2H),1.00(d,6H)。
实施例38:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(4-(甲磺酰基)哌嗪-1-基)戊-2-烯-3-基)2-氟硫代苯甲酸酯(化合物38)的甲酸盐的合成
Figure PCTCN2022097105-appb-000056
步骤1:于100mL单口瓶中加入1a(1.4g)、38b(0.7g)、乙腈(2.0g)和N,N-二甲基甲酰胺(6.0g),升温至100~110℃搅拌3小时。将反应物冷却到室温,加入丙酮,产物析出,过滤,滤饼用20mL乙腈打浆,过滤,滤饼40℃真空干燥得到中间体38c(3.3g)。
步骤2:于100mL单口瓶中加入中间体38c(3.3g),水(4.4g),滴加30%NaOH调pH至11.0,搅拌10分钟,复测pH大于11.0;滴加邻氟苯甲酰氯/四氢呋喃(0.3g/2mL),加入乙酸乙酯5mL,分液,水相用5mL乙酸乙酯萃取两次,合并有机相,干燥,旋干后用甲醇溶解,制备色谱法纯化得到化合物38的甲酸盐(白色固体)。
MS m/z(ESI):551[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ8.15(s,1H),7.84(s,1H),7.82(s,1H),7.69(t,2H),7.38-7.32(m,2H),6.69(s,2H),4.40(s,2H),3.05(t,4H),2.87(s,3H),2.55(t,2H),2.43-2.40(m,6H),2.17(s,3H),2.14(s,3H).
实施例39:(Z)-S-(5-乙酰胺基-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)戊-2-烯-3-基)硫代苯甲酸酯(化合物39)的合成
Figure PCTCN2022097105-appb-000057
步骤1:将39b(1.8g,0.01mol)和1a(5.6g,0.02mol)加入8mLDMF中,加热到110℃,然后搅拌2小时;冷却到0~10℃,加入MTBE使产物析出,过滤,滤饼用MTBE洗涤,将滤饼烘干,得到中间体粗产物39c(5.5g,黄色固体)
步骤2:将粗产物39c(3.4g,0.01mol)加入6.8g水中,搅拌溶解,用30%氢氧化钠溶液调节pH值至10-11,滴加苯甲酰氯(1.4g,0.01mol)的四氢呋喃溶液,保持pH值10-11反应0.5小时,反应液用二氯甲烷萃取两次,然后浓缩干,然后通过柱色谱法分离,二氯甲烷∶甲醇=10∶1洗脱出产物,将粗产物通过制备色谱法纯化,产物冻干,得到标题化合物(0.1g,白色固体)。
MS m/z(ESI):428[M+1] +.
1H NMR(500MHz,DMSO-d 6):δ7.91(s,1H),7.88(t,1H),7.83(s,1H),7.73-7.67(m,3H),7.54(t,2H),6.63(br,2H),4.39(s,2H),3.17(q,2H),2.52(t,2H),2.12(s,3H),2.11(s,3H),1.78(s,3H)。
实施例40:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(甲基(苯基)氨基)戊-2-烯-3-基)2-氟硫代苯甲酸酯(化合物40)的合成
Figure PCTCN2022097105-appb-000058
步骤1:将40b(1.0g,0.0043mol)加入5mL DMF中,然后加入1a(1.6g,0.0057mol),加热到110℃回流3小时,然后冷却到室温,过滤,滤饼用乙腈洗涤,减压干燥得到中间体40c(1.7g,白色固体)。
步骤2:将40c(1.7g,0.004mol)溶解在15g水中,搅拌溶解,开始滴加氢氧化钠溶液(30%)调节pH至10-12,搅拌10分钟,复测pH,调节pH至10-12直至稳定不变,搅拌0.1小时,保持在10℃以下滴加邻氟苯甲酰氯(0.7g,0.0044mol)和10mL四氢呋喃的溶液,滴加过程中加入氢氧化钠溶液保持pH 10~12,滴加结束后保温反应0.5小时,二氯甲烷萃取两次,将有机相通过硅胶柱色谱法(甲醇∶二氯甲烷=1∶20)纯化,得到标题化合物40(0.13g,黄色固体)。
MS m/z(ESI):494[M+1] +.
1H NMR(500MHz,DMSO-d 6):δ7.83(s,1H),7.72-7.68(m,1H),7.67-7.62(m,2H),7.41-7.34(m,2H),7.14(t,2H),6.68(d,2H),6.60(t,1H),4.39(s,2H),3.49(t,2H),2.80(s,3H),2.63(t,2H),2.16(s,3H),2.07(s,3H)。
实施例41:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(甲磺酰胺基)戊-2-烯-3-基)2-氟硫代苯甲酸酯(化合物41)的合成
Figure PCTCN2022097105-appb-000059
步骤1:将41b(1.8g,0.0088mol)与1a(3.2g,0.0125mol)溶于DMF(15g)与乙腈(5g)的混合溶液中,油浴加热至110℃反应3小时。反应液冷却至室温,过滤,滤饼用乙腈洗涤,将滤饼烘干得到中间体41c(2.71g,浅灰黄色固体)。
步骤2:将中间体41c(2.71g)溶解在水中(20mL),搅拌溶解;向反应液中滴加30%的氢氧化钠溶液,调节pH至10~11,冰浴降温至10℃,保温10分钟。10℃下滴加邻氟苯甲酰氯的四氢呋喃 (5mL)溶液,在滴加过程中控制pH至10~11。滴加完毕,保温并保持pH值继续反应15分钟,调节反应液pH至7~8,用二氯甲烷萃取三次,二氯甲烷层用无水硫酸钠干燥,除去溶剂,粗品通过柱色谱法纯化。柱色谱法纯化产品用纯净水溶解,冻干得到标题化合物41(0.31g,类白色固体)。
MS m/z(ESI):482[M+1] +.
1H NMR(500MHz,DMSO-d 6):δ7.92(s,1H),7.82(s,1H),7.68-7.63(m,2H),7.36-7.31(m,2H),7.07(br,1H),6.65(br,2H),4.38(s,2H),3.05(q,2H),2.86(s,3H),2.58(t,2H),2.16(s,3H),2.08(s,3H)。
实施例42:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-6-(甲基氨基)-6-氧代己-2-烯-3-基)硫代苯甲酸酯(化合物42)的合成
Figure PCTCN2022097105-appb-000060
步骤1:于100mL单口瓶中,依次加入1a(1.54g)、42b(1.67g)、无水乙腈(2g)和无水DMF(6g),搅拌,升温至110℃回流反应3h,反应完全,冷却至室温,加入无水乙腈100mL,过滤,滤饼用MeOH/CH 3CN溶清,减压浓缩除去溶剂,得中间产物42c(1.25g)。
步骤2:于100mL单口瓶中,依次加入42c(1.25g)、H 2O(3g)搅拌溶清,滴加30%NaOH调节pH至10-12,搅拌0.5h,滴加苯甲酰氯(0.189g),HPLC检测,加入DCM,搅拌10min静置,分出有机相,水相用DCM洗涤两次,合并有机相,旋干,MeOH溶清,制备色谱法纯化,冻干,得到标题化合物42(白色固体)。
MS m/z(ESI):428[M+1] +.
1H NMR(500MHz,DMSO-d 6):δ7.84(s,1H),7.82(s,1H),7.78(q,1H),7.76(d,1H),7.70-7.69(t,1H),7.56(t,2H),6.67(br,2H),4.40(s,2H),2.65(t,2H),2.55(d,3H),2.21-2.19(m,5H),2.15(s,3H).
实施例43:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-6-(二甲氨基)-6-氧代己-2-烯-3-基)硫代苯甲酸酯(化合物43)的合成
Figure PCTCN2022097105-appb-000061
除了将实施例42步骤1中的42b替换为43b之外,采用与实施例42相同的合成路线,制得标题化合物43(白色固体)。
MS m/z(ESI):442[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.84(s,1H),7.82(s,1H),7.75(d,2H),7.68(t,1H),7.55(t,2H),6.67(br,2H),4.39(s,2H),2.90(s,3H),2.80(s,3H),2.65(t,2H),2.43(t,2H),2.18(s,3H),2.15(s,3H).
实施例44:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)戊-2-烯-3-基)硫代苯甲酸甲酯(化合物44)的合成
Figure PCTCN2022097105-appb-000062
步骤1:于100mL单口瓶中加入乙腈,1a(0.0079mol)、44b(0.0079mol),加热至110℃回流,回流反应2h,有固体析出,过滤,得到固体减压浓缩除去溶剂,用少量MeOH溶解,加入EA,固体析出,过滤,减压浓缩除去溶剂得到中间体44c(2.0g)。
步骤2:于100mL单口瓶中,一次加入2.0g中间体44c、4.0g H 2O,搅拌溶清;滴加30%NaOH反应30min,控制pH于10-12;滴加苯甲酰氯0.20g(0.00141mol),反应1h;调节pH至4.0,固体析出,过滤,滤饼用EA打浆处理,然后用MeOH打浆处理,烘干得到标题化合物44(类白色固体)。
MS m/z(ESI):371[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.85(s,1H),7.84(s,1H),7.76(d,2H),7.71(t,1H),7.55(t,2H),6.68(s,2H),4.40(s,2H),2.43(t,2H),2.20(s,3H),2.14(s,3H),0.98(t,3H).
实施例45:(Z)-S-(3-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)丁-2-烯-2-基)硫代苯甲酸酯(化合物45)的合成
Figure PCTCN2022097105-appb-000063
除了将实施例44步骤1中的44b替换为45b之外,采用与实施例44相同的合成路线,制得到标题化合物45(白色固体)。
MS m/z(ESI):357[M+1] +.
1H NMR(500MHz,DMSO-d 6):δ7.87(s,1H),7.85(s,1H),7.74(d,2H),7.71(t,1H),7.55(t,2H),6.71(br,2H),4.41(s,2H),2.17(s,3H),2.13(s,3H),2.07(s,3H)。
实施例46:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(甲硫基)戊-2-烯-3-基)硫代苯甲酸酯(化合物46)的合成
Figure PCTCN2022097105-appb-000064
步骤1:将46b(1.4g)和1a(4.4g)加入10mL DMF中,加热到110℃,回流三小时。然后将反应物冷却到室温,滴加甲基叔丁基醚,产品析出,得到黄色油状物1.8g,将该粗产物直接用于下一步反应。
步骤2:将上述粗产物(1.8g)加入10g水中,搅拌溶解。用30%氢氧化钠溶液调节pH至10-11。滴加苯甲酰氯的四氢呋喃溶液,保持pH值10-11反应0.5小时,反应液用二氯甲烷萃取两次,然后浓缩至干,得到黄色油状液体,制备液相色谱法纯化,产物冻干,得到标题化合物46(0.03g,类白色固体)。
MS m/z(ESI):417[M+1] +.
1H NMR(500MHz,DMSO-d 6):δ7.90-7.88(m,3H),7.78(s,1H),7.74(t,1H),7.59(t,2H),6.76(br,2H),3.64(br,2H),2.80(s,3H),2.70(t,2H),2.59(t,2H),2.26(s,3H),2.10(s,3H).
实施例47:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(苄氧基)戊-2-烯-3-基)硫代苯甲酸酯(化合物47)的合成
Figure PCTCN2022097105-appb-000065
步骤1:将2.02g化合物1a和2.3g化合物47b溶解在6.9g DMF中,加热至110℃反应4h,冷却后加入20mL乙腈,搅拌析出固体。过滤,滤饼用乙腈冲洗,烘干后得到粗品3.4g。
步骤2:将3.4g粗产品溶解在10g水中,搅拌溶解。滴加氢氧化钠溶液(30%)调节pH至10-11。将pH稳定在10-11下,冰浴降温搅拌10min;保持在10℃以下滴加苯甲酰氯的四氢呋喃溶液,滴加过程中加入氢氧化钠溶液保持pH为10-11。滴加完成,保温反应10min。加入二氯甲烷萃取两次,弃去有机相,浓缩得到粗品,制备HPL纯化,冻干得到标题化合物47(类白色固体)。
MS m/z(ESI):477[M+1] +.
1H NMR(400MHz,DMSO-d 6):δ7.82(s,2H),7.73-7.68(m,3H),7.55(t,2H),7.34-7.27(m,5H),6.67(br,2H),4.43-4.41(m,4H),3.51(t,2H),2.72(t,2H),2.18(s,3H),2.16(s,3H).
实施例48:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-羟基戊-2-烯-3-基)硫代苯甲 酸酯(化合物48)的合成
Figure PCTCN2022097105-appb-000066
将VB1(33.7g,0.1mol)加入100mL水中,搅拌溶清,滴加30%NaOH溶液调节pH=10-12,反应0.5小时,然后在0-5℃,保持pH=10-12下滴加苯甲酰氯(14.2g,0.1mol),反应1小时,萃取,有机相硅胶柱色谱法(甲醇∶二氯甲烷=1∶20)纯化,浓缩得到白色固体(12.8g,产率33.1%)。
MS m/z(ESI):387[M+1] +.
1H NMR(500MHz,CD 3OD):δ8.01(s,1H),7.85(s,1H),7.80(dd,2H),7.67-7.63(m,1H),7.51-7.47(m,2H),4.56(br,2H),3.71(t,2H),2.75(t,2H),2.27(s,3H),2.19(s,3H)。
实施例49:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)戊-1,3-二烯-3-基)硫代苯甲酸酯(化合物49)的合成
Figure PCTCN2022097105-appb-000067
步骤1:将1a(2.8g,0.01mol)和49b(1.2g,0.01mol)加入12mL DMF和4mL乙腈的混合溶液中,110℃下反应2h。冷却后加乙腈,析出固体,过滤,得到粗产物约1.2g。
步骤2:向步骤1的粗产物中加入3g水,30%氢氧化钠溶液调节pH值到10~12,搅拌半小时,滴加苯甲酰氯(0.4g)的四氢呋喃(2mL)溶液,保持pH值10~12搅拌半小时。加入二氯甲烷50mL萃取,无水硫酸钠干燥,硅胶柱色谱法(二氯甲烷∶甲醇=30∶1)纯化,得粗品32mg,然后液相制备色谱法纯化,冻干得标题化合物49(10mg,黄色固体)。
MS m/z(ESI):369[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ7.91(s,1H),7.86(s,1H),7.81(d,2H),7.71(t,1H),7.56(t,2H),6.97(dd,1H),6.67(br,2H),5.46(d,1H),5.31(d,1H),4.49(s,2H),2.30(s,3H),2.22(s,3H).
实施例50:(Z)-S-(6-氨基-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-6-氧代己-2-烯-3-基)硫代苯甲酸酯(化合物50)的合成
Figure PCTCN2022097105-appb-000068
除了将实施例49步骤1中的49b替换为50b之外,采用与实施例49相同的合成路线,制得标题化合物50(白色固体)。
MS m/z(ESI):414[M+1] +.
1H NMR(500MHz,DMSO-d 6):δ7.86(s,1H),7.84(s,1H),7.76(d,2H),7.56(t,1H),7.53(t,2H),6.67(br,2H),4.40(s,2H),2.65(t,2H),2.23-2.16(m,8H)。
实施例51:(Z)-S-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-6-吗啉代-6-氧代己-2-烯-3-基)3-溴硫代苯甲酸酯(化合物51)的合成
Figure PCTCN2022097105-appb-000069
向反应瓶中依次加入化合物31(0.20g,0.4mmol,1.0eq.)、二氯甲烷(10mL)、吗啉(0.035g,0.4 mmol,1.0eq.)、HATU(0.18g,0.48mmol,1.2eq.)和N,N-二异丙基乙胺(0.10g,0.8mmol,2.0eq.)。所得反应液室温搅拌16小时,减压浓缩后用制备HPLC分离纯化,收集目标组分冻干得到标题化合物51(90mg,类白色固体,收率:40%)。
MS m/z(ESI):562,564[M+1] +.
1H NMR(400Hz,DMSO-d 6):δ7.90-7.84(m,3H),7.76-7.72(m,2H),7.49(t,1H),6.83(br,2H),4.39(br,2H),3.54-3.50(m,4H),3.39-3.36(m,4H),2.64(t,2H),2.47(t,2H),2.17(s,3H),2.16(s,3H).
实施例52:(Z)-S-(2-(N-((4-氨基-2-苯基嘧啶-5-基)甲基)甲酰胺基)-5-甲氧基戊-2-烯-3-基)硫代苯甲酸酯(化合物52)的合成
Figure PCTCN2022097105-appb-000070
步骤1:将52a(31.3g,0.2mol)加入200mL无水乙醇中,加入甲醇钠(10.8g,0.2mol)搅拌3小时;过滤,滤液加入500mL反应瓶中,降温到0~10℃;加入乙氧基亚甲基丙二腈(24.4g,0.2mol),有黄色固体析出,室温搅拌12h,过滤,滤饼用无水乙醇洗涤2次,滤饼40℃真空干燥得到52b(23.5g,60%收率)。
步骤2:将52b(23.5g)和RaneyNi(24.5g)加入125g甲酸和24.5g水中,加热到60℃,回流三小时。将反应物过滤,滤饼用甲酸洗涤。将滤液冷却到0℃,滴加氨水,产品析出,搅拌1小时;过滤,滤饼真空烘干得到淡黄色粗产物25g。将粗产物加入150mL甲醇中,用冷水浴降温到0℃分批加入硼氢化钠(4.8g,0.126mol),搅拌3小时,LC-MS监测表明反应完成,硅胶柱色谱法(二氯甲烷∶甲醇=10∶1)纯化,40℃真空浓缩得到52c(白色固体13.5g,收率50%)。
步骤3:将52c(6.1g,0.03mol)和DMAP(6.6g,0.054mol)加入100mL二氯甲烷中,用冷水浴降温到0℃,滴加甲磺酰氯(5.2g,0.045mol),然后搅拌2小时。减压浓缩,蒸干溶剂。
步骤4:在步骤3的产物中加入DMF 20mL和5-(2-甲氧基乙基)-4-甲基噻唑(4.7g,0.03mol),加热到110℃回流3小时,LC-MS监测表明反应完成,冷却到室温,加入MTBE析出产物,分离清夜,残留物减压浓缩得到油状液体52e(14g),将其在未进一步纯化下直接用于下一步反应。
步骤5:将步骤4中粗产物52e(4.3g,0.01mol)加入30g水中,搅拌溶解,用30%氢氧化钠溶液调节pH值10-11,滴加苯甲酰氯的四氢呋喃溶液,保持pH值10-11反应0.5小时,反应液用二氯甲烷萃取两次,然后浓缩至干,得到黄色油状液体,制备液相色谱法纯化,产物冻干,得到标题化合物52(0.06g,白色固体)。
MS m/z(ESI):463.0[M+1] +.
1H NMR(400MHz,DMSO-d 6):δ8.21(dd,2H),8.07(s,1H),7.87(s,1H),7.66-7.62(m,3H),7.45-7.40(m,5H),6.82(br,2H),4.51(s,2H),3.39(t,2H),3.21(s,3H),2.66(t,2H),2.20(s,3H).
实施例53:(Z)-S-(2-(N-((4-氨基-2-苯基嘧啶-5-基)甲基)甲酰胺基)-5-甲氧基戊-2-烯-3-基)呋喃-2-硫代甲酸酯(化合物53)的合成
Figure PCTCN2022097105-appb-000071
除了将实施例52步骤5中苯甲酰氯替换为53b之外,采用与实施例52相同的合成路线,制得标题化合物53(类白色固体)
MS m/z(ESI):453.0[M+1] +.
1H NMR(500MHz,DMSO-d 6)δ8.25-8.23(m,2H),8.06(s,1H),7.96(d,1H),7.86(s,1H),7.46-7.45(m,3H),7.19(d,1H),6.82(br,2H),6.69(dd,1H),4.48(s,2H),3.38(t,2H),3.20(s,3H),2.63(t,2H),2.17(s,3H).
实施例54:(Z)-S-(2-(N-((4-氨基-2-(吡啶-2-基)嘧啶-5-基)甲基)甲酰胺基)-5-甲氧基戊-2-烯-3-基)硫代苯甲酸酯(化合物54)的合成
Figure PCTCN2022097105-appb-000072
步骤1:于500mL单口瓶中加入54a(50.0g,318.5mmol,1.0eq)和甲醇(500mL),搅拌下加入MeONa(18g,333.3mmol,1.05eq),室温下搅拌0.5小时,加入乙氧基亚甲基丙二腈(38.8g,318.5mmol,1.0eq),室温下搅拌2小时,过滤,滤饼干燥得到54b(黄色固体,40g,收率:63.7%)。
步骤2:于250mL三口瓶中加入54b(40g,203mmol,1.0eq)、30%NaOH(200mL)和甲醇(200mL),升温至90℃搅拌反应4小时,冷却至室温,2M HCl调节pH=5,过滤,滤饼烘干后得白色固体32g。将白色固体转移至1000mL三口瓶中,加入甲醇(1000mL)和氯化亚砜(19.8g,167mmol,1.2eq),升温至90℃搅拌反应4小时,冷却至室温,饱和碳酸氢钠调节pH=7-8,过滤,滤饼烘干后得54c(黄色固体,25g)。
步骤3:于500mL单口瓶中加入54c(10.0g,43.5mmol,1.0eq),氮气保护下加入THF(100mL),冰浴降温,滴加LiAlH 4(52mL,52mmol,1.2eq),搅拌2小时,加水淬灭,加入EA萃取,将有机相用无水硫酸钠干燥,浓缩得到粗品,通过硅胶柱分离纯化(洗脱剂为DCM∶MeOH=20∶1~5∶1),得到54d(黄色固体,8.9g)。
步骤4:于100mL单口瓶中加入54d(6g,29.7mmol,1.0eq)和33%HBr醋酸溶液(18g),升温至100℃搅拌反应2小时,冷却,加入乙腈,过滤得54e(黄色固体,6.5g,收率82.5%)。
步骤5:于100mL单口瓶中加入5-(2-甲氧基乙基)-4-甲基噻唑(2.67g,17mmol,1.5eq),54e(3.0g,11.4mmol,1.0eq)和DMF(30mL),升温至110℃搅拌3小时,冷却,加入乙腈搅拌过滤,滤饼干燥得到54f(黄色固体,2.6g,收率54%)。
步骤6:将54f(2.6g,6.4mmol,1.0eq)溶解在10g水中,滴加30%氢氧化钠溶液调节pH至10-12,搅拌1小时,复测pH,调节pH至10-12直至稳定不变,保持在10℃以下滴加苯甲酰氯(0.89g,6.4mmol,1.0eq),加毕,保温反应10分钟,调节pH至6,加入乙酸乙酯,分液,调节水相的pH至4,过滤,滤液浓缩后得粗品,该粗品通过制备HPLC分离纯化(洗脱剂:0.1%甲酸水溶液∶MeOH=10%~80%),收集目标组分冻干得到标题化合物(54,红褐色固体)。
MS m/z(ESI):464[M+1] +.
1H NMR(400MHz,DMSO-d 6)δ8.65(d,1H),8.18-8.11(m,2H),7.88-7.82(m,2H),7.68-7.60(m,3H),7.49-7.36(m,3H),6.97(br,2H),4.52(s,2H),3.36(t,2H),3.18(s,3H),2.64(t,2H),2.19(s,3H).
实施例55:(Z)-S-(2-(N-((4-氨基-2-(噻吩-2-基)嘧啶-5-基)甲基)甲酰胺基)-5-甲氧基戊-2-烯-3-基)硫代苯甲酸酯(化合物55)
Figure PCTCN2022097105-appb-000073
步骤1:于500mL单口瓶中加入55a(50.0g,458.7mmol,1.0eq)和甲醇(50mL),搅拌下,加入20%HCl二氧六环溶液350g,室温下搅拌12小时。然后加入甲醇钠(49.5g,917.4mmol,2.0eq)搅拌2小时,加入NH 3甲醇溶液(100mL),室温下搅拌0.5小时,浓缩,除去溶剂。然后加入甲醇(100mL)和甲醇钠(49.5g,917.4mmol,2.0eq),室温下搅拌0.5小时,加入乙氧基亚甲基丙二腈(56g,458.7mmol,1.0eq),室温下搅拌2小时,过滤,滤液浓缩,浓缩得到粗品,通过硅胶柱分离纯化(洗脱剂:DCM∶MeOH=30∶1~10∶1),得到55b(黄色固体,26g,收率:28.1%)
步骤2:除了将实施例52中步骤2中的52b替换为55b之外,采用与之相同的合成路线制备55c(黄色固体)。
步骤3至步骤5:除了将实施例54中步骤4中的54d替换为55c之外,采用与实施例54中步骤4至步骤6相同的合成步骤和方法,制得标题化合物55(白色固体)。
MS m/z(ESI):469[M+1] +.
1H NMR(400MHz,DMSO-d 6)δ7.97(s,1H),7.86(s,1H),7.73-7.61(m,5H),7.42(t,2H),7.13(t,1H),6.91(br,2H),4.47(s,2H),3.38(t,2H),3.18(s,3H),2.64(t,2H),2.18(s,3H).
实施例56:(Z)-S-(2-(N-((4-氨基-2-环己基嘧啶-5-基)甲基)甲酰胺基)-5-甲氧基戊-2-烯-3-基)硫代苯甲酸酯(化合物56)的合成
Figure PCTCN2022097105-appb-000074
除了将实施例55步骤1中的55a替换为环己腈外,采用与实施例55相同的合成路线,制备标题化合物56(类白色固体)。
MS m/z(ESI):469[M+1] +.
1H NMR(400MHz,CD 3OD):δ7.93(d,2H),7.75(d,2H),7.63(t,1H),7.47(t,2H),4.54(br,2H),3.48(t,2H),3.29(s,3H),2.75(t,2H),2.48-2.41(m,1H),2.22(s,3H),1.77-1.67(m,5H),1.43-1.17(m,5H)。
实施例57:(Z)-S-(2-(N-((4-氨基-2-环丁基嘧啶-5-基)甲基)甲酰胺基)-5-甲氧基戊-2-烯-3-基)硫代苯甲酸酯(化合物57)的合成
Figure PCTCN2022097105-appb-000075
除了将实施例55步骤1中的55a替换为环丁腈外,采用与实施例55相同的合成路线,制备标题化合物57(白色固体)
MS m/z(ESI):441[M+1] +.
1H NMR(400MHz,DMSO-d 6)δ7.87(s,1H),7.82(s,1H),7.73-7.66(m,3H),7.51(t,2H),6.64(br,2H),4.40(s,2H),3.37-3.33(m,3H),3.19(s,3H),2.64(t,2H),2.26-2.02(m,7H),1.94-1.84(m,1H),1.77-1.71(m,1H).
生物学测试
实验例1
BCA蛋白浓度测定试剂盒购于碧云天,Aβ40及Aβ42检测试剂盒购于wako公司,细胞培养相关试剂均购于Gibco公司。
将HEK293APP/sw过表达细胞用DMEM培养液(含10%FBS、100μg/mL G418(Geneticin,遗传霉素)及双抗(1×Penicillin,Streptomycin)培养于48孔板中。取4mM化合物储备液(化合物溶于DMEM培养液中配制得到),用0.22μm无菌过滤器过滤后于-20℃下储存备用。于70%细胞密度时,向每孔中加入40μL化合物测试溶液,终浓度为400μM,培养24小时。
取培养液上清液,其中一部分加入BCA试剂,在室温下孵育30min后,在酶标仪570nm处测各个孔吸光值(即OD值),并根据蛋白标准曲线计算总蛋白浓度;同时将另一部分上清液(100μL)加入到已包备的96孔板中4℃孵育过夜,除去溶液并洗净试剂后加入HRP(辣根氧化物酶)标记抗体,在4℃孵育2小时,除去并洗净试剂后加入TMB显色液,室温孵育30min后加入终止液终止反应,在酶标仪450nm处测各个孔吸光值(即OD值),并根据Aβ40及Aβ42的标准曲线分别算出Aβ40及Aβ42的浓度,最后用总蛋白浓度对Aβ40及Aβ42的浓度进行调整得出最终浓度。测试结果如下表中所示。
化合物编号 Aβ40含量(pmol/L) Aβ42含量(pmol/L)
5 46.68 4.5
7 46.6 4.78
8 46.9 3.93
9 47.77 4.69
15 38.18 3.42
21 42.8 4.4
22 41.77 4.2
23 31.37 4.43
24 34.6 3.28
26 39.65 4.1
34 39.5 1.9
35 49.45 3.76
36的甲酸盐 40.09 3.36
44 38.59 3.6
45 33.95 4.13
48 68.41 4.45
52 58.05 5.23
空白对照* 127.81 11.08
*在空白对照中不加入化合物测试溶液。
由以上实验结果可见,本发明的化合物可以显著降低Aβ42或/和Aβ40的水平。
实验例2.毒性实验
2.1实验目的
本实施例通过CCK-8试剂盒来测试化合物毒性。CCK-8试剂盒,是一种基于WST-8(化学名为2-(2-甲氧基-4-硝苯基)-3-(4-硝苯基)-5-(2,4-二磺基苯)-2H-四唑单钠盐)的用于细胞增殖和毒性检测的试剂盒。其检测原理是在电子耦合试剂存在的情况下,WST-8可被线粒体内的脱氢酶还原生成高度水溶性的橙黄色的甲臜产物(formazan)。颜色的深浅与活细胞数量成正比,与细胞毒性成反比。通过酶标仪在450nm波长处测定OD值来反映细胞增殖与毒性水平。
2.2.实验方法
2.2.1实验材料
试剂名称 品牌 货号
CCK-8试剂盒 MK MX3008
DMSO sigma D2650-100ML
DMEM(1×) gibco 11995-065
DPBS basic(1×) gibco C14190500BT
0.25%Typsin-EDTA(1×) gibco 25200-056
二氧化碳培养箱 松下健康医疗器械株式会社 MCO-18AC-PC
生物安全柜 苏洁医疗器械(苏州)有限公司 BSC-1300IIA2
离心机 安亭 TDL-80-2B
2.2.2实验步骤
1)细胞铺板
1.1待HEK293-APP细胞密度在生长到80%~90%,通过消化离心来收集,然后移除上清液,加入5ml培养基并将其混匀。
1.2完全混匀后取20μL细胞悬液加入180μL培养基稀释10倍,并对细胞计数。
1.3另取相应DMEM完全培养基放入15ml离心管内,将细胞悬液加入培养基内调整细胞个数,使各细胞的终稀释浓度为2.4×10 5个/ml;
1.4为防止液体蒸发应在96孔板边缘孔加入无菌100μl PBS填充。
1.5将培养基加入加样槽内轻柔吹打以每孔100μL进行铺板,使每孔细胞数为2.4×10 4个。
1.6将接种好的细胞培养板放入培养箱中培养。
2)加入待测化合物
2.1将待测化合物用DMEM培养液配成4mM储备液,用0.22μm无菌过滤器过滤后-20℃储存备用。
2.2细胞完全贴壁后加入上述4mM储备液,每孔10μL,终浓度为400μM,设3个复孔。
2.3将细胞培养板在5%CO 2,37℃孵育24h。
3)加CCK-8试剂
3.1每孔加入10μL CCK-8试剂,继续培养1h。
3.2培养1h后,在450nm测定吸光度。
2.3.实验结果
抑制率=(1-测试组吸光度/对照组吸光度)*100%,实验结果如下表所示。
化合物编号 抑制率
4 -3.02%
5 1.49%
7 -3.10%
8 -6.81%
9 -10.30%
15的盐酸盐 -2.60%
23 1.95%
24 -0.43%
26 2.70%
32 -8.65%
33 -14.22%
34 -6.19%
35 -11.13%
36的甲酸盐 -7.41%
38的甲酸盐 -14.26%
43 -0.27%
44 4.98%
实验结果表明本发明化合物安全性良好。
除本文中描述的那些外,根据前述描述,本发明的各种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (13)

  1. 化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中所述化合物具有式(I)的结构:
    Figure PCTCN2022097105-appb-100001
    其中
    R选自H、卤素、羟基、氨基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(=NH)NH 2、-C(=O)R 3、-OC(=O)R 3、-C(=O)OR 3、-OR 3、-SR 3、-S(=O)R 3、-S(=O) 2R 3、-S(=O) 2NR 3R 4、-NR 3R 4、-C(=O)NR 3R 4、-NR 3-C(=O)R 4、-NR 3-C(=O)OR 4、-NR 3-S(=O) 2-R 4、-NR 3-C(=O)-NR 3R 4、-C 1-6亚烷基-NR 3R 4和-O-C 1-6亚烷基-NR 3R 4
    L 1和L 2各自独立地选自直接键、C 1-6亚烷基和C 2-6亚烯基;
    R 1和R 2各自独立地选自H、卤素、羟基、氧代、氨基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、=N-OR 3、-C(=NH)NH 2、-C(=O)R 3、-OC(=O)R 3、-C(=O)OR 3、-OR 3、-SR 3、-S(=O)R 3、-S(=O) 2R 3、-S(=O) 2NR 3R 4、-NR 3R 4、-C(=O)NR 3R 4、-NR 3-C(=O)R 4、-NR 3-C(=O)OR 4、-NR 3-S(=O) 2-R 4、-NR 3-C(=O)-NR 3R 4、-C 1-6亚烷基-NR 3R 4和-O-C 1-6亚烷基-NR 3R 4
    R 3和R 4在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基;
    上述烷基、亚烷基、烯基、亚烯基、炔基、环烃基、杂环基、芳基、杂芳基和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代:卤素、羟基、氧代、氨基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、=N-OR 5、-C(=NH)NH 2、-C(=O)R 5、-OC(=O)R 5、-C(=O)OR 5、-OR 5、-SR 5、-S(=O)R 5、-S(=O) 2R 5、-S(=O) 2NR 5R 6、-NR 5R 6、-C(=O)NR 5R 6、-NR 5-C(=O)R 6、-NR 5-C(=O)OR 6、-NR 5-S(=O) 2-R 6、-NR 5-C(=O)-NR 5R 6、-C 1-6亚烷基-NR 5R 6和-O-C 1-6亚烷基-NR 5R 6,所述烷基、烯基、炔基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代:卤素、羟基、氧代、氨基、氰基、硝基、C 1-6烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基;
    R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基;
    条件是当-L 2-R 2共同构成C 1-6烷基时,-L 1-R 1不是未取代的苯基;并且
    当-L 2-R 2共同构成-(CH 2) 2-OC(=O)-(C 1-7烷基)时,-L 1-R 1不是未取代的苯基和未取代的呋喃基。
  2. 权利要求1的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中L 1为直接键或C 2-6烯基,优选为直接键或亚乙烯基。
  3. 权利要求1或2的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中R 1选自C 3-6环烃基、C 6-10芳基和5-14元杂芳基,其任选地被一个或多个独立地选自卤素和-O-(C 1-6烷基)的取代基取代;
    优选地,R 1选自环己烷基、苯基和呋喃基,其任选地被一个或多个独立地选自F、Cl、Br、I和-OCH 3的取代基取代。
  4. 权利要求1-3中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、 多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中-L 1-R 1选自
    Figure PCTCN2022097105-appb-100002
    Figure PCTCN2022097105-appb-100003
  5. 权利要求1-4中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中L 2为直接键、C 1-4亚烷基或C 2-4亚烯基;
    优选地,L 2为直接键、亚甲基、亚乙基或亚乙烯基。
  6. 权利要求1-5中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中
    R 2选自H、卤素、羟基、C 1-6烷基、C 2-6烯基、C 1-6卤代烷基、3-10元杂环基、-C(=O)R 3、-OC(=O)R 3、-OR 3、-SR 3、-NR 3-C(=O)R 4、-NR 3-S(=O) 2-R 4、-NR 3R 4、-C(=O)NR 3R 4和-C(=O)OR 3;其中R 3和R 4各自独立地选自H、C 1-6烷基、3-10元杂环基、C 6-10芳基和C 6-12芳烷基,优选地,R 3和R 4各自独立地选自H、甲基、乙基、吗啉基、苯基(Ph)和苄基(Bn);
    最优选地,R 2为H、F、Cl、羟基、甲基、乙基、乙烯基、-CH 2CH 2F、-CH 2CH 2Cl、-OC(=O)CH 3、-OC(=O)Ph、-SCH 3、-OCH 3、-OCH 2CH 3、-OBn、-NHC(=O)CH 3、-NHS(=O) 2CH 3、-N(CH 3)Ph、-C(=O)NH 2、-C(=O)NHCH 3、-C(=O)N(CH 3) 2、-C(=O)OH、-C(=O)OCH 2CH 3
    Figure PCTCN2022097105-appb-100004
    Figure PCTCN2022097105-appb-100005
  7. 权利要求1-6中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中-L 2-R 2选自甲基、乙基、乙烯 基、
    Figure PCTCN2022097105-appb-100006
    Figure PCTCN2022097105-appb-100007
  8. 权利要求1的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中所述化合物具有式(II)或式(III)的结构:
    Figure PCTCN2022097105-appb-100008
  9. 权利要求1-8中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、 多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药,其中所述化合物为
    Figure PCTCN2022097105-appb-100009
    Figure PCTCN2022097105-appb-100010
  10. 药物组合物,其包含预防或治疗有效量的权利要求1-9中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药以及一种或多种药学上可接受的载体。
  11. 权利要求1-9中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者权利要求10的药物组合物在制备用于预防或治疗神经退行性疾病或者减轻神经退行性疾病的症状的药物中的用途。
  12. 权利要求11的用途,其中所述神经退行性疾病选自阿尔茨海默病、克-雅氏病、亨廷顿氏病、多发性硬化、格林-巴利综合征、帕金森病、洛盖赫里格病、由逐渐的神经细胞死亡导致的麻痹性痴呆和进行性失调所引起的疾病;优选为阿尔茨海默病。
  13. 式(I)的化合物的制备方法:
    Figure PCTCN2022097105-appb-100011
    其中:
    Hal 1和Hal 2各自独立地选自F、Cl、Br和I;
    其余各基团如权利要求1-9中任一项所定义;
    所述方法包括以下步骤:
    步骤(I):使式(I)-a的化合物或其盐与式(I)-b的化合物反应,以得到式(I)-c的化合物;以及
    步骤(II):使式(I)-c的化合物与式(I)-d的化合物反应,以得到式(I)的化合物。
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