WO2023283921A1 - Dpd抑制剂及其药物组合物和用途 - Google Patents

Dpd抑制剂及其药物组合物和用途 Download PDF

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WO2023283921A1
WO2023283921A1 PCT/CN2021/106708 CN2021106708W WO2023283921A1 WO 2023283921 A1 WO2023283921 A1 WO 2023283921A1 CN 2021106708 W CN2021106708 W CN 2021106708W WO 2023283921 A1 WO2023283921 A1 WO 2023283921A1
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substituted
alkyl
halogen
aryl
optionally
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PCT/CN2021/106708
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English (en)
French (fr)
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曲显俊
万升标
崔淑香
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北京深蓝泰医药科技有限公司
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Priority to PCT/CN2021/106708 priority Critical patent/WO2023283921A1/zh
Publication of WO2023283921A1 publication Critical patent/WO2023283921A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a novel DPD inhibitor, its pharmaceutical composition and application, especially the application in reversing the drug resistance that occurs when fluorouracil drugs treat tumors.
  • Chemotherapy plays an extremely important role in cancer treatment. Since the synthesis of 5-fluorouracil by Duschinsky et al. in 1957, 5-fluorouracil and its derivatives have been the basic drugs for chemotherapy of digestive tract tumors, head and neck tumors and other tumors, such as lung cancer and breast cancer. However, as with other anticancer drugs, tumor resistance to them is the main reason for the failure of chemotherapy for the aforementioned cancers. In fact, dihydropyrimidine dehydrogenase (DPD) in tumor cells is the main rate-limiting enzyme that degrades 5-fluorouracil into cancer cells. Since 5-fluorouracil in cells is degraded into inactive products, tumor cells develop drug resistance. sex.
  • DPD dihydropyrimidine dehydrogenase
  • the application provides a compound of formula I, or a pharmaceutically acceptable salt or tautomer thereof:
  • L is a direct bond or an alkenylene group
  • R is selected from hydrogen, alkyl and haloalkyl ;
  • R is selected from hydrogen or optionally substituted alkyl
  • Each R is independently selected from alkyl optionally substituted with aryl, cycloalkyl having at least 4 ring-forming carbon atoms, aryl optionally substituted with halogen or alkoxy, hetero Aryl;
  • R 4 , R 5 and R 6 are each independently selected from hydrogen, or optionally substituted alkyl
  • Ring B is an aromatic ring or a heteroaryl ring
  • Each R is independently selected from halogen, alkyl, alkoxy optionally substituted with halogen, amino substituted with alkyl, amino substituted with heteroaryl substituted by heteroaryl;
  • x is an integer from 1 to 2;
  • y is an integer of 0, 1, 2 or 3;
  • R1 is a haloalkyl group or x is 2;
  • R 3 is an alkoxy substituted aryl group
  • R 1 is hydrogen
  • R 3 is an unsubstituted aryl group
  • R 1 is a haloalkyl group or at least one R 7 substituent is not a halogen
  • R1 is hydrogen
  • at least one R3 is aryl substituted by halogen or alkoxy, or alkyl substituted by aryl or at least one R7 substituent is not halogen.
  • the application provides the following compounds, or their pharmaceutically acceptable salts, or tautomers:
  • the application provides a compound of formula II, or a pharmaceutically acceptable salt or tautomer thereof:
  • Ar 1 is heteroaryl substituted by one or more independently selected from halogen and alkoxy;
  • Ar is selected from triazinyl, pyrrolopyrimidinyl, pyrazolo[1,5-a]pyridin- 2 -yl, pyridyl and phenyl, each of which is optionally selected from one or more independently selected from Heterocycloalkyl, amino optionally substituted by alkyl or aryl, alkyl optionally substituted by aryl, halogen, aryl optionally substituted by alkoxy, alkoxy and cycloalkyloxy substituent substitution;
  • L 1 is a direct bond or —NR c —;
  • R a , R b and R c are each independently selected from hydrogen, or optionally substituted alkyl
  • Ar 1 and Ar 2 are not exactly the same.
  • the application provides the following compounds, or their pharmaceutically acceptable salts, or tautomers:
  • the present application provides a pharmaceutical composition, which comprises the compound described in any aspect above, its pharmaceutically acceptable salt, or tautomer, and pharmaceutically acceptable excipients.
  • the present application provides the above-mentioned compound, its pharmaceutically acceptable salt, or tautomer, or the above-mentioned pharmaceutical composition, or their combination with one or more other therapeutic agents in the preparation for inhibiting Use in a medicament for the expression of DPD; or use in the manufacture of a medicament for the prevention and/or treatment of a disease, disorder or condition that benefits from inhibition of DPD expression; or in the manufacture of a medicament for the prevention and/or treatment of tumors purposes; or in the preparation of drugs for resisting and/or reversing fluorouracil drug resistance.
  • test kit which includes:
  • the application provides the above-mentioned compound, its pharmaceutically acceptable salt, or tautomer, or the above-mentioned pharmaceutical composition for inhibiting the expression of DPD, or they and one or more other therapeutic agents The combination.
  • the present application provides the above-mentioned compound, its pharmaceutically acceptable salt, or tautomer, or the above-mentioned pharmaceutical combination for preventing and/or treating a disease, disorder or condition benefiting from the suppression of DPD expression substances, or their combination with one or more other therapeutic agents.
  • the present application provides the above-mentioned compounds, their pharmaceutically acceptable salts, or tautomers, or the above-mentioned pharmaceutical compositions for resisting and/or reversing resistance to fluorouracil drugs, or combining them with a combination of one or more other therapeutic agents.
  • the present application provides a method for inhibiting the expression of DPD, comprising administering a therapeutically effective amount of the above-mentioned compound, a pharmaceutically acceptable salt thereof, or a tautoconverter to a subject in need (such as a mammal, such as a human). isomers, or the above pharmaceutical compositions, or their combination with one or more other therapeutic agents.
  • the present application provides a method for preventing and/or treating a disease, disease or condition benefiting from suppression of DPD expression, comprising administering a therapeutically effective amount of the above-mentioned Compounds, pharmaceutically acceptable salts, or tautomers thereof, or the aforementioned pharmaceutical compositions, or combinations thereof with one or more other therapeutic agents.
  • the present application provides a method for resisting and/or reversing fluorouracil drug resistance, including:
  • the fluorouracil drugs are administered in combination with the above-mentioned compounds of the present invention, their pharmaceutically acceptable salts, or tautomers, or the above-mentioned pharmaceutical compositions.
  • the application provides the above-mentioned compound, its pharmaceutically acceptable salt, or tautomer, or the above-mentioned pharmaceutical composition, or their combination with one or more other therapeutic agents in the inhibition of DPD use in expressions.
  • the application provides the above-mentioned compound, its pharmaceutically acceptable salt, or tautomer, or the above-mentioned pharmaceutical composition, or their combination with one or more other therapeutic agents in the prevention and/or Or use in the treatment of a disease, disorder or condition that would benefit from inhibition of DPD expression.
  • the application provides the above-mentioned compound, its pharmaceutically acceptable salt, or tautomer, or the above-mentioned pharmaceutical composition, or their combination with one or more other therapeutic agents in the resistance and/or Or use in reversing resistance to fluorouracils.
  • Figure 1 shows the experimental results of the comparative compound and the compound of the present invention inhibiting the expression of DPD in vitro.
  • Figure 2 shows the changes in tumor volume of nude mice in each group during the treatment with different concentrations of the compound of the present invention.
  • Figure 3 shows the differences in the expression of DPD in tumor and liver tissues from nude mice in each group.
  • member means the number of skeletal atoms constituting a ring.
  • 3-12 members means that the number of skeleton atoms constituting the ring is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • halo by itself or as part of another substituent denotes a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom.
  • alkyl refers to a linear or branched saturated hydrocarbon group, which may be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • alkyl groups include C 1-12 (e.g.
  • hydroxyalkyl refers to -alkyl-OH, wherein “alkyl” is as defined above, and “optionally substituted hydroxyalkyl” means that the alkyl group is substituted or unsubstituted.
  • alkoxy refers to -O-alkyl, wherein “alkyl” is as defined above, and examples of “alkoxy” include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy , n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentyloxy.
  • Optionally substituted alkoxy means that the alkyl group in the group is substituted or unsubstituted.
  • alkenyl refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group with at least one double bond consisting of carbon atoms and hydrogen atoms, such as C 2-6 alkenyl, C 2-4 alkenyl, etc.
  • alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • the term includes cis and trans isomers or mixtures of these isomers.
  • alkynyl refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group with at least one triple bond consisting of carbon atoms and hydrogen atoms, such as C 2-6 alkynyl, C 2-4 alkynyl, C 2 -3 alkynyl etc.
  • alkynyl include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C- CH3 ), 2-propynyl ( -CH2 -C ⁇ CH), 1,3-Butadiynyl (-C ⁇ CC ⁇ CH), etc.
  • cycloalkyl refers to a fully saturated non-aromatic ring composed of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings.
  • the cycloalkyl group may be a monocyclic ring, a fused polycyclic ring, a bridged ring or a spiro ring structure.
  • Non-limiting examples of cycloalkyl groups include, but are not limited to, C 3-18 (e.g., C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 ) cycloalkyl, C 4-16 cycloalkyl, C 5-12 cycloalkyl, C 6-10 cycloalkyl, C 6-8 cycloalkane Base, C 6-7 cycloalkyl, etc., such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro [3.3] heptyl, norbornyl (bicyclo [2.2.1] heptyl ), bicyclo[2.2.2]octyl, adamantyl, bicyclo[1.1.1]pent
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the heterocycle is typically a ring containing 1 to 5 (eg, 1, 2, 3, 4, 5) heteroatoms independently selected from sulfur, oxygen and/or nitrogen.
  • 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thioethyl, cycloazaethyl
  • 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetyl, Cyclic, thiabutanyl
  • 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine , imidazolidinyl, tetrahydropyrazolyl
  • 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazin
  • cycloalkenyl refers to a non-aromatic mono- or polycyclic ring system containing at least one carbon-carbon double bond.
  • a cycloalkenyl ring contains, for example, 3-10 ring atoms, 5-10 ring atoms, or 5-7 ring atoms.
  • suitable monocyclic cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
  • a non-limiting example of a suitable multicyclic cycloalkenyl is norbornenyl.
  • heterocycloalkenyl refers to a non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond or carbon-nitrogen double bond and consisting only of carbon and hydrogen atoms, wherein one or more of the ring system 1 ring atom is an element other than carbon, for example 1, 2, 3, 4, 5 ring atoms are each independently a heteroatom selected from nitrogen, oxygen, and sulfur.
  • the heterocycloalkenyl ring contains, for example, 5-10 ring atoms, 5-8 ring atoms, 5-7 ring atoms, or, 5-6 ring atoms.
  • the prefix aza, oxa or thia before the heterocycloalkenyl root name indicates that at least one nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • suitable monocyclic azacycloalkenyl groups include 1,2,3,4 tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6 -tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 2-pyrazolinyl and the like.
  • Non-limiting examples of suitable oxetanyl groups include 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, and the like.
  • a non-limiting example of a suitable polyepoxyheterocycloalkenyl is 7-oxabicyclo[2.2.1]heptenyl.
  • cycloalkynyl refers to a non-aromatic monocyclic or polycyclic ring having at least one carbon-carbon triple bond and consisting only of carbon and hydrogen atoms, such as 4-15, 5-15, 6-10, 7 - 10-membered or 8-10-membered rings, such as 8- to 10-membered monocyclic rings or 12- to 15-membered bicyclic rings. It may contain one or more fused or bridged rings. Unless otherwise specified, a cycloalkynyl ring may be attached at any carbon atom which results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. Exemplary cycloalkynyl groups include cyclooctynyl, cyclononynyl, cyclodecynyl, 2-methylcyclooctynyl, and the like.
  • heterocycloalkynyl means that at least one carbon-carbon single bond in a heterocycloalkyl group is replaced by a carbon-carbon triple bond.
  • aryl refers to an aromatic ring or an aromatic or partially aromatic ring system composed of carbon atoms and hydrogen atoms. It may be a single ring or may be a polycyclic ring (two or more rings such as a bicyclic ring) fused together or linked covalently.
  • Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, tetralin, and the like.
  • an aryl group can be a monovalent group or a divalent group, ie, an arylene group.
  • C 6 -C 18 aryl or “aromatic ring” means a group having 6 to 18 carbon atoms (e.g. 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms) aryl or aromatic ring as defined above.
  • Heteroaryl or “heteroaromatic ring” refers to an aromatic group consisting of carbon atoms and at least one (for example 1 to 5, such as 1, 2, 3, 4, 5) heteroatoms selected from nitrogen, oxygen and sulfur ring group.
  • the heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can contain fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally Oxidized; nitrogen atoms can be optionally quaternized.
  • Examples include, but are not limited to, triazinyl, pyrrolopyrimidinyl, pyrazolo[1,5-a]pyridin-2-yl, azepinenyl, acridinyl, benzimidazolyl, benzothiazolyl, benzo Indolyl, benzothiadiazolyl, benzonaphthofuryl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzo Pyrone group, benzofuryl group, benzofuranone group, benzothienyl group (benzophenylthio group), benzotriazolyl group, benzo[4,6]imidazo[1,2-a] Pyridyl, carbazolyl, cinnolinyl, dibenzofuryl, furyl, thienyl, furanone, isothiazolyl, imidazolyl, indolyl, indazolyl, is
  • C 1 -C 18 heteroaryl means a group having carbon atoms other than 1 to 18 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms) in addition to at least one heteroatom selected from N, O, and S as ring-forming atoms (such as 1, 2, 3, 4, 5 heteroatoms ) of the aromatic ring group.
  • heterocyclyl or “heterocycle” refers to a ring structure which may be saturated or unsaturated, aromatic or non-aromatic, wherein the ring structure contains at least one carbon and at least one A heteroatom selected from O, N, S, examples of which include heterocycloalkyl, heteroaryl, heterocycloalkenyl and heterocycloalkynyl.
  • C 1 -C 18 heterocyclyl refers to a group having carbon atoms other than 1 to 18 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms) in addition to at least one heteroatom selected from N, O, and S as ring atoms (for example, 1, 2, 3, 4 or 5 heteroatoms ) of heterocyclyl as defined above.
  • a double line consisting of a dotted line and a solid line in this specification Indicates a single or double bond.
  • carboxyalkyl refers to a group having the structure -alkyl-COOH, wherein alkyl is as defined above.
  • Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl ( -CH2CO2H ), 2 -carboxyethyl, and the like.
  • Optionally substituted carboxyalkyl means that the alkyl portion of the group is substituted or unsubstituted.
  • optionally substituted amino refers to -NH2 , mono- or di-substituted amino, and 5- to 7-membered cyclic amino.
  • ester group refers to a group having the structure -C(O)OR' or -OC(O)R', wherein R' is optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl.
  • R' is alkyl, haloalkyl, aryl, heteroaryl, alkaryl, alkylheteroaryl.
  • R' is alkyl or haloalkyl.
  • R' is C 1-6 alkyl.
  • "Optionally substituted ester group” means that the R' moiety in the group is substituted or unsubstituted.
  • acyl refers to a group having the structure -C(O)R', wherein R' is as defined above. "Optionally substituted acyl” means that the R' moiety in the group is substituted or unsubstituted.
  • sulfonyl refers to a group having the structure -SO2R ', wherein R' is as defined above. "Optionally substituted sulfonyl” means that the R' moiety in the group is substituted or unsubstituted.
  • substituents eg 1 to 4, 1 to 3 or 1 to 2
  • substituents eg 1 to 4, 1 to 3 or 1 to 2
  • the substituent is Individually and independently one or more groups selected from the following: halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl , Alkoxy, aryloxy, heteroaryloxy, mercapto, alkylthio, arylthio, cyano, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thioamino Formyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonylamino, N-sulfonylamino, carboxyl, C-carboxy, O-carbox
  • substituents can be the same or different, any substituted functional group herein can be substituted in 1 to 4 different positions, and those 1 to 4 substituents can be substituted in 1 Up to 4 positions were each independently substituted.
  • pharmaceutically acceptable salt refers to a salt that retains the biological effectiveness of the free acid and free base of the specified compound and has no adverse effects, biological or otherwise.
  • “Pharmaceutically acceptable salt” includes “pharmaceutically acceptable acid addition salt” and “pharmaceutically acceptable base addition salt”.
  • the compounds of the present application may exist specific tautomers, and all these isomers and their mixtures are included in the scope of the present application.
  • the present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • Certain isotopically labeled compounds of the present application are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (ie3H ) and carbon- 14 (ie14C) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present application can generally be prepared by following procedures similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • substitution with heavier isotopes such as deuterium may confer certain therapeutic advantages resulting from greater metabolic stability (e.g. increased in vivo half-life or reduced dosage requirements), and thus in some cases
  • deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of compounds are included within the scope of the present application.
  • the term "individual” includes humans and animals, for example, mammals (such as primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep and birds, etc.).
  • treating means administering a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes: preventing a disease or disease state from occurring in a mammal, especially when Such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state.
  • an effective amount refers to the amount of at least one agent or compound which, when administered, is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. The result may be a reduction and/or alleviation of a sign, symptom or cause, or any other desired change in a biological system.
  • a therapeutically “effective amount” is the amount of a composition comprising a compound disclosed herein required to provide clinically significant disease-modifying effect. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation assays.
  • composition refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical ingredient including, but not limited to, carriers, stabilizers, , diluent, dispersant, suspending agent, thickener and/or excipient.
  • “Pharmaceutically acceptable excipients” include but are not limited to any adjuvants, carriers, excipients, glidants, sweeteners, diluents, Preservatives, dyes/colorants, fragrance enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers, etc., which have no side effects on the composition of the pharmaceutical composition form of excipients.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, lozenges, ointments, syrups, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • suitable pharmaceutically acceptable auxiliary materials for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, lozenges, ointments, syrups, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration or routes of administration of the compounds of the present application, their pharmaceutically acceptable salts, tautomers, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, transmucosal, topical, transdermal, inhalation, gastrointestinal Topical, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous and intravenous administration.
  • the compounds or compositions of the present invention can be formulated and used in the following dosage forms: tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions, suspensions for parenteral administration; Transdermal patches and subcutaneous deposits, etc.
  • Injectables can be prepared in conventional forms as solutions or suspensions, solid dosage forms suitable for solution or suspension prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like.
  • the pharmaceutical composition for injection may contain minor amounts of non-toxic auxiliary substances, such as wetting agents, pH buffering agents, etc., if necessary. Absorption enhancers (eg, liposomes) can also be used if desired.
  • Formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or other organic oils such as soybean oil, grapefruit oil, or almond oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes .
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the pharmaceutical composition of the present application can be prepared by methods known in the art, such as conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, and freeze-drying methods.
  • the pharmaceutical compositions of the present application are in oral form.
  • the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable adjuvants or excipients well known in the art. These adjuvants or excipients enable the compound of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, powders, granules, liquids, syrups, emulsions, gels, slurries, suspensions etc., for oral administration to patients.
  • Solid pharmaceutical compositions suitable for oral administration can be prepared by conventional mixing, filling or tabletting methods.
  • oral compositions in solid form can be obtained by mixing the active compound with a solid adjuvant or excipient, optionally grinding the resulting mixture, adding other suitable adjuvants or excipients if desired, and then The mixture is processed into granules to obtain tablets or dragee cores.
  • suitable auxiliary materials or excipients include, but are not limited to: fillers, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • compositions for oral administration can be obtained, for example, by combining the active compound with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, adding suitable auxiliaries if desired. After that, tablets or dragee cores are obtained.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, Methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrants can be added, for example cross-linked polyvinylpyrrolidone, agar or alginic acid or alginate such as sodium alginate.
  • a suitable coating is applied to the dragee core.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixture.
  • dyestuffs or pigments can be added to the tablets or dragee coatings. These formulations can be manufactured using methods well known in the art.
  • the dose administered per day can be, for example, 0.001-300 mg/kg body weight, such as 0.01-300 mg/kg body weight, or 10-200 mg/kg body weight, in single doses or divided administered in dosage form.
  • fluorouracil drugs includes but not limited to fluorouracil or its derivatives, or drugs containing fluorouracil structures, for example, 5-fluorouracil (5-FU), 5'-2'-deoxyuridine, tegafur , Fluoxuridine, Camofur, Doxifluridine, Tegafur/Uracil, Capecitabine, S-1, Youfudine, Pyrifluridine, Flutterolone and Xeloda, etc.
  • 5-FU 5-fluorouracil
  • 5-FU 5-fluorouracil
  • tegafur Fluoxuridine
  • Camofur Doxifluridine
  • Tegafur/Uracil Capecitabine
  • S-1 Youfudine
  • Pyrifluridine Pyrifluridine
  • Flutterolone Flutterolone
  • Xeloda Xeloda
  • Diseases, disorders or conditions that benefit from inhibition of DPD expression includes, but is not limited to: gastrointestinal tumors, lung cancer, breast cancer, metastatic non-small cell lung cancer, metastatic breast cancer, metastatic pancreatic cancer, metastatic bile duct cancer Carcinoma, head and neck tumors (such as oral cancer), advanced nasopharyngeal carcinoma, etc.
  • the application provides a compound of formula I, or a pharmaceutically acceptable salt or tautomer thereof:
  • L is a direct bond or an alkenylene group
  • R is selected from hydrogen, alkyl and haloalkyl ;
  • R is selected from hydrogen or optionally substituted alkyl
  • Each R is independently selected from alkyl optionally substituted with aryl, cycloalkyl having at least 4 ring-forming carbon atoms, aryl optionally substituted with halogen or alkoxy, hetero Aryl;
  • R 4 , R 5 and R 6 are each independently selected from hydrogen, or optionally substituted alkyl
  • Ring B is an aromatic ring or a heteroaryl ring
  • Each R is independently selected from halogen, alkyl, alkoxy optionally substituted with halogen, amino substituted with alkyl, amino substituted with heteroaryl substituted by heteroaryl;
  • x is an integer from 1 to 2;
  • y is an integer of 0, 1, 2 or 3;
  • R1 is a haloalkyl group or x is 2;
  • R 3 is an alkoxy substituted aryl group
  • R 1 is hydrogen
  • R 3 is an unsubstituted aryl group
  • R 1 is a haloalkyl group or at least one R 7 substituent is not a halogen
  • R1 is hydrogen
  • at least one R3 is aryl substituted by halogen or alkoxy, or alkyl substituted by aryl or at least one R7 substituent is not halogen.
  • L is a direct bond
  • y is an integer of 2 or 3.
  • L is alkenylene and y is 0.
  • R 1 is selected from hydrogen, C 1-6 alkyl, and haloC 1-6 alkyl.
  • R 1 is selected from hydrogen, C 1-4 alkyl and haloC 1-4 alkyl.
  • R is selected from hydrogen, methyl, and trifluoromethyl.
  • R is selected from hydrogen , optionally substituted C 1-6 alkyl.
  • R 2 is selected from C 1-6 alkyl.
  • R 2 is methyl
  • each R 3 is independently selected from C 1-6 alkyl optionally substituted by C 6-18 aryl, 4-12 membered cycloalkyl, optionally halogen or C 1-6 alkoxy C 6-18 aryl substituted by radical, C 2-18 heteroaryl optionally substituted by halogen. In some embodiments, each R 3 is independently selected from C 1-6 alkyl optionally substituted by C 6-12 aryl, 5-8 membered cycloalkyl, optionally halogen or C 1-6 alkoxy C 6-12 aryl substituted by radical, C 2-12 heteroaryl substituted by halogen, C 2-12 heteroaryl containing S.
  • each R 3 is independently selected from C 1-4 alkyl, C 1-4 alkyl substituted by C 6-10 aryl, 6-8 membered cycloalkyl, C 6-10 aryl , C 6-10 aryl substituted by halogen, C 6-10 aryl substituted by C 1-4 alkoxy, C 2-8 heteroaryl substituted by halogen, C 2-8 heteroaryl containing S base.
  • each R is independently selected from methyl, n-propyl, isopropyl, benzyl, cyclohexyl, phenyl, p-fluorophenyl, p-methoxyphenyl, 3-chloro- 2-thienyl.
  • R 4 , R 5 , and R 6 are each independently selected from hydrogen, or optionally substituted C 1-6 alkyl.
  • R 4 , R 5 , and R 6 are each independently selected from hydrogen, or C 1-4 alkyl.
  • R4, R5 , and R6 are each independently selected from hydrogen or methyl.
  • R4, R5 , and R6 are all hydrogen.
  • Ring B is a C 6-18 aromatic ring or a C 2-18 heteroaryl ring.
  • Ring B is a C 6-12 aromatic ring or a 5-10 membered heteroaromatic ring.
  • Ring B is a C6-10 aromatic ring or a 5-8 membered heteroaryl ring.
  • Ring B is a benzene ring or a pyridine ring.
  • heteroaryl ring appearing in the definition of ring B is optionally substituted with 2 or 3 R groups ortho to the heteroatom.
  • selected from benzene rings or pyridine rings substituted by 0-3 R groups independently selected from: fluorine, chlorine, bromine, methyl, methoxy, n - propoxy, isopropoxy, n-butyl Oxy, 2-fluoroethoxy, diethylamino and (4-(pyridin-3-yl)pyrimidin-2-yl)amino.
  • each R 7 is independently selected from halogen, C 1-8 alkyl, C 1-8 alkoxy optionally substituted by halogen, C 1-8 alkyl substituted amino, C 2-18 Heteroaryl-substituted C 2-18 heteroaryl-substituted amino.
  • each R is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy optionally substituted with halogen, C 1-6 alkyl substituted amino, C 2-12 Heteroaryl-substituted C 2-12 heteroaryl-substituted amino.
  • each R 7 is independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy optionally substituted with halogen, C 1-4 alkyl substituted amino, C 2-8 Heteroaryl-substituted C 2-8 heteroaryl-substituted amino.
  • each R is independently selected from fluoro, chloro, bromo, methyl, methoxy, n-propoxy, isopropoxy, n-butoxy, 2-fluoroethoxy, diethyl ylamino, (4-(pyridin-3-yl)pyrimidin-2-yl)amino.
  • R 3 is alkyl and R 1 is haloalkyl.
  • one R3 is alkyl, and x is 2 and the other R3 is aryl-substituted alkyl.
  • R 3 is unsubstituted aryl, and R 1 is haloalkyl.
  • R3 is unsubstituted aryl, and at least one R7 substituent is alkoxy.
  • ring B is a heteroaryl ring
  • R is aryl substituted by halogen or alkoxy
  • at least one R is selected from C2-8 alkoxy, C2-8 substituted by halogen Alkoxy, C 1-8 alkyl substituted amino.
  • ring B is a heteroaryl ring
  • R is aryl substituted by halogen or alkoxy
  • at least one R is selected from C 2-6 alkoxy, C 2-6 substituted by halogen Alkoxy, C 2-6 alkyl substituted amino.
  • Ring B is pyridine
  • R is p-fluorophenyl or p-methoxyphenyl
  • at least one R is selected from n - propoxy, isopropoxy, n-butoxy, 2- Fluoroethoxy, diethylamino.
  • R is alkyl, at least one R is selected from cycloalkyl having at least 4 ring-forming carbon atoms, aryl substituted by halogen, heteroaryl substituted by halogen, and is heteroaryl optionally substituted by halogen or aryl substituted by halogen, preferably is heteroaryl, dihaloheteroaryl, dihaloaryl; still more preferably is heteroaryl, 4-substituted 2,6-dihaloheteroaryl, 3,5-dihaloaryl; still more preferably For pyridyl, 4-substituted 2,6-dichloropyridyl, 3,5-difluorophenyl.
  • R is haloalkyl, at least one R is selected from alkyl and aryl, and is a halogen substituted heteroaryl, preferably is a dihaloheteroaryl; still more preferably For 4-substituted 2,6-dichloropyridyl.
  • R 1 is hydrogen and at least one R 3 is aryl substituted with halo or alkoxy, or alkyl substituted with aryl.
  • R1 is hydrogen
  • R3 is unsubstituted aryl and at least one R7 substituent is alkoxy.
  • the application provides the following compounds, or their pharmaceutically acceptable salts, or tautomers:
  • the application provides a compound of formula II, or a pharmaceutically acceptable salt or tautomer thereof:
  • Ar 1 is heteroaryl substituted by one or more independently selected from halogen and alkoxy;
  • Ar is selected from triazinyl, pyrrolopyrimidinyl, pyrazolo[1,5-a]pyridin- 2 -yl, pyridyl and phenyl, each of which is optionally selected from one or more independently selected from Heterocycloalkyl, amino optionally substituted by alkyl or aryl, alkyl optionally substituted by aryl, halogen, aryl optionally substituted by alkoxy, alkoxy and cycloalkyloxy substituent substitution;
  • L 1 is a direct bond or —NR c —;
  • R a , R b and R c are each independently selected from hydrogen, or optionally substituted alkyl
  • Ar 1 and Ar 2 are not exactly the same.
  • Ar 1 is monocyclic heteroaryl substituted with 1 or more substituents independently selected from halogen, alkoxy.
  • Ar is a monocyclic heteroaryl substituted by one or more substituents independently selected from halogen, alkoxy, wherein at least one of the one or more substituents is halogen.
  • Ar 1 is monocyclic C 2-18 heteroaryl substituted with one or more substituents independently selected from halogen, C 1-6 alkoxy.
  • Ar 1 is monocyclic C 2-12 heteroaryl substituted with 1 or more substituents independently selected from halogen, C 1-6 alkoxy.
  • Ar 1 is monocyclic C 2-10 heteroaryl substituted with 1 or more substituents independently selected from halogen, C 1-4 alkoxy.
  • Ar 1 is pyridyl substituted with 1 or more substituents independently selected from halogen, C 1-4 alkoxy.
  • Ar 1 is pyridyl substituted with one or more substituents independently selected from chloro, methoxy, ethoxy, isopropoxy.
  • Ar is 4 -substituted 2,6-dichloropyridyl, 4-substituted 2-chloro-6-methoxypyridine, 4-substituted 2-chloro-6-ethoxy pyridine, or 4-substituted 2-chloro-6-isopropoxypyridine.
  • Ar is selected from 1,3,5-triazin- 2 -yl, pyrrolo[2,3-d]pyrimidin-4-yl, pyrrolo[2,3-d]pyrimidin-2 -yl, pyrazolo[1,5-a]pyridin-2-yl, pyridyl and phenyl, each of which is optionally selected from 1 or more independently selected from heterocycloalkyl, optionally alkyl or aryl-substituted amino, optionally aryl-substituted alkyl, halogen, optionally alkoxy-substituted aryl, alkoxy, and cycloalkyloxy substituents.
  • Ar is selected from 1,3,5-triazin- 2 -yl, pyrrolo[2,3-d]pyrimidin-4-yl, pyrrolo[2,3-d]pyrimidin-2 -yl, pyrazolo[1,5-a]pyridin-2-yl, pyridyl and phenyl, each of which is optionally selected from 1 or more independently selected from 3-12 membered heterocycloalkyl, C 6-18 aryl substituted amino, C 6-18 aryl substituted C 1-6 alkyl, C 1-6 alkyl substituted amino, C 1-6 alkyl, halogen, C 6-18 aryl, Substituents of C 1-6 alkoxy substituted C 6-18 aryl, C 1-6 alkoxy and 3-12 membered cycloalkyloxy.
  • Ar is selected from 1,3,5-triazin- 2 -yl, pyrrolo[2,3-d]pyrimidin-4-yl, pyrrolo[2,3-d]pyrimidin-2 -yl, pyrazolo[1,5-a]pyridin-2-yl, pyridyl and phenyl, each of which is optionally selected from 1 or more independently selected from 3-10 membered heterocycloalkyl, C 6-12 aryl substituted amino, C 6-12 aryl substituted C 1-6 alkyl, C 1-6 alkyl substituted amino, C 1-6 alkyl, halogen, C 6-12 aryl, Substituents of C 1-6 alkoxy substituted C 6-12 aryl, C 1-6 alkoxy and 3-10 membered cycloalkyloxy.
  • Ar is selected from 1,3,5-triazin- 2 -yl, pyrrolo[2,3-d]pyrimidin-4-yl, pyrrolo[2,3-d]pyrimidin-2 -yl, pyrazolo[1,5-a]pyridin-2-yl, pyridyl and phenyl, each of which is optionally selected from 1 or more independently selected from 3-8 membered heterocycloalkyl, C 6-10 aryl substituted amino, C 6-10 aryl substituted C 1-4 alkyl, C 1-4 alkyl substituted amino, C 1-4 alkyl, halogen, C 6-10 aryl, Substituents of C 1-4 alkoxy substituted C 6-10 aryl, C 1-4 alkoxy and 3-8 membered cycloalkyloxy.
  • Ar is selected from 1,3,5-triazin- 2 -yl, pyrrolo[2,3-d]pyrimidin-4-yl, pyrrolo[2,3-d]pyrimidin-2 -yl, pyrazolo[1,5-a]pyridin-2-yl, pyridyl and phenyl, each of which is optionally selected from 1 or more independently selected from pyrrolidinyl, phenylamino, benzyl , dimethylamino, methyl, chlorine, bromine, phenyl, methoxyphenyl, methoxy, ethoxy, isopropoxy and cyclopentyloxy substituents.
  • the substituents on the pyrimidine moiety when present, are acyclic groups.
  • the substituent on the pyrimidine moiety when present, is amino optionally substituted with alkyl.
  • the triazinyl is substituted with heterocycloalkyl.
  • the triazinyl is substituted with pyrrolidin-1-yl.
  • Ar 2 when Ar 2 is pyridyl or phenyl, said pyridyl or phenyl is substituted with at least one halogen.
  • Ar when Ar is pyridyl or phenyl, said pyridyl or phenyl is substituted with one or more substituents independently selected from halogen, alkoxy, and cycloalkyloxy, And at least one of the one or more substituents is halogen.
  • L 1 is a direct bond.
  • Ra , Rb , and Rc are each independently selected from hydrogen, or optionally substituted C 1-6 alkyl.
  • R a , R b and R c are each independently selected from hydrogen, or C 1-4 alkyl.
  • Ra , Rb , and Rc are each independently selected from hydrogen or methyl.
  • Ra , Rb , and Rc are all hydrogen.
  • the application provides the following compounds, or their pharmaceutically acceptable salts, or tautomers:
  • the present application provides a pharmaceutical composition, which comprises the compound described in any aspect above, its pharmaceutically acceptable salt, or tautomer, and pharmaceutically acceptable excipients.
  • the pharmaceutical composition further comprises one or more additional therapeutic agents.
  • the other therapeutic agent is an antineoplastic drug.
  • the antineoplastic drug is selected from fluorouracil drugs.
  • the antineoplastic drug is selected from 5-fluorouracil, 5'-2'-deoxyuridine, tegafur, hexuridine, carmofur, doxifluridine, uracil tegafur , Capecitabine, S-1, Youfudine, Pyrifludin, Flutroxolone and Xeloda.
  • the present application provides the above-mentioned compound, its pharmaceutically acceptable salt, or tautomer, or the above-mentioned pharmaceutical composition, or their combination with one or more other therapeutic agents in the preparation for inhibiting Use in a medicament for the expression of DPD; or use in the manufacture of a medicament for the prevention and/or treatment of a disease, disorder or condition that benefits from inhibition of DPD expression; or in the manufacture of a medicament for the prevention and/or treatment of tumors purposes; or in the preparation of drugs for resisting and/or reversing fluorouracil drug resistance.
  • the disease, disorder or condition that would benefit from inhibition of DPD expression is selected from tumors.
  • the disease, disorder or condition or the tumor is selected from gastrointestinal tumors, head and neck tumors, lung cancer, breast cancer, and the like; optionally, the head and neck tumors include oral cavity cancer, and the like.
  • the tumor is a fluorouracil-resistant tumor.
  • the one or more other therapeutic agents are antineoplastic drugs.
  • the antineoplastic drug is selected from fluorouracil drugs.
  • said inhibiting the expression of DPD is especially inhibiting the expression of DPD in the liver.
  • the fluorouracil drugs are selected from 5-fluorouracil, 5'-2'-deoxyuridine, tegafur, hexuridine, carmofur, doxifluridine, uracil tegafur , Capecitabine, S-1, Youfudine, Pyrifludin, Flutroxolone and Xeloda.
  • the present application provides a method for inhibiting the expression of DPD in a cell, which comprises administering to the cell an effective amount of the above-mentioned compound, its pharmaceutically acceptable salt, or a tautomer, or the above-mentioned drug combination substances, or their combination with one or more other therapeutic agents, wherein the method is performed in vitro.
  • the cells are cell lines, or cells from a subject.
  • the cells are selected from tumor cells.
  • the tumor cells are selected from breast cancer cells, liver cancer cells, lung cancer cells, esophageal cancer cells, gastric cancer cells, pancreatic cancer cells, bile duct cancer cells, head and neck tumor cells, nasopharyngeal cancer cells, and the like.
  • the present application provides a method for resisting/reversing drug resistance in cells, which includes administering to the cells an effective amount of the above compound, a pharmaceutically acceptable salt thereof, or a tautomer, or the above drug Compositions, or their combination with one or more other therapeutic agents, wherein the method is performed in vitro.
  • the cells are cell lines, or cells from a subject.
  • the cells are selected from tumor cells.
  • the tumor cells are selected from breast cancer cells, liver cancer cells, lung cancer cells, esophageal cancer cells, gastric cancer cells, pancreatic cancer cells, bile duct cancer cells, head and neck tumor cells, nasopharyngeal cancer cells, and the like.
  • test kit which includes:
  • the kit further includes instructions for use.
  • the antineoplastic drug is selected from fluorouracil drugs.
  • the application provides the above-mentioned compound, its pharmaceutically acceptable salt, or tautomer, or the above-mentioned pharmaceutical composition for inhibiting the expression of DPD, or they and one or more other therapeutic agents The combination.
  • said inhibiting the expression of DPD is especially inhibiting the expression of DPD in the liver.
  • the application provides the above-mentioned compound, its pharmaceutically acceptable salt, or tautomer, or the above-mentioned drug for preventing and/or treating a disease, disorder or condition benefiting from the suppression of DPD expression Compositions, or their combination with one or more other therapeutic agents.
  • the disease, disorder or condition or the tumor is selected from gastrointestinal tumors, head and neck tumors, lung cancer, breast cancer, and the like; optionally, the head and neck tumors include oral cavity cancer, and the like.
  • the tumor is a fluorouracil-resistant tumor.
  • the one or more other therapeutic agents are antineoplastic drugs.
  • the antineoplastic drug is selected from fluorouracil drugs.
  • the fluorouracil drugs are selected from 5-fluorouracil, 5'-2'-deoxyuridine, tegafur, hexuridine, carmofur, doxifluridine, uracil tegafur , Capecitabine, S-1, Youfudine, Pyrifludin, Flutroxolone and Xeloda.
  • the present application provides the above-mentioned compound, its pharmaceutically acceptable salt, or tautomer, or the above-mentioned pharmaceutical composition, or their combination with Combinations of one or more other therapeutic agents.
  • the present application provides a method for inhibiting the expression of DPD, comprising administering a therapeutically effective amount of the above-mentioned compound, a pharmaceutically acceptable salt thereof, or a tautoconverter to a subject in need (such as a mammal, such as a human) isomers, or the above pharmaceutical compositions, or their combination with one or more other therapeutic agents.
  • a subject in need such as a mammal, such as a human
  • said inhibiting the expression of DPD is especially inhibiting the expression of DPD in the liver.
  • the present application provides a method for preventing and/or treating a disease, disorder or condition benefiting from suppression of DPD expression, comprising administering a therapeutically effective amount of the above-mentioned Compounds, pharmaceutically acceptable salts, or tautomers thereof, or the aforementioned pharmaceutical compositions, or combinations thereof with one or more other therapeutic agents.
  • the tumor is a fluorouracil-resistant tumor.
  • the one or more other therapeutic agents are antineoplastic drugs.
  • the antineoplastic drug is selected from fluorouracil drugs.
  • the fluorouracil drugs are selected from 5-fluorouracil, 5'-2'-deoxyuridine, tegafur, hexuridine, carmofur, doxifluridine, uracil tegafur , Capecitabine, S-1, Youfudine, Pyrifludin, Flutroxolone and Xeloda.
  • the present application provides a method for resisting and/or reversing fluorouracil drug resistance, including:
  • the fluorouracil drugs are administered in combination with the above-mentioned compounds of the present invention, their pharmaceutically acceptable salts, or tautomers, or the above-mentioned pharmaceutical compositions.
  • the application provides the above-mentioned compound, its pharmaceutically acceptable salt, or tautomer, or the above-mentioned pharmaceutical composition, or their combination with one or more other therapeutic agents in the inhibition of DPD use in expressions.
  • said inhibiting the expression of DPD is especially inhibiting the expression of DPD in the liver.
  • the application provides the above-mentioned compound, its pharmaceutically acceptable salt, or tautomer, or the above-mentioned pharmaceutical composition, or their combination with one or more other therapeutic agents in the prevention and/or Or use in the treatment of a disease, disorder or condition that would benefit from inhibition of DPD expression.
  • the present application provides the above-mentioned compound, its pharmaceutically acceptable salt, or tautomer, or the above-mentioned pharmaceutical composition, or their combination with one or more other therapeutic agents in the resistance and/or Or use in reversing resistance to fluorouracils.
  • Described synthetic route I comprises the following steps:
  • step 1
  • Step 3-2
  • 2,6-dichloropyridine-4-carboxylic acid (26mmol) was placed in a two-necked flask, 30mL of 1,4-dioxane was added under nitrogen protection, triethylamine (39mmol) was added dropwise, and the Add diphenylphosphoryl azide DPPA (39mmol), react overnight, TLC detects that the reaction is complete, wash with saturated aqueous sodium chloride, extract with dichloromethane, combine the organic layers, use anhydrous MgSO Dry, spin to dry the solvent, column Chromatography afforded 8 as a white solid.
  • In vitro cell activity test In a variety of colon cancer and normal colon cell lines, the DPD expression level was verified by preliminary pharmacodynamic activity screening and Western Blotting, and HCT116 and SW620 were determined to be cell lines with significant 5-FU resistance . Collect the HCT116 and SW620 cells in the logarithmic phase, adjust the concentration of the cell suspension, add 100 ⁇ L to each well, and plate to adjust the density of the cells to be tested to 1000-10000 wells (the edge wells are filled with sterile PBS). Incubate at 37° C. in 5% CO 2 until the cell monolayer covers the bottom of the well (96-well flat-bottom plate), and then add the above compound at a gradient concentration and 5-FU at a constant concentration.
  • the cell survival rate is represented by T/C%, T is the OD value of the drug-treated cells, and C is the OD value of the control cells.
  • the EC 50 and IC 50 were calculated according to the cell viability of each concentration gradient, and the results are shown in Table 1.
  • EC 50 is the EC 50 value of the above inhibitor compounds combined with 5-FU, where the concentration of 5-FU is 20 ⁇ M.
  • IC 50 is the IC 50 value of the compound alone, 5-FU is the no inhibitor group, DMSO is the solvent group, HCT116, SW620 are 5-FU resistant cells, -- means no cell death or not detected. NT means not determined.
  • the two kinds of cells showed 5-FU drug resistance under the action of 20 ⁇ M 5-fluorouracil, and the compound of the present invention can reverse the drug resistance of 5-fluorouracil, and the combination with 5-fluorouracil can effectively inhibit the proliferation of drug-resistant cells.
  • the compounds of the present invention have smaller EC 50 values against the SW620 cell line, indicating that the compounds of the present invention have more excellent inhibitory activity.
  • Embodiment 2 Inhibitor of the present invention inhibits DPD expression experiment in vitro
  • HCT116 cells (solvent control group, 10 ⁇ M administration group in which the compound in Table 1 was administered alone) and SW620 cells (solvent control group, 10 ⁇ M administration group in which the compound in Table 2 was administered alone) were taken out and then subjected to cell scraper, protein extraction and quantification.
  • Cell protein extraction first wash the cells with PBS, pre-cool the cells in each group at 4°C, and prepare the cell lysate: NP-40 (960 ⁇ L) + PPI (40 ⁇ L) + PMSF (40 ⁇ L). Discard the PBS, add 100-200 ⁇ L of lysate depending on the cell density, and place at 4°C for 40 minutes. Scrape the cells with a cell scraper, collect the cells in a 1.5mL centrifuge tube, and centrifuge at 12000rpm for 15min.
  • Nude mice are used to subcutaneously inoculate the tumor model to carry out combined administration of 5-fluorouracil and the inhibitor of the present invention.
  • BALB/c nude mice aged 6-8 weeks were purchased, 6 in each group, and raised in a clean (SPF) environment free of specific pathogens.
  • the above-mentioned 5-FU resistant SW620 cells were inoculated subcutaneously. Two weeks later, when the tumor mass increased to a certain size, the tumor mass was aseptically separated, evenly cut, and then inoculated into the armpit of each nude mouse. Two mice were raised in a sterile environment. Weeks, after the size of the tumor mass in each group was consistent, the administration began.
  • the tumor tissues and liver tissues of nude mice in each group were taken out and then subjected to tissue grinding, protein extraction and quantification. After SDS-PAGE electrophoresis, membrane transfer and blocking, DPD and ⁇ -actin ( ⁇ -actin) antibody were incubated overnight. Then wash the membrane and incubate with the secondary antibody, and then develop the PVDF membrane after washing the membrane again.

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Abstract

本申请涉及新型的DPD表达抑制剂和其药物组合物及用途，特别是在逆转在氟尿嘧啶类药物治疗肿瘤时出现的耐药性中的用途。

Description

DPD抑制剂及其药物组合物和用途 技术领域
本发明属于医药领域，具体涉及新型的DPD抑制剂、其药物组合物及用途，特别是在逆转在氟尿嘧啶类药物治疗肿瘤时出现的耐药性中的用途。
背景技术
化疗在癌症治疗中占有极其重要的地位。自1957Duschinsky等合成5-氟尿嘧啶以来，5-氟尿嘧啶及其衍生物一直是消化道肿瘤、头颈部肿瘤和其他肿瘤，例如肺癌和乳腺癌的化疗的基础用药。然而，与其他抗癌药物一样，肿瘤对其产生耐药性是上述癌症化疗失败的主要原因。实际上，肿瘤细胞内二氢嘧啶脱氢酶(DPD)是降解进入癌细胞内的5-氟尿嘧啶的主要限速酶，由于细胞内5-氟尿嘧啶被降解成为无活性产物，导致肿瘤细胞产生耐药性。但是，目前对于调控DPD表达的机制尚未明了，导致对于新靶点发现与靶向设计5-氟尿嘧啶耐药逆转剂无从谈起，这也恰是临床大夫翘首以盼的急需药物。因此，确认参与5-氟尿嘧啶耐药产生过程中调控DPD表达的关键分子并确认其为设计耐药逆转剂靶点至关重要。
发明内容
第一方面，本申请提供了式I化合物，或者其药学上可接受的盐、或互变异构体：
Figure PCTCN2021106708-appb-000001
其中：
L为直连键或亚烯基；
R 1选自氢、烷基和卤代烷基；
R 2选自氢或任选取代的烷基；
各R 3独立地选自任选被芳基取代的烷基、具有至少4个成环碳原子的环烷基、任选被卤素或烷氧基取代的芳基、任选被卤素取代的杂芳基；
R 4、R 5和R 6各自独立地选自氢、或任选取代的烷基；
环B为芳环或杂芳环；
各R 7独立地选自卤素、烷基、任选被卤素取代的烷氧基、烷基取代的氨基、杂芳基取代的杂芳基取代的氨基；
x为1至2的整数；以及
y为0、1、2或3的整数；
条件是：
当一个R 3为烷基时，R 1为卤代烷基或x为2；
当R 3为烷氧基取代的芳基时，R 1为氢；
当R 3为未取代的芳基时，R 1为卤代烷基或者至少一个R 7取代基不为卤素；
当R 1为氢时，至少一个R 3为被卤素或烷氧基取代的芳基、或芳基取代的烷基或者至少一个R 7取代基不为卤素。
第二方面，本申请提供了以下化合物，或者其药学上可接受的盐、或互变异构体：
Figure PCTCN2021106708-appb-000002
第三方面，本申请提供了式II化合物，或者其药学上可接受的盐、或互变异构体：
Figure PCTCN2021106708-appb-000003
其中：
Ar 1是被1个或多个独立地选自卤素、烷氧基取代的杂芳基；
Ar 2选自三嗪基、吡咯并嘧啶基、吡唑并[1,5-a]吡啶-2-基、吡啶基和苯基，其各自任选地被1个或多个独立地选自杂环烷基、任选被烷基或芳基取代的氨基、任选被芳基取代的烷基、卤素、任选被烷氧基取代的芳基、烷氧基和环烷基氧基的取代基取代；
L 1是直连键或—NR c—；
R a、R b和R c各自独立地选自氢、或任选取代的烷基；以及
Ar 1和Ar 2不完全相同。
第四方面，本申请提供了以下化合物，或者其药学上可接受的盐、或互变异构体：
Figure PCTCN2021106708-appb-000004
第五方面，本申请提供了药物组合物，其包含上述任一方面所述的化合物、其药学上可接受的盐、或互变异构体，以及药学上可接受的辅料。
第六方面，本申请提供了上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合在制备用于抑制DPD的表达的药物中的用途；或在制备用于预防和/或治疗受益于DPD表达的抑制的疾病、病症或病况的药物中的用途；或在制备预防和/或治疗肿瘤的药物中的用途；或在制备用于抵抗和/或逆转氟尿嘧啶类药物耐药性的药物中的用途。
第七方面，本申请提供了试剂盒，其包括：
上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物；以及
任选的抗肿瘤药物。
第八方面，本申请提供了用于抑制DPD的表达的上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合。
第九方面，本申请提供了用于预防和/或治疗受益于DPD表达的抑制的疾病、病症或病况的上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合。
第十方面，本申请提供了用于抵抗和/或逆转氟尿嘧啶类药物耐药性的上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合。
第十一方面，本申请提供了抑制DPD的表达的方法，包括对有需要的对象(例如哺乳动物，如人类)，给予治疗有效量的上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合。
第十二方面，本申请提供了预防和/或治疗受益于DPD表达的抑制的疾病、病症或病况的方法，包括对有需要的对象(例如哺乳动物，如人类)，给予治疗有效量的上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合。
第十三方面，本申请提供了抵抗和/或逆转氟尿嘧啶类药物耐药性的方法，包括：
将氟尿嘧啶类药物与本发明的上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物联合施用。
第十四方面，本申请提供了上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合在抑制DPD的表达中的用途。
第十五方面，本申请提供了上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合在预防和/或治疗受益于DPD表达的抑制的疾病、病症或病况中的用途。
第十六方面，本申请提供了上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合在抵抗和/或逆转氟尿嘧啶类药物耐药性中的用途。
附图说明
图1示出的是对比化合物和本发明的化合物的体外抑制DPD表达的实验结果。
[根据细则91更正 23.08.2021]　
图2示出的是用不同浓度的本发明化合物治疗的过程中各组裸鼠肿瘤体积变化。
[根据细则91更正 23.08.2021]　
图3示出的是各组裸鼠取材后肿瘤及肝脏组织DPD表达差异。
详细描述
定义
提供以下定义和方法用以更好地界定本申请以及在本申请实践中指导本领域普通技术人员。除非另作说明，术语按照相关领域普通技术人员的常规用法理解。本文所引用的所有专利文献、学术论文及其他公开出版物，其中的全部内容整体并入本文作为参考。
词语“包括/包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
本文中表示碳原子数的数字范围，是指给定范围中的各个整数，例如，“C 1-C 18”或“C 1- 18”是指该基团可具有1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18个碳原子。
术语“元”是表示构成环的骨架原子的个数。例如“3-12元”是表示构成环的骨架原子的个数为3、4、5、6、7、8、9、10、11或12个。
术语“卤”、“卤代”或“卤素”本身或作为另一取代基的一部分表示氟(F)、氯(Cl)、溴(Br)或碘(I)原子。
术语“烷基”是指直链或支链的饱和烃基，其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的实例包括C 1-12(例如C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、C 12)烷基、C 1-10烷基、C 1-8烷基、C 2-8烷基、C 1-6烷基、C 2-6烷基、C 1-4烷基、C 2-4烷基等，例如甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等；例如，术语“C 1-6烷基”指含有1至6(例如1、2、3、4、5、6)个碳原子的烷基(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、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。
术语“羟烷基”是指-烷基-OH，其中“烷基”定义如上，“任选取代的羟烷基”是指该基团中的烷基被取代或未取代。
术语“烷氧基”是指-O-烷基，其中“烷基”定义如上，“烷氧基”的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、异戊氧基。“任选取代的烷氧基”是指该基团中的烷基被取代或未取代。
术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基，如C 2-6烯基、C 2-4烯基等。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基、1,3-丁二烯基等。该术语包括顺式和反式异构体或这些异构体的混合物。
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基，如C 2-6炔基、C 2-4炔基、C 2-3炔基等。炔基的非限制性实例包括但不限于乙炔基(-C≡CH)、1-丙炔基(-C≡C-CH 3)、2-丙炔基(-CH 2-C≡CH)、1,3-丁二炔基(-C≡C-C≡CH)等。
术语“环烷基”是指由碳原子和氢原子组成的完全饱和的非芳香性环，优选包含1或2个环。所述环烷基可以是单环、稠合多环、桥环或螺环结构。环烷基的非限制性实例包括但不限于C 3-18(例如C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、C 12、C 13、C 14、C 15、C 16、C 17、C 18)环烷基、C 4-16环烷基、C 5-12环烷基、C 6-10环烷基、C 6-8环烷基、C 6-7环烷基等，例如环丙基、环丁基、环戊基、环己基、环庚基、螺[3.3]庚基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、二环[1.1.1]戊-1-基等。
术语“杂环烷基”是指完全饱和的并且可以以单环、桥环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至5个(如1、2、3、4、5个)独立地选自硫、氧和/或氮的杂原子的环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷 基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。
术语“环烯基”是指含有至少一个碳-碳双键的非芳香单-或多环环系。在一些实施方案中，环烯基环含有例如3-10个环原子、5-10个环原子，或5-7个环原子。合适单环环烯基的非限制实例包括环戊烯基、环己烯基、环庚烯基等。合适多环环烯基的非限制实例是降莰烯基。
术语“杂环烯基”是指含有至少一个碳-碳双键或碳-氮双键并且仅仅由碳和氢原子组成的非芳香单环或多环环系，其中环系中的一个或多个环原子是除碳以外的元素，例如1、2、3、4、5个环原子各自独立地为选自氮、氧、和硫的杂原子。在环系中不存在相邻氧和/或硫原子，在一些实施方案中，杂环烯基环含有例如5-10个环原子，5-8个环原子、5-7个环原子或、5-6个环原子。在杂环烯基根名称前的前辍氮杂、氧杂或硫杂表示至少一个氮、氧或硫原子分别作为环原子存在。合适的单环氮杂环烯基的非限制实例包括1，2，3，4四氢吡啶、1，2-二氢吡啶基、1，4-二氢吡啶基、1，2，3，6-四氢吡啶、1，4，5，6-四氢嘧啶、2-吡咯烷基、3-吡咯烷基、2-咪唑啉基、2-吡唑啉基等。合适氧杂环烯基的非限制实例包括3，4-二氢-2H-吡喃、二氢呋喃基、氟二氢呋喃基等。合适多环氧杂环烯基的非限制实例是7-氧杂双环[2.2.1]庚烯基。
术语“环炔基”是指具有至少一个碳-碳三键并且仅仅由碳和氢原子组成的非芳香单环或多环，例如4-15元、5-15元、6-10元、7-10元或8-10元环，诸如8-至10-元单环或12-至15-元双环。其可以包含一个或多个稠合或桥连的环。除非另有说明，环炔基环可以在任何碳原子处被连接，其产生一种稳定结构，并且，如果被取代的话，可以在任何合适的碳原子处被取代，其产生一种稳定结构。示例性的环炔基基团包括环辛炔基、环壬炔基、环癸炔基、2-甲基环辛炔基等等。
术语“杂环炔基”是指杂环烷基中至少某一个碳碳单键被一个碳碳三键所取代。
术语“芳基”或“芳环”是指由碳原子和氢原子组成的芳环或芳族的或部分芳族的环系统。其可为单环或可为稠合在一起或共价连接的多环(如双环等2个以上的环)。芳基的非限制性实例包括但不限于苯基、萘基、蒽基和1,2,3,4-四氢化萘等。根据结构，芳基可以是单价基团或双价基团，即亚芳基。
术语“C 6-C 18芳基”或“芳环”是指具有6至18个碳原子(例如6、7、8、9、10、11、12、13、14、15、16、17或18个碳原子)的如上所定义的芳基或芳环。
“杂芳基”或“杂芳环”指由碳原子和至少一个(例如1至5个，如1、2、3、4、5个)选自氮、氧和硫的杂原子组成的芳环基团。杂芳基基团可以是单环、双环、三环或四环环体系，其可以包含稠合的或桥联的环体系；并且杂芳基基团中的氮、碳或硫原子可以任意地被氧化；氮原子可以任意地季铵化。实例包括但不限于三嗪基、吡咯并嘧啶基、吡唑并[1,5-a]吡啶-2-基、氮杂卓基、吖啶基、苯并咪唑基、苯并噻唑基、苯并吲哚基、苯并噻二唑基、苯并萘并呋喃基、苯并噁唑基、苯并间二氧杂环戊烯基、苯并二噁英基、苯并吡喃 基、苯并吡喃酮基、苯并呋喃基、苯并呋喃酮基、苯并噻吩基(苯并苯硫基)、苯并三唑基、苯并[4,6]咪唑并[1,2-a]吡啶基、咔唑基、噌啉基、二苯并呋喃基、呋喃基、噻吩基、呋喃酮基、异噻唑基、咪唑基、吲哚基、吲唑基、异吲哚基、二氢吲哚基、异二氢吲哚基、中氮茚基、异噁唑基、萘啶基、噁二唑基、2-氧代氮杂卓基、噁唑基、环氧乙烷基、吩嗪基、吩噻嗪基、吩噁嗪基、2,3-二氮杂萘基、喋啶基、嘌呤基、吡咯基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、喹唑啉基、喹喔啉基、喹啉基、奎宁环基、异喹啉基、噻唑基、噻二唑基、三唑基、四唑基、以及苯硫基。
术语“C 1-C 18杂芳基”是指具有除了1个至18个碳原子(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个碳原子)之外还含有作为成环原子的选自N、O、和S中的至少一个杂原子(例如1、2、3、4、5个杂原子)的芳环基团。
除非另有指明，术语“杂环基”或“杂环”是指可为饱和或不饱和的、芳香性或非芳香性的环状结构，其中所述环状结构含有至少一个碳和至少一个选自O、N、S的杂原子，其实例包括杂环烷基、杂芳基、杂环烯基和杂环炔基。
术语“C 1-C 18杂环基”是指具有除了1个至18个碳原子(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个碳原子)之外还含有作为成环原子的选自N、O、和S中的至少一个杂原子(例如1、2、3、4或5个杂原子)的如上述所定义的杂环基。
在本说明书中，
Figure PCTCN2021106708-appb-000005
意指连接位置。
在本说明书中由虚线和实线构成的双线
Figure PCTCN2021106708-appb-000006
表示单键或双键。
术语“羧基烷基”是指具有-烷基-COOH结构的基团，其中烷基如上所定义。羧基烷基的代表性实例包括但不限于，羧甲基(-CH 2CO 2H)，2-羧乙基等。“任选取代的羧基烷基”是指该基团中的烷基部分被取代或未取代。
术语“任选取代的氨基”是指-NH 2，单-或二-取代氨基，以及5-至7-元环状氨基。
本文中所用的术语“酯基”是指具有-C(O)OR'或-OC(O)R'结构的基团，其中R'为如上所定义的任选取代的烷基、任选取代的芳基或任选取代的杂芳基。在一些实施方案中，R'为烷基、卤代烷基、芳基、杂芳基、烷芳基、烷基杂芳基。在一些实施方案中，R'为烷基或卤代烷基。在一些实施方案中，R'为C 1-6烷基。“任选取代的酯基”是指该基团中的R'部分被取代或未取代。
本文中所用的术语“酰基”是指具有-C(O)R'结构的基团，其中R'如上所定义。“任选取代的酰基”是指该基团中的R'部分被取代或未取代。
本文中所用的术语“磺酰基”是指具有-SO 2R'结构的基团，其中R'如上所定义。“任选取代的磺酰基”是指该基团中的R'部分被取代或未取代。
术语“任选取代的”是指基团未被取代或者被一个或多个取代基(例如1至4个、1至3个或1至2个)取代，当被取代时，取代基团是单独地并且独立地选自下列的一个或多个基团：卤素、羟基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基、烷氧基、芳氧基、杂芳氧基、巯基、烷硫基、芳硫基、氰基、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、羧基、C-羧基、O-羧基、异氰酸根合、氰硫基、 异硫氰酸根合、硝基、酯基、甲硅烷基、三卤代甲烷磺酰基、或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物等。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
当基团被多于一个的取代基取代时，取代基可以相同或不同，本文中任何取代的官能团可以在1至4个不同的位置被取代，并且那些1至4个取代基团能够在1至4个位置各自独立地被取代。
术语“药学上可接受的盐”是指保留了指定化合物的游离酸和游离碱的生物效力，并且在生物学或其它方面上没有不良作用的盐。“药学上可接受的盐”包括“药学上可接受的酸加合盐”和“药学上可接受的碱加合盐”。
本申请的化合物可以存在特定的互变异构体，所有这些异构体以及它们的混合物均包括在本申请的范围之内。
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
某些同位素标记的本申请化合物(例如用 3H及 14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代，所有这样的形式的化合物包含于本申请的范围内。
本发明中，术语“个体”包括人和动物，例如，哺乳动物(如灵长类动物，牛，马，猪，狗，猫，小鼠，大鼠，兔，山羊，绵羊以及禽类等)。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“有效量”、或“治疗有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临 床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
术语“组合物”或“药物组合物”是指任选地混合有至少一种药学上可接受的化学成分的生物活性化合物，所述药学上可接受的化学成分包括但不限于载体、稳定剂、稀释剂、分散剂、悬浮剂、增稠剂和/或赋形剂。
“药学上可接受的辅料”包括但不限于已经被美国食品与药品管理局认可的而可用于人类或动物的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、香味增强剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗压剂、溶剂或乳化剂等对组成药物组合物无副作用的各种形式的辅料。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、锭剂、膏剂、糖浆剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
本申请化合物、其药学上可接受的盐、互变异构体或者其药物组合物的典型的给药途径或施用途径包括但不限于口服、直肠、透黏膜、局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下和静脉内给药。
本发明的化合物或组合物可按配方制造且作为以下剂型使用：供口服给药的片剂、胶囊或酏剂；供直肠给药的栓剂；供注射给药的无菌溶液，悬浮液；供透皮给药的贴片以及皮下沉积物等。注射剂可以下列常规形式制备：溶液或悬浮液、在注射前适合制成溶液或悬浮液的固体剂型、或乳剂。适合的赋形剂是，例如，水、盐水、葡萄糖、甘露醇、乳糖、卵磷脂、白蛋白、谷氨酸钠、半胱氨酸盐酸盐等。另外，如果需要，所述的注射用药物组合物可包含较少量的无毒性辅助物，例如湿润剂、pH缓冲剂等。如果需要，也可使用吸收增强剂(例如，脂质体)。
用于非肠道给药的制剂包括以水溶性形式存在的所述活性化合物的水溶液。另外，所述活性化合物的悬浮液可制备成合适的油状注射悬液。适合的亲脂性溶剂或载体包括诸如芝麻油的脂肪油，或其它诸如大豆油、柚油或杏仁油的有机油，或诸如油酸乙酯或甘油三酯的合成的脂肪酸酯，或脂质体。水性注射悬液可包含增加所述悬液粘度的物质，例如羧甲基纤维素钠、山梨糖醇或葡聚糖。任意地，所述的混悬液可包含适合的稳定剂或提高所述化合物的溶解性的试剂，使得可制备高浓度的溶液。
本申请的药物组合物可以采用本领域已知的方法制备，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法和冷冻干燥法等。
在一些实施方案中，本申请的药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料或赋形剂混合来配制该药物组合物。这些辅料或赋形剂能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、粉剂、颗粒剂、液体、糖浆剂、乳剂、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备适于口服给药的固体药物组合物。例如，可通过下述方法获得固体形式的口服组合物：将活性化合物与固体辅料或赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料或赋形剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。合适的辅料或赋形剂包括但不限于：填 充剂、粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。例如用于口服的药物制剂可通过下述方法获得：将所述的活性化合物与固体赋形剂结合，任意地碾磨所得的混合物，以及加工该颗粒混合物，如果需要，在加入适合的辅助剂后得到了片剂或糖衣剂核。适合的赋形剂是，具体而言，诸如糖的填充剂，包括乳糖、蔗糖、甘露醇或山梨糖醇；纤维素制剂例如玉米淀粉、小麦淀粉、米淀粉、马铃薯淀粉、明胶、黄芪胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、和\或者聚乙烯吡咯酮(PVP)。如果需要，可加入崩解剂，例如交联聚乙烯吡咯烷酮、琼脂或藻酸或诸如藻酸钠的藻酸盐。对糖衣剂核进行适合的包被。为了这个目的，可使用浓缩的糖溶液，该溶液可任意地包含阿拉伯胶、滑石、聚乙烯吡咯烷酮、聚羧乙烯凝胶、聚乙二醇和\或二氧化钛、紫胶漆溶液和适合的有机溶剂或溶剂混合物。为了识别或表示活性化合物剂量的不同组合的特征，可向片剂或糖衣剂包衣中加入染料或色素。使用本领域中公知的方法可制造这些制剂。
本文所述的化合物或组合物的所有施用方法中，每天给药的剂量可以例如为0.001-300mg/kg体重，如0.01-300mg/kg体重、或10-200mg/kg体重，以单独剂量或分开剂量的形式给药。
术语“氟尿嘧啶类药物”包括但不限于氟尿嘧啶或其衍生物、或者含有氟尿嘧啶结构的药物，例如，5-氟尿嘧啶(5-FU)、5'-2'-脱氧尿苷、替加氟(tegafur)、氟脲苷、卡莫氟、去氧氟尿苷、替加氟/尿嘧啶、卡培他滨(capecitabine)，替吉奥、优福啶，嘧福啶，氟铁龙和希罗达等。
表述“受益于DPD表达的抑制的疾病、病症或病况”包括但不限于：消化道肿瘤、肺癌、乳腺癌、在转移性非小细胞肺癌、转移性乳腺癌、转移性胰腺癌、转移性胆管癌、头颈部肿瘤(例如口腔癌)、中晚期鼻咽癌等。
第一方面，本申请提供了式I化合物，或者其药学上可接受的盐、或互变异构体：
Figure PCTCN2021106708-appb-000007
其中：
L为直连键或亚烯基；
R 1选自氢、烷基和卤代烷基；
R 2选自氢或任选取代的烷基；
各R 3独立地选自任选被芳基取代的烷基、具有至少4个成环碳原子的环烷基、任选被卤素或烷氧基取代的芳基、任选被卤素取代的杂芳基；
R 4、R 5和R 6各自独立地选自氢、或任选取代的烷基；
环B为芳环或杂芳环；
各R 7独立地选自卤素、烷基、任选被卤素取代的烷氧基、烷基取代的氨基、杂芳基取代的杂芳基取代的氨基；
x为1至2的整数；以及
y为0、1、2或3的整数；
条件是：
当一个R 3为烷基时，R 1为卤代烷基或x为2；
当R 3为烷氧基取代的芳基时，R 1为氢；
当R 3为未取代的芳基时，R 1为卤代烷基或者至少一个R 7取代基不为卤素；
当R 1为氢时，至少一个R 3为被卤素或烷氧基取代的芳基、或芳基取代的烷基或者至少一个R 7取代基不为卤素。
在一些实施方案中，L为直连键，并且y为2或3的整数。
在一些实施方案中，L为亚烯基，并且y为0。
在一些实施方案中，R 1选自氢、C 1-6烷基和卤代C 1-6烷基。
在一些实施方案中，R 1选自氢、C 1-4烷基和卤代C 1-4烷基。
在一些实施方案中，R 1选自氢、甲基和三氟甲基。
在一些实施方案中，R 2选自氢、任选取代的C 1-6烷基。
在一些实施方案中，R 2选自C 1-6烷基。
在一些实施方案中，R 2为甲基。
在一些实施方案中，各R 3独立地选自任选被C 6-18芳基取代的C 1-6烷基、4-12元环烷基、任选被卤素或C 1-6烷氧基取代的C 6-18芳基、任选被卤素取代的C 2-18杂芳基。在一些实施方案中，各R 3独立地选自任选被C 6-12芳基取代的C 1-6烷基、5-8元环烷基、任选被卤素或C 1-6烷氧基取代的C 6-12芳基、被卤素取代的C 2-12杂芳基、含S的C 2-12杂芳基。
在一些实施方案中，各R 3独立地选自C 1-4烷基、被C 6-10芳基取代的C 1-4烷基、6-8元环烷基、C 6-10芳基、被卤素取代的C 6-10芳基、被C 1-4烷氧基取代的C 6-10芳基、被卤素取代的C 2-8杂芳基、含S的C 2-8杂芳基。
在一些实施方案中，各R 3独立地选自甲基、正丙基、异丙基、苄基、环已基、苯基、对氟苯基、对甲氧基苯基、3-氯-2-噻吩基。
在一些实施方案中，R 4、R 5和R 6各自独立地选自氢、或任选取代的C 1-6烷基。
在一些实施方案中，R 4、R 5和R 6各自独立地选自氢、或C 1-4烷基。
在一些实施方案中，R 4、R 5和R 6各自独立地选自氢或甲基。
在一些实施方案中，R 4、R 5和R 6均为氢。
在一些实施方案中，环B为C 6-18芳环或C 2-18杂芳环。
在一些实施方案中，环B为C 6-12芳环或5-10元杂芳环。
在一些实施方案中，环B为C 6-10芳环或5-8元杂芳环。
在一些实施方案中，环B为苯环或吡啶环。
在一些实施方案中，当L为直连键时，环B的定义中出现的所述杂芳环在杂原子的邻位任选被2或3个R 7基团取代。
在一些实施方案中，
Figure PCTCN2021106708-appb-000008
选自被0-3个独立地选自以下的R 7基团取代的苯环或吡啶环：氟、氯、溴、甲基、甲氧基、正丙氧基、异丙氧基、正丁氧基、2-氟乙氧基、二乙基氨基和(4-(吡啶-3-基)嘧啶-2-基)氨基。
在一些实施方案中，
Figure PCTCN2021106708-appb-000009
选自：
Figure PCTCN2021106708-appb-000010
在一些实施方案中，各R 7独立地选自卤素、C 1-8烷基、任选被卤素取代的C 1-8烷氧基、C 1-8烷基取代的氨基、C 2-18杂芳基取代的C 2-18杂芳基取代的氨基。
在一些实施方案中，各R 7独立地选自卤素、C 1-6烷基、任选被卤素取代的C 1-6烷氧基、C 1-6烷基取代的氨基、C 2-12杂芳基取代的C 2-12杂芳基取代的氨基。
在一些实施方案中，各R 7独立地选自卤素、C 1-4烷基、任选被卤素取代的C 1-4烷氧基、C 1-4烷基取代的氨基、C 2-8杂芳基取代的C 2-8杂芳基取代的氨基。
在一些实施方案中，各R 7独立地选自氟、氯、溴、甲基、甲氧基、正丙氧基、异丙氧基、正丁氧基、2-氟乙氧基、二乙基氨基、(4-(吡啶-3-基)嘧啶-2-基)氨基。
在一些实施方案中，R 3为烷基，并且R 1为卤代烷基。
在一些实施方案中，一个R 3为烷基，并且x为2且另一个R 3为芳基取代的烷基。
在一些实施方案中，R 3为未取代的芳基，并且R 1为卤代烷基。
在一些实施方案中，R 3为未取代的芳基，并且至少一个R 7取代基为烷氧基。
在一些实施方案中，环B为杂芳环，R 3为被卤素或烷氧基取代的芳基，并且至少一个R 7选自C 2-8烷氧基、被卤素取代的C 2-8烷氧基、C 1-8烷基取代的氨基。
在一些实施方案中，环B为杂芳环，R 3为被卤素或烷氧基取代的芳基，并且至少一个R 7选自C 2-6烷氧基、被卤素取代的C 2-6烷氧基、C 2-6烷基取代的氨基。
在一些实施方案中，环B为吡啶，R 3为对氟苯基或对甲氧基苯基，并且至少一个R 7选自正丙氧基、异丙氧基、正丁氧基、2-氟乙氧基、二乙基氨基。
在一些实施方案中，R 1为烷基，至少一个R 3选自具有至少4个成环碳原子的环烷基、被卤素取代的芳基、被卤素取代的杂芳基，并且
Figure PCTCN2021106708-appb-000011
为任选地被卤素取代的杂芳基或卤素取代的芳基，优选
Figure PCTCN2021106708-appb-000012
为杂芳基、二卤代杂芳基、二卤代芳基；还更优选
Figure PCTCN2021106708-appb-000013
为杂芳基、4-取代的2,6-二卤代杂芳基、3,5-二卤代芳基；还更优选
Figure PCTCN2021106708-appb-000014
为吡啶基、4-取代的2,6-二氯吡啶基、3,5-二氟苯基。
在一些实施方案中，R 1为卤代烷基，至少一个R 3选自烷基和芳基，并且
Figure PCTCN2021106708-appb-000015
为卤素取代的杂芳基，优选
Figure PCTCN2021106708-appb-000016
为二卤代杂芳基；还更优选
Figure PCTCN2021106708-appb-000017
为4-取代的2,6-二氯吡啶基。
在一些实施方案中，R 1为氢，至少一个R 3为被卤素或烷氧基取代的芳基、或芳基取代的烷基。
在一些实施方案中，R 1为氢，R 3为未取代的芳基并且至少一个R 7取代基为烷氧基。
第二方面，本申请提供了以下化合物，或者其药学上可接受的盐、或互变异构体：
Figure PCTCN2021106708-appb-000018
Figure PCTCN2021106708-appb-000019
第三方面，本申请提供了式II化合物，或者其药学上可接受的盐、或互变异构体：
Figure PCTCN2021106708-appb-000020
其中：
Ar 1是被1个或多个独立地选自卤素、烷氧基取代的杂芳基；
Ar 2选自三嗪基、吡咯并嘧啶基、吡唑并[1,5-a]吡啶-2-基、吡啶基和苯基，其各自任选地被1个或多个独立地选自杂环烷基、任选被烷基或芳基取代的氨基、任选被芳基取代的烷基、卤素、任选被烷氧基取代的芳基、烷氧基和环烷基氧基的取代基取代；
L 1是直连键或—NR c—；
R a、R b和R c各自独立地选自氢、或任选取代的烷基；以及
Ar 1和Ar 2不完全相同。
在一些实施方案中，Ar 1是被1个或多个独立地选自卤素、烷氧基的取代基取代的单环杂芳基。
在一些实施方案中，Ar 1是被1个或多个独立地选自卤素、烷氧基的取代基取代的单环杂芳基，其中所述1个或多个取代基中的至少一个是卤素。
在一些实施方案中，Ar 1是被1个或多个独立地选自卤素、C 1-6烷氧基的取代基取代的单环C 2-18杂芳基。
在一些实施方案中，Ar 1是被1个或多个独立地选自卤素、C 1-6烷氧基的取代基取代的单环C 2-12杂芳基。
在一些实施方案中，Ar 1是被1个或多个独立地选自卤素、C 1-4烷氧基的取代基取代的单环C 2-10杂芳基。
在一些实施方案中，Ar 1是被1个或多个独立地选自卤素、C 1-4烷氧基的取代基取代的吡啶基。
在一些实施方案中，Ar 1是被1个或多个独立地选自氯、甲氧基、乙氧基、异丙氧基的取代基取代的吡啶基。
在一些实施方案中，Ar 1是4-取代的2,6-二氯吡啶基、4-取代的2-氯-6-甲氧基吡啶、4-取代的2-氯-6-乙氧基吡啶、或4-取代的2-氯-6-异丙氧基吡啶。
在一些实施方案中，Ar 2选自1,3,5-三嗪-2-基、吡咯并[2,3-d]嘧啶-4-基、吡咯并[2,3-d]嘧啶-2-基、吡唑并[1,5-a]吡啶-2-基、吡啶基和苯基，其各自任选地被1个或多个独立地选自杂环烷基、任选被烷基或芳基取代的氨基、任选被芳基取代的烷基、卤素、任选被烷氧基取代的芳基、烷氧基和环烷基氧基的取代基取代。
在一些实施方案中，Ar 2选自1,3,5-三嗪-2-基、吡咯并[2,3-d]嘧啶-4-基、吡咯并[2,3-d]嘧啶-2-基、吡唑并[1,5-a]吡啶-2-基、吡啶基和苯基，其各自任选地被1个或多个独立地选自3-12元杂环烷基、C 6-18芳基取代的氨基、C 6-18芳基取代的C 1-6烷基、C 1-6烷基取代的氨基、C 1-6烷基、卤素、C 6-18芳基、C 1-6烷氧基取代的C 6-18芳基、C 1-6烷氧基和3-12元环烷基氧基的取代基取代。
在一些实施方案中，Ar 2选自1,3,5-三嗪-2-基、吡咯并[2,3-d]嘧啶-4-基、吡咯并[2,3-d]嘧啶-2-基、吡唑并[1,5-a]吡啶-2-基、吡啶基和苯基，其各自任选地被1个或多个独立地选自3-10元杂环烷基、C 6-12芳基取代的氨基、C 6-12芳基取代的C 1-6烷基、C 1-6烷基取代的氨基、C 1-6烷基、卤素、C 6-12芳基、C 1-6烷氧基取代的C 6-12芳基、C 1-6烷氧基和3-10元环烷基氧基的取代基取代。
在一些实施方案中，Ar 2选自1,3,5-三嗪-2-基、吡咯并[2,3-d]嘧啶-4-基、吡咯并[2,3-d]嘧啶-2-基、吡唑并[1,5-a]吡啶-2-基、吡啶基和苯基，其各自任选地被1个或多个独立地选自3-8元杂环烷基、C 6-10芳基取代的氨基、C 6-10芳基取代的C 1-4烷基、C 1-4烷基取代的氨基、C 1-4烷基、卤素、C 6-10芳基、C 1-4烷氧基取代的C 6-10芳基、C 1-4烷氧基和3-8元环烷基氧基的取代基取代。
在一些实施方案中，Ar 2选自1,3,5-三嗪-2-基、吡咯并[2,3-d]嘧啶-4-基、吡咯并[2,3-d]嘧啶-2-基、吡唑并[1,5-a]吡啶-2-基、吡啶基和苯基，其各自任选地被1个或多个独立地选自吡咯烷基、苯基氨基、苄基、二甲基氨基、甲基、氯、溴、苯基、甲氧基苯基、甲氧基、乙氧基、异丙氧基和环戊基氧基的取代基取代。
在一些实施方案中，当Ar 2是吡咯并嘧啶基时，所述嘧啶部分上的取代基当存在时为非环状基团。
在一些实施方案中，当Ar 2是吡咯并嘧啶基时，所述嘧啶部分上的取代基当存在时为任选被烷基取代的氨基。
在一些实施方案中，当Ar 2是三嗪基时，所述三嗪基被杂环烷基取代。
在一些实施方案中，当Ar 2是三嗪基时，所述三嗪基被吡咯烷-1-基取代。
在一些实施方案中，当Ar 2是吡唑并[1,5-a]吡啶-2-基时，所述吡唑并[1,5-a]吡啶-2-基任选地被卤素、芳基或烷氧基芳基取代。
在一些实施方案中，当Ar 2是吡啶基或苯基时，所述吡啶基或苯基被至少一个卤素取代。
在一些实施方案中，当Ar 2是吡啶基或苯基时，所述吡啶基或苯基被1个或多个独立地选自卤素、烷氧基和环烷基氧基的取代基取代，并且所述1个或多个取代基中的至少一个为卤素。
在一些实施方案中，当Ar 2是吡唑并[1,5-a]吡啶-2-基、吡啶基或苯基时，L 1是直连键。
在一些实施方案中，R a、R b和R c各自独立地选自氢、或任选取代的C 1-6烷基。
在一些实施方案中，R a、R b和R c各自独立地选自氢、或C 1-4烷基。
在一些实施方案中，R a、R b和R c各自独立地选自氢或甲基。
在一些实施方案中，R a、R b和R c均为氢。
第四方面，本申请提供了以下化合物，或者其药学上可接受的盐、或互变异构体：
Figure PCTCN2021106708-appb-000021
第五方面，本申请提供了药物组合物，其包含上述任一方面所述的化合物、其药学上可接受的盐、或互变异构体，以及药学上可接受的辅料。
在一些实施方案中，所述药物组合物还包含一种或多种其它治疗剂。
在一些实施方案中，所述其它治疗剂为抗肿瘤药物。
在一些实施方案中，所述抗肿瘤药物选自氟尿嘧啶类药物。
在一些实施方案中，所述抗肿瘤药物选自5-氟尿嘧啶、5'-2'-脱氧尿苷、替加氟、氟脲苷、卡莫氟、去氧氟尿苷、尿嘧啶替加氟、卡培他滨，替吉奥、优福啶，嘧福啶，氟铁龙和希罗达。
第六方面，本申请提供了上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合在制备用于抑制DPD的表达的药物中的用途；或在制备用于预防和/或治疗受益于DPD表达的抑制的疾病、病症或病况的药物中的用途；或在制备预防和/或治疗肿瘤的药物中的用途；或在制备用于抵抗和/或逆转氟尿嘧啶类药物耐药性的药物中的用途。
在一些实施方案中，所述受益于DPD表达的抑制的疾病、病症或病况选自肿瘤。
在一些实施方案中，所述疾病、病症或病况或者所述肿瘤选自消化道肿瘤、头颈部肿瘤、肺癌、乳腺癌等；任选地，所述头颈部肿瘤包括口腔癌等。
在一些实施方案中，所述肿瘤为对于氟尿嘧啶类药物具有耐药性的肿瘤。
在一些实施方案中，所述一种或多种其它治疗剂为抗肿瘤药物。
在一些实施方案中，所述抗肿瘤药物选自氟尿嘧啶类药物。
在一些实施方案中，所述抑制DPD的表达尤其是抑制肝脏中的DPD的表达。
在一些实施方案中，所述氟尿嘧啶类药物选自5-氟尿嘧啶、5'-2'-脱氧尿苷、替加氟、氟脲苷、卡莫氟、去氧氟尿苷、尿嘧啶替加氟、卡培他滨，替吉奥、优福啶，嘧福啶，氟铁龙和希罗达。
第七方面，本申请提供了用于抑制细胞中DPD表达的方法，其包括给所述细胞施用有效量的上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合，其中所述方法在体外进行。
在一些实施方案中，所述细胞为细胞系，或者来自受试者的细胞。
在一些实施方案中，所述细胞选自肿瘤细胞。在一些实施方案中，所述肿瘤细胞选自乳腺癌细胞、肝癌细胞、肺癌细胞、食道癌细胞、胃癌细胞、胰腺癌细胞、胆管癌细胞、头颈部肿瘤细胞、鼻咽癌细胞等。
第八方面，本申请提供了用于抵抗/逆转细胞耐药的方法，其包括给所述细胞施用有效量的上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合，其中所述方法在体外进行。
在一些实施方案中，所述细胞为细胞系，或者来自受试者的细胞。
在一些实施方案中，所述细胞选自肿瘤细胞。在一些实施方案中，所述肿瘤细胞选自乳腺癌细胞、肝癌细胞、肺癌细胞、食道癌细胞、胃癌细胞、胰腺癌细胞、胆管癌细胞、头颈部肿瘤细胞、鼻咽癌细胞等。
第九方面，本申请提供了试剂盒，其包括：
上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物；以及
任选的抗肿瘤药物。
在一些实施方案中，所述试剂盒还包括使用说明书。
在一些实施方案中，所述抗肿瘤药物选自氟尿嘧啶类药物。
第十方面，本申请提供了用于抑制DPD的表达的上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合。在一些实施方案中，所述抑制DPD的表达尤其是抑制肝脏中的DPD的表达。
第十一方面，本申请提供了用于预防和/或治疗受益于DPD表达的抑制的疾病、病症或病况的上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合。
在一些实施方案中，所述疾病、病症或病况或者所述肿瘤选自消化道肿瘤、头颈部肿瘤、肺癌、乳腺癌等；任选地，所述头颈部肿瘤包括口腔癌等。
在一些实施方案中，所述肿瘤为对于氟尿嘧啶类药物具有耐药性的肿瘤。
在一些实施方案中，所述一种或多种其它治疗剂为抗肿瘤药物。
在一些实施方案中，所述抗肿瘤药物选自氟尿嘧啶类药物。
在一些实施方案中，所述氟尿嘧啶类药物选自5-氟尿嘧啶、5'-2'-脱氧尿苷、替加氟、氟脲苷、卡莫氟、去氧氟尿苷、尿嘧啶替加氟、卡培他滨，替吉奥、优福啶，嘧福啶，氟铁龙和希罗达。
第十二方面，本申请提供了用于抵抗和/或逆转氟尿嘧啶类药物耐药性的上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合。
第十三方面，本申请提供了抑制DPD的表达的方法，包括对有需要的对象(例如哺乳动物，如人类)，给予治疗有效量的上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合。在一些实施方案中，所述抑制DPD的表达尤其是抑制肝脏中的DPD的表达。
第十四方面，本申请提供了预防和/或治疗受益于DPD表达的抑制的疾病、病症或病况的方法，包括对有需要的对象(例如哺乳动物，如人类)，给予治疗有效量的上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合。
在一些实施方案中，所述肿瘤为对于氟尿嘧啶类药物具有耐药性的肿瘤。
在一些实施方案中，所述一种或多种其它治疗剂为抗肿瘤药物。
在一些实施方案中，所述抗肿瘤药物选自氟尿嘧啶类药物。
在一些实施方案中，所述氟尿嘧啶类药物选自5-氟尿嘧啶、5'-2'-脱氧尿苷、替加氟、氟脲苷、卡莫氟、去氧氟尿苷、尿嘧啶替加氟、卡培他滨，替吉奥、优福啶，嘧福啶，氟铁龙和希罗达。
第十五方面，本申请提供了抵抗和/或逆转氟尿嘧啶类药物耐药性的方法，包括：
将氟尿嘧啶类药物与本发明的上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物联合施用。
第十六方面，本申请提供了上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合在抑制DPD的表达中的用途。在一些实施方案中，所述抑制DPD的表达尤其是抑制肝脏中的DPD的表达。
第十七方面，本申请提供了上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合在预防和/或治疗受益于DPD表达的抑制的疾病、病症或病况中的用途。
第十八方面，本申请提供了上述化合物、其药学上可接受的盐、或互变异构体，或者上述药物组合物，或者它们与一种或多种其它治疗剂的组合在抵抗和/或逆转氟尿嘧啶类药物耐药性中的用途。
具体实施方式
下面结合实施例，对本发明的具体实施方式作进一步详细描述。以下实施例仅用于说明的目的，而非用来限制本申请的范围。
制备例1
通过通用合成路线I合成了化合物9-1至9-9：
Figure PCTCN2021106708-appb-000022
所述合成路线I包括下述步骤：
步骤1a：
Figure PCTCN2021106708-appb-000023
步骤1：
Figure PCTCN2021106708-appb-000024
步骤2：
Figure PCTCN2021106708-appb-000025
以及下述步骤3-1或步骤3-2：
步骤3-1：
Figure PCTCN2021106708-appb-000026
步骤3-2：
Figure PCTCN2021106708-appb-000027
化合物9-1的合成：
Figure PCTCN2021106708-appb-000028
以1甲基-5-氨基吡唑(1)和2,6-二氯吡啶-4甲酸为初始原料，通过上述反应制备：即1甲基-5-氨基吡唑(1,30.93mmol)和异丁酰乙酸乙酯(37.11mmol)以醋酸为溶剂，140℃回流20h，冷却至室温，旋干溶剂，加入10mL乙酸乙酯，搅拌十分钟，之后抽滤得白色固体1。
化合物2(1.95mmol)与POBr 3(2.54mmol)以苯甲醚为溶剂，120℃回流3h，冷却至室温，用饱和饱和氯化钠水溶液洗涤，二氯甲烷萃取，合并有机层，用无水MgSO 4干燥，旋干溶剂，柱层析得白色固体3。
化合物3(200mg,0.89mmol),NIS(200mg,0.89mmol),48％HBF 4(391mg,4.44mmol)溶于CH 3CN(5mL)，80℃回流2h。TLC检测反应完全，将反应液倒入1M NaHCO 3水溶液中,过滤，水洗得到化合物4(237mg,产率76％)。 1H NMR(600MHz,DMSO-d 6)δ7.13(s,1H),3.90(s,3H),2.62(s,3H). 13C NMR(125MHz,DMSO-d 6)δ149.51,145.89,141.64,122.09,116.71,89.24,34.61,17.33.
化合物4(1.0g,2.85mmol)，Cs 2CO 3(1.9g,5.7mmol),PdCl 2(PPh 3) 2(100mg,0.14mmol)，和4-吡啶硼酸(350mg,2.85mmol)溶于1,4-二氧六环/H 2O(15mL,v/v 3/1)的混合溶液。反应体系除去空气，通入氮气保护，80℃搅拌12h。TLC检测反应完全，反应液用水和饱和的NaCl水溶液洗涤，二氯甲烷萃取，无水MgSO 4干燥，过滤，旋干溶剂，柱层析得化合物5-1(410mg,52％)。 1H NMR(500MHz,DMSO-d 6)δ8.81(d,J＝2.3Hz,1H),8.66(d,J＝4.8Hz,1H),8.05(dt,J＝8.0,1.9Hz,1H),7.53(dd,J＝7.9,4.8Hz,1H),7.29(s,1H),4.05(s,3H),2.37(s,3H). 13C NMR(125MHz,DMSO-d 6)δ150.59,150.20,149.94,146.27,141.52,141.37,137.49,129.60,123.81,122.10,113.11,34.56,19.68.
化合物5-1(1.80mmol)与80％的水合肼(89.89mmol)以乙醇为溶剂，100℃回流10h，冷却至室温，旋干溶剂，用饱和饱和氯化钠水溶液洗涤，二氯甲烷萃取，合并有机层，用无水MgSO 4干燥，旋干溶剂，得白色固体6-1。
2,6-二氯吡啶-4-甲酸(26mmol)置于双口瓶中，氮气保护条件下加入30mL1,4-二氧六环，滴加三乙胺(39mmol)，冰浴条件下逐滴加入叠氮磷酸二苯酯DPPA(39mmol)，过夜反应，TLC检测反应完全，用饱和饱和氯化钠水溶液洗涤，二氯甲烷萃取，合并有机层，用无水MgSO 4干燥，旋干溶剂，柱层析得白色固体8。
化合物8(1.68mmol)溶于3mL甲苯中，80℃加热3h，TLC检测全部转换为异氰酸酯，降温至50℃，加入化合物6-1(1.68mmol)的四氢呋喃溶液，反应5h，TLC检测反应完全，冷却至室温，旋干溶剂，用饱和氯化钠水溶液洗涤，二氯甲烷萃取，合并有机层，用无水MgSO 4干燥，旋干溶剂，柱层析得白色固体9-1。
9-1： 1H NMR(500MHz,DMSO-d 6)δ9.80(d,J＝86.4Hz,1H),9.16–8.74(m,3H),8.63(d,J＝4.8Hz,1H),8.02(dd,J＝7.8,2.1Hz,1H),7.98–7.37(m,3H),6.42(s,1H),3.91(s,3H),2.29(s,3H). 13C NMR(125MHz,DMSO-d 6)δ159.87,151.97,151.15,149.90,149.85,149.25,143.46,140.88,137.42,130.73,123.76,111.65,108.72,105.13,33.84,20.32.
下述其它化合物可参照以上合成路线制备得到或参照文献或专利(包括但不限于例如上述背景技术部分中提及的那些)报道的合成方法或合成路线制备得到：
9-2： 1H NMR(500MHz,DMSO-d 6)δ9.70(s,1H),8.93(d,J＝43.5Hz,2H),7.85(dd,J＝60.5,8.1Hz,6H),6.42(s,1H),3.89(s,3H),2.30(s,3H). 13C NMR(125MHz,DMSO-d 6)δ151.98,149.84,142.38,139.44,132.54,130.67,119.25,110.97,33.90,20.65.
9-3： 1H NMR(500MHz,DMSO-d 6)δ9.77(d,J＝101.5Hz,1H),8.88(d,J＝64.7Hz,2H),8.02–7.02(m,5H),6.33(s,1H),3.86(s,3H),2.04(d,J＝53.6Hz,6H). 13C NMR(125MHz,DMSO-d 6)δ163.35,161.41,151.97,150.56,149.84,142.23,140.48,132.78,130.89,116.78,112.67,33.67,20.10,18.48.
9-4： 1H NMR(500MHz,DMSO-d 6)δ9.70(s,1H),8.78(s,2H),8.00–7.33(m,4H),7.05–6.88(m,2H),6.35(s,1H),4.06–3.79(m,5H),2.27(s,3H),1.73(m,J＝7.1Hz,2H),0.98(t,J＝7.4Hz,3H). 13C NMR(125MHz,DMSO-d 6)δ158.98,151.99,150.98,149.83,143.92,131.12,126.89,114.40,69.39,33.63,22.51,20.32,10.8.
9-5： 1H NMR(500MHz,DMSO-d 6)δ9.58(s,2H),8.76(s,2H),7.35(d,J＝8.2Hz,4H),6.83(d,J＝8.2Hz,2H),6.34(s,1H),3.85(s,3H),2.27(s,3H). 13C NMR(125MHz,DMSO-d 6)δ159.58,157.76,151.97,150.94,149.83,144.28,143.82,131.13,125.38,115.30,111.73,108.58,104.42,33.59,20.29.
9-6： 1H NMR(500MHz,DMSO-d 6)δ9.67(s,1H),8.84(d,J＝94.9Hz,2H),7.96–7.41(m,2H),6.34(s,1H),5.99(d,J＝3.3Hz,1H),4.21(s,2H),3.80(q,J＝4.2,3.1Hz,5H),2.45(s,5H). 13C NMR(125MHz,DMSO-d 6)δ159.51,151.97,150.83,149.82,144.29,143.84,129.25,128.29,111.71,104.75,65.16,64.13,33.60,28.91,20.56.
9-7： 1H NMR(500MHz,DMSO-d 6)δ9.70(s,1H),8.83(s,2H),8.31(d,J＝2.5Hz,1H),7.86(dd,J＝8.5,2.5Hz,3H),6.81(d,J＝8.5Hz,1H),6.37(s,1H),5.28(m,J＝6.2Hz,1H),3.87(s,3H),2.28(s,3H),1.30(d,J＝6.2Hz,6H). 13C NMR(125MHz,DMSO-d 6)δ162.99,151.98,151.05,149.83,147.37,141.00,140.53,123.68,110.92,104.82,68.13,33.73,22.34,20.23.
9-8： 1H NMR(500MHz,DMSO-d 6)δ9.69(s,1H),8.80(s,2H),8.02–7.32(m,4H),6.80(d,J＝2.0Hz,1H),6.36(s,1H),3.84(s,3H),2.44(s,3H). 13C NMR(125MHz,DMSO-d 6)δ159.65,151.99,150.98,149.83,143.70,141.82,135.94,119.66,112.11,111.85,104.64,33.64,20.44.
9-9： 1H NMR(500MHz,DMSO-d 6)δ9.71(s,1H),8.82(s,2H),7.93–7.50(m,4H),7.45–7.36(m,2H),7.21–7.12(m,1H),7.12–7.02(m,4H),6.38(s,1H),3.87(s,3H),2.30(s,3H). 13C NMR(125MHz,DMSO-d 6)δ157.20,156.71,151.97,151.03,149.84,143.47,131.57,130.56,129.76,124.21,119.49,118.27,33.69,20.42.
9-10:
Figure PCTCN2021106708-appb-000029
1H NMR(500MHz,DMSO-d 6)δ9.80(s,1H),8.99(s,2H),8.07–7.34(m,8H),6.74(s,1H),3.91(s,3H). 13C NMR(125MHz,DMSO-d 6)δ159.98,151.92,150.81,149.87,144.49,137.46,131.62,129.74,129.65,128.26,111.72,108.39,102.03,33.88.
9-11:
Figure PCTCN2021106708-appb-000030
1H NMR(500MHz,DMSO-d 6)δ9.76(d,J＝103.0Hz,1H),8.78(s,2H),7.89(d,J＝58.4Hz,3H),6.40(s,1H),3.82(s,3H),3.28–3.08(m,1H),1.28(d,J＝6.9Hz,6H). 13C NMR(125MHz,DMSO-d 6)δ159.85,153.42,152.01,150.34,149.83,131.22,111.70,100.38,33.70,32.03,22.86.
9-12:
Figure PCTCN2021106708-appb-000031
1H NMR(500MHz,DMSO-d 6)δ9.65(s,1H),8.67(s,2H),7.86(d,J＝39.3Hz,3H),6.17(s,1H),3.81(s,3H),2.20(tt,J＝8.7,4.9Hz,1H),1.17–1.05(m,2H),0.92(dt,J＝6.9,3.4Hz,2H). 13C NMR(125MHz,DMSO-d 6)δ159.80,151.99,150.13,149.82,130.90,111.69,109.59,98.47,33.70,14.18,10.51.
9-13:
Figure PCTCN2021106708-appb-000032
1H NMR(500MHz,DMSO-d 6)δ9.69(s,1H),8.75(s,2H),7.87(d,J＝35.1Hz,2H),6.37(s,1H),3.83(s,3H),2.45(s,3H). 13C NMR(125MHz,DMSO-d 6)δ159.82,152.00,150.00,149.83,131.29,111.75,103.65,55.35,33.74,18.62.
9-14:
Figure PCTCN2021106708-appb-000033
1H NMR(500MHz,DMSO-d 6)δ9.76(d,J＝91.1Hz,1H),8.67(s,2H),7.69(d,J＝136.7Hz,2H),6.26(s,1H),3.72(s,3H),2.49(s,3H),2.45(s,3H). 13C NMR(125MHz,DMSO-d 6)δ159.74,151.99,150.98,149.81,143.99,140.16,111.69,103.26,33.21,19.23,14.91.
9-15:
Figure PCTCN2021106708-appb-000034
1H NMR(500MHz,DMSO-d 6)δ9.72(s,1H),8.89(d,J＝53.2Hz,2H),7.82(s,2H),7.40(d,J＝8.6Hz,2H),7.06(d,J＝8.7Hz,2H),6.33(s,1H),3.79(d,J＝8.8Hz,6H),2.07(s,3H). 13C NMR(125MHz,DMSO-d 6)δ160.07,159.34,151.98,151.36,149.82,146.56,139.65,130.38,130.20,114.28,111.70,103.19,55.65,33.36,15.50.
9-16:
Figure PCTCN2021106708-appb-000035
1H NMR(500MHz,DMSO-d 6)δ9.63(s,1H),8.73(d,J＝106.9Hz,2H),7.69(d,J＝121.4Hz,2H),6.00(s,1H),3.72(s,3H),2.53(s,3H),2.33(td,J＝8.5,8.0,4.0Hz,1H),1.07(h,J＝4.2Hz,2H),0.76–0.68(m,2H).
9-17:
Figure PCTCN2021106708-appb-000036
1H NMR(600MHz,DMSO-d 6)δ9.74(d,J＝115.8Hz,1H),8.66(s,2H),7.66(d,J＝162.4Hz,2H),6.26(s,1H),3.70(s,3H),2.76(t,J＝7.8Hz,2H),2.41(s,3H),1.58(h,J＝7.5Hz,2H), 0.92(t,J＝7.3Hz,3H).碳 13-NMR(150MHz,DMSO-D6)δ159.71,152.08,151.30,149.93,139.64,34.47,33.29,23.85,15.08,14.20.
Figure PCTCN2021106708-appb-000037
16-1：
Figure PCTCN2021106708-appb-000038
1H NMR(500MHz,DMSO-d 6)δ9.46(d,J＝471.6Hz,1H),8.58(s,2H),7.90(s,1H),7.58(s,2H),7.30–7.09(m,5H),4.09(s,2H),3.80(s,3H),2.36(s,3H). 13C NMR(125MHz, DMSO-d 6)δ156.96,149.91,148.30,140.93,139.95,131.28,128.68,128.50,126.30,111.27,33.46,30.90,15.90.
16-2：
Figure PCTCN2021106708-appb-000039
1H NMR(500MHz,DMSO-d 6)δ9.73(s,1H),8.97(s,2H),7.99(s,1H),7.91–7.44(m,4H),7.38(t,J＝8.8Hz,2H),6.66(s,1H),3.88(s,3H). 13C NMR(125MHz,DMSO-d 6)δ164.17,162.21,159.94,151.97,150.77,149.83,143.28,133.82,131.57,130.50,130.43,116.78,116.61,111.73,33.89.
16-3：
Figure PCTCN2021106708-appb-000040
1H NMR(500MHz,DMSO-d 6)δ9.81(d,J＝88.3Hz,1H),8.95(d,J＝42.2Hz,2H),7.71(d,J＝8.2Hz,5H),7.11(d,J＝8.3Hz,2H),6.63(s,1H),3.84(d,J＝28.7Hz,6H). 13C NMR(125MHz,DMSO-d 6)δ160.70,159.95,151.99,150.85,149.83,144.07,131.72,105.64,98.04,129.63,115.17,111.82,101.12,55.76,33.86.
16-15:
Figure PCTCN2021106708-appb-000041
1H NMR(600MHz,DMSO-d 6)δ9.77(d,J＝94.0Hz,1H),8.92(d,J＝47.9Hz,2H),7.49(s,4H),7.32(s,2H),6.33(s,1H),3.77(s,3H),2.00(s,3H). 13C NMR(125MHz,DMSO-d 6)δ163.77,161.82,159.31,151.96,151.27,149.83,145.62,139.54,134.36,131.19,131.13,115.91,115.74,33.38,15.30.
16-16:
Figure PCTCN2021106708-appb-000042
1H NMR(400MHz,DMSO-d 6)δ9.69(s,1H),8.71(s,2H),7.72(d,J＝98.5Hz,2H),6.36(s,1H),3.74(s,3H),3.04(s,1H),2.48(s,3H),1.97–1.67(m,5H),1.53–1.33(m,4H),1.33–1.23(m,1H). 13C NMR(100MHz,DMSO-d 6)δ159.82,153.48,152.06,151.20,149.88,139.22,111.76,99.28,33.55,33.22,26.58,26.15,15.19.
16-17:
Figure PCTCN2021106708-appb-000043
1H NMR(400MHz,DMSO-d 6)δ9.76(s,1H),8.99(s,2H),7.81(s,2H),7.44–7.19(m,2H),6.46(s,1H),3.81(s,3H),2.27(s,3H). 13C NMR(100MHz,DMSO-d 6)δ151.95,151.54,149.88,139.52,137.63,137.50,129.89,129.09,128.26,111.69,33.44,15.67.
16-20:
Figure PCTCN2021106708-appb-000044
1H NMR(400MHz,DMSO-d 6)δ9.47(s,1H),8.82(d,J＝48.6Hz,2H),8.01(s,1H),7.73(d,J＝8.5Hz,2H),7.14(d,J＝8.4Hz,4H),6.65(s,1H),5.09(p,J＝6.2Hz,1H),3.87(d,J＝23.7Hz,6H),1.25(d,J＝6.2Hz,6H). 13C NMR(100MHz,DMSO-d 6)δ163.69,160.71,151.72,150.92,144.02,131.73,129.73,129.63,115.20,68.85,55.78,33.88,22.22.
16-21:
Figure PCTCN2021106708-appb-000045
1H NMR(400MHz,DMSO-d 6)δ9.48(s,1H),8.81(d,J＝43.8Hz,2H),8.01(s,1H),7.72(d,J＝8.4Hz,2H),7.46–6.60(m,5H),4.10(t,J＝6.6Hz,2H),3.87(d,J＝21.4Hz,6H),1.68(q,J＝7.1Hz,2H),0.93(t,J＝7.4Hz,3H). 13C NMR(100MHz,DMSO-d 6)δ164.32,160.72,151.72,150.93,131.74,129.64,115.21,68.08,55.79,33.88,22.21,10.80.
16-22:
Figure PCTCN2021106708-appb-000046
1H NMR(400MHz,DMSO-d 6)δ9.49(s,1H),8.83(d,J＝43.4Hz,2H),8.02(s,1H),7.79–7.68(m,2H),7.14(d,J＝8.8Hz,4H),6.65(s,1H),4.15(t,J＝6.6Hz,2H),3.87(d,J＝23.9Hz,6H),1.65(dd,J＝8.4,6.2Hz,2H),1.47–1.31(m,2H),0.91(t,J＝7.4Hz,3H). 13C NMR(100MHz,DMSO-d 6)δ164.31,160.72,160.17,151.72,150.92,147.99,144.02,131.74,129.73,129.64,115.21,68.07,55.80,33.88,22.21,10.80.
16-23:
Figure PCTCN2021106708-appb-000047
1H NMR(400MHz,DMSO-d 6)δ9.52(s,1H),8.86(d,J＝62.1Hz,2H),8.01(s,1H),7.83–7.72(m,2H),7.63–7.48(m,3H),7.44–6.92(m,2H),6.70(s,1H),3.91(s,3H),3.79(s,3H). 13C NMR(100MHz,DMSO-d 6)δ164.53,160.15,151.72,150.88,148.05,144.40,137.51,131.66,129.86,129.79,128.29,54.21,33.91.
16-24:
Figure PCTCN2021106708-appb-000048
1H NMR(400MHz,DMSO-d 6)δ9.70(s,1H),8.97(d,J＝34.2Hz,2H),8.18–7.62(m,5H),7.13(d,J＝8.4Hz,2H),6.66(s,1H),3.87(d,J＝24.9Hz,6H). 13C NMR(100MHz,DMSO-d 6)δ160.73,160.00,151.30,150.89,144.10,140.39,131.76,129.66,115.19,55.78,33.89.
16-27:
Figure PCTCN2021106708-appb-000049
白色固体,产率52％. 1H NMR(400MHz,DMSO-d 6)δ9.49(s,1H),8.85(d,J＝66.5Hz,2H),8.00(s,1H),7.81(dd,J＝8.7,5.5Hz,2H),7.51–6.87(m,4H),6.67(s,1H),4.15(t,J＝6.5Hz,2H),3.91(s,3H),1.64(dq,J＝8.6,6.6Hz,2H),1.46–1.32(m,2H),0.91(t,J＝7.4Hz,3H). 13C NMR(100MHz,DMSO-d 6)δ164.30,151.68,150.86,143.24,133.92,131.58,130.52,130.43,116.84,116.62,66.27,33.90,30.92,19.14,14.13.HRESIMS m/z 484.1660[M+H] +(计算值C 23H 24ClFN 7O 2 484.1664).
16-28:
Figure PCTCN2021106708-appb-000050
黄色固体,产率23％. 1H NMR(400MHz,DMSO-d 6)δ9.21(s,1H),8.89(s,1H),8.61(s,1H),8.00(s,1H),7.88–7.74(m,2H),7.47–7.35(m,2H),6.70(d,J＝18.6Hz,3H),3.92(s,3H),3.38(t,J＝7.0Hz,4H),1.06(t,J＝6.9Hz,6H). 13C NMR(100MHz,DMSO-d 6)δ160.32, 157.90,150.88,150.42,149.33,133.94,131.57,130.51,130.42,116.83,116.61,108.13,101.98,100.62,91.88,42.42,33.91,13.17.HRESIMS m/z 483.1823[M+H] +(计算值C 23H 25ClFN 8O483.1824).
16-29:
Figure PCTCN2021106708-appb-000051
白色固体,产率48％. 1H NMR(400MHz,DMSO-d 6)δ9.56(s,1H),8.89(d,J＝59.0Hz,2H),8.01(s,1H),7.82(ddd,J＝8.6,5.1,2.2Hz,2H),7.42(td,J＝9.0,2.3Hz,4H),6.69(d,J＝2.4Hz,1H),4.82–4.73(m,1H),4.70–4.60(m,1H),4.43(dt,J＝30.3,3.9Hz,2H),3.91(s,3H). 13C NMR(100MHz,DMSO-d 6)δ163.69,160.11,151.92,150.85,147.88,143.26,133.88,131.59,130.53,130.44,116.84,116.62,83.19,81.54,65.98,65.80,33.91.HRESIMS m/z 474.1257[M+H] +(计算值C 21H 19ClF 2N 7O 2 474.1257).
16-30:
Figure PCTCN2021106708-appb-000052
淡黄色固体，产率32％. 1H NMR(400MHz,DMSO-d 6)δ9.24(d,J＝2.2Hz,1H),8.86(d,J＝20.5Hz,3H),8.63(dd,J＝4.8,1.7Hz,1H),8.53–8.41(m,2H),8.28(s,1H),7.98(s,1H),7.80(td,J＝5.4,2.2Hz,3H),7.41(ddd,J＝11.4,9.7,7.0Hz,4H),7.22(dd,J＝8.2,2.2Hz,1H),7.10(d,J＝8.3Hz,1H),6.69(s,1H),3.90(s,3H),2.17(s,3H). 13C NMR(100MHz,DMSO-d 6)δ162.01,161.62,160.60,159.90,156.88,151.71,150.95,148.55,143.09,138.25,138.20,134.93,132.70,131.53,130.51,130.48,130.39,126.17,124.24,116.82,116.60,116.10,115.68,107.93,107.88,101.94,33.88,17.95.HRESIMS m/z 561.2276[M+H] +(计算值C 30H 26FN 10O 561.2275).
16-31:
Figure PCTCN2021106708-appb-000053
白色固体,产率51％. 1H NMR(400MHz,DMSO-d 6)δ9.31(s,1H),8.92(s,1H),8.67(s,1H),8.01(s,1H),7.88–7.63(m,4H),7.41(t,J＝8.8Hz,2H),7.13(t,J＝1.9Hz,1H),6.69(s,1H),3.92(s,3H). 13C NMR(100MHz,DMSO-d 6)δ160.26,150.89,143.19,142.96,134.31,133.96,131.57,130.51,130.43,121.27,117.20,116.84,116.63,108.10,102.01,33.90.HRESIMS m/z 445.0736[M+H] +(计算值C 20H 16Cl 2FN 6O 445.0747).
16-32:
Figure PCTCN2021106708-appb-000054
白色固体,产率39％. 1H NMR(400MHz,DMSO-d 6)δ9.34(s,1H),8.91(s,1H),8.62(s,1H),8.00(s,1H),7.86–7.76(m,2H),7.40(q,J＝11.9,10.4Hz,4H),6.79–6.66(m,2H),3.91(s,3H). 13C NMR(100MHz,DMSO-d 6)δ164.43,164.20,161.98,161.80,161.64,160.32,150.89,143.21,143.18,133.96,133.93,131.57,130.51,130.42,116.83,116.62,108.10,101.94,97.11,33.90.HRESIMS m/z 413.1331[M+H] +(计算值C 20H 16F 3N 6O 413.1338).
16-33:
Figure PCTCN2021106708-appb-000055
白色固体,产率52％. 1H NMR(400MHz,DMSO-d 6)δ9.36(d,J＝10.4Hz,1H),8.91(s,1H),8.64(s,1H),8.43(s,1H),8.32–8.23(m,1H),8.01(s,1H),7.89–7.69(m,3H),7.55–7.37(m,3H),7.25(dd,J＝8.0,4.7Hz,1H),6.66(s,1H),6.13(d,J＝14.7Hz,1H),3.92(s,3H). 13C NMR(100MHz,DMSO-d 6)δ160.31,150.93,147.01,146.72,143.17,133.95,133.77,131.57,131.18,130.49,130.40,127.59,124.09,116.85,116.63,108.03,105.10,101.88,33.92.HRESIMS m/z 404.1629[M+H] +(计算值C 21H 19FN 7O 404.1635).
16-34：
Figure PCTCN2021106708-appb-000056
白色固体,产率55％. 1H NMR(400MHz,DMSO-d 6)δ8.82(d,J＝12.9Hz,2H),8.33(s,1H),8.00(s,1H),7.86–7.77(m,2H),7.46–7.35(m,2H),6.97(s,2H),6.69(s,1H),3.92(s,3H),3.71(s,6H),3.59(s,3H). 13C NMR(100MHz,DMSO-d 6)δ160.60,156.81,153.12,150.94,143.16,136.46,132.82,131.55,130.48,130.40,116.84,116.62,108.04,101.90,96.81,60.54,56.08,33.91.HRESIMS m/z 467.1836[M+H] +(计算值C 23H 24FN 6O 4 467.1843).
16-35：
Figure PCTCN2021106708-appb-000057
白色固体(55％). 1H NMR(400MHz,DMSO-d 6)δ9.72(d,J＝95.6Hz,1H),9.16(s,1H),8.72(s,2H),7.99–7.47(m,4H),7.06(d,J＝131.0Hz,3H),3.49(s,4H),1.90(s,4H). 13C NMR(150MHz,DMSO-d 6)δ164.45,163.76,152.21,140.95,130.17,128.78,128.63,121.87,120.05,111.88,46.52,46.34,31.82,29.56,29.24,29.11,25.32,22.63,14.50.HRESIMS m/z 460.1149[M+H] +(计算值C 19H 20Cl 2N 9O 460.1168).
16-36：
Figure PCTCN2021106708-appb-000058
白色固体(42％). 1H NMR(500MHz,DMSO-d 6)δ9.69(s,1H),9.35(s,1H),9.09(s,1H),8.25(s,1H),7.87–7.49(m,2H),7.34(s,1H),7.31–7.18(m,5H),6.58(s,1H),5.37(s,2H). 13C NMR(125MHz,DMSO-d 6)δ151.89,151.53,149.88,138.53,128.97,127.85,127.72,126.09,111.33,99.44,47.61.HRESIMS m/z 428.0786[M+H] +(计算值C 19H 16Cl 2N 7O428.0793).
16-38：
Figure PCTCN2021106708-appb-000059
白色固体(46％). 1H NMR(500MHz,DMSO-d 6)δ9.58(s,1H),8.44(d,J＝97.7Hz,1H),8.08(s,1H),7.85(s,1H),6.85(d,J＝3.6Hz,1H),6.45(d,J＝3.6Hz,1H),3.53(s,3H),3.19(s,6H). 13C NMR(125MHz,DMSO-d 6)δ159.16,157.76,152.87,152.25,149.71,122.68,111.66,101.69,98.27,38.71,31.05.HRESIMS m/z 417.0710[M+Na] +(计算值C 15H 16Cl 2N 8ONa 417.0722).
16-41：
Figure PCTCN2021106708-appb-000060
白色固体(39％). 1H NMR(600MHz,DMSO-d 6)δ9.80(s,1H),9.74(s,1H),8.51(d,J＝7.7Hz,1H),7.58(s,2H),7.53(dt,J＝8.8,1.1Hz,1H),7.16(ddd,J＝8.7,6.7,1.0Hz,1H),6.78–6.75(m,1H),6.62(s,1H). 13C NMR(150MHz,DMSO-d 6)δ151.61,151.41,150.15,149.75,141.01,128.69,124.76,117.43,111.66,111.58,86.10.HRESIMS m/z 322.0260[M+H] +(计算值C 13H 10Cl 2N 5O 322.0262).
16-42：
Figure PCTCN2021106708-appb-000061
白色固体(46％). 1H NMR(600MHz,DMSO-d 6)δ9.93(s,1H),9.82(s,1H),8.90(s,1H),7.57(s,2H),7.54(d,J＝9.4Hz,1H),7.29(dd,J＝9.3,1.7Hz,1H),6.68(s,1H). 13C NMR(125MHz,DMSO-d 6)δ151.48,151.24,150.09,150.05,139.56,128.73,127.68,118.33,111.49,104.84,87.00.HRESIMS m/z 399.9362[M+H] +(计算值C 13H 9Cl 2BrN 5O 399.9368).
16-43：
Figure PCTCN2021106708-appb-000062
白色固体(42％). 1H NMR(600MHz,DMSO-d 6)δ9.89(s,1H),9.81(s,1H),8.86(s,1H),7.72–7.70(m,2H),7.64–7.62(m,1H),7.59(s,2H),7.54(dd,J＝9.2,1.6Hz,1H),7.44(t,J＝7.8Hz,2H),7.34(t,J＝7.4Hz,1H),6.64(s,1H). 13C NMR(125MHz,DMSO-d 6)δ 151.49,151.27,150.16,150.06,139.95,136.89,129.49,128.02,126.85,125.73,124.67,124.47,117.43,111.51,86.08.HRESIMS m/z 398.0575[M+H] +(计算值C 19H 14Cl 2N 5O 398.0575).
16-44：
Figure PCTCN2021106708-appb-000063
白色固体(57％). 1H NMR(500MHz,DMSO-d 6)δ9.90(s,1H),9.83(s,1H),8.92(s,1H),7.66–7.60(m,3H),7.57(dd,J＝9.2,1.7Hz,1H),7.37(t,J＝7.9Hz,1H),7.31–7.27(m,2H),6.93(dd,J＝8.2,1.7Hz,1H),6.67(s,1H),3.83(s,3H).HRESIMS m/z 428.0673[M+H] +(计算值C 20H 16Cl 2N 5O 2 428.0681).
16-45：
Figure PCTCN2021106708-appb-000064
白色固体(33％). 1H NMR(500MHz,DMSO-d 6)δ9.90(d,J＝111.2Hz,2H),9.36(s,1H),8.06–7.98(m,1H),7.74(d,J＝7.4Hz,2H),7.57–7.52(m,2H),7.52–7.47(m,1H),6.86(s,1H),3.96(s,3H),3.38(s,3H). 13C NMR(125MHz,DMSO-d 6)δ160.53,151.82,150.63,149.84,144.55,137.55,131.59,129.84,129.72,128.38,33.84.HRESIMS m/z442.0945[M+H] +(计算值C 20H 18Cl 2N 7O 422.0950).
16-47：
Figure PCTCN2021106708-appb-000065
白色固体(51％). 1H NMR(400MHz,DMSO-d 6)δ9.81(s,1H),9.11(d,J＝34.2Hz,2H),8.25(d,J＝5.1Hz,2H),7.38(t,J＝7.4Hz,1H),7.33–7.12(m,4H),6.95(d,J＝5.2Hz,2H),6.60(s,1H),4.00(s,3H). 13C NMR(100MHz,DMSO-d 6)δ159.72,151.99,151.82,149.90,149.00,146.31,141.32,141.13,137.96,129.16,128.97,128.77,123.63,111.69,106.01,105.26,34.15.HRESIMS m/z 442.0945[M+H] +(计算值C 20H 18Cl 2N 7O 422.0950).
16-48：
Figure PCTCN2021106708-appb-000066
白色固体(59％). 1H NMR(400MHz,DMSO-d 6)δ10.03(s,2H),7.55(s,2H),7.18(d,J＝1.5Hz,1H),6.89(d,J＝1.5Hz,1H),3.83(s,3H). 13C NMR(100MHz,DMSO-d 6)δ164.59,151.97,151.32,150.65,150.08,148.34,111.74,106.76,96.87,54.36.HRESIMS m/z 346.9868[M+H] +(计算值C 12H 10Cl 3N 4O 2 346.9869).
16-49：
Figure PCTCN2021106708-appb-000067
白色固体(37％). 1H NMR(400MHz,DMSO-d 6)δ9.74(d,J＝50.9Hz,2H),7.54(s,2H),7.16(d,J＝1.5Hz,1H),6.82(d,J＝1.4Hz,1H),4.24(q,J＝7.0Hz,2H),1.30(t,J＝7.0Hz,3H). 13C NMR(100MHz,DMSO-d 6)δ164.17,151.70,151.04,150.49,150.09,148.32,111.74,106.63,97.10,62.57,14.80.HRESIMS m/z 361.0024[M+H] +(计算值C 13H 12Cl 3N 4O 2361.0026).
16-50：
Figure PCTCN2021106708-appb-000068
白色固体(64％). 1H NMR(400MHz,DMSO-d 6)δ9.81(s,2H),7.55(s,2H),7.16(d,J＝1.5Hz,1H),6.79(d,J＝1.5Hz,1H),5.12(hept,J＝6.1Hz,1H),1.28(d,J＝6.2Hz,6H). 13C NMR(100MHz,)δ111.79,40.62,40.41,40.20,39.99,39.78,39.57,39.37,22.20.HRESIMS m/z 375.0180[M+H] +(计算值C 14H 14Cl 3N 4O 2 375.0182).
16-51：
Figure PCTCN2021106708-appb-000069
白色固体(48％). 1H NMR(400MHz,DMSO-d 6)δ9.67(d,J＝63.3Hz,2H),7.47(s,2H),7.06(s,1H),6.74(s,1H),5.17(tt,J＝5.7,2.6Hz,1H),1.92–1.75(m,2H),1.73–1.45(m,6H). 13C NMR(100MHz,DMSO-d 6)δ163.91,151.70,151.05,150.43,150.08,148.30,111.71,106.40,97.54,78.68,32.69,23.83.HRESIMS m/z 401.0338[M+H] +(计算值C 16H 16Cl 3N 4O 2 401.0339).
16-52：
Figure PCTCN2021106708-appb-000070
白色固体(77％). 1H NMR(400MHz,DMSO-d 6)δ9.48(s,2H),7.13(s,2H),6.80(s,2H),4.23(q,J＝7.1Hz,4H),1.29(t,J＝6.9Hz,6H). 13C NMR(100MHz,DMSO-d 6)δ164.16,151.82,150.70,148.29,106.49,96.86,62.52,14.80.HRESIMS m/z 371.0673[M+H] +(计算值C 15H 17Cl 3N 4O 2 371.0678).
16-54：
Figure PCTCN2021106708-appb-000071
白色固体(49％). 1H NMR(400MHz,DMSO-d 6)δ9.58(d,J＝72.3Hz,2H),7.55–7.50(m,4H),7.18(t,J＝1.9Hz,1H). 13C NMR(100MHz,DMSO-d 6)δ151.91,151.26,150.04,141.61,134.59,122.42,117.47,111.56.HRESIMS m/z 349.9423[M+H] +(计算值C 12H 8Cl 4N 3O 349.9421).
16-57：
Figure PCTCN2021106708-appb-000072
白色固体(56％). 1H NMR(400MHz,DMSO-d 6)δ9.79(s,2H),8.23(d,J＝5.6Hz,1H),7.64(d,J＝1.8Hz,1H),7.55(s,2H),7.37(dd,J＝5.6,1.9Hz,1H). 13C NMR(100MHz,DMSO-d 6)δ151.71,151.45,150.94,150.53,150.08,148.68,112.77,112.39,111.72.HRESIMS m/z 316.9763[M+H] +(计算值C 11H 8Cl 3N 4O 316.9764).
16-58：
Figure PCTCN2021106708-appb-000073
白色固体(49％). 1H NMR(400MHz,DMSO-d 6)δ9.74(s,1H),9.37(s,1H),7.57(d,J＝15.0Hz,4H),3.79(s,3H). 13C NMR(100MHz,DMSO-d 6)δ152.04,151.43,150.04,147.24,136.46,128.62,119.66,111.56,61.12.HRESIMS m/z 379.9524[M+H] +(计算值C 13H 10Cl 4N 3O 2 379.9527).
16-59：
Figure PCTCN2021106708-appb-000074
白色固体,产率47％. 1H NMR(400MHz,DMSO-d 6)δ9.71(s,1H),9.06(d,J＝71.5Hz,2H),7.63(s,2H),6.69(s,1H),3.92(s,3H),3.29(p,J＝6.7Hz,1H),1.27(d,J＝6.8Hz,6H). 13C NMR(100MHz,DMSO-d 6)δ160.55,153.24,151.97,151.47,149.91,130.84,130.47,111.69,34.36,30.05,23.29.HRESIMS m/z 462.0814[M+H] +(计算值C 17H 17Cl 2F 3N 7O462.0824).
16-60：
Figure PCTCN2021106708-appb-000075
白色固体,产率61％. 1H NMR(400MHz,DMSO-d 6)δ9.73(s,1H),9.07(d,J＝61.8Hz,2H),7.78(s,2H),6.60(s,1H),3.93(s,3H),2.79(t,J＝7.7Hz,2H),1.64(h,J＝7.4Hz,2H),0.97(t,J＝7.3Hz,3H). 13C NMR(150MHz,DMSO-d 6)δ152.02,151.55,149.95,131.00,130.75,130.50,124.93,123.15,121.38,111.94,105.96,34.63,34.44,22.98,14.25.HRESIMS m/z 462.0822[M+H] +(计算值C 17H 17Cl 2F 3N 7O 462.0824).
16-61：
Figure PCTCN2021106708-appb-000076
白色固体,产率57％. 1H NMR(400MHz,DMSO-d 6)δ9.80(s,1H),9.19(d,J＝101.0Hz,2H),8.02–7.28(m,7H),6.58(s,1H),3.98(s,3H). 13C NMR(100MHz,DMSO-d 6)δ151.91,151.43,149.92,145.79,138.23,129.20,128.70,128.34,111.72,34.52.HRESIMS m/z496.0667[M+H] +(计算值C 20H 15Cl 2F 3N 7O 496.0667).
实施例1：
体外细胞活性实验
对上述化合物进行体外细胞活性实验。
体外细胞活性实验：在多种结肠癌及正常结肠细胞系中通过前期药效学活性筛选及蛋白质印记(Western Blotting)进行DPD表达水平验证，确定HCT116和SW620为显著5-FU耐药的细胞系。收集对数期生长的HCT116和SW620细胞，调整细胞悬液浓度，每孔加入100μL，铺板使待测细胞调密度至1000-10000孔，(边缘孔用无菌PBS填充)。5％CO 2，37℃孵育，至细胞单层铺满孔底(96孔平底板)，加入浓度梯度的上述化合物和恒定浓度的5-FU。设置6个浓度梯度，每孔100μL，共3个复孔。5％CO 2，37℃孵育24h，倒置显微镜下观察。每孔加入20μL MTT溶液(5mg/mL，即0.5％MTT)，继续培养4h。终止培养，小心吸去孔内培养液。每孔加入150μL二甲基亚砜，置摇床上低速振荡0.5min，使结晶物充分溶解。在酶联免疫检测仪OD 560nm处测量各孔的吸光值。细胞存活率以T/C％表示，T为加药细胞的OD值，C为对照细胞的OD值。根据各浓度梯度细胞存活率计算EC 50和IC 50，结果如表1所示。
表1
Figure PCTCN2021106708-appb-000077
Figure PCTCN2021106708-appb-000078
Figure PCTCN2021106708-appb-000079
注：EC 50为上述抑制剂化合物与5-FU联用下的EC 50值，其中5-FU浓度为20μM。IC 50为化合物单用下的IC 50值，5-FU为不加抑制剂组，DMSO为溶剂组，HCT116，SW620为5-FU耐药细胞，--表示无细胞死亡或未检出。NT表示未测定。
结果显示20μM 5-氟尿嘧啶作用下两种细胞均出现5-FU耐药的现象，本发明的化合物可以逆转5-氟尿嘧啶的耐药性，与5-氟尿嘧啶联用可以有效抑制耐药细胞的增殖，并且与比较化合物9-1至9-25相比，本发明的化合物具有更小的对SW620细胞系的EC 50值，表明本发明的化合物具有更优异的抑制活性。
实施例2：本发明抑制剂体外抑制DPD表达实验
将HCT116细胞(溶剂对照组、表1中化合物单独给药的10μM给药组)以及SW620细胞(溶剂对照组、表2中化合物单独给药的10μM给药组分别取出后进行细胞刮板、蛋白提取及定量。
细胞蛋白提取：首先PBS清洗细胞，将各组细胞置4℃预冷，配制细胞裂解液：NP-40(960μL)+PPI(40μL)+PMSF(40μL)。弃去PBS，视细胞密度加入100-200μL裂解液，置于4℃，40min。细胞刮板刮下细胞，收集细胞于1.5mL离心管，12000rpm，15min离心。收集上清液于另一批1.5mL离心管中，96孔板中，加入G250染色液90μL，分别加入10μL蛋白标准液、10μL样品，制作复孔。酶标仪确定细胞浓度，将各组细胞浓度调节一致，并加入5x上样缓冲液使其浓度为1x，金属浴煮沸5min。
蛋白质印记检测：配制分离胶与浓缩胶后，浸泡于电泳液中。等量20μg蛋白样品加入上样孔中，加入标志物或1x上样缓冲液封边。80V恒压电泳至蛋白下降于分离胶后，改为120V，继续恒压电泳。使用PVDF膜进行100V，90min转膜。1 x TBST于摇床清洗PVDF膜，5min一次，共2次。封闭液封闭PVDF膜1h，4℃孵育DPD一抗过夜。1 x TBST于摇床清洗PVDF膜，10min一次，共3次。二抗孵育40min。1 x TBST于摇床清洗PVDF膜，10min一次，共3次。ECL发光液配制，均匀淋于PVDF膜上，ChemiDoc XRS和分子成像仪(molecular imager)曝光。计算Bio-Rad Quantity One分析印记灰度比值，计算公式：目的蛋白相对表达水平＝(目的蛋白灰度值-背景灰度值)/(内参蛋白灰度值-背景灰度值)。
结果显示，与内参相比，本发明的抑制剂可有效地降低该细胞中的DPD表达(参见图1)。
实施例3：
利用裸鼠皮下接种肿瘤模型进行5-氟尿嘧啶和本发明的抑制剂联用给药。
购买6-8周大BALB/c裸鼠，每组数目各6只，在无特定病原体的洁净(SPF)环境中饲养。采用皮下接种上述5-FU耐药的SW620细胞，两周后待其瘤块增至一定大小，进行瘤块无 菌分离、均匀切分后接种到每只裸鼠腋下，无菌环境饲养两周，待各组瘤块体积大小一致后开始给药。连续三周半每天尾静脉注射给药，与5-氟尿嘧啶单用组以及溶剂组对比，其中溶剂体积比组成为2％DMSO+30％PEG 300+5％Tween 80+ddH 2O，全程记录裸鼠体重及瘤体积变化(每4天测量一次)。而后将小鼠处死，取出肿瘤样本及其它组织，进行蛋白表达的相关检测与分析。
结果显示，接种上述SW620细胞株的裸鼠肿瘤对5-氟尿嘧啶治疗出现了明显耐药现象，化合物16-2可明显提高其抑制率，可见本发明的抑制剂能有效逆转肿瘤细胞对于5-氟尿嘧啶的耐药性(参见图2，其中溶剂组为不给5-FU和化合物组，只给DMSO和水的溶剂组)。
实施例4：
对各组裸鼠的肿瘤组织及肝组织DPD表达差异进行蛋白质印记检测。
将各组裸鼠肿瘤组织及肝组织分别取出后进行组织研磨和蛋白提取及定量，利用SDS-PAGE电泳、转膜及封闭后，进行DPD及β肌动蛋白(β-actin)抗体孵育过夜，而后进行洗膜及二抗孵育，再次洗膜后对PVDF膜进行显影。
结果显示，与内参相比，5-氟尿嘧啶对于各组织的DPD表达无明显影响，而化合物16-2可有效地降低肿瘤组织及肝组织DPD表达水平(参见图3，其中溶剂组为不给5-FU和化合物组，只给DMSO和水的溶剂组)。
上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。

Claims (24)

  1. 式I化合物，或者其药学上可接受的盐、或互变异构体：
    Figure PCTCN2021106708-appb-100001
    其中：
    L为直连键或亚烯基；
    R 1选自氢、烷基和卤代烷基；
    R 2选自氢或任选取代的烷基；
    各R 3独立地选自任选被芳基取代的烷基、具有至少4个成环碳原子的环烷基、任选被卤素或烷氧基取代的芳基、任选被卤素取代的杂芳基；
    R 4、R 5和R 6各自独立地选自氢、或任选取代的烷基；
    环B为芳环或杂芳环；
    各R 7独立地选自卤素、烷基、任选被卤素取代的烷氧基、烷基取代的氨基、杂芳基取代的杂芳基取代的氨基；
    x为1至2的整数；以及
    y为0、1、2或3的整数；
    条件是：
    当一个R 3为烷基时，R 1为卤代烷基或x为2；
    当R 3为烷氧基取代的芳基时，R 1为氢；
    当R 3为未取代的芳基时，R 1为卤代烷基或者至少一个R 7取代基不为卤素；
    当R 1为氢时，至少一个R 3为被卤素或烷氧基取代的芳基、或芳基取代的烷基或者至少一个R 7取代基不为卤素。
  2. 如权利要求1所述的化合物，或者其药学上可接受的盐、或互变异构体，其中：
    L为直连键，并且y为2或3的整数；或者
    L为亚烯基，并且y为0。
  3. 如权利要求1或2所述的化合物，或者其药学上可接受的盐、或互变异构体，其中：
    R 1选自氢、C 1-6烷基和卤代C 1-6烷基；或者
    R 1选自氢、C 1-4烷基和卤代C 1-4烷基；或者
    R 1选自氢、甲基和三氟甲基。
  4. 如权利要求1至3中任一项所述的化合物，或者其药学上可接受的盐、或互变异构体，其中：
    R 2选自氢、任选取代的C 1-6烷基；或者
    R 2选自C 1-6烷基；或者
    R 2为甲基。
  5. 如权利要求1至4中任一项所述的化合物，或者其药学上可接受的盐、或互变异构体，其中：
    各R 3独立地选自任选被C 6-18芳基取代的C 1-6烷基、4-12元环烷基、任选被卤素或C 1-6烷氧基取代的C 6-18芳基、任选被卤素取代的C 2-18杂芳基；或者
    各R 3独立地选自任选被C 6-12芳基取代的C 1-6烷基、5-8元环烷基、任选被卤素或C 1-6烷氧基取代的C 6-12芳基、被卤素取代的C 2-12杂芳基、含S的C 2-12杂芳基；或者
    各R 3独立地选自C 1-4烷基、被C 6-10芳基取代的C 1-4烷基、6-8元环烷基、C 6-10芳基、被卤素取代的C 6-10芳基、被C 1-4烷氧基取代的C 6-10芳基、被卤素取代的C 2-8杂芳基、含S的C 2-8杂芳基；或者
    各R 3独立地选自甲基、正丙基、异丙基、苄基、环已基、苯基、对氟苯基、对甲氧基苯基、3-氯-2-噻吩基。
  6. 如权利要求1至5中任一项所述的化合物，或者其药学上可接受的盐、或互变异构体，其中：
    R 4、R 5和R 6各自独立地选自氢、或任选取代的C 1-6烷基；
    R 4、R 5和R 6各自独立地选自氢、或C 1-4烷基；或者
    R 4、R 5和R 6各自独立地选自氢或甲基；或者
    R 4、R 5和R 6均为氢。
  7. 如权利要求1至6中任一项所述的化合物，或者其药学上可接受的盐、或互变异构体，其中：
    环B为C 6-18芳环或C 2-18杂芳环；或者
    环B为C 6-12芳环或5-10元杂芳环；或者
    环B为C 6-10芳环或5-8元杂芳环；或者
    环B为苯环或吡啶环；或者
    当L为直连键时，环B的定义中出现的所述杂芳环在杂原子的邻位任选被2或3个R 7基团取代；或者
    Figure PCTCN2021106708-appb-100002
    选自被0-3个独立地选自以下的R 7基团取代的苯环或吡啶环：氟、氯、溴、甲基、甲氧基、正丙氧基、异丙氧基、正丁氧基、2-氟乙氧基、二乙基氨基和(4-(吡啶-3-基)嘧啶-2-基)氨基；或者
    Figure PCTCN2021106708-appb-100003
    选自：
    Figure PCTCN2021106708-appb-100004
  8. 如权利要求1至7中任一项所述的化合物，或者其药学上可接受的盐、或互变异构体，其中：
    各R 7独立地选自卤素、C 1-8烷基、任选被卤素取代的C 1-8烷氧基、C 1-8烷基取代的氨基、C 2- 18杂芳基取代的C 2-18杂芳基取代的氨基；或者
    各R 7独立地选自卤素、C 1-6烷基、任选被卤素取代的C 1-6烷氧基、C 1-6烷基取代的氨基、C 2- 12杂芳基取代的C 2-12杂芳基取代的氨基；或者
    各R 7独立地选自卤素、C 1-4烷基、任选被卤素取代的C 1-4烷氧基、C 1-4烷基取代的氨基、C 2- 8杂芳基取代的C 2-8杂芳基取代的氨基；或者
    各R 7独立地选自氟、氯、溴、甲基、甲氧基、正丙氧基、异丙氧基、正丁氧基、2-氟乙氧基、二乙基氨基、(4-(吡啶-3-基)嘧啶-2-基)氨基。
  9. 如权利要求1至8中任一项所述的化合物，或者其药学上可接受的盐、或互变异构体，其中：
    R 3为烷基，并且R 1为卤代烷基；或者
    一个R 3为烷基，并且x为2且另一个R 3为芳基取代的烷基；或者
    R 3为未取代的芳基，并且R 1为卤代烷基；或者
    R 3为未取代的芳基，并且至少一个R 7取代基为烷氧基；或者
    环B为杂芳环，R 3为被卤素或烷氧基取代的芳基，并且至少一个R 7选自C 2-8烷氧基、被卤素取代的C 2-8烷氧基、C 1-8烷基取代的氨基；或者
    环B为杂芳环，R 3为被卤素或烷氧基取代的芳基，并且至少一个R 7选自C 2-6烷氧基、被卤素取代的C 2-6烷氧基、C 2-6烷基取代的氨基；或者
    环B为吡啶，R 3为对氟苯基或对甲氧基苯基，并且至少一个R 7选自正丙氧基、异丙氧基、正丁氧基、2-氟乙氧基、二乙基氨基；或者
    R 1为烷基，至少一个R 3选自具有至少4个成环碳原子的环烷基、被卤素取代的芳基、被卤素取代的杂芳基，并且
    Figure PCTCN2021106708-appb-100005
    为任选地被卤素取代的杂芳基或卤素取代的芳基，优选
    Figure PCTCN2021106708-appb-100006
    为杂芳基、二卤代杂芳基、二卤代芳基；还更优选
    Figure PCTCN2021106708-appb-100007
    为杂芳基、4-取代的2,6-二卤代杂芳基、3,5-二卤代芳基；还更优选
    Figure PCTCN2021106708-appb-100008
    为吡啶基、4-取代的2,6-二氯吡啶基、 3,5-二氟苯基；或者
    R 1为卤代烷基，至少一个R 3选自烷基和芳基，并且
    Figure PCTCN2021106708-appb-100009
    为卤素取代的杂芳基，优选
    Figure PCTCN2021106708-appb-100010
    为二卤代杂芳基；还更优选
    Figure PCTCN2021106708-appb-100011
    为4-取代的2,6-二氯吡啶基；或者
    R 1为氢，至少一个R 3为被卤素或烷氧基取代的芳基、或芳基取代的烷基；或者
    R 1为氢，R 3为未取代的芳基并且至少一个R 7取代基为烷氧基。
  10. 以下化合物，或者其药学上可接受的盐、或互变异构体：
    Figure PCTCN2021106708-appb-100012
    Figure PCTCN2021106708-appb-100013
  11. 式II化合物，或者其药学上可接受的盐、或互变异构体：
    Figure PCTCN2021106708-appb-100014
    其中：
    Ar 1是被1个或多个独立地选自卤素、烷氧基取代的杂芳基；
    Ar 2选自三嗪基、吡咯并嘧啶基、吡唑并[1,5-a]吡啶-2-基、吡啶基和苯基，其各自任选地被1个或多个独立地选自杂环烷基、任选被烷基或芳基取代的氨基、任选被芳基取代的烷基、卤素、任选被烷氧基取代的芳基、烷氧基和环烷基氧基的取代基取代；
    L 1是直连键或—NR c—；
    R a、R b和R c各自独立地选自氢、或任选取代的烷基；以及
    Ar 1和Ar 2不完全相同。
  12. 如权利要求11所述的化合物，或者其药学上可接受的盐、或互变异构体，其中：
    Ar 1是被1个或多个独立地选自卤素、烷氧基的取代基取代的单环杂芳基；或者
    Ar 1是被1个或多个独立地选自卤素、烷氧基的取代基取代的单环杂芳基，其中所述1个或多个取代基中的至少一个是卤素；或者
    Ar 1是被1个或多个独立地选自卤素、C 1-6烷氧基的取代基取代的单环C 2-18杂芳基；或者
    Ar 1是被1个或多个独立地选自卤素、C 1-6烷氧基的取代基取代的单环C 2-12杂芳基；或者
    Ar 1是被1个或多个独立地选自卤素、C 1-4烷氧基的取代基取代的单环C 2-10杂芳基；或者
    Ar 1是被1个或多个独立地选自卤素、C 1-4烷氧基的取代基取代的吡啶基；或者
    Ar 1是被1个或多个独立地选自氯、甲氧基、乙氧基、异丙氧基的取代基取代的吡啶基；或者
    Ar 1是4-取代的2,6-二氯吡啶基、4-取代的2-氯-6-甲氧基吡啶、4-取代的2-氯-6-乙氧基吡啶、或4-取代的2-氯-6-异丙氧基吡啶。
  13. 如权利要求11或12所述的化合物，或者其药学上可接受的盐、或互变异构体，其中：
    Ar 2选自1,3,5-三嗪-2-基、吡咯并[2,3-d]嘧啶-4-基、吡咯并[2,3-d]嘧啶-2-基、吡唑并[1,5-a]吡啶-2-基、吡啶基和苯基，其各自任选地被1个或多个独立地选自杂环烷基、任选被烷基 或芳基取代的氨基、任选被芳基取代的烷基、卤素、任选被烷氧基取代的芳基、烷氧基和环烷基氧基的取代基取代；或者
    Ar 2选自1,3,5-三嗪-2-基、吡咯并[2,3-d]嘧啶-4-基、吡咯并[2,3-d]嘧啶-2-基、吡唑并[1,5-a]吡啶-2-基、吡啶基和苯基，其各自任选地被1个或多个独立地选自3-12元杂环烷基、C 6-18芳基取代的氨基、C 6-18芳基取代的C 1-6烷基、C 1-6烷基取代的氨基、C 1-6烷基、卤素、C 6-18芳基、C 1-6烷氧基取代的C 6-18芳基、C 1-6烷氧基和3-12元环烷基氧基的取代基取代；或者
    Ar 2选自1,3,5-三嗪-2-基、吡咯并[2,3-d]嘧啶-4-基、吡咯并[2,3-d]嘧啶-2-基、吡唑并[1,5-a]吡啶-2-基、吡啶基和苯基，其各自任选地被1个或多个独立地选自3-10元杂环烷基、C 6-12芳基取代的氨基、C 6-12芳基取代的C 1-6烷基、C 1-6烷基取代的氨基、C 1-6烷基、卤素、C 6-12芳基、C 1-6烷氧基取代的C 6-12芳基、C 1-6烷氧基和3-10元环烷基氧基的取代基取代；或者
    Ar 2选自1,3,5-三嗪-2-基、吡咯并[2,3-d]嘧啶-4-基、吡咯并[2,3-d]嘧啶-2-基、吡唑并[1,5-a]吡啶-2-基、吡啶基和苯基，其各自任选地被1个或多个独立地选自3-8元杂环烷基、C 6-10芳基取代的氨基、C 6-10芳基取代的C 1-4烷基、C 1-4烷基取代的氨基、C 1-4烷基、卤素、C 6-10芳基、C 1-4烷氧基取代的C 6-10芳基、C 1-4烷氧基和3-8元环烷基氧基的取代基取代；或者
    Ar 2选自1,3,5-三嗪-2-基、吡咯并[2,3-d]嘧啶-4-基、吡咯并[2,3-d]嘧啶-2-基、吡唑并[1,5-a]吡啶-2-基、吡啶基和苯基，其各自任选地被1个或多个独立地选自吡咯烷基、苯基氨基、苄基、二甲基氨基、甲基、氯、溴、苯基、甲氧基苯基、甲氧基、乙氧基、异丙氧基和环戊基氧基的取代基取代；或者
    当Ar 2是吡咯并嘧啶基时，所述嘧啶部分上的取代基当存在时为非环状基团；或者
    当Ar 2是吡咯并嘧啶基时，所述嘧啶部分上的取代基当存在时为任选被烷基取代的氨基；或者
    当Ar 2是三嗪基时，所述三嗪基被杂环烷基取代；或者
    当Ar 2是三嗪基时，所述三嗪基被吡咯烷-1-基取代；或者
    当Ar 2是吡唑并[1,5-a]吡啶-2-基时，所述吡唑并[1,5-a]吡啶-2-基任选地被卤素、芳基或烷氧基芳基取代；或者
    当Ar 2是吡啶基或苯基时，所述吡啶基或苯基被至少一个卤素取代；或者
    当Ar 2是吡啶基或苯基时，所述吡啶基或苯基被1个或多个独立地选自卤素、烷氧基和环烷基氧基的取代基取代，并且所述1个或多个取代基中的至少一个为卤素；或者
    当Ar 2是吡唑并[1,5-a]吡啶-2-基、吡啶基或苯基时，L 1是直连键。
  14. 如权利要求11至13中任一项所述的化合物，或者其药学上可接受的盐、或互变异构体，其中：
    R a、R b和R c各自独立地选自氢、或任选取代的C 1-6烷基；或者
    R a、R b和R c各自独立地选自氢、或C 1-4烷基；或者
    R a、R b和R c各自独立地选自氢或甲基；或者
    R a、R b和R c均为氢。
  15. 以下化合物，或者其药学上可接受的盐、或互变异构体：
    Figure PCTCN2021106708-appb-100015
  16. 药物组合物，其包含权利要求1-15中任一项所述的化合物、其药学上可接受的盐、或互变异构体，以及药学上可接受的辅料；
    任选地，所述药物组合物还包含一种或多种其它治疗剂；
    任选地，所述其它治疗剂为抗肿瘤药物；
    任选地，所述抗肿瘤药物选自氟尿嘧啶类药物；
    任选地，所述抗肿瘤药物选自5-氟尿嘧啶、5'-2'-脱氧尿苷、替加氟、氟脲苷、卡莫氟、去氧氟尿苷、尿嘧啶替加氟、卡培他滨，替吉奥、优福啶，嘧福啶，氟铁龙和希罗达。
  17. 权利要求1-15中任一项所述的化合物、其药学上可接受的盐、或互变异构体，或者权利要求16所述的药物组合物，或者它们与一种或多种其它治疗剂的组合在制备用于抑制DPD的表达的药物中的用途；或在制备用于预防和/或治疗受益于DPD表达的抑制的疾病、病症或病况的药物中的用途；或在制备预防和/或治疗肿瘤的药物中的用途；或在制备用于抵抗和/或逆转氟尿嘧啶类药物耐药性的药物中的用途；
    任选地，所述受益于DPD表达的抑制的疾病、病症或病况选自肿瘤；
    任选地，所述疾病、病症或病况或者所述肿瘤选自消化道肿瘤、头颈部肿瘤、肺癌、乳腺癌；任选地，所述头颈部肿瘤选自口腔癌；
    任选地，所述肿瘤为对于氟尿嘧啶类药物具有耐药性的肿瘤；
    任选地，所述一种或多种其它治疗剂为抗肿瘤药物；
    任选地，所述抗肿瘤药物选自氟尿嘧啶类药物；
    任选地，所述氟尿嘧啶类药物选自5-氟尿嘧啶、5'-2'-脱氧尿苷、替加氟、氟脲苷、卡莫氟、去氧氟尿苷、尿嘧啶替加氟、卡培他滨、替吉奥、优福啶、嘧福啶、氟铁龙和希罗达；
    任选地，所述抑制DPD的表达是抑制肝脏中的DPD的表达。
  18. 试剂盒，其包括：
    权利要求1-15中任一项所述的化合物、其药学上可接受的盐、或互变异构体，或者权利要求16所述的药物组合物，
    任选的抗肿瘤药物，优选地，所述抗肿瘤药物选自氟尿嘧啶类药物；
    且任选地还包括使用说明书。
  19. 用于抑制DPD的表达的权利要求1-15中任一项所述的化合物、其药学上可接受的盐、或互变异构体，或者权利要求16所述的药物组合物，或者它们与一种或多种其它治疗剂的组合；
    任选地，所述抑制DPD的表达是抑制肝脏中的DPD的表达。
  20. 用于预防和/或治疗受益于DPD表达的抑制的疾病、病症或病况的权利要求1-15中任一项所述的化合物、其药学上可接受的盐、或互变异构体，或者权利要求16所述的药物组合物，或者它们与一种或多种其它治疗剂的组合；
    任选地，所述疾病、病症或病况选自肿瘤；
    任选地，所述疾病、病症或病况或者所述肿瘤选自消化道肿瘤、头颈部肿瘤、肺癌、乳腺癌；任选地，所述头颈部肿瘤选自口腔癌；
    任选地，所述肿瘤为对于氟尿嘧啶类药物具有耐药性的肿瘤；
    任选地，所述一种或多种其它治疗剂为抗肿瘤药物；
    任选地，所述抗肿瘤药物选自氟尿嘧啶类药物；
    任选地，所述氟尿嘧啶类药物选自5-氟尿嘧啶、5'-2'-脱氧尿苷、替加氟、氟脲苷、卡莫氟、去氧氟尿苷、尿嘧啶替加氟、卡培他滨，替吉奥、优福啶，嘧福啶，氟铁龙和希罗达。
  21. 用于抵抗和/或逆转氟尿嘧啶类药物耐药性的权利要求1-15中任一项所述的化合物、其药学上可接受的盐、或互变异构体，或者权利要求16所述的药物组合物，或者它们与一种或多种其它治疗剂的组合。
  22. 抑制DPD的表达的方法，包括对有需要的对象给予治疗有效量的权利要求1-15中任一项所述的化合物、其药学上可接受的盐、或互变异构体，或者权利要求16所述的药物组合物，或者它们与一种或多种其它治疗剂的组合；
    任选地，所述抑制DPD的表达是抑制肝脏中的DPD的表达。
  23. 预防和/或治疗受益于DPD表达的抑制的疾病、病症或病况的方法，包括对有需要的对象给予治疗有效量的权利要求1-15中任一项所述的化合物、其药学上可接受的盐、或互变异构体，或者权利要求16所述的药物组合物，或者它们与一种或多种其它治疗剂的组合；
    任选地，所述疾病、病症或病况选自肿瘤；
    任选地，所述疾病、病症或病况或者所述肿瘤选自消化道肿瘤、头颈部肿瘤、肺癌、乳腺癌；任选地，所述头颈部肿瘤选自口腔癌；
    任选地，所述肿瘤为对于氟尿嘧啶类药物具有耐药性的肿瘤；
    任选地，所述一种或多种其它治疗剂为抗肿瘤药物；
    任选地，所述抗肿瘤药物选自氟尿嘧啶类药物；
    任选地，所述氟尿嘧啶类药物选自5-氟尿嘧啶、5'-2'-脱氧尿苷、替加氟、氟脲苷、卡莫氟、去氧氟尿苷、尿嘧啶替加氟、卡培他滨，替吉奥、优福啶，嘧福啶，氟铁龙和希罗达。
  24. 抵抗和/或逆转氟尿嘧啶类药物耐药性的方法，包括：
    将氟尿嘧啶类药物与权利要求1-15中任一项所述的化合物、其药学上可接受的盐、或互变异构体，或者权利要求16所述的药物组合物联合施用。
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