WO2022067566A1 - Pyrimidinedione compound containing saturated oxygen-containing heterocyclic group and use thereof - Google Patents

Pyrimidinedione compound containing saturated oxygen-containing heterocyclic group and use thereof Download PDF

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WO2022067566A1
WO2022067566A1 PCT/CN2020/119029 CN2020119029W WO2022067566A1 WO 2022067566 A1 WO2022067566 A1 WO 2022067566A1 CN 2020119029 W CN2020119029 W CN 2020119029W WO 2022067566 A1 WO2022067566 A1 WO 2022067566A1
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alkyl
atoms
compound
group
methyl
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PCT/CN2020/119029
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French (fr)
Chinese (zh)
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金传飞
钟文和
朱俊陵
余天喜
周克军
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广东东阳光药业有限公司
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Priority to PCT/CN2020/119029 priority Critical patent/WO2022067566A1/en
Priority to CN202080103762.8A priority patent/CN116096371A/en
Publication of WO2022067566A1 publication Critical patent/WO2022067566A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of pharmaceutical technology, and relates to compounds and pharmaceutical compositions for preventing or treating sex hormone-dependent diseases, as well as methods and uses thereof.
  • the present invention relates to pyrimidinediones containing saturated oxygen-containing heterocyclic groups and their uses as gonadotropin-releasing hormone receptor antagonists.
  • hypothalamic hormones The secretion of anterior pituitary hormones is feedback-controlled by peripheral hormones secreted from the target organs of the corresponding hormones and by secretory-regulatory hormones from the hypothalamus, which is the upper central organ of the anterior pituitary gland (hereinafter, in the specification). , these hormones are commonly referred to as "hypothalamic hormones").
  • hypothalamic hormones nine hormones have been identified as hypothalamic hormones, including, for example, thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (GnRH, sometimes referred to as LH-RH (luteinizing hormone-releasing hormone)).
  • hypothalamic hormones are thought to exhibit their effects through receptors thought to be present in the anterior pituitary gland; and efforts have been made to find receptor-gene expression specific for these hormones, including in humans of.
  • antagonists or agonists that act specifically and selectively at these receptors should control hypothalamic hormone action and anterior pituitary hormone secretion. Therefore, such antagonists or agonists are expected to prevent or treat anterior pituitary hormone-dependent diseases.
  • GnRH-derived linear peptides US 5,140,009 and US 5,171,835), bicyclic peptide derivatives (Journal of Medicinal Chemistry, Vol.36, pp. 3265-3273 (1993)), a decapeptide compound modified at position 5 or 6 (WO 9846634 A1) and a decapeptide compound modified at position 8 (EP 0277829 B1) and the like.
  • Peptide compounds present many unsolved problems related to oral absorbability, dosage form, dose volume, drug stability, sustained action, and metabolic stability. Therefore, there is a strong need for oral GnRH antagonists, especially antagonists based on non-peptide compounds, which have excellent therapeutic effects on sex hormone-dependent diseases such as prostate cancer, endometriosis, precocious puberty, etc. Not only shows instantaneous pituitary-gonadotropin action (sharp action) but also has excellent oral absorption.
  • the present invention relates to a novel class of pyrimidinedione compounds containing saturated oxygen-containing heterocyclic groups, which have unexpectedly excellent GnRH antagonistic activity, and can be used as gonadotropin-releasing hormone receptor antagonists, so that they can be used for prevention Or treat sex hormone-dependent diseases, including but not limited to, prostate cancer, endometriosis, uterine fibroids, precocious puberty, and the like.
  • the compound of the present invention has stable properties, good safety, and has the advantages of pharmacodynamics and pharmacokinetics, such as good brain/plasma ratio, good bioavailability or good metabolic stability, etc. good clinical application prospects.
  • the present invention also provides methods of preparing such compounds and pharmaceutical compositions containing such compounds.
  • the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrated compound represented by formula (I) compound, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
  • R 1 , R 2a , R 2b , R 2c , R 2d , R 3 , R 4 , R 5a , R 5b , R 5c , R 5d , R 5e , Z and R have the meanings as described in the present invention.
  • Z is NH, O, or S.
  • R is wherein X, Y, U, R 6 and m have the meanings as described in the present invention.
  • X is CH or N.
  • Y is CH or N.
  • U is CH or N.
  • R 6 is a saturated oxygen-containing heterocyclyl consisting of 3-8 atoms.
  • m is 0, 1, 2, or 3.
  • R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, hydroxy substituted C 1 -C 6 alkyl, cyano substituted C 1 -C 6 alkyl, amino substituted C 1 -C 6 alkyl, C 3-6 cycloalkyl , a heterocyclic group consisting of 3-8 atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-10 atoms.
  • R 3 and R 4 are each independently H, D, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3-6 cycloalkyl, heterocyclic group consisting of 3-8 atoms, C 6-10 aryl, 5- Heteroaryl consisting of 10 atoms, C 3-6 cycloalkyl-C 1-6 alkylene, (heterocyclyl consisting of 3-8 atoms)-C 1-6 alkylene, C 6-10 Aryl-C 1-6 alkylene or (heteroaryl consisting of 5-10 atoms)-C 1-6 alkylene.
  • R 6 is a saturated oxygen-containing heterocyclyl consisting of 3-6 atoms.
  • R 6 is
  • R 1 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, hydroxy substituted C 1 -C 4 alkyl, cyano substituted C 1 -C 4 alkyl, amino substituted C 1 -C 4 alkyl, C 3-6 cycloalkyl , a heterocyclic group consisting of 3-6 atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-6 atoms.
  • R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl, 1-methylpropyl, vinyl, propylene group, allyl, ethynyl, propynyl, propargyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, isopropoxy, -OCF 3 , hydroxymethyl, 2-hydroxyethyl, -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 CH2CN , -CH2NH2 , -CH2CH2NH2 , -CH2CH2CH2NH2 , cyclopropyl , cyclobutyl , cyclopen
  • R 3 and R 4 are each independently H, D, -OH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 aryl, 5- Heteroaryl composed of 6 atoms, C 3-6 cycloalkyl-C 1-4 alkylene, (heterocyclyl composed of 3-6 atoms)-C 1-4 alkylene, C 6-10 Aryl-C 1-4 alkylene or (heteroaryl consisting of 5-6 atoms)-C 1-4 alkylene.
  • R3 and R4 are each independently H, D, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl , 1-methylpropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, -CHF 2 , -CF 3 , methoxy, ethoxy, isopropoxy , -OCF 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl , naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,
  • the compound of the present invention is a compound represented by formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of the compound represented by formula (II) , hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
  • R 1 , R 3 , R 4 , R 6 , X, Y and m have the meanings as described in the present invention.
  • the compound of the present invention is a compound represented by formula (III) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of the compound represented by formula (III) , hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
  • R 1 , R 3 , R 4 , R 6 , U and m have the meanings as described in the present invention.
  • the compound described in the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of a compound having one of the following structures , hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein.
  • compositions of the present invention further comprise pharmaceutically acceptable excipients, carriers, adjuvants or any combination thereof.
  • the sex hormone-dependent disease of the present invention is sex hormone-dependent cancer, bone metastases of sex hormone-dependent cancer, prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, Amenorrhea, Premenstrual Syndrome, Dysmenorrhea, Polylocular Ovarian Syndrome, Polycystic Ovary Syndrome, Acne, Alopecia, Alzheimer's Disease, Infertility, Irritable Bowel Syndrome, Hormone-Independent LH-RH (luteinizing hormone-releasing hormone) sensitive benign or malignant tumors or flushing.
  • the present invention relates to the use of a compound or pharmaceutical composition disclosed herein in the manufacture of a medicament useful as a reproduction regulator, contraceptive, ovulation inducer, or the Drugs are used to prevent recurrence of sex hormone-dependent cancers after surgery.
  • the present invention relates to the use of a compound or a pharmaceutical composition disclosed in the present invention in the preparation of a medicament for antagonizing gonadotropin-releasing hormone (GnRH).
  • GnRH gonadotropin-releasing hormone
  • the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I), formula (II) or formula (III).
  • the biological test results show that the compounds of the present invention have strong antagonistic activity to gonadotropin-releasing hormone (GnRH), so the compounds provided by the present invention can be used as better GnRH antagonists.
  • GnRH gonadotropin-releasing hormone
  • any embodiment of any aspect of the invention may be combined with other embodiments so long as they do not appear to be inconsistent.
  • any technical feature may be applicable to that technical feature in other embodiments, as long as they do not contradict.
  • the articles “a”, “an” and “the” are intended to include “at least one” or “one or more” unless stated otherwise or otherwise clearly contradicted by context.
  • these articles refer to articles of one or more than one (ie, at least one) object.
  • a component refers to one or more components, ie, there may be more than one component contemplated for use or use in the implementation of the described embodiments.
  • patient refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to a human.
  • stereoisomers refers to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric (cis/trans) isomers, atropisomers, and the like.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible through a low energy barrier. A chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution).
  • protontautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.
  • “Pharmaceutically acceptable” means compounds, materials, compositions, and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergy, or compatibility with reasonable The benefit/risk ratio is symmetric with other problems and complications and is effective for the intended use.
  • C1 - C6 alkyl specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups.
  • linking substituents are described.
  • the Markush variables listed for that group should be understood to be the linking group.
  • the Markush group definition for that variable recites “alkyl” or “aryl”, it should be understood that the “alkyl” or “aryl” respectively represents the linking An alkylene group or an arylene group.
  • halogen and “halo” are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • alkyl or “alkyl group” used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group can be optionally is substituted with one or more substituents described herein.
  • alkyl groups contain 1-6 carbon atoms; in other embodiments, alkyl groups contain 1-4 carbon atoms; in still other embodiments, alkyl groups contain 1 -3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), n - propyl (n - Pr, -CH2CH2CH3 ) ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH ) (CH 3 ) 2 (2-methylpropyl)), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 (1-methylpropyl)), tert-butyl (t-Bu , -C(CH 3 ) 3 ), etc.
  • alkylene refers to a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, alkylene groups contain 1-10 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, the alkylene group contains 1-4 carbon atoms; in still other embodiments, the alkylene group The group contains 1-2 carbon atoms. Such examples include, but are not limited to, methylene ( -CH2- ), ethylene ( -CH2CH2- ) , propylene ( -CH2CH2CH2- ) , isopropylene (-CH( CH3 )CH2- ) , etc.
  • the alkylene group is optionally substituted with one or more substituents described herein.
  • alkenyl refers to a linear or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp 2 double bond, wherein the alkenyl group A group can be optionally substituted with one or more substituents described herein, including the “cis” and “trans” positions, or the "E” and “Z” positions.
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms.
  • alkynyl refers to a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group Can be optionally substituted with one or more of the substituents described herein.
  • the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH2C ⁇ CH), 1 -propynyl (ie, propynyl, -C ⁇ C -CH 3 ), etc.
  • alkoxy means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; in still other embodiments, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-propoxy, n -PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (isopropoxy, i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1- Butoxy (n-BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH (CH 3 ) 2 ), 2-butoxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC( CH3 ) 3 ), and the like.
  • alkylthio means that an alkyl group is attached to the remainder of the molecule through a sulfur atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkylthio group contains 1-12 carbon atoms. In some embodiments, alkylthio groups contain 1-6 carbon atoms; in other embodiments, alkylthio groups contain 1-4 carbon atoms; in still other embodiments, alkylthio groups The group contains 1-3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described herein. Examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH3 ), ethylthio ( EtS , -SCH2CH3 ), and the like.
  • alkylamino or “alkylamino” describe an amino group independently substituted with one or two alkyl groups, respectively, including “N-alkylamino” and “N,N-dialkylamino", where the alkyl group has the meaning as defined in the present invention.
  • Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N -Dimethylamino (dimethylamino), N,N-diethylamino (diethylamino), etc.
  • the alkylamino group is optionally substituted with one or more substituents described herein.
  • hydroxy-substituted alkyl means that an alkyl group is substituted with one or more hydroxyl groups (-OH), wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the hydroxy-substituted alkyl groups contain 1-12 carbon atoms.
  • hydroxy-substituted alkyl groups contain 1-6 carbon atoms, eg, hydroxy-substituted C1 - C6 alkyl; in other embodiments, hydroxy-substituted alkyl groups contain 1 -4 carbon atoms, eg, hydroxy-substituted C1 - C4 alkyl; in yet other embodiments, hydroxy-substituted alkyl groups contain 1-3 carbon atoms, eg, hydroxy-substituted C1 -C 3 alkyl.
  • Such examples include, but are not limited to, hydroxymethyl, hydroxyethyl (eg 2-hydroxyethyl), 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2,3-dihydroxy Propyl and so on.
  • cyano-substituted alkyl means that an alkyl group is substituted with one or more cyano groups (-CN), wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the cyano-substituted alkyl groups contain 1-12 carbon atoms.
  • cyano-substituted alkyl groups contain 1-6 carbon atoms, eg, cyano-substituted C1 - C6 alkyl groups; in other embodiments, cyano-substituted alkyl groups groups contain 1-4 carbon atoms, eg, cyano-substituted C1 - C4 alkyl; in yet other embodiments, cyano-substituted alkyl groups contain 1-3 carbon atoms, eg, cyano Substituted C 1 -C 3 alkyl.
  • Such examples include, but are not limited to, cyanomethyl (-CH2CN), cyanoethyl (eg 2 -cyanoethyl, -CH2CH2CN ), 2 -cyano-1-propane (-CH 2 CH(CN)CH 3 ), 3-cyano-1-propyl (-CH 2 CH 2 CH 2 CN), 2,3-dicyanopropyl (-CH 2 CH(CN) CH 2 CN) and so on.
  • cyanomethyl -CH2CN
  • cyanoethyl eg 2 -cyanoethyl, -CH2CH2CN
  • 2 -cyano-1-propane -CH 2 CH(CN)CH 3
  • 3-cyano-1-propyl -CH 2 CH 2 CH 2 CN
  • 2,3-dicyanopropyl -CH 2 CH(CN) CH 2 CN
  • amino-substituted alkyl means that an alkyl group is substituted with one or more amino groups ( -NH2 ), wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the amino-substituted alkyl groups contain 1-12 carbon atoms.
  • amino-substituted alkyl groups contain 1-6 carbon atoms, eg, amino-substituted C1 - C6 alkyl groups; in other embodiments, amino-substituted alkyl groups contain 1 -4 carbon atoms, eg, amino-substituted C1 - C4 alkyl; in yet other embodiments, amino-substituted alkyl groups contain 1-3 carbon atoms, eg, amino-substituted C1 -C 3 alkyl.
  • Such examples include, but are not limited to, aminomethyl ( -CH2NH2 ), aminoethyl (eg 2 -aminoethyl, -CH2CH2NH2 ) , 2 -amino-1-propyl ( -CH2CH( NH2 ) CH3 ), 3 -amino- 1 -propyl ( -CH2CH2CH2NH2 ), 2,3 - diaminopropyl (-CH2CH( NH2 ) CH 2 NH 2 ) and so on.
  • aminomethyl -CH2NH2
  • aminoethyl eg 2 -aminoethyl, -CH2CH2NH2
  • 2 -amino-1-propyl -CH2CH( NH2 ) CH3
  • 3 -amino- 1 -propyl -CH2CH2CH2NH2
  • 2,3 - diaminopropyl -CH2CH( NH2 ) CH 2
  • haloalkyl or “haloalkoxy” means that an alkyl or alkoxy group is substituted with one or more halogen atoms, wherein the alkyl and alkoxy groups have the meaning as described herein, such that Examples include, but are not limited to, -CHF2 , -CF3 , -CHFCH2F , -CF2CHF2 , -CH2CHF2 , -CH2CF3 , -CH2CF2CHF2 , -OCHF2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 and the like.
  • C 1 -C 6 haloalkyl comprises fluorine substituted C 1 -C 6 alkyl; in other embodiments, C 1 -C 4 haloalkyl comprises fluorine substituted C 1 -C 4 alkyl ; In still other embodiments, the C 1 -C 2 haloalkyl group comprises a fluorine substituted C 1 -C 2 alkyl group.
  • cycloalkyl denotes a saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring carbon atoms.
  • the cycloalkyl group contains 3-10 ring carbon atoms, such as C 3-10 cycloalkyl; in other embodiments, the cycloalkyl group contains 3-8 ring carbon atoms, such as C 3- 8 cycloalkyl; in yet other embodiments, cycloalkyl contains 3-6 ring carbon atoms, eg, C3-6 cycloalkyl.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • C 3-8 cycloalkyl includes C 3-6 cycloalkyl; the C 3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl .
  • the cycloalkyl group may be optionally substituted with one or more substituents described herein.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system comprising 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms; wherein the Heterocyclyl groups are non-aromatic and do not contain any aromatic rings.
  • Ring sulfur atoms can optionally be oxidized to S-oxides.
  • Ring nitrogen atoms can optionally be oxidized to N-oxides.
  • heterocyclyl is used interchangeably with the term “heterocycle.”
  • the heterocyclyl group can be composed of 3-8 atoms or 3-6 atoms, the atoms are optionally selected from C, N, O or S and at least one atom is N, O or S; wherein, the heterocyclic group composed of 3-8 atoms includes a heterocyclic group composed of 3-6 atoms; the heterocyclic group composed of 3-6 atoms includes a heterocyclic group composed of 3-5 atoms Heterocyclyl.
  • the heterocyclic group consisting of 3-6 atoms includes, but is not limited to, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl , tetrahydrothienyl, thiazolidinyl, pyrazolidine, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl and the like.
  • the heterocyclyl group may be optionally substituted with one or more substituents described herein.
  • saturated oxygen-containing heterocyclyl refers to a saturated heterocyclyl group having at least one ring atom selected from oxygen atoms, wherein the heterocyclyl group has the meaning as defined herein.
  • the saturated oxygen-containing heterocyclyl group may consist of 3-8 atoms or 3-6 atoms optionally selected from C, N, O or S and having at least one atom is O; wherein, the saturated oxygen-containing heterocyclic group composed of 3-8 atoms includes a saturated oxygen-containing heterocyclic group composed of 3-6 atoms; the saturated oxygen-containing heterocyclic group composed of 3-6 atoms A saturated oxygen-containing heterocyclic group consisting of 3-5 atoms.
  • the saturated oxygen-containing heterocyclic group consisting of 3-6 atoms includes, but is not limited to,
  • aryl refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic , and has one or more points of attachment to the rest of the molecule.
  • aryl is used interchangeably with the term “aromatic ring” or "aromatic ring”.
  • Examples of aryl groups may include phenyl, indenyl, 2,3-dihydro-1H-indenyl, naphthyl, and anthracenyl.
  • the aryl group may be optionally substituted with one or more substituents described herein.
  • the group “ C6-10 aryl” refers to an aryl group containing 6-10 ring carbon atoms.
  • heteroaryl denotes monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic, and At least one ring contains 1, 2, 3 or 4 ring heteroatoms selected from nitrogen, oxygen, sulfur, and the heteroaryl group has one or more points of attachment to the rest of the molecule.
  • the heteroaryl group may be attached to the remainder of the molecule (eg, the host structure in the formula) through any reasonable site (which may be C or N).
  • heteroaryl may be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic”.
  • the heteroaryl group may be optionally substituted with one or more substituents described herein.
  • the heteroaryl group is a heteroaryl group of 5-10 atoms, meaning that the heteroaryl group contains 1-9 ring carbon atoms and 1, 2, 3, or 4 atoms selected from O, S, and N Ring heteroatom; in other embodiments, heteroaryl is a heteroaryl group consisting of 5-6 atoms, meaning that the heteroaryl group contains 1-5 ring carbon atoms and 1, 2, 3, or 4 selected from O , S, and N ring heteroatoms; examples of heteroaryl groups of 5-6 atoms include, but are not limited to, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, Pyridyl, pyrimidinyl, pyridazinyl
  • j-k atoms means that the cyclic group consists of j-k ring atoms, and the ring atoms include carbon atoms and/or heteroatoms such as O, N, S, P, etc.; the j and k Each is independently any non-zero natural number, and k>j; the "j-k” includes j, k and any natural number in between.
  • “consisting of 3-8 atoms”, “consisting of 3-6 atoms”, “consisting of 5-10 atoms” or “consisting of 5-6 atoms” means that the cyclic group consists of 3 -8 (ie, 3, 4, 5, 6, 7, or 8), 3-6 (ie, 3, 4, 5, or 6), 5-10 (ie, 5, 6, 7, 8, 9, or 10 ) or 5-6 (ie, 5 or 6) ring atoms including carbon atoms and/or heteroatoms such as O, N, S, P, etc.
  • cycloalkyl-alkylene refers to the cycloalkyl, heterocyclyl , aryl or heteroaryl are each independently attached to the rest of the molecule through an alkylene group, wherein said cycloalkyl, heterocyclyl, aryl, heteroaryl and alkylene have the meanings described herein .
  • examples of arylalkylene groups include, but are not limited to, phenyl-methylene, phenyl-ethylene, phenyl-propylene, and the like.
  • the cycloalkyl-alkylene, heterocyclyl-alkylene, aryl-alkylene, heteroaryl-alkylene are each independently optionally substituted with one or more substituents described herein .
  • prodrug refers to the conversion of a compound into a compound of formula (I), formula (II) or formula (III) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue.
  • the prodrug compounds of the present invention can be esters.
  • esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters.
  • a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form.
  • Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent.
  • Metal refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
  • pharmaceutically acceptable salts refer to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange method described in books and literature these salts.
  • the present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group.
  • Water- or oil-soluble or dispersible products can be obtained by quaternization.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -C 8 sulfonates and aromatic sulfonates.
  • a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
  • Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof.
  • hydrate refers to an association in which the solvent molecule is water.
  • the term "hydrate" may be used.
  • one molecule of the compound of the present invention may be associated with one molecule of water, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate In yet another embodiment, one molecule of a compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compounds.
  • any disease or disorder in some embodiments refers to ameliorating the disease or disorder (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by a patient. In other embodiments, “treating” refers to modulating a disease or disorder physically (eg, stabilizing an observable symptom) or physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.
  • prevent refers to a reduction in the risk of acquiring a disease or disorder (ie: stopping the development of at least one clinical symptom of a disease in a subject who may be facing or predisposed to facing the disease, but also not experience or exhibit symptoms of disease).
  • terapéuticaally effective amount refers to an amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect the treatment of such disease.
  • a “therapeutically effective amount” can vary depending on the compound, the disease and severity, and the condition, age, weight, sex, etc. of the subject to be treated.
  • stereochemistry of any particular chiral atom when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated within the present invention and are included in the present invention as compounds disclosed herein .
  • stereochemistry is indicated by a solid wedge or a dashed line representing a particular configuration, then the stereoisomers of that structure are well defined and defined.
  • Nitrogen oxides of the compounds of the present invention are also included within the scope of the present invention. Oxidation of the corresponding nitrogen-containing basic species can be accomplished by using common oxidizing agents such as hydrogen peroxide at elevated temperature in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as in dichloromethane , ethyl acetate or methyl acetate react with peracetic acid, or react with 3-chloroperoxybenzoic acid in chloroform or dichloromethane to prepare nitrogen oxides of the compounds of the present invention.
  • common oxidizing agents such as hydrogen peroxide at elevated temperature in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as in dichloromethane , ethyl acetate or methyl acetate react with peracetic acid, or react with 3-chloroperoxybenzoic acid in chloroform or dichloromethane to prepare nitrogen oxides of the
  • compositions of formula (I), formula (II) or formula (III) may exist in the form of salts.
  • the salt refers to a pharmaceutically acceptable salt.
  • pharmaceutically acceptable means that a substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated with it.
  • the salt is not necessarily a pharmaceutically acceptable salt, but can be used for the preparation and/or purification of the compound represented by formula (I), formula (II) or formula (III) and/or with Intermediates for separating enantiomers of compounds represented by formula (I), formula (II) or formula (III).
  • Isotopically enriched compounds have the structures depicted by the general formulae given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number.
  • Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the present invention relates to intermediates for the preparation of compounds of formula (I), formula (II) or formula (III).
  • the present invention provides a pharmaceutical composition, comprising a compound represented by formula (I), formula (II) or formula (III) or its individual stereoisomers, racemic or non-racemic mixtures of isomers or A pharmaceutically acceptable salt or solvate thereof.
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, other therapeutic and/or prophylactic ingredients.
  • Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel H.C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro A.R. et al ., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.
  • compositions of the present invention may exist in free form or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of these esters, or can provide, directly or indirectly, the invention described herein when administered to a patient in need thereof. Any additional adducts or derivatives of the compound or its metabolites or residues.
  • Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form chosen. Furthermore, pharmaceutically acceptable excipients can be selected based on their particular function in the composition. Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvent, co-solvent, suspending agent, emulsifier, sweetener, flavoring agent, taste masking agent, coloring agent, anti-caking agent, humectant, chelating agent, plasticizer, tackifier, antioxidant, Preservatives, stabilizers, surfactants and buffers.
  • diluents fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvent, co-solvent, suspending agent, emulsifier, sweetener, flavoring agent, taste masking agent, coloring agent,
  • compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. A description of some commonly used methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the present invention relates to a process for preparing a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, the process comprising Mix various ingredients.
  • Pharmaceutical compositions containing compounds of the present disclosure can be prepared by mixing, for example, at ambient temperature and atmospheric pressure.
  • dosage forms include those suitable for the following routes of administration: (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, Solutions, emulsions, sachets, and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes , sprays, foams and gels.
  • routes of administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, Solutions, emulsions, sachets, and cachets
  • parenteral administration such as sterile solutions, suspensions, and reconstituted powders
  • transdermal administration such as
  • the compounds disclosed herein can be formulated into oral dosage forms. In other embodiments, the compounds disclosed herein may be formulated in a dosage form for inhalation. In other embodiments, the compounds disclosed herein may be formulated for nasal administration. In yet other embodiments, the compounds disclosed herein can be formulated for transdermal administration. In still some embodiments, the compounds disclosed herein can be formulated for topical administration.
  • compositions provided by the present invention can be provided as compressed tablets, triturated tablets, chewable lozenges, fast-dissolving tablets, recompressed tablets, enteric-coated tablets, sugar-coated or film-coated tablets.
  • compositions provided by the present invention can be provided in soft capsules or hard capsules, which can be prepared from gelatin, methylcellulose, starch or calcium alginate.
  • compositions provided by the present invention can be parenterally administered by injection, infusion or implantation for local or systemic administration.
  • Parenteral administration as used in the present invention includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.
  • compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and in liquid prior to injection Solid forms are prepared as solutions or suspensions.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical sciences (see Remington: The Science and Practice of Pharmacy, supra).
  • compositions disclosed herein can be formulated into any dosage form suitable for inhalation administration to a patient, such as dry powder, aerosol, suspension or solution compositions.
  • compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of a patient for an extended period of time.
  • the active ingredient can be delivered from the patch by iontophoresis, as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the compounds and pharmaceutical compositions provided by the present invention have excellent GnRH antagonistic activity and low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproduction toxicity, cardiotoxicity, drug interactions, and carcinogenicity). Also, the compound or pharmaceutical composition is excellent in oral absorbability, sustainability of action, stability and pharmacokinetics. Furthermore, the compounds or pharmaceutical compositions are rarely affected by plasma components.
  • the compounds or pharmaceutical compositions of the present invention can be safely used in mammals (eg, humans, monkeys, bovines, horses, dogs, cats, rabbits, rats and mice, etc.) by utilizing GnRH receptor antagonism to Control plasma sex hormone concentrations to inhibit gonadotropin secretion, thereby preventing and/or treating diseases that are dependent on male or female hormones and diseases caused by excess of these hormones.
  • mammals eg, humans, monkeys, bovines, horses, dogs, cats, rabbits, rats and mice, etc.
  • the compounds or pharmaceutical compositions of the present invention are suitable for preventing and/or treating sex hormone-dependent cancers (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), bone metastases of sex hormone-dependent cancers, prostate cancer Hypertrophy, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multilocular ovary syndrome, polycystic ovary syndrome, acne, Alopecia, Alzheimer's disease (Alzheimer's disease, Alzheimer's type and its mixed type senile dementia), etc.
  • sex hormone-dependent cancers eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.
  • sex hormone-dependent cancers eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.
  • bone metastases of sex hormone-dependent cancers
  • the compounds of the present invention are also suitable for modulating male and female reproduction (eg, pregnancy regulators and menstrual cycle regulators, etc.).
  • the compounds or pharmaceutical compositions of the present invention may also be used as male or female contraceptives or as ovulation inducers in females. Based on the rebound effect after drug withdrawal, the compounds or pharmaceutical compositions of the present invention can be used to treat infertility. Also, the compounds or pharmaceutical compositions of the present invention can be used as agents for the prevention and/or treatment of hormone-independent and LH-RH-sensitive benign or malignant tumors.
  • the compounds or pharmaceutical compositions of the present invention are useful as agents for preventing and/or treating irritable bowel syndrome and preventing postoperative recurrence of hormone-dependent cancers (agents for preventing postoperative recurrence of prostate cancer; preventing before or after menopause) Agents for the recurrence of breast or ovarian cancer after surgery; in particular for the prevention of premenopausal breast or ovarian cancer recurrence after surgery).
  • the compounds or pharmaceutical compositions of the present invention are suitable for use in animal husbandry for regulating estrus, improving meat quality and promoting animal growth.
  • the compounds of the present invention are also suitable for use in fishspawning promoters.
  • the compounds or pharmaceutical compositions of the present invention may also be used to inhibit transient increases in plasma testosterone concentrations (flare phenomenon) observed with administration of GnRH superagonists such as leuprolide acetate Instantaneous rise.
  • GnRH superagonists such as leuprolide acetate Instantaneous rise.
  • the compounds of the present invention can be combined with leuprolide acetate, gonadorelin, buserelin, triptorelin, goserelin, nafarelin ), histrelin (histrelin), deslorelin (deslorelin), meterelin (meterelin) and lecirelin (lecirelin) and other super agonists in combination.
  • leuprolide acetate is especially preferred.
  • the compounds or pharmaceutical compositions of the invention can also be used particularly advantageously in combination with at least one selected from the group consisting of steroidal or non-steroidal anti-androgens or anti-estrogens, chemical Therapeutic agent, GnRH antagonist peptide (antagonistic peptide), alpha-reductase inhibitor, alpha-receptor inhibitor, aromatase inhibitor, 17beta-hydroxysteroid dehydrogenase inhibitor, adrenal androgen production inhibitor, kinase inhibitor , hormone therapy drugs and drugs that inhibit cell growth factors or their receptors.
  • chemotherapeutic agents include ifosfamide, doxorubicin, peplomycin, cisplatin, cyclophosphamide, 5-FU, UFT, Methotrexate (methotrexate), mitomycin C (mitomycin C), mitoxantrone (mitoxantrone), etc.
  • GnRH antagonistic peptide includes parenteral GnRH antagonistic peptides such as cetrorelix, ganirelix, abarrelix and the like.
  • the compounds and pharmaceutical compositions of the present invention may also be used in veterinary treatment of mammals in pets, introduced species and farm animals. Examples of other animals include horses, dogs and cats.
  • the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
  • a compound of the present disclosure or a pharmaceutical composition comprising a compound of the present disclosure may be administered at one time, or several times at different time intervals over a specified period of time, depending on the dosing regimen.
  • the disclosed compounds may be administered concurrently with, prior to or subsequent to one or more other therapeutic agents.
  • the compounds of the present invention can be administered separately with other therapeutic agents by the same or different route of administration, or in the same pharmaceutical composition.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the substituents are as defined in formula (I), formula (II) or formula (III).
  • the following reaction schemes and examples serve to further illustrate the content of the present invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether were obtained by refluxing and drying with metallic sodium.
  • Anhydrous dichloromethane and chloroform were obtained by refluxing with calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.
  • reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dry.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Factory.
  • the measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 ⁇ 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL/min.
  • Mobile phase 5 %-95% ( CH3CN with 0.1% formic acid) in ( H2O with 0.1% formic acid) using electrospray ionization (ESI) at 210 nm/254 nm with UV detection.
  • ESI electrospray ionization
  • the intermediate compound represented by the formula ( 11 ) can be prepared by the following process: the compound represented by the formula ( 1 ) reacts with the ethyl cyanoacetate represented by the formula ( 2 ) to obtain the compound represented by the formula ( 3 ); Then the compound represented by formula ( 3 ) is ring-closed under the action of sulfur powder to obtain the compound represented by formula ( 4 ). The compound represented by the formula ( 4 ) is reacted with ethyl chloroformate to obtain the compound represented by the formula ( 5 ).
  • the compound represented by the formula ( 5 ) reacts with the compound represented by the formula ( 6 ) to obtain the compound represented by the formula ( 7 ); the compound represented by the formula ( 7 ) is brominated to obtain the compound represented by the formula ( 8 ).
  • the compound represented by the formula ( 8 ) is reacted with the compound represented by the formula ( 9 ) to obtain the compound represented by the formula ( 10 ).
  • the compound represented by formula ( 10 ) is subjected to ester hydrolysis to obtain the intermediate compound represented by formula ( 11 ).
  • the compound represented by the formula ( 17 ) can be prepared by the following process: the compound represented by the formula ( 11 ) reacts with the compound represented by the formula ( 12 ) to obtain the compound represented by the formula ( 13 ); represented by the formula ( 13 ) The compound represented by the formula ( 14 ) is obtained by ring closure of the compound; the nitro group of the compound represented by the formula ( 14 ) is reduced to obtain the compound represented by the formula ( 15 ); the compound represented by the formula ( 15 ) and the formula ( 16 ) The indicated compound was reacted to obtain the target product indicated by ( 17 ).
  • the compound represented by formula ( 17' ) can be prepared by the following process: the compound represented by formula ( 11 ) reacts with the compound represented by formula ( 12' ) to obtain the compound represented by formula ( 13' ); formula ( 13 ) The compound represented by ' ) is closed to obtain the compound represented by the formula ( 14' ); the nitro group of the compound represented by the formula ( 14' ) is reduced to obtain the compound represented by the formula ( 15' ); the compound represented by the formula ( 15' ) The compound is reacted with the compound represented by formula ( 16 ) to obtain the target product represented by ( 17' ).
  • Ethyl 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate (12 g, 39.2 mmol), pyridine (11 mL, 140 mmol) and dichloromethane ( 100mL) was added to a 250mL single-neck round-bottomed flask, ethyl chloroformate (6.7mL, 70mmol) was added, and the reaction was continued to stir for 2 hours; the reaction was stopped, water (50mL) was added, the liquid was separated, the organic phase was collected, and anhydrous sodium sulfate was added.
  • Step 11 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(5-(oxetan-3-yloxy) yl)pyridin-2-yl)-2,4-dioxo -Synthesis of 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea
  • Step 1) (2,6-Difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrophenyl)-3-((6-(oxetine- 3-yloxy)pyridin-3-yl)carbamoyl Synthesis of ethyl)thiophen-2-yl)carbamate
  • Step 2) 1-(2,6-Difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-3-(6-(oxetine) yl-3-yloxy)pyridin-3-yl)thio Synthesis of pheno[2,3-d]pyrimidine-2,4(1H,3H)-dione
  • Step 4) 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-yloxy) yl)pyridin-3-yl)-2,4-dioxo -Synthesis of 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea
  • the title compound of this step was prepared according to the method described in step 11 of Example 1, namely 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino) Methyl)-3-(6-(oxetan-3-yloxy)pyridin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 0.9 g, 1.52 mmol), phenyl N-methoxycarbamate (0.763 g, 4.56 mmol), triethylamine (0.634 mL, 4.56 mmol) and 4-dimethylaminopyridine (19 mg, 0.15 mmol)
  • Step 1) (2,6-Difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrophenyl)-3-((6-(oxetine- 3-yloxy)pyridazin-3-yl)carbamoyl Synthesis of ethyl)thiophen-2-yl)carbamate
  • Step 2) 1-(2,6-Difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-3-(6-(oxetine) yl-3-yloxy)pyridazin-3-yl)thio Synthesis of pheno[2,3-d]pyrimidine-2,4(1H,3H)-dione
  • Step 4) 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-yloxy) yl)pyridazin-3-yl)-2,4-dioxo -Synthesis of 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea
  • Step 2) 1-(2,6-Difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-3-(6-(oxetine) yl-3-yloxy)pyridin-2-yl)thio Synthesis of pheno[2,3-d]pyrimidine-2,4(1H,3H)-dione
  • Step 4) 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-yloxy) yl)pyridin-2-yl)-2,4-dioxo -Synthesis of 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea
  • the title compound of this step was prepared according to the method described in step 11 of Example 1, namely 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino) Methyl)-3-(6-(oxetan-3-yloxy)pyridin-2-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 1.1 g, 1.9 mmol), phenyl N-methoxycarbamate (1.2 g, 7.2 mmol), triethylamine (0.78 mL, 5.6 mmol) and 4-dimethylaminopyridine (11 mg, 0.1 mmol)
  • Step 1) (2,6-Difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrophenyl)-3-((5-(oxetine- 3-ylmethoxy)pyridin-2-yl)amino Synthesis of ethyl formyl)thiophen-2-yl)carbamate
  • Step 4) 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(5-(oxetan-3-ylmethyl) oxy)pyridin-2-yl)-2,4-dioxo -Synthesis of 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea
  • Step 1) (2,6-Difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrophenyl)-3-((6-(oxetine- 3-ylmethoxy)pyridin-3-yl)carbamate Synthesis of Acyl)thiophen-2-yl)carbamate
  • Step 4) 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-ylmethyl) oxy)pyridin-3-yl)-2,4-dioxo -Synthesis of 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea
  • Step 1) (2,6-Difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrophenyl)-3-((6-(oxetine- 3-ylmethoxy)pyridazin-3-yl)carbamate Synthesis of Acyl)thiophen-2-yl)carbamate
  • Step 4) 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-ylmethyl) oxy)pyridazin-3-yl)-2,4-dioxo -Synthesis of 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea
  • Example 8 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-ylmethyl) oxy)pyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methyl Synthesis of Oxyurea
  • Step 1) (2,6-Difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrophenyl)-3-((6-(oxetine- 3-ylmethoxy)pyridin-2-yl)carbamate Synthesis of Acyl)thiophen-2-yl)carbamate
  • Step 4) 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-ylmethyl) oxy)pyridin-2-yl)-2,4-dioxo -Synthesis of 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea
  • the antagonism of the compounds of the present invention on the transfected humanized GnRH receptors in RBL-1 cells was evaluated by using fluorescence method to detect cytoplasmic calcium flux.
  • Example B Pharmacokinetic evaluation of the compounds of the present invention after intravenous or gavage quantification in rats and dogs
  • the present invention evaluates the pharmacokinetic studies of the compounds of the present invention in rats and/or dogs, and the animal information is shown in Table B.
  • the compounds of the present invention were administered to test animals in the form of 10% DMSO+10% Kolliphor HS15+78% Saline+2% (2% HCl) solution or 78% Saline+2% (2% HCl)+20% PEG400 solution. Before administration, animals were fasted for 12 hours and had free access to water.
  • the dose was 1 mg/kg (rats) or 0.5 mg/kg (dogs), and blood was collected at the following time points after administration (about 0.2 mL of blood): 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h (dog) or 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h (rat), EDTA-K 2 was pre-added in the blood collection tube as an anticoagulant.
  • the administration dose was 5 mg/kg (rats) or 2.5 mg/kg (dogs), and intravenous blood was collected at the following time points after administration (about 0.2 mL of blood): 0.25, 0.5 , 1.0, 2.0, 4.0, 6.0, 8.0 and 24h (dog) or 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h (rat), EDTA-K 2 was pre-added into the blood collection tube as an anticoagulant. Blood samples were centrifuged at 12,000 rpm for 2 minutes, and plasma was collected and stored at -20°C or -70°C. .
  • the analysis results show that the compounds of the present invention have good pharmacokinetic properties in rats and/or dogs. It shows that the compound of the present invention has good drug-forming property and good clinical application prospect.

Abstract

A pyrimidinedione compound containing a saturated oxygen-containing heterocyclic group and the use thereof, and a pharmaceutical composition comprising such compounds, which can be used as a gonadotropin releasing hormone receptor antagonist. The present invention also relates to a method for preparing such compounds and the pharmaceutical composition, and the use thereof in the prevention or treatment of sex hormone dependent diseases, including, but not limited to, prostate cancer, endometriosis, hysteromyoma, precocious puberty and other diseases.

Description

含有饱和含氧杂环基的嘧啶二酮类化合物及其用途Pyrimidinedione compounds containing saturated oxygen-containing heterocyclic group and use thereof 技术领域technical field
本发明属于药物技术领域，涉及用于预防或治疗性激素依赖性疾病的化合物和药物组合物，及其使用方法和用途。特别地，本发明所述的是可以作为促性腺激素释放激素受体拮抗剂的含有饱和含氧杂环基的嘧啶二酮类化合物及其用途。The present invention belongs to the field of pharmaceutical technology, and relates to compounds and pharmaceutical compositions for preventing or treating sex hormone-dependent diseases, as well as methods and uses thereof. In particular, the present invention relates to pyrimidinediones containing saturated oxygen-containing heterocyclic groups and their uses as gonadotropin-releasing hormone receptor antagonists.
背景技术Background technique
垂体前叶激素的分泌是通过从相应激素的靶器官分泌出来的外周激素以及通过来自丘脑下部(其为垂体前叶的上部中枢器官)的分泌-调节激素而进行反馈控制的(以下，在说明书中，这些激素通称为″丘脑下部激素″)。目前，已经证实作为丘脑下部激素，存在九种激素，包括，例如促甲状腺素释放激素(TRH)和促性腺素释放激素(GnRH，有时称为LH-RH(促黄体素释放激素))。这些丘脑下部激素被认为是通过受体而表现出它们的作用，而这些受体被认为存在于垂体前叶中；并且已经努力地寻找对这些激素特异的受体-基因表达，包括在人体内的。因而，特异地和选择地作用于这些受体的拮抗剂或激动剂应当控制丘脑下部激素的作用和垂体前叶激素的分泌。因此，这种拮抗剂或激动剂被期待可以预防或治疗垂体前叶激素依赖性疾病。The secretion of anterior pituitary hormones is feedback-controlled by peripheral hormones secreted from the target organs of the corresponding hormones and by secretory-regulatory hormones from the hypothalamus, which is the upper central organ of the anterior pituitary gland (hereinafter, in the specification). , these hormones are commonly referred to as "hypothalamic hormones"). Currently, nine hormones have been identified as hypothalamic hormones, including, for example, thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (GnRH, sometimes referred to as LH-RH (luteinizing hormone-releasing hormone)). These hypothalamic hormones are thought to exhibit their effects through receptors thought to be present in the anterior pituitary gland; and efforts have been made to find receptor-gene expression specific for these hormones, including in humans of. Thus, antagonists or agonists that act specifically and selectively at these receptors should control hypothalamic hormone action and anterior pituitary hormone secretion. Therefore, such antagonists or agonists are expected to prevent or treat anterior pituitary hormone-dependent diseases.
目前已知的具有GnRH拮抗活性的化合物多为肽化合物，例如，GnRH衍生的线性肽(linear peptides)(US 5,140,009和US 5,171,835)，双环肽衍生物(Journal of Medicinal Chemistry，Vol.36，pp.3265-3273(1993))，5或6位修饰的十肽化合物(WO 9846634 A1)和8位修改的十肽化合物(EP 0277829 B1)等。Currently known compounds with GnRH antagonistic activity are mostly peptide compounds, for example, GnRH-derived linear peptides (US 5,140,009 and US 5,171,835), bicyclic peptide derivatives (Journal of Medicinal Chemistry, Vol.36, pp. 3265-3273 (1993)), a decapeptide compound modified at position 5 or 6 (WO 9846634 A1) and a decapeptide compound modified at position 8 (EP 0277829 B1) and the like.
肽化合物存在许多待解决的问题，这些问题与口服吸收性、剂型、剂量体积、药物稳定性、持续作用和代谢稳定性等有关。因此，强烈需要口服GnRH拮抗剂，特别是基于非肽化合物的拮抗剂，该拮抗剂对例如前列腺癌、子宫内膜异位症、性早熟等性激素依赖性疾病具有优异的治疗效果，该拮抗剂不仅表现出瞬间垂体-促性腺作用(急剧作用)并且具有优异的口服吸收性。Peptide compounds present many unsolved problems related to oral absorbability, dosage form, dose volume, drug stability, sustained action, and metabolic stability. Therefore, there is a strong need for oral GnRH antagonists, especially antagonists based on non-peptide compounds, which have excellent therapeutic effects on sex hormone-dependent diseases such as prostate cancer, endometriosis, precocious puberty, etc. Not only shows instantaneous pituitary-gonadotropin action (sharp action) but also has excellent oral absorption.
发明内容SUMMARY OF THE INVENTION
以下仅概括说明本发明的一些方面，并不局限于此。这些方面和其他部分在后面有更完整的说明。本说明书中的所有参考文献通过整体引用于此。当本说明书的公开内容与引用文献有差异时，以本说明书的公开内容为准。The following only outlines some aspects of the present invention, and is not limited thereto. These and other sections are described more fully later. All references in this specification are hereby incorporated by reference in their entirety. When there is a discrepancy between the disclosure content of this specification and the cited documents, the disclosure content of this specification shall prevail.
本发明涉及一类新颖的含有饱和含氧杂环基的嘧啶二酮类化合物，其具有意料不到的优异的GnRH拮抗活性，可以作为促性腺激素释放激素受体拮抗剂，从而可以用于预防或治疗性激素依赖性疾病，包括但不限于，前列腺癌、子宫内膜异位症、子宫肌瘤、性早熟等。The present invention relates to a novel class of pyrimidinedione compounds containing saturated oxygen-containing heterocyclic groups, which have unexpectedly excellent GnRH antagonistic activity, and can be used as gonadotropin-releasing hormone receptor antagonists, so that they can be used for prevention Or treat sex hormone-dependent diseases, including but not limited to, prostate cancer, endometriosis, uterine fibroids, precocious puberty, and the like.
本发明化合物性质稳定，安全性良好，具有药效学和药代动力学优势，例如良好的脑/血浆比(brain plasma ratio)、良好的生物利用度或良好的代谢稳定性等，因此具备较好的临床应用前景。The compound of the present invention has stable properties, good safety, and has the advantages of pharmacodynamics and pharmacokinetics, such as good brain/plasma ratio, good bioavailability or good metabolic stability, etc. good clinical application prospects.
本发明还提供制备这类化合物的方法以及含有此类化合物的药物组合物。The present invention also provides methods of preparing such compounds and pharmaceutical compositions containing such compounds.
一方面，本发明涉及一种化合物，其为式(I)所示的化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrated compound represented by formula (I) compound, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure PCTCN2020119029-appb-000001
Figure PCTCN2020119029-appb-000001
其中，R 1、R 2a、R 2b、R 2c、R 2d、R 3、R 4、R 5a、R 5b、R 5c、R 5d、R 5e、Z和R具有如本发明所述的含义。 Wherein, R 1 , R 2a , R 2b , R 2c , R 2d , R 3 , R 4 , R 5a , R 5b , R 5c , R 5d , R 5e , Z and R have the meanings as described in the present invention.
在一些实施方案中，Z为NH、O或S。In some embodiments, Z is NH, O, or S.
在一些实施方案中，R为
Figure PCTCN2020119029-appb-000002
其中X、Y、U、R 6和m具有如本发明所述的含义。 In some embodiments, R is
Figure PCTCN2020119029-appb-000002
wherein X, Y, U, R 6 and m have the meanings as described in the present invention.
在一些实施方案中，X为CH或N。In some embodiments, X is CH or N.
在一些实施方案中，Y为CH或N。In some embodiments, Y is CH or N.
在一些实施方案中，U为CH或N。In some embodiments, U is CH or N.
在一些实施方案中，R 6为3-8个原子组成的饱和含氧杂环基。 In some embodiments, R 6 is a saturated oxygen-containing heterocyclyl consisting of 3-8 atoms.
在一些实施方案中，m为0、1、2或3。In some embodiments, m is 0, 1, 2, or 3.
在一些实施方案中，R 1为C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、羟基取代的C 1-C 6烷基、氰基取代的C 1-C 6烷基、氨基取代的C 1-C 6烷基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基。 In some embodiments, R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, hydroxy substituted C 1 -C 6 alkyl, cyano substituted C 1 -C 6 alkyl, amino substituted C 1 -C 6 alkyl, C 3-6 cycloalkyl , a heterocyclic group consisting of 3-8 atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-10 atoms.
在一些实施方案中，各R 2a、R 2b、R 2c和R 2d独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 6烷基)、-C(＝O)-(C 1-C 6烷氧基)、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烷硫基、C 1-C 6烷氨基或羟基取代的C 1-C 6烷基。 In some embodiments, each R 2a , R 2b , R 2c and R 2d is independently H, D, F, Cl, Br, I, -CN, -NO2 , -NH2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 -C 6 alkyl) , -C(=O)-(C 1 -C 6 alkoxy), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl , C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino or hydroxy substituted C 1 -C 6 alkyl.
在一些实施方案中，R 3和R 4各自独立地为H、D、-OH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基、5-10个原子组成的杂芳基、C 3-6环烷基-C 1-6亚烷基、(3-8个原子组成的杂环基)-C 1-6亚烷基、C 6-10芳基-C 1-6亚烷基或(5-10个原子组成的杂芳基)-C 1-6亚烷基。 In some embodiments, R 3 and R 4 are each independently H, D, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3-6 cycloalkyl, heterocyclic group consisting of 3-8 atoms, C 6-10 aryl, 5- Heteroaryl consisting of 10 atoms, C 3-6 cycloalkyl-C 1-6 alkylene, (heterocyclyl consisting of 3-8 atoms)-C 1-6 alkylene, C 6-10 Aryl-C 1-6 alkylene or (heteroaryl consisting of 5-10 atoms)-C 1-6 alkylene.
在一些实施方案中，R 5a、R 5b、R 5c、R 5d和R 5e各自独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 6烷基)、-C(＝O)-(C 1-C 6烷氧基)、-NHS(＝O) 2-(C 1-C 6烷基)、-N(C 1-6烷基)S(＝O) 2-(C 1-C 6烷基)、-S(＝O) 2-(C 1-C 6烷基)、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烷硫基、C 1-C 6烷氨基、羟基取代的C 1-C 6烷基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基。 In some embodiments, R 5a , R 5b , R 5c , R 5d , and R 5e are each independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O) NH2 , -C(=O) NHCH3 , -C(=O)N( CH3 ) 2 , -C(=O)-( C1 - C6 alkyl), -C(=O)-(C 1 -C 6 alkoxy), -NHS(=O) 2 -(C 1 -C 6 alkyl), -N(C 1-6 alkyl) S(=O) 2 -(C 1 -C 6 alkyl), -S(=O) 2 -(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl , C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkane Amino group, hydroxy-substituted C 1 -C 6 alkyl group, C 3-6 cycloalkyl group, heterocyclic group consisting of 3-8 atoms, C 6-10 aryl group or heteroaryl group consisting of 5-10 atoms.
在一些实施方案中，R 6为3-6个原子组成的饱和含氧杂环基。 In some embodiments, R 6 is a saturated oxygen-containing heterocyclyl consisting of 3-6 atoms.
在另一些实施方案中，R 6为
Figure PCTCN2020119029-appb-000003
In other embodiments, R 6 is
Figure PCTCN2020119029-appb-000003
在一些实施方案中，R 1为C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、羟基取代的C 1-C 4烷基、氰基取代的C 1-C 4烷基、氨基取代的C 1-C 4烷基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基。 In some embodiments, R 1 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, hydroxy substituted C 1 -C 4 alkyl, cyano substituted C 1 -C 4 alkyl, amino substituted C 1 -C 4 alkyl, C 3-6 cycloalkyl , a heterocyclic group consisting of 3-6 atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-6 atoms.
在另一些实施方案中，R 1为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、2-甲基丙基、1-甲基丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、异丙氧基、-OCF 3、羟甲基、2-羟基乙基、-CH 2CN、-CH 2CH 2CN、-CH 2CH 2CH 2CN、-CH 2NH 2、-CH 2CH 2NH 2、-CH 2CH 2CH 2NH 2、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、茚基、萘基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基。 In other embodiments, R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl, 1-methylpropyl, vinyl, propylene group, allyl, ethynyl, propynyl, propargyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, isopropoxy, -OCF 3 , hydroxymethyl, 2-hydroxyethyl, -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 CH2CN , -CH2NH2 , -CH2CH2NH2 , -CH2CH2CH2NH2 , cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl, azetidine , pyrrole Alkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
在一些实施方案中，各R 2a、R 2b、R 2c和R 2d独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 4烷基)、-C(＝O)-(C 1-C 4烷氧基)、C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 1-C 4烷硫基、C 1-C 4烷氨基或羟基取代的C 1-C 4烷基。 In some embodiments, each R 2a , R 2b , R 2c and R 2d is independently H, D, F, Cl, Br, I, -CN, -NO2 , -NH2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 -C 4 alkyl) , -C(=O)-(C 1 -C 4 alkoxy), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl , C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylamino or hydroxy substituted C 1 -C 4 alkyl.
在另一些实施方案中，各R 2a、R 2b、R 2c和R 2d独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-OCH 3、甲基、乙基、正丙基、异丙基、叔丁基、乙烯基、-CHF 2、-CF 3、甲氧基、-OCF 3、甲氨基、二甲氨基或羟甲基。 In other embodiments, each of R 2a , R 2b , R 2c and R 2d is independently H, D, F, Cl, Br, I, -CN, -NO2 , -NH2 , -OH, -SH , -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-CH 3 , -C(=O )-OCH 3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, -CHF 2 , -CF 3 , methoxy, -OCF 3 , methylamino, dimethylamino or hydroxy methyl.
在一些实施方案中，R 3和R 4各自独立地为H、D、-OH、C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基、5-6个原子组成的杂芳基、C 3-6环烷基-C 1-4亚烷基、(3-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基-C 1-4亚烷基或(5-6个原子组成的杂芳基)-C 1-4亚烷基。 In some embodiments, R 3 and R 4 are each independently H, D, -OH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 aryl, 5- Heteroaryl composed of 6 atoms, C 3-6 cycloalkyl-C 1-4 alkylene, (heterocyclyl composed of 3-6 atoms)-C 1-4 alkylene, C 6-10 Aryl-C 1-4 alkylene or (heteroaryl consisting of 5-6 atoms)-C 1-4 alkylene.
在另一些实施方案中，R 3和R 4各自独立地为H、D、-OH、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、2-甲基丙基、1-甲基丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、-CHF 2、-CF 3、甲氧基、乙氧基、异丙氧基、-OCF 3、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、茚基、萘基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、C 3-6环烷基-亚甲基、C 3-6环烷基-亚乙基、C 3-6环烷基-亚丙基、(3-6个原子组成的杂环基)-亚甲基、(3-6个原子组成的杂环基)-亚乙基、苯基-亚甲基、苯基-亚乙基、苯基-亚丙基、吡啶基-亚甲基、嘧啶基-亚甲基、吡咯基-亚甲基、吡唑基-亚甲基、三氮唑基-亚甲基或四氮唑基-亚甲基。 In other embodiments, R3 and R4 are each independently H, D, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl , 1-methylpropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, -CHF 2 , -CF 3 , methoxy, ethoxy, isopropoxy , -OCF 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl , naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl , C 3-6 cycloalkyl-methylene, C 3-6 cycloalkyl-ethylene, C 3-6 cycloalkyl-propylene, (heterocyclyl composed of 3-6 atoms)- Methylene, (heterocyclyl of 3-6 atoms)-ethylene, phenyl-methylene, phenyl-ethylene, phenyl-propylene, pyridyl-methylene, pyrimidine yl-methylene, pyrrolyl-methylene, pyrazolyl-methylene, triazolyl-methylene or tetrazolyl-methylene.
在一些实施方案中，R 5a、R 5b、R 5c、R 5d和R 5e各自独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 4烷基)、-C(＝O)-(C 1-C 4烷氧基)、-S(＝O) 2-(C 1-C 4烷基)、C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 1-C 4烷硫基、C 1-C 4烷氨基或羟基取代的C 1-C 4烷基。 In some embodiments, R 5a , R 5b , R 5c , R 5d , and R 5e are each independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O) NH2 , -C(=O) NHCH3 , -C(=O)N( CH3 ) 2 , -C(=O)-( C1 - C4 alkyl), -C(=O)-(C 1 -C 4 alkoxy), -S(=O) 2 -(C 1 -C 4 alkyl), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylamino or hydroxy substituted C 1 -C 4 alkyl.
在另一些实施方案中，R 5a、R 5b、R 5c、R 5d和R 5e各自独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-OCH 3、-S(＝O) 2-CH 3、甲基、乙基、正丙基、异丙基、叔丁基、乙烯基、-CHF 2、-CF 3、甲氧基、-OCF 3、甲氨基、二甲氨基或羟甲基。 In other embodiments, R5a , R5b , R5c , R5d , and R5e are each independently H, D, F, Cl, Br, I, -CN, -NO2 , -NH2 , -OH , -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-CH 3 , -C (=O)-OCH 3 , -S(=O) 2 -CH 3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, -CHF 2 , -CF 3 , methoxy group, -OCF 3 , methylamino, dimethylamino or hydroxymethyl.
在一些实施方案中，本发明所述的化合物，其为式(II)所示化合物或式(II)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，In some embodiments, the compound of the present invention is a compound represented by formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of the compound represented by formula (II) , hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure PCTCN2020119029-appb-000004
Figure PCTCN2020119029-appb-000004
其中，R 1、R 3、R 4、R 6、X、Y和m具有如本发明所述的含义。 Wherein, R 1 , R 3 , R 4 , R 6 , X, Y and m have the meanings as described in the present invention.
在一些实施方案中，本发明所述的化合物，其为式(III)所示化合物或式(III)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，In some embodiments, the compound of the present invention is a compound represented by formula (III) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of the compound represented by formula (III) , hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure PCTCN2020119029-appb-000005
Figure PCTCN2020119029-appb-000005
其中，R 1、R 3、R 4、R 6、U和m具有如本发明所述的含义。 Among them, R 1 , R 3 , R 4 , R 6 , U and m have the meanings as described in the present invention.
在一些实施方案中，本发明所述的化合物，其为具有下列之一结构的化合物或具有下列之一结构的化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药：In some embodiments, the compound described in the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of a compound having one of the following structures , hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:
Figure PCTCN2020119029-appb-000006
Figure PCTCN2020119029-appb-000006
Figure PCTCN2020119029-appb-000007
Figure PCTCN2020119029-appb-000007
另一方面，本发明涉及一种药物组合物，所述药物组合物包含本发明公开的化合物。In another aspect, the present invention relates to a pharmaceutical composition comprising a compound disclosed herein.
在一些实施方案中，本发明涉及的药物组合物，进一步包含药学上可接受的赋形剂、载体、佐剂或它们的任意组合。In some embodiments, the pharmaceutical compositions of the present invention further comprise pharmaceutically acceptable excipients, carriers, adjuvants or any combination thereof.
另一方面，本发明涉及本发明公开的化合物或药物组合物在制备药物中的用途，所述药物用于预防或治疗性激素依赖性疾病。In another aspect, the present invention relates to the use of the compounds or pharmaceutical compositions disclosed in the present invention in the preparation of medicaments for preventing or treating sex hormone-dependent diseases.
在一些实施方案中，本发明所述性激素依赖性疾病为性激素依赖性癌症、性激素依赖性癌症的骨质转移、前列腺肥大、子宫肌瘤、子宫内膜异位症、子宫纤维瘤、性早熟、闭经、月经前期综合症、痛经、多房性卵巢综合症、多囊性卵巢综合症、痤疮、脱毛症、阿尔茨海默病、不育症、过敏性肠综合症、不依赖于激素且对LH-RH(促黄体素释放激素)敏感的良性或恶性肿瘤或潮红。In some embodiments, the sex hormone-dependent disease of the present invention is sex hormone-dependent cancer, bone metastases of sex hormone-dependent cancer, prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, Amenorrhea, Premenstrual Syndrome, Dysmenorrhea, Polylocular Ovarian Syndrome, Polycystic Ovary Syndrome, Acne, Alopecia, Alzheimer's Disease, Infertility, Irritable Bowel Syndrome, Hormone-Independent LH-RH (luteinizing hormone-releasing hormone) sensitive benign or malignant tumors or flushing.
一方面，本发明涉及本发明公开的化合物或药物组合物在制备药物中的用途，所述药物可用作生殖调节物(reproduction regulator)、避孕药、排卵诱发物(ovulation inducer)、或者所述药物用于预防性激素依赖性癌症的手术后复发。In one aspect, the present invention relates to the use of a compound or pharmaceutical composition disclosed herein in the manufacture of a medicament useful as a reproduction regulator, contraceptive, ovulation inducer, or the Drugs are used to prevent recurrence of sex hormone-dependent cancers after surgery.
另一方面，本发明涉及本发明公开的化合物或药物组合物在制备药物中的用途，所述药物用于拮抗促性腺素释放激素(GnRH)。In another aspect, the present invention relates to the use of a compound or a pharmaceutical composition disclosed in the present invention in the preparation of a medicament for antagonizing gonadotropin-releasing hormone (GnRH).
另一方面，本发明涉及式(I)、式(II)或式(III)所示化合物的制备、分离和纯化的方法。In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I), formula (II) or formula (III).
生物试验结果表明，本发明化合物对促性腺素释放激素(GnRH)具有较强的拮抗活性，因此本发明提供的化合物可作为较好的GnRH拮抗剂。The biological test results show that the compounds of the present invention have strong antagonistic activity to gonadotropin-releasing hormone (GnRH), so the compounds provided by the present invention can be used as better GnRH antagonists.
本发明的任一方面的任一实施方案，可以与其它实施方案进行组合，只要它们不会出现矛盾。此外，在本发明任一方面的任一实施方案中，任一技术特征可以适用于其它实施方案中的该技术特征，只要它们不会出现矛盾。Any embodiment of any aspect of the invention may be combined with other embodiments so long as they do not appear to be inconsistent. Furthermore, in any embodiment of any aspect of the present invention, any technical feature may be applicable to that technical feature in other embodiments, as long as they do not contradict.
本发明的详细说明书Detailed Description of the Invention
定义和一般术语Definitions and General Terms
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本发明所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本发明所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which are included within the scope of the present invention as defined by the claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, terms defined, uses of terms, techniques described, etc.), this Application shall prevail.
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of multiple separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
除非另外说明，应当应用本发明所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,和“March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本发明。Unless otherwise stated, the following definitions used herein shall apply. For the purposes of the present invention, chemical elements are in accordance with the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007 , the entire contents of which are incorporated herein by reference.
除非另有说明或者上下文中有明显的冲突，本发明所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本发明所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。As used herein, the articles "a", "an" and "the" are intended to include "at least one" or "one or more" unless stated otherwise or otherwise clearly contradicted by context. Thus, as used herein, these articles refer to articles of one or more than one (ie, at least one) object. For example, "a component" refers to one or more components, ie, there may be more than one component contemplated for use or use in the implementation of the described embodiments.
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
术语“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何(顺/反)异构体、阻转异构体，等等。The term "stereoisomers" refers to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric (cis/trans) isomers, atropisomers, and the like.
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible through a low energy barrier. A chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution). For example, protontautomers (also known as prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.
“药学上可接受的”是指这样一些化合物、原料、组合物和/或剂型，它们在合理医学判断的范围内，适用于与患者组织接触而无过度毒性、刺激性、变态反应或与合理的利益/风险比相对称的其他问题和并发症，并有效用于既定用途。"Pharmaceutically acceptable" means compounds, materials, compositions, and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergy, or compatibility with reasonable The benefit/risk ratio is symmetric with other problems and complications and is effective for the intended use.
术语“任选地被…….所取代”，可以与术语“未取代或被…..所取代”交换使用，即所述结构是未取代的或者被一个或多个本发明所述的取代基取代，本发明所述的取代基包括，但不限于D，F，Cl，Br，I，N 3，-CN，-NO 2，-NH 2，-OH，-SH，-COOH，-C(＝O)NH 2，-C(＝O)NHCH 3，-C(＝O)N(CH 3) 2，-C(＝O)-烷基，-C(＝O)- 烷氧基，-NHS(＝O) 2-烷基，-N(烷基)S(＝O) 2-烷基，-S(＝O) 2-烷基，烷基，烷氧基，烷硫基，烷氨基，烯基，炔基，卤代烷基，卤代烷氧基，羟基取代的烷基，氰基取代的烷基，氨基取代的烷基，环烷基，杂环基，芳基，杂芳基，环烷基-亚烷基，杂环基-亚烷基，芳基-亚烷基，杂芳基-亚烷基等等。 The term "optionally substituted by" is used interchangeably with the term "unsubstituted or substituted by", ie the structure is unsubstituted or substituted by one or more of the present invention Substituents in the present invention include, but are not limited to, D, F, Cl, Br, I, N 3 , -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C (=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-alkyl, -C(=O)-alkoxy, -NHS(=O) 2 -alkyl, -N(alkyl)S(=O) 2 -alkyl, -S(=O) 2 -alkyl, alkyl, alkoxy, alkylthio, alkane amino, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxy substituted alkyl, cyano substituted alkyl, amino substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ring Alkyl-alkylene, heterocyclyl-alkylene, aryl-alkylene, heteroaryl-alkylene, and the like.
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-C 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。 In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges. For example, the term " C1 - C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups.
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the linking An alkylene group or an arylene group.
术语“卤素”和“卤代”在本发明中可互换使用，是指氟(F)、氯(Cl)、溴(Br)或碘(I)。The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
本发明使用的术语“烷基”或“烷基基团”，表示含有1-20个碳原子、饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。在一些实施方案中，烷基基团含有1-6个碳原子；在另一些实施方案中，烷基基团含有1-4个碳原子；还在一些实施方案中，烷基基团含有1-3个碳原子。烷基基团的实例包含，但并不限于，甲基(Me、-CH 3)，乙基(Et、-CH 2CH 3)，正丙基(n-Pr、-CH 2CH 2CH 3)，异丙基(i-Pr、-CH(CH 3) 2)，正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2(2-甲基丙基))，仲丁基(s-Bu、-CH(CH 3)CH 2CH 3(1-甲基丙基))，叔丁基(t-Bu、-C(CH 3) 3)，等等。 The term "alkyl" or "alkyl group" used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group can be optionally is substituted with one or more substituents described herein. In some embodiments, alkyl groups contain 1-6 carbon atoms; in other embodiments, alkyl groups contain 1-4 carbon atoms; in still other embodiments, alkyl groups contain 1 -3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), n - propyl (n - Pr, -CH2CH2CH3 ) ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH ) (CH 3 ) 2 (2-methylpropyl)), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 (1-methylpropyl)), tert-butyl (t-Bu , -C(CH 3 ) 3 ), etc.
术语“亚烷基”是指从饱和的直链或支链烃中去掉两个氢原子所得到的饱和的二价烃基基团。除非另外详细说明，亚烷基基团含有1-10个碳原子。在一些实施方案中，亚烷基基团含有1-6个碳原子；在另一些实施方案中，亚烷基基团含有1-4个碳原子；在又一些实施方案中，亚烷基基团含有1-2个碳原子。这样的实例包括，但并不限于，亚甲基(-CH 2-)、亚乙基(-CH 2CH 2-)、亚丙基(-CH 2CH 2CH 2-)、亚异丙基(-CH(CH 3)CH 2-)，等等。所述亚烷基基团任选地被一个或多个本发明所描述的取代基所取代。 The term "alkylene" refers to a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, alkylene groups contain 1-10 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, the alkylene group contains 1-4 carbon atoms; in still other embodiments, the alkylene group The group contains 1-2 carbon atoms. Such examples include, but are not limited to, methylene ( -CH2- ), ethylene ( -CH2CH2- ) , propylene ( -CH2CH2CH2- ) , isopropylene (-CH( CH3 )CH2- ) , etc. The alkylene group is optionally substituted with one or more substituents described herein.
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp 2双键，其中，所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代，其包括“cis”和“trans”的定位，或者“E”和“Z”的定位。在一实施方案中，烯基基团包含2-8个碳原子；在另一实施方案中，烯基基团包含2-6个碳原子；在又一实施方案中，烯基基团包含2-4个碳原子。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH 2)、烯丙基(-CH 2CH＝CH 2)、1-丙烯基(即，丙烯基，-CH＝CH-CH 3)，等等。 The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp 2 double bond, wherein the alkenyl group A group can be optionally substituted with one or more substituents described herein, including the "cis" and "trans" positions, or the "E" and "Z" positions. In one embodiment, the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), 1-propenyl (ie, propenyl, -CH=CH -CH 3 ), etc.
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，炔基基团包含2-8个碳原子；在另一实施方案中，炔基基团包含2-6个碳原子；在又一实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH 2C≡CH)、1-丙炔基(即，丙炔基，-C≡C-CH 3)，等等。 The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group Can be optionally substituted with one or more of the substituents described herein. In one embodiment, the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), 1 -propynyl (ie, propynyl, -C≡C -CH 3 ), etc.
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一些实施方案中，烷氧基基团含有1-6个碳原子；在另一些实施方案中，烷氧基基团含有1-4个碳原子；在又一些实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH 3)，乙氧基(EtO、-OCH 2CH 3)，1-丙氧基(正丙氧基、n-PrO、n-丙氧基、-OCH 2CH 2CH 3)，2-丙氧基(异丙氧基、i-PrO、i-丙氧基、-OCH(CH 3) 2)，1-丁氧基(n-BuO、n-丁氧基、-OCH 2CH 2CH 2CH 3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH 2CH(CH 3) 2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH 3)CH 2CH 3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH 3) 3)，等等。 The term "alkoxy" means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; in still other embodiments, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-propoxy, n -PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (isopropoxy, i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1- Butoxy (n-BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH (CH 3 ) 2 ), 2-butoxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC( CH3 ) 3 ), and the like.
术语“烷硫基”表示烷基基团通过硫原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷硫基基团含有1-12个碳原子。在一些实施方案中，烷硫基基团含有1-6个碳原子；在另一些实施方案中，烷硫基基团含有1-4个碳原子；在又一些实施方案中，烷硫基基团含有1-3个碳原子。所述烷硫基基团可以任选地被一个或多个本发明描述的取代基所取代。烷硫基基团的实例包括，但并不限于，甲硫基(MeS、-SCH 3)，乙硫基(EtS、-SCH 2CH 3)，等等。 The term "alkylthio" means that an alkyl group is attached to the remainder of the molecule through a sulfur atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkylthio group contains 1-12 carbon atoms. In some embodiments, alkylthio groups contain 1-6 carbon atoms; in other embodiments, alkylthio groups contain 1-4 carbon atoms; in still other embodiments, alkylthio groups The group contains 1-3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described herein. Examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH3 ), ethylthio ( EtS , -SCH2CH3 ), and the like.
术语“烷氨基”或“烷基氨基”表述氨基基团分别独立地被一个或两个烷基基团所取代，包括“N-烷基氨基”和“N,N-二烷基氨基”，其中烷基基团具有如本发明所述的含义。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于，N-甲氨基(甲氨基)，N-乙氨基(乙氨基)，N,N-二甲氨基(二甲氨基)，N,N-二乙氨基(二乙氨基)等等。所述烷氨基基团任选地被一个或多个本发明所描述的取代基所取代。The terms "alkylamino" or "alkylamino" describe an amino group independently substituted with one or two alkyl groups, respectively, including "N-alkylamino" and "N,N-dialkylamino", where the alkyl group has the meaning as defined in the present invention. Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N -Dimethylamino (dimethylamino), N,N-diethylamino (diethylamino), etc. The alkylamino group is optionally substituted with one or more substituents described herein.
术语“羟基取代的烷基”表示烷基基团被一个或多个羟基(-OH)所取代，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述羟基取代的烷基基团含有1-12个碳原子。在一些实施方案中，羟基取代的烷基基团含有1-6个碳原子，例如，羟基取代的C 1-C 6烷基；在另一些实施方案中，羟基取代的烷基基团含有1-4个碳原子，例如，羟基取代的C 1-C 4烷基；在又一些实施方案中，羟基取代的烷基基团含有1-3个碳原子，例如，羟基取代的C 1-C 3烷基。这样的实例包含，但并不限于，羟甲基、羟基乙基(例如2-羟基乙基)、2-羟基-1-丙基、3-羟基-1-丙基、2,3-二羟基丙基等等。 The term "hydroxy-substituted alkyl" means that an alkyl group is substituted with one or more hydroxyl groups (-OH), wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the hydroxy-substituted alkyl groups contain 1-12 carbon atoms. In some embodiments, hydroxy-substituted alkyl groups contain 1-6 carbon atoms, eg, hydroxy-substituted C1 - C6 alkyl; in other embodiments, hydroxy-substituted alkyl groups contain 1 -4 carbon atoms, eg, hydroxy-substituted C1 - C4 alkyl; in yet other embodiments, hydroxy-substituted alkyl groups contain 1-3 carbon atoms, eg, hydroxy-substituted C1 -C 3 alkyl. Such examples include, but are not limited to, hydroxymethyl, hydroxyethyl (eg 2-hydroxyethyl), 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2,3-dihydroxy Propyl and so on.
术语“氰基取代的烷基”表示烷基基团被一个或多个氰基(-CN)所取代，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述氰基取代的烷基基团含有1-12个碳原子。在一些实施方案中，氰基取代的烷基基团含有1-6个碳原子，例如，氰基取代的C 1-C 6烷基；在另一些实施方案中，氰基取代的烷基基团含有1-4个碳原子，例如，氰基取代的C 1-C 4烷基；在又一些实施方案中，氰基取代的烷基基团含有1-3个碳原子，例如，氰基取代的C 1-C 3烷基。这样的实例包含，但并不限于，氰基甲基(-CH 2CN)、氰基乙基(例如2-氰基乙基，-CH 2CH 2CN)、2-氰基-1-丙基(-CH 2CH(CN)CH 3)、3-氰基-1-丙基(-CH 2CH 2CH 2CN)、2,3-二氰基丙基(-CH 2CH(CN)CH 2CN)等等。 The term "cyano-substituted alkyl" means that an alkyl group is substituted with one or more cyano groups (-CN), wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the cyano-substituted alkyl groups contain 1-12 carbon atoms. In some embodiments, cyano-substituted alkyl groups contain 1-6 carbon atoms, eg, cyano-substituted C1 - C6 alkyl groups; in other embodiments, cyano-substituted alkyl groups groups contain 1-4 carbon atoms, eg, cyano-substituted C1 - C4 alkyl; in yet other embodiments, cyano-substituted alkyl groups contain 1-3 carbon atoms, eg, cyano Substituted C 1 -C 3 alkyl. Such examples include, but are not limited to, cyanomethyl (-CH2CN), cyanoethyl (eg 2 -cyanoethyl, -CH2CH2CN ), 2 -cyano-1-propane (-CH 2 CH(CN)CH 3 ), 3-cyano-1-propyl (-CH 2 CH 2 CH 2 CN), 2,3-dicyanopropyl (-CH 2 CH(CN) CH 2 CN) and so on.
术语“氨基取代的烷基”表示烷基基团被一个或多个氨基(-NH 2)所取代，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述氨基取代的烷基基团含有1-12个碳原子。在一些实施方案中，氨基取代的烷基基团含有1-6个碳原子，例如，氨基取代的C 1-C 6烷基；在另一些实施方案中，氨基取代的烷基基团含有1-4个碳原子，例如，氨基取代的C 1-C 4烷基；在又一些实施方案中，氨基取代的烷基基团含有1-3个碳原子，例如，氨基取代的C 1-C 3烷基。这样的实例包含，但并不限于，氨基甲基(-CH 2NH 2)、氨基乙基(例如2-氨基乙基，-CH 2CH 2NH 2)、2-氨基-1-丙基(-CH 2CH(NH 2)CH 3)、3-氨基-1-丙基(-CH 2CH 2CH 2NH 2)、2,3-二氨基丙基(-CH 2CH(NH 2)CH 2NH 2)等等。 The term "amino-substituted alkyl" means that an alkyl group is substituted with one or more amino groups ( -NH2 ), wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the amino-substituted alkyl groups contain 1-12 carbon atoms. In some embodiments, amino-substituted alkyl groups contain 1-6 carbon atoms, eg, amino-substituted C1 - C6 alkyl groups; in other embodiments, amino-substituted alkyl groups contain 1 -4 carbon atoms, eg, amino-substituted C1 - C4 alkyl; in yet other embodiments, amino-substituted alkyl groups contain 1-3 carbon atoms, eg, amino-substituted C1 -C 3 alkyl. Such examples include, but are not limited to, aminomethyl ( -CH2NH2 ), aminoethyl (eg 2 -aminoethyl, -CH2CH2NH2 ) , 2 -amino-1-propyl ( -CH2CH( NH2 ) CH3 ), 3 -amino- 1 -propyl ( -CH2CH2CH2NH2 ), 2,3 - diaminopropyl (-CH2CH( NH2 ) CH 2 NH 2 ) and so on.
术语“卤代烷基”或“卤代烷氧基”表示烷基或烷氧基基团被一个或多个卤素原子所取代，其中烷基和烷氧基基团具有如本发明所述的含义，这样的实例包含，但并不限于，-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2等。在一些实施方案中，C 1-C 6卤代烷基包含氟取代的C 1-C 6烷基；在另一些实施方案中，C 1-C 4卤代烷基包含氟取代的C 1-C 4烷基；在又一些实施方案中，C 1-C 2卤代烷基包含氟取代的C 1-C 2烷基。 The term "haloalkyl" or "haloalkoxy" means that an alkyl or alkoxy group is substituted with one or more halogen atoms, wherein the alkyl and alkoxy groups have the meaning as described herein, such that Examples include, but are not limited to, -CHF2 , -CF3 , -CHFCH2F , -CF2CHF2 , -CH2CHF2 , -CH2CF3 , -CH2CF2CHF2 , -OCHF2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 and the like. In some embodiments, C 1 -C 6 haloalkyl comprises fluorine substituted C 1 -C 6 alkyl; in other embodiments, C 1 -C 4 haloalkyl comprises fluorine substituted C 1 -C 4 alkyl ; In still other embodiments, the C 1 -C 2 haloalkyl group comprises a fluorine substituted C 1 -C 2 alkyl group.
术语“环烷基”表示含有3-12个环碳原子的饱和单环、双环或三环体系。在一些实施方案中，环烷基包含3-10个环碳原子，例如C 3-10环烷基；在另一些实施方案中，环烷基包含3-8个环碳原子，例如C 3-8环烷基；在又一些实施方案中，环烷基包含3-6个环碳原子，例如C 3-6环烷基。环烷基基团的实例包括，但并不限于，环丙基、环丁基、环戊基、环己基、环庚基、环辛基，等等。其中，如本发明所述的，C 3-8环烷基包括C 3-6环烷基；所述的C 3-6环烷基包括环丙基、环丁基、环戊基和环己基。所述环烷基基团可以任 选地被一个或多个本发明描述的取代基所取代。 The term "cycloalkyl" denotes a saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring carbon atoms. In some embodiments, the cycloalkyl group contains 3-10 ring carbon atoms, such as C 3-10 cycloalkyl; in other embodiments, the cycloalkyl group contains 3-8 ring carbon atoms, such as C 3- 8 cycloalkyl; in yet other embodiments, cycloalkyl contains 3-6 ring carbon atoms, eg, C3-6 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Wherein, as described in the present invention, C 3-8 cycloalkyl includes C 3-6 cycloalkyl; the C 3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl . The cycloalkyl group may be optionally substituted with one or more substituents described herein.
术语“杂环基”是指包含3-12个环原子的，饱和或部分不饱和的单环、双环或三环体系，其中至少一个环原子选自氮、硫和氧原子；其中，所述杂环基是非芳香性的，且不包含任何芳香环。除非另外说明，杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化物。术语“杂环基”可以与术语“杂环”交换使用。如本发明所述的，所述杂环基可以由3-8个原子或3-6个原子组成，所述原子任选地选自C、N、O或S且至少有一个原子为N、O或S；其中，所述3-8个原子组成的杂环基包括3-6个原子组成的杂环基；所述3-6个原子组成的杂环基包括3-5个原子组成的杂环基。具体地，所述3-6个原子组成的杂环基包括但不限于，环氧乙烷基、氮杂环丙烷基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、噻唑烷基、吡唑烷基、吡唑啉基、噁唑烷基、咪唑烷基、哌啶基、哌嗪基或吗啉基等。所述杂环基基团可以任选地被一个或多个本发明描述的取代基所取代。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system comprising 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms; wherein the Heterocyclyl groups are non-aromatic and do not contain any aromatic rings. Unless otherwise specified, heterocyclyl can be carbon or nitrogen, and -CH2- groups can be optionally replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxides. The term "heterocyclyl" is used interchangeably with the term "heterocycle." According to the present invention, the heterocyclyl group can be composed of 3-8 atoms or 3-6 atoms, the atoms are optionally selected from C, N, O or S and at least one atom is N, O or S; wherein, the heterocyclic group composed of 3-8 atoms includes a heterocyclic group composed of 3-6 atoms; the heterocyclic group composed of 3-6 atoms includes a heterocyclic group composed of 3-5 atoms Heterocyclyl. Specifically, the heterocyclic group consisting of 3-6 atoms includes, but is not limited to, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl , tetrahydrothienyl, thiazolidinyl, pyrazolidine, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl and the like. The heterocyclyl group may be optionally substituted with one or more substituents described herein.
术语“饱和含氧杂环基”是指至少一个环原子选自氧原子的饱和杂环基，其中杂环基基团具有如本发明所述的含义。如本发明所述的，所述饱和含氧杂环基可以由3-8个原子或3-6个原子组成，所述原子任选地选自C、N、O或S且至少有一个原子为O；其中，所述3-8个原子组成的饱和含氧杂环基包括3-6个原子组成的饱和含氧杂环基；所述3-6个原子组成的饱和含氧杂环基包括3-5个原子组成的饱和含氧杂环基。具体地，所述3-6个原子组成的饱和含氧杂环基包括但不限于，
Figure PCTCN2020119029-appb-000008
Figure PCTCN2020119029-appb-000009
The term "saturated oxygen-containing heterocyclyl" refers to a saturated heterocyclyl group having at least one ring atom selected from oxygen atoms, wherein the heterocyclyl group has the meaning as defined herein. According to the present invention, the saturated oxygen-containing heterocyclyl group may consist of 3-8 atoms or 3-6 atoms optionally selected from C, N, O or S and having at least one atom is O; wherein, the saturated oxygen-containing heterocyclic group composed of 3-8 atoms includes a saturated oxygen-containing heterocyclic group composed of 3-6 atoms; the saturated oxygen-containing heterocyclic group composed of 3-6 atoms A saturated oxygen-containing heterocyclic group consisting of 3-5 atoms. Specifically, the saturated oxygen-containing heterocyclic group consisting of 3-6 atoms includes, but is not limited to,
Figure PCTCN2020119029-appb-000008
Figure PCTCN2020119029-appb-000009
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环是芳香族的，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”或“芳环”交换使用。芳基基团的实例可以包括苯基、茚基、2,3-二氢-1H-茚基、萘基和蒽基。所述芳基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外说明，基团“C 6-10芳基”表示含有6-10个环碳原子的芳基基团。 The term "aryl" refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic , and has one or more points of attachment to the rest of the molecule. The term "aryl" is used interchangeably with the term "aromatic ring" or "aromatic ring". Examples of aryl groups may include phenyl, indenyl, 2,3-dihydro-1H-indenyl, naphthyl, and anthracenyl. The aryl group may be optionally substituted with one or more substituents described herein. Unless otherwise specified, the group " C6-10 aryl" refers to an aryl group containing 6-10 ring carbon atoms.
术语“杂芳基”表示含有5-12个环原子，或5-10个环原子，或5-6个环原子的单环、双环和三环体系，其中至少一个环是芳香族的，且至少一个环包含1、2、3或4个选自氮、氧、硫的环杂原子，同时，所述杂芳基有一个或多个附着点与分子其余部分相连。当杂芳基基团中存在-CH 2-基团时，所述的-CH 2-基团可以任选地被-C(＝O)-替代。除非另外说明，所述的杂芳基基团可以通过任何合理的位点(可以为C或者N)连接到分子其余部分(例如通式中的主体结构)上。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。所述杂芳基基团可以任选地被一个或多个本发明描述的取代基所取代。在一些实施方案中，杂芳基为5-10个原子组成的杂芳基，表示杂芳基含有1-9个环碳原子和1、2、3或4个选自O、S和N的环杂原子；在另一些实施方案中，杂芳基为5-6个原子组成的杂芳基，表示杂芳基含有1-5个环碳原子和1、2、3或4个选自O、S和N的环杂原子；5-6个原子组成的杂芳基的实例包括，但并不限于，呋喃基、咪唑基、异噁唑基、噁唑基、吡咯基、吡唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻吩基、噻唑基、三氮唑基、四氮唑基等。 The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic, and At least one ring contains 1, 2, 3 or 4 ring heteroatoms selected from nitrogen, oxygen, sulfur, and the heteroaryl group has one or more points of attachment to the rest of the molecule. When a -CH2- group is present in a heteroaryl group, the -CH2- group can optionally be replaced by -C(=O)-. Unless otherwise specified, the heteroaryl group may be attached to the remainder of the molecule (eg, the host structure in the formula) through any reasonable site (which may be C or N). The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic". The heteroaryl group may be optionally substituted with one or more substituents described herein. In some embodiments, the heteroaryl group is a heteroaryl group of 5-10 atoms, meaning that the heteroaryl group contains 1-9 ring carbon atoms and 1, 2, 3, or 4 atoms selected from O, S, and N Ring heteroatom; in other embodiments, heteroaryl is a heteroaryl group consisting of 5-6 atoms, meaning that the heteroaryl group contains 1-5 ring carbon atoms and 1, 2, 3, or 4 selected from O , S, and N ring heteroatoms; examples of heteroaryl groups of 5-6 atoms include, but are not limited to, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, Pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl and the like.
术语“j-k个原子组成的”表示所述环状基团由j-k个环原子所组成，所述的环原子包括碳原子和/或O、N、S、P等杂原子；所述j和k各自独立地为任意非零的自然数，且k>j；所述“j-k”包括j、k和两者之间的任意自然数。例如，“3-8个原子组成的”、“3-6个原子组成的”、“5-10个原子组成的”或“5-6个原子组成的”表示所述环状基团由3-8(即，3、4、5、6、7或8)、3-6(即，3、4、5或6)、5-10(即，5、6、7、8、 9或10)或5-6(即，5或6)个环原子所组成，所述的环原子包括碳原子和/或O、N、S、P等杂原子。The term "consisting of j-k atoms" means that the cyclic group consists of j-k ring atoms, and the ring atoms include carbon atoms and/or heteroatoms such as O, N, S, P, etc.; the j and k Each is independently any non-zero natural number, and k>j; the "j-k" includes j, k and any natural number in between. For example, "consisting of 3-8 atoms", "consisting of 3-6 atoms", "consisting of 5-10 atoms" or "consisting of 5-6 atoms" means that the cyclic group consists of 3 -8 (ie, 3, 4, 5, 6, 7, or 8), 3-6 (ie, 3, 4, 5, or 6), 5-10 (ie, 5, 6, 7, 8, 9, or 10 ) or 5-6 (ie, 5 or 6) ring atoms including carbon atoms and/or heteroatoms such as O, N, S, P, etc.
术语“环烷基-亚烷基”、“杂环基-亚烷基”、“芳基-亚烷基”、“杂芳基-亚烷基”表示所述的环烷基、杂环基、芳基或杂芳基各自独立地通过亚烷基与分子其余部分相连，其中，所述环烷基、杂环基、芳基、杂芳基和亚烷基均具有本发明所述的含义。例如，芳基亚烷基的实例包括但不限于，苯基-亚甲基、苯基-亚乙基、苯基-亚丙基等。所述环烷基-亚烷基、杂环基-亚烷基、芳基-亚烷基、杂芳基-亚烷基各自独立任选地被一个或多个本发明描述的取代基所取代。The terms "cycloalkyl-alkylene", "heterocyclyl-alkylene", "aryl-alkylene", "heteroaryl-alkylene" refer to the cycloalkyl, heterocyclyl , aryl or heteroaryl are each independently attached to the rest of the molecule through an alkylene group, wherein said cycloalkyl, heterocyclyl, aryl, heteroaryl and alkylene have the meanings described herein . For example, examples of arylalkylene groups include, but are not limited to, phenyl-methylene, phenyl-ethylene, phenyl-propylene, and the like. The cycloalkyl-alkylene, heterocyclyl-alkylene, aryl-alkylene, heteroaryl-alkylene are each independently optionally substituted with one or more substituents described herein .
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)、式(II)或式(III)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。 The term "prodrug" as used in the present invention refers to the conversion of a compound into a compound of formula (I), formula (II) or formula (III) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form. Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent.
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。"Metabolite" refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-C 8磺酸化物和芳香磺酸化物。 As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange method described in books and literature these salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -C 8 sulfonates and aromatic sulfonates.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸、乙醇胺或其混合物。术语“水合物”是指溶剂分子是水所形成的缔合物。A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association in which the solvent molecule is water.
当所述溶剂为水时，可以使用术语“水合物”。在一实施方案中，一个本发明化合物分子可以与一个水分子相结合，比如一水合物；在另一实施方案中，一个本发明化合物分子可以与多于一个的水分子相结合，比如二水合物；在又一实施方案中，一个本发明化合物分子可以与少于一个的水分子相结合，比如半水合物。应注意，本发明所述的水合物保留有非水合形式的所述化合物的生物有效性。When the solvent is water, the term "hydrate" may be used. In one embodiment, one molecule of the compound of the present invention may be associated with one molecule of water, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate In yet another embodiment, one molecule of a compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compounds.
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。The term "treating" any disease or disorder, as used herein, in some embodiments refers to ameliorating the disease or disorder (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by a patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (eg, stabilizing an observable symptom) or physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.
术语“防止”或“预防”指获病或障碍的风险的减少(即：使疾病的至少一种临床症状在主体内停止发展，该主体可能面对或预先倾向面对这种疾病，但还没有经历或表现出疾病的症状)。The terms "prevent" or "prevent" refer to a reduction in the risk of acquiring a disease or disorder (ie: stopping the development of at least one clinical symptom of a disease in a subject who may be facing or predisposed to facing the disease, but also not experience or exhibit symptoms of disease).
术语“治疗有效量”是指当给药于主体来治疗疾病时，化合物的分量足够对这种疾病的治疗起效。“治疗有效量”可以随着化合物，疾病和严重程度，以及有待治疗的主体的条件，年龄，体重，性别等而改变。The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect the treatment of such disease. A "therapeutically effective amount" can vary depending on the compound, the disease and severity, and the condition, age, weight, sex, etc. of the subject to be treated.
除非另作说明，本发明的化合物所有合适的同位素变化、立体异构体、互变异构体、溶剂化物、代谢产物、药学上可接受的盐和它的前药都包含在本发明范围内。Unless otherwise specified, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts and prodrugs thereof of the compounds of the present invention are included within the scope of the present invention .
在本发明公开的结构中，当任意特定的手性原子的立体化学未指明时，则该结构的所有立体异构体都考虑在本发明之内，并且作为本发明公开化合物包括在本发明中。当立体化学被表示特定构型的实楔形线(solid wedge)或虚线指明时，则该结构的立体异构体就此明确和定义。In a structure disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated within the present invention and are included in the present invention as compounds disclosed herein . When stereochemistry is indicated by a solid wedge or a dashed line representing a particular configuration, then the stereoisomers of that structure are well defined and defined.
本发明化合物的氮氧化物也包含在本发明的范围之内。可以通过在升温下使用常用氧化剂(例如过氧化氢)，在有例如乙酸的酸存在下，氧化相应的含氮碱性物质，或者通过在适合的溶剂中与过酸反应，例如在二氯甲烷、乙酸乙酯或乙酸甲酯中与过乙酸反应，或在氯仿或二氯甲烷中与3-氯过氧苯甲酸反应，制备本发明化合物的氮氧化物。Nitrogen oxides of the compounds of the present invention are also included within the scope of the present invention. Oxidation of the corresponding nitrogen-containing basic species can be accomplished by using common oxidizing agents such as hydrogen peroxide at elevated temperature in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as in dichloromethane , ethyl acetate or methyl acetate react with peracetic acid, or react with 3-chloroperoxybenzoic acid in chloroform or dichloromethane to prepare nitrogen oxides of the compounds of the present invention.
式(I)、式(II)或式(III)所示化合物可以以盐的形式存在。在一些实施方案中，所述盐是指药学上可接受的盐。术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。在另一些实施方案中，所述盐不一定是药学上可接受的盐，可以是用于制备和/或提纯式(I)、式(II)或式(III)所示化合物和/或用于分离本式(I)、式(II)或式(III)所示化合物的对映体的中间体。Compounds of formula (I), formula (II) or formula (III) may exist in the form of salts. In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that a substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated with it. In other embodiments, the salt is not necessarily a pharmaceutically acceptable salt, but can be used for the preparation and/or purification of the compound represented by formula (I), formula (II) or formula (III) and/or with Intermediates for separating enantiomers of compounds represented by formula (I), formula (II) or formula (III).
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如 2H、 3H、 11C、 13C、 14C、 15N、 17O、 18O、 18F、 31P、 32P、 35S、 36Cl和 125I。 Any structural formula given herein is also intended to represent both isotopically unenriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures depicted by the general formulae given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
另一方面，本发明涉及制备式(I)、式(II)或式(III)所示化合物的中间体。In another aspect, the present invention relates to intermediates for the preparation of compounds of formula (I), formula (II) or formula (III).
本发明化合物的药物组合物、制剂和给药PHARMACEUTICAL COMPOSITIONS, FORMULATIONS AND ADMINISTRATION OF THE COMPOUNDS OF THE INVENTION
本发明提供一种药物组合物，包括式(I)、式(II)或式(III)所示化合物或其单独的立体异构体，异构体的外消旋或非外消旋混合物或其药学上可接受的盐或溶剂化物。在本发明的一些实施方式中，所述药物组合物进一步包含至少一种药学上可接受的载体、辅剂或赋形剂，以及任选地，其它的治疗和/或预防成分。The present invention provides a pharmaceutical composition, comprising a compound represented by formula (I), formula (II) or formula (III) or its individual stereoisomers, racemic or non-racemic mixtures of isomers or A pharmaceutically acceptable salt or solvate thereof. In some embodiments of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, other therapeutic and/or prophylactic ingredients.
合适的载体、辅剂和赋形剂对于本领域技术人员是熟知的并且详细描述于例如Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；Gennaro A.R.et al.,Remington：The Science and Practice of Pharmacy(2000)Lippincott,Williams&Wilkins,Philadelphia；和Rowe R.C.,Handbook of Pharmaceutical Excipients(2005)Pharmaceutical Press,Chicago中。Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel H.C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro A.R. et al ., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.
也应认识到，在用于治疗时，本发明的某些化合物可以以游离形式存在，或者如果适当可以以其药学上可接受的衍生物的形式存在。药学上可接受衍生物的一些非限制性的实施方案包括药学上可接受的前药，盐，酯，这些酯的盐，或者对有需要的患者给药时能直接或间接提供本发明所述化合物或其代谢产物或残留物的任何另外的加合物或衍生物。It will also be recognized that when used in therapy, certain compounds of the present invention may exist in free form or, where appropriate, in the form of their pharmaceutically acceptable derivatives. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of these esters, or can provide, directly or indirectly, the invention described herein when administered to a patient in need thereof. Any additional adducts or derivatives of the compound or its metabolites or residues.
合适的药学上可接受的赋形剂会依所选具体剂型而不同。此外，可根据它们在组合物中的特定功能来选择药学上可接受的赋形剂。合适的药学上可接受的赋形剂包括以下类型的赋形剂：稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、造粒剂、包衣剂、润湿剂、溶剂、共溶剂、助悬剂、乳化剂、甜味剂、矫味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、塑化剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。技术人员可认识到，某些药学上可接受的赋形剂可提供不止一种功能，并提供可供 选择的功能，这取决于制剂中存在多少该赋形剂和制剂中存在哪些其他赋形剂。Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form chosen. Furthermore, pharmaceutically acceptable excipients can be selected based on their particular function in the composition. Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvent, co-solvent, suspending agent, emulsifier, sweetener, flavoring agent, taste masking agent, coloring agent, anti-caking agent, humectant, chelating agent, plasticizer, tackifier, antioxidant, Preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may serve more than one function, and provide alternative functions, depending on how much of that excipient is present in the formulation and what other excipients are present in the formulation. agent.
本发明公开的药物组合物使用本领域技术人员已知的技术和方法来制备。本领域一些常用方法的描述可参见Remington's Pharmaceutical Sciences(Mack Publishing Company)。The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. A description of some commonly used methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).
因此，另一方面，本发明涉及制备药物组合物的工艺，所述药物组合物包含本发明公开化合物和药学上可接受的赋形剂，载体，辅剂，溶媒或它们的组合，该工艺包括混合各种成分。包含本发明公开化合物的药物组合物，可以在例如环境温度和大气压下混合来制备。Accordingly, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, the process comprising Mix various ingredients. Pharmaceutical compositions containing compounds of the present disclosure can be prepared by mixing, for example, at ambient temperature and atmospheric pressure.
本发明公开的化合物通常被配制成适合于通过所需途径对患者给药的剂型。例如，剂型包括那些适合于以下给药途径的剂型：(1)口服给药，例如片剂、胶囊剂、囊片剂、丸剂、含片剂、粉剂、糖浆剂、酏剂、混悬剂、溶液剂、乳剂、香包剂和扁囊剂；(2)胃肠外给药，例如无菌溶液剂、混悬剂和复溶粉末；(3)透皮给药，例如透皮贴片剂；(4)直肠给药，例如栓剂；(5)吸入，例如气雾剂、溶液剂和干粉剂；和(6)局部给药，例如乳膏剂、油膏剂、洗剂、溶液剂、糊剂、喷雾剂、泡沫剂和凝胶剂。The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by the desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, Solutions, emulsions, sachets, and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes , sprays, foams and gels.
在一些实施方案中，本发明公开的化合物可以配制成口服剂型。在另一些实施方案中，本发明公开的化合物可以配制成吸入剂型。在另一些实施方案中，本发明公开的化合物可以配制成经鼻给药剂型。在又一些实施方案中，本发明公开的化合物可以配制成透皮给药剂型。还在一些实施方案中，本发明公开的化合物可以配制成局部给药剂型。In some embodiments, the compounds disclosed herein can be formulated into oral dosage forms. In other embodiments, the compounds disclosed herein may be formulated in a dosage form for inhalation. In other embodiments, the compounds disclosed herein may be formulated for nasal administration. In yet other embodiments, the compounds disclosed herein can be formulated for transdermal administration. In still some embodiments, the compounds disclosed herein can be formulated for topical administration.
本发明提供的药物组合物可以以压制片、研制片、可咀嚼锭剂、速溶片、复压片、肠溶片、糖衣或薄膜衣片来提供。The pharmaceutical compositions provided by the present invention can be provided as compressed tablets, triturated tablets, chewable lozenges, fast-dissolving tablets, recompressed tablets, enteric-coated tablets, sugar-coated or film-coated tablets.
本发明提供的药物组合物可以以软胶囊或硬胶囊来提供，其可以由明胶、甲基纤维素、淀粉或海藻酸钙来制备。The pharmaceutical compositions provided by the present invention can be provided in soft capsules or hard capsules, which can be prepared from gelatin, methylcellulose, starch or calcium alginate.
本发明提供的药物组合物可以通过注射、输注或植入肠胃外给药，用于局部或全身给药。如本发明使用的肠胃外给药包括静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、胸骨内、颅内、肌内、滑膜内和皮下给药。The pharmaceutical compositions provided by the present invention can be parenterally administered by injection, infusion or implantation for local or systemic administration. Parenteral administration as used in the present invention includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.
本发明提供的药物组合物可以配制成适于肠胃外给药的任何剂型，包括溶液、混悬剂、乳剂、胶束、脂质体、微球、纳米体系和适于在注射前在液体中制成溶液或混悬液的固体形式。这样的剂型可以根据药物科学领域的技术人员已知的常规方法来制备(参见Remington:The Science和Practice of Pharmacy,同上)。The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and in liquid prior to injection Solid forms are prepared as solutions or suspensions. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical sciences (see Remington: The Science and Practice of Pharmacy, supra).
另一方面，本发明所公开的药物组合物可以配制成适于对患者吸入给药的任何剂型，例如干粉剂、气雾剂、混悬剂或溶液组合物。On the other hand, the pharmaceutical compositions disclosed herein can be formulated into any dosage form suitable for inhalation administration to a patient, such as dry powder, aerosol, suspension or solution compositions.
适合于透皮给药的药物组合物可制备成不连续的贴片剂，意在与患者的表皮保持紧密接触一段延长的时间。例如，可通过离子渗透从贴片剂中递送活性成分，如Pharmaceutical Research,3(6),318(1986)中的一般描述。Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of a patient for an extended period of time. For example, the active ingredient can be delivered from the patch by iontophoresis, as generally described in Pharmaceutical Research, 3(6), 318 (1986).
适合于局部给药的药物组合物可以被配制成油膏剂、乳膏剂、混悬剂、洗剂、粉剂、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂或油剂。Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
本发明化合物和药物组合物的用途Use of the Compounds and Pharmaceutical Compositions of the Invention
本发明提供的化合物和药物组合物具有优异的GnRH拮抗活性和低毒性(例如，急性毒性、慢性毒性、遗传性毒性、生殖毒性(reproduction toxicity)、心脏毒素、药物相互作用和致癌力)。并且，所述化合物或药物组合物在口服吸收性、作用可持续性、稳定性和药代动力学方面是优异的。此外，所述化合物或药物组合物很少受到血浆成分的影响。因此本发明的化合物或药物组合物可安全地用在哺乳动物上(例如，人、猴、牛、马、犬、猫、兔、大鼠和小鼠等)，通过利用GnRH受体拮抗作用来控制血浆性激素浓度，以抑制促性腺素分泌，从而预防和/或治疗依赖于雄性或雌性激素的疾病以及由于这些激素过量而引起的疾病 等。The compounds and pharmaceutical compositions provided by the present invention have excellent GnRH antagonistic activity and low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproduction toxicity, cardiotoxicity, drug interactions, and carcinogenicity). Also, the compound or pharmaceutical composition is excellent in oral absorbability, sustainability of action, stability and pharmacokinetics. Furthermore, the compounds or pharmaceutical compositions are rarely affected by plasma components. Thus the compounds or pharmaceutical compositions of the present invention can be safely used in mammals (eg, humans, monkeys, bovines, horses, dogs, cats, rabbits, rats and mice, etc.) by utilizing GnRH receptor antagonism to Control plasma sex hormone concentrations to inhibit gonadotropin secretion, thereby preventing and/or treating diseases that are dependent on male or female hormones and diseases caused by excess of these hormones.
具体而言，本发明的化合物或药物组合物适用于预防和/或治疗性激素依赖性癌症(例如，前列腺癌、子宫癌、乳腺癌、垂体瘤等)、性激素依赖性癌症的骨质转移、前列腺肥大、子宫肌瘤、子宫内膜异位症、子宫纤维瘤、性早熟、闭经、月经前期综合症、痛经、多房性卵巢综合症(multilocular ovary syndrome)、多囊性卵巢综合症、痤疮、脱毛症、阿尔茨海默病(阿尔茨海默病、阿尔茨海默型及其混合型的老年性痴呆)等。本发明的化合物也适用于调节雄性和雌性的生殖(例如，妊娠调节剂和月经周期调节剂等)。本发明的化合物或药物组合物还可用作雄性或雌性避孕药或用作雌性排卵诱发物。基于停药后的回弹作用，本发明的化合物或药物组合物可用于治疗不育症。并且，本发明的化合物或药物组合物可用作预防和/或治疗不依赖于激素且对LH-RH敏感的良性或恶性肿瘤的药剂。此外，本发明的化合物或药物组合物可用作预防和/或治疗过敏性肠综合症和预防性激素依赖性癌症的手术后复发的药剂(预防前列腺癌手术后复发的药剂；预防绝经之前或之后乳腺癌或卵巢癌手术后复发的药剂；特别是预防绝经之前乳腺癌或卵巢癌手术后复发的药剂)。Specifically, the compounds or pharmaceutical compositions of the present invention are suitable for preventing and/or treating sex hormone-dependent cancers (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), bone metastases of sex hormone-dependent cancers, prostate cancer Hypertrophy, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multilocular ovary syndrome, polycystic ovary syndrome, acne, Alopecia, Alzheimer's disease (Alzheimer's disease, Alzheimer's type and its mixed type senile dementia), etc. The compounds of the present invention are also suitable for modulating male and female reproduction (eg, pregnancy regulators and menstrual cycle regulators, etc.). The compounds or pharmaceutical compositions of the present invention may also be used as male or female contraceptives or as ovulation inducers in females. Based on the rebound effect after drug withdrawal, the compounds or pharmaceutical compositions of the present invention can be used to treat infertility. Also, the compounds or pharmaceutical compositions of the present invention can be used as agents for the prevention and/or treatment of hormone-independent and LH-RH-sensitive benign or malignant tumors. In addition, the compounds or pharmaceutical compositions of the present invention are useful as agents for preventing and/or treating irritable bowel syndrome and preventing postoperative recurrence of hormone-dependent cancers (agents for preventing postoperative recurrence of prostate cancer; preventing before or after menopause) Agents for the recurrence of breast or ovarian cancer after surgery; in particular for the prevention of premenopausal breast or ovarian cancer recurrence after surgery).
此外，本发明的化合物或药物组合物适用于在畜牧业中调节动物动情期，改进肉的质量和促进动物生长。本发明的化合物也适用于鱼类产卵促进剂(fishspawning promoter)。Furthermore, the compounds or pharmaceutical compositions of the present invention are suitable for use in animal husbandry for regulating estrus, improving meat quality and promoting animal growth. The compounds of the present invention are also suitable for use in fishspawning promoters.
本发明的化合物或药物组合物也可用于抑制血浆睾酮浓度的瞬时升高(突发现象(flare phenomenon))，在给药如醋酸亮丙瑞琳等GnRH超激动剂时观察到血浆睾酮浓度的瞬时升高。本发明的化合物可与醋酸亮丙瑞琳、格那瑞林(gonadorelin)、布舍瑞林(buserelin)、曲普瑞林(triptorelin)、戈舍瑞林(goserelin)、纳发阮林(nafarelin)、组氨瑞林(histrelin)、地洛瑞林(deslorelin)、咪特瑞林(meterelin)和高舍瑞林(lecirelin)等超激动剂联合使用。尤其优选为醋酸亮丙瑞琳。The compounds or pharmaceutical compositions of the present invention may also be used to inhibit transient increases in plasma testosterone concentrations (flare phenomenon) observed with administration of GnRH superagonists such as leuprolide acetate Instantaneous rise. The compounds of the present invention can be combined with leuprolide acetate, gonadorelin, buserelin, triptorelin, goserelin, nafarelin ), histrelin (histrelin), deslorelin (deslorelin), meterelin (meterelin) and lecirelin (lecirelin) and other super agonists in combination. Especially preferred is leuprolide acetate.
也可尤其有利地将本发明的化合物或药物组合物与选自下述物质中的至少一种联合使用，所述物质为类固醇类或非类固醇类的抗雄激素剂或抗雌激素剂、化学治疗剂、GnRH拮抗肽(antagonistic peptide)、α-还原酶抑制剂、α-受体抑制剂、芳香酶抑制剂、17β-羟基类固醇脱氢酶抑制剂、肾上腺雄激素产生抑制剂、激酶抑制剂、激素治疗用药和抑制细胞生长因子或其受体的药物。The compounds or pharmaceutical compositions of the invention can also be used particularly advantageously in combination with at least one selected from the group consisting of steroidal or non-steroidal anti-androgens or anti-estrogens, chemical Therapeutic agent, GnRH antagonist peptide (antagonistic peptide), alpha-reductase inhibitor, alpha-receptor inhibitor, aromatase inhibitor, 17beta-hydroxysteroid dehydrogenase inhibitor, adrenal androgen production inhibitor, kinase inhibitor , hormone therapy drugs and drugs that inhibit cell growth factors or their receptors.
上述“化学治疗剂”包括异环磷酰胺(ifosfamide)、多柔比星(adriamycin)、培洛霉素(peplomycin)、顺铂(cisplatin)、环磷酰胺(cyclophosphamide)、5-FU、UFT、甲氨蝶呤(methotrexate)、丝裂霉素C(mitomycin C)、米托蒽醌(mitoxantrone)等。上述“GnRH拮抗肽”包括非口服GnRH拮抗肽，例如西曲瑞克(cetrorelix)、加尼瑞克(ganirelix)和阿巴瑞克(abarelix)等。The above "chemotherapeutic agents" include ifosfamide, doxorubicin, peplomycin, cisplatin, cyclophosphamide, 5-FU, UFT, Methotrexate (methotrexate), mitomycin C (mitomycin C), mitoxantrone (mitoxantrone), etc. The above-mentioned "GnRH antagonistic peptide" includes parenteral GnRH antagonistic peptides such as cetrorelix, ganirelix, abarrelix and the like.
本发明的化合物及药物组合物除了对人类治疗有益以外，还可应用于兽医治疗宠物、引进品种的动物和农场的动物中的哺乳动物。另外一些动物的实例包括马、狗和猫。在此，本发明的化合物包括其药学上可接受的衍生物。In addition to their therapeutic benefits in humans, the compounds and pharmaceutical compositions of the present invention may also be used in veterinary treatment of mammals in pets, introduced species and farm animals. Examples of other animals include horses, dogs and cats. Here, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
在一些实施方案中，本发明公开化合物或包含本发明公开化合物的药物组合物可以一次性给药，或者根据给药方案，在指定时间段内，在不同的时间间隔给药若干次。本发明公开化合物可以与一种或多种其它治疗剂同时，或在其之前或之后给药。本发明化合物可以与其他治疗剂通过相同或不同给药途径分别给药，或与之以同一药物组合物形式给药。In some embodiments, a compound of the present disclosure or a pharmaceutical composition comprising a compound of the present disclosure may be administered at one time, or several times at different time intervals over a specified period of time, depending on the dosing regimen. The disclosed compounds may be administered concurrently with, prior to or subsequent to one or more other therapeutic agents. The compounds of the present invention can be administered separately with other therapeutic agents by the same or different route of administration, or in the same pharmaceutical composition.
一般合成步骤General synthetic steps
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。To illustrate the invention, the following examples are set forth. It is to be understood, however, that the invention is not limited to these examples, but merely provides methods of practicing the invention.
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)、式(II)或式(III)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。In general, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the substituents are as defined in formula (I), formula (II) or formula (III). The following reaction schemes and examples serve to further illustrate the content of the present invention.
所属领域的专业人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合 物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described in this invention can be used to suitably prepare many other compounds of this invention, and that other methods for preparing compounds of this invention are considered to be within the scope of this invention. Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modifying methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described herein, or by combining The reaction conditions were modified routinely. In addition, the reactions disclosed herein or known reaction conditions are also acknowledged to be applicable to the preparation of other compounds of the present invention.
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，天津市福晨化学试剂厂，武汉鑫华远科技发展有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.
无水四氢呋喃，二氧六环，甲苯，乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether were obtained by refluxing and drying with metallic sodium. Anhydrous dichloromethane and chloroform were obtained by refluxing with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。The following reactions are generally carried out under positive nitrogen or argon pressure or a drying tube is set over anhydrous solvent (unless otherwise indicated), the reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dry.
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.
1H NMR谱使用Bruker 400MHz或600MHz核磁共振谱仪记录。 1H NMR谱以CDC1 3、DMSO-d 6、CD 3OD或丙酮-d 6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)，d(doublet，双峰)，t(triplet，三重峰)，q(quartet，四重峰)，m(multiplet，多重峰)，br(broadened，宽峰)，brs(broadened singlet，宽的单峰)，dd(doublet of doublets，双二重峰)，ddd(doublet of doublet of doublets，双双二重峰)，ddt(doublet of doublet of triplets，双双三重峰)，dt(doublet of triplets，双三重峰)，dq(doublet of quartets，双四重峰)，td(triplet of doublets，三双重峰)，tt(triplet of triplets，三三重峰)，qd(quartet of doublets，四双重峰)。偶合常数J，用赫兹(Hz)表示。 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1H NMR spectra were performed with CDC13, DMSO - d6, CD3OD or acetone - d6 as solvent (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are present, the following abbreviations are used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), brs (broadened singlet, broad singlet), dd (doublet of doublets, double doublet), ddd (doublet of doublet of doublets, double double doublet), ddt (doublet of doublet of triplets, double double triplet), dt (doublet of triplets, double triplet), dq (doublet of quartets, double quartet), td (triplet of doublets, triple doublet), tt (triplet of triplets, triple triplet), qd (quartet of doublets, quadruple doublet). The coupling constant, J, is expressed in Hertz (Hz).
低分辨率质谱(MS)数据的测定条件是：Agilent 6120四级杆HPLC-M(柱子型号：Zorbax SB-C18,2.1×30mm,3.5微米,6min,流速为0.6mL/min。流动相：5％-95％(含0.1％甲酸的CH 3CN)在(含0.1％甲酸的H 2O)中的比例，采用电喷雾电离(ESI)，在210nm/254nm下，用UV检测。 The measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 × 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL/min. Mobile phase: 5 %-95% ( CH3CN with 0.1% formic acid) in ( H2O with 0.1% formic acid) using electrospray ionization (ESI) at 210 nm/254 nm with UV detection.
纯的化合物使用Agilent 1260 pre-HPLC或Calesep pump 250 pre-HPLC(柱子型号：NOVASEP 50/80mm DAC)，在210nm/254nm用UV检测。Pure compounds were detected by UV at 210nm/254nm using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80mm DAC).
下面简写词的使用贯穿本发明：The following abbreviations are used throughout this disclosure:
Figure PCTCN2020119029-appb-000010
Figure PCTCN2020119029-appb-000010
下列合成方案描述了制备本发明公开化合物的步骤，除非另外说明，其中，R 1、R 6、X、Y、U和m具有本发明所述的定义。 The following synthetic schemes describe steps for the preparation of compounds disclosed herein, wherein R1, R6 , X, Y, U, and m have the definitions described herein, unless otherwise specified.
中间体制备方案1Intermediate preparation scheme 1
式( 11)所示的中间体化合物可以通过下列过程制备得到：式( 1)所示的化合物与式( 2)所示的氰基乙酸乙酯反应，得到式( 3)所示的化合物；然后式( 3)所示的化合物在硫粉作用下关环，得到式( 4)所示的化合物。式( 4)所示的化合物与氯甲酸乙酯反应，得到式( 5)所示的化合物。式( 5)所示的化合物与式( 6)所示的化合物反应得到式( 7)所示的化合物；式( 7)所示的化合物经溴代，得到式( 8)所示的化合物。式( 8)所示的化合物与式( 9)所示的化合物反应，得到式( 10)所示的化合物。式( 10)所示的化合物经过酯水解得到式( 11)所示的中间体化合物。 The intermediate compound represented by the formula ( 11 ) can be prepared by the following process: the compound represented by the formula ( 1 ) reacts with the ethyl cyanoacetate represented by the formula ( 2 ) to obtain the compound represented by the formula ( 3 ); Then the compound represented by formula ( 3 ) is ring-closed under the action of sulfur powder to obtain the compound represented by formula ( 4 ). The compound represented by the formula ( 4 ) is reacted with ethyl chloroformate to obtain the compound represented by the formula ( 5 ). The compound represented by the formula ( 5 ) reacts with the compound represented by the formula ( 6 ) to obtain the compound represented by the formula ( 7 ); the compound represented by the formula ( 7 ) is brominated to obtain the compound represented by the formula ( 8 ). The compound represented by the formula ( 8 ) is reacted with the compound represented by the formula ( 9 ) to obtain the compound represented by the formula ( 10 ). The compound represented by formula ( 10 ) is subjected to ester hydrolysis to obtain the intermediate compound represented by formula ( 11 ).
Figure PCTCN2020119029-appb-000011
Figure PCTCN2020119029-appb-000011
合成方案1Synthesis Scheme 1
式( 17)所示的化合物可以通过下列过程制备得到：式( 11)所示的化合物与式( 12)所示的化合物反应，得到式( 13)所示的化合物；式( 13)所示的化合物关环得到式( 14)所示的化合物；式( 14)所示的化合物的硝基还原得到式( 15)所示的化合物；式( 15)所示的化合物与式( 16)所示的化合物反应得到( 17)所示的目标产物。 The compound represented by the formula ( 17 ) can be prepared by the following process: the compound represented by the formula ( 11 ) reacts with the compound represented by the formula ( 12 ) to obtain the compound represented by the formula ( 13 ); represented by the formula ( 13 ) The compound represented by the formula ( 14 ) is obtained by ring closure of the compound; the nitro group of the compound represented by the formula ( 14 ) is reduced to obtain the compound represented by the formula ( 15 ); the compound represented by the formula ( 15 ) and the formula ( 16 ) The indicated compound was reacted to obtain the target product indicated by ( 17 ).
Figure PCTCN2020119029-appb-000012
Figure PCTCN2020119029-appb-000012
合成方案2Synthesis Scheme 2
式( 17’)所示的化合物可以通过下列过程制备得到：式( 11)所示的化合物与式( 12’)所示的化合物反应，得到式( 13’)所示的化合物；式( 13’)所示的化合物关环得到式( 14’)所示的化合物；式( 14’)所 示的化合物的硝基还原得到式( 15’)所示的化合物；式( 15’)所示的化合物与式( 16)所示的化合物反应得到( 17’)所示的目标产物。 The compound represented by formula ( 17' ) can be prepared by the following process: the compound represented by formula ( 11 ) reacts with the compound represented by formula ( 12' ) to obtain the compound represented by formula ( 13' ); formula ( 13 ) The compound represented by ' ) is closed to obtain the compound represented by the formula ( 14' ); the nitro group of the compound represented by the formula ( 14' ) is reduced to obtain the compound represented by the formula ( 15' ); the compound represented by the formula ( 15' ) The compound is reacted with the compound represented by formula ( 16 ) to obtain the target product represented by ( 17' ).
Figure PCTCN2020119029-appb-000013
Figure PCTCN2020119029-appb-000013
以下结合实施例对本发明提供的化合物、药物组合物及其应用进行进一步说明。The compounds, pharmaceutical compositions and applications provided by the present invention will be further described below with reference to the examples.
实施例Example
实施例1 1-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(5-(氧杂环丁-3-基氧基)吡啶-2-基)-2,4-二氧代-1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲的合成Example 1 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(5-(oxetan-3-yloxy) yl)pyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxy Synthesis of base urea
Figure PCTCN2020119029-appb-000014
Figure PCTCN2020119029-appb-000014
步骤1)(E/Z)-2-氰基-3-甲基-4-(4-硝基苯基)-2-丁烯酸乙酯的合成Step 1) Synthesis of (E/Z)-2-cyano-3-methyl-4-(4-nitrophenyl)-2-butenoic acid ethyl ester
将对硝基苯丙酮(5.3g,29.6mmol)和氰基乙酸乙酯(9.64ml,88.8mmol)加入到250mL单口圆底烧瓶中，然后加入正庚酸(4.37mL,29.6mmol)、苄胺(3.6mL,32mmol)和甲苯(50mL)，接分水器，130℃下反应12小时；反应结束后，冷却至室温，减压旋干，柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝18/1)得到标题化合物为淡黄色油状物(7.24g,89.2％)。p-Nitropropiophenone (5.3g, 29.6mmol) and ethyl cyanoacetate (9.64ml, 88.8mmol) were added to a 250mL single-neck round-bottom flask, followed by n-heptanoic acid (4.37mL, 29.6mmol), benzylamine (3.6mL, 32mmol) and toluene (50mL), connected to a water separator, and reacted at 130 ° C for 12 hours; after the reaction was completed, cooled to room temperature, spin-dried under reduced pressure, and separated and purified by column chromatography (petroleum ether/ethyl acetate (petroleum ether/ethyl acetate) v/v)=18/1) to give the title compound as a pale yellow oil (7.24 g, 89.2%).
MS(ESI,neg.ion)m/z:273.3[M-H] -. MS(ESI,neg.ion)m/z:273.3[MH] - .
步骤2)2-氨基-4-甲基-5-(4-硝基苯基)噻吩-3-羧酸乙酯的合成Step 2) Synthesis of ethyl 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate
将(E/Z)-2-氰基-3-甲基-4-(4-硝基苯基)-2丁烯酸乙酯(7.2g,26.2mmol)、硫粉(1.68g,52.4mmol)和乙醇(80mL)加入到250mL单口圆底烧瓶中，加入二乙胺(6.8mL,65mmol)，搅拌反应15分钟后，转移至65℃继续反应3小时；停止反应，冷却至室温，减压旋干，柱层析分离纯化(石油醚/二氯甲烷(v/v)＝5/1)得到标题化合物为棕红色固体(5.23g,65.1％)。(E/Z)-2-cyano-3-methyl-4-(4-nitrophenyl)-2-butenoic acid ethyl ester (7.2g, 26.2mmol), sulfur powder (1.68g, 52.4mmol) ) and ethanol (80mL) were added to a 250mL single-neck round-bottomed flask, diethylamine (6.8mL, 65mmol) was added, and after stirring for 15 minutes, the reaction was transferred to 65°C and continued for 3 hours; the reaction was stopped, cooled to room temperature, and reduced in pressure. Spin to dryness, column chromatography separation and purification (petroleum ether/dichloromethane (v/v)=5/1) to obtain the title compound as a brown-red solid (5.23 g, 65.1%).
MS(ESI,pos.ion)m/z:307.1[M+H] +； MS(ESI, pos.ion) m/z: 307.1[M+H] + ;
1H NMR(600MHz,CDCl 3)δ(ppm):8.22(d,J＝8.9Hz,2H),7.48(d,J＝8.9Hz,2H),6.27(s,2H),4.33(q,J＝7.1Hz,2H),2.40(s,3H),1.38(t,J＝7.1Hz,3H). 1 H NMR (600 MHz, CDCl 3 ) δ (ppm): 8.22 (d, J=8.9 Hz, 2H), 7.48 (d, J=8.9 Hz, 2H), 6.27 (s, 2H), 4.33 (q, J ＝7.1Hz, 2H), 2.40(s, 3H), 1.38(t, J＝7.1Hz, 3H).
步骤3)2-((乙氧羰酰基)氨基)-4-甲基-5-(4-硝基苯基)噻吩-3-羧酸乙酯的合成Step 3) Synthesis of 2-((ethoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethyl ester
在25℃下将2-氨基-4-甲基-5-(4-硝基苯基)噻吩-3-羧酸乙酯(12g,39.2mmol)、吡啶(11mL,140mmol)和二氯甲烷(100mL)加入到250mL单口圆底烧瓶中，加入氯甲酸乙酯(6.7mL,70mmol)，继续搅拌反 应2小时；停止反应，加入水(50mL)，分液，收集有机相，加入无水硫酸钠(1.5g)干燥，过滤，滤液减压旋干，柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝12/1)得到标题化合物为淡黄色固体(10.2g,68.8％)。Ethyl 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate (12 g, 39.2 mmol), pyridine (11 mL, 140 mmol) and dichloromethane ( 100mL) was added to a 250mL single-neck round-bottomed flask, ethyl chloroformate (6.7mL, 70mmol) was added, and the reaction was continued to stir for 2 hours; the reaction was stopped, water (50mL) was added, the liquid was separated, the organic phase was collected, and anhydrous sodium sulfate was added. (1.5g) was dried, filtered, the filtrate was spin-dried under reduced pressure, separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v)=12/1) to obtain the title compound as a pale yellow solid (10.2g, 68.8%) .
MS(ESI,pos.ion)m/z:379.1[M+H] +. MS(ESI,pos.ion)m/z:379.1[M+H] + .
步骤4)2-((2,6-二氟苄基)(乙氧羰酰基)氨基)-4-甲基-5-(4-硝基苯基)噻吩-3-羧酸乙酯的合成Step 4) Synthesis of 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate ethyl ester
在25℃下将2-((乙氧羰酰基)氨基)-4-甲基-5-(4-硝基苯基)噻吩-3-羧酸乙酯(21.4g,56.6mmol)、碘化钾(18.8g,113mmol)、碳酸钾(15.8g,113mmol)和DMF(120mL)加入到500mL单口圆底烧瓶中，然后加入2,6-二氟氯苄(18.4g,113mmol)，继续反应12小时；停止反应，加入水(150mL)淬灭，然后用二氯甲烷萃取(100mL)，无水硫酸钠(2g)干燥；过滤，滤液减压旋干，柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝20/1)得到标题化合物为淡黄色固体(24.2g,84.8％)。2-((Ethoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate ethyl ester (21.4 g, 56.6 mmol), potassium iodide ( 18.8g; The reaction was stopped, quenched by adding water (150 mL), then extracted with dichloromethane (100 mL), and dried over anhydrous sodium sulfate (2 g); filtered, the filtrate was spin-dried under reduced pressure, and separated and purified by column chromatography (petroleum ether/ethyl acetate) (v/v)=20/1) to give the title compound as a pale yellow solid (24.2 g, 84.8%).
MS(ESI,pos.ion)m/z:505.1[M+H] +. MS(ESI,pos.ion)m/z:505.1[M+H] + .
步骤5)4-(溴甲基)-2-((2,6-二氟苄基)(乙氧羰酰基)氨基)-5-(4-硝基苯基)噻吩-3-羧酸乙酯的合成Step 5) Ethyl 4-(bromomethyl)-2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-5-(4-nitrophenyl)thiophene-3-carboxylate Synthesis of Esters
将2-((2,6-二氟苄基)(乙氧羰酰基)氨基)-4-甲基-5-(4-硝基苯基)噻吩-3-羧酸乙酯(12g,23.8mmol)、偶氮二异丁腈(0.81g,4.8mmol)、N-溴代琥珀酰亚胺(5.62g,30.9mmol)和氯苯(60mL)加入到250mL单口圆底烧瓶中，氮气保护下油浴80℃反应10小时；停止反应，冷却至室温，加入饱和碳酸氢钠溶液(50mL)，分液，有机相无水硫酸钠(1g)干燥；过滤，滤液减压旋干得到标题化合物为黄色固体(12.8g,92.5％)。Ethyl 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate (12 g, 23.8 mmol), azobisisobutyronitrile (0.81g, 4.8mmol), N-bromosuccinimide (5.62g, 30.9mmol) and chlorobenzene (60mL) were added to a 250mL single-neck round bottom flask, under nitrogen protection The reaction was carried out in an oil bath at 80°C for 10 hours; the reaction was stopped, cooled to room temperature, saturated sodium bicarbonate solution (50 mL) was added, the layers were separated, and the organic phase was dried with anhydrous sodium sulfate (1 g); filtered, and the filtrate was spin-dried under reduced pressure to obtain the title compound as Yellow solid (12.8 g, 92.5%).
步骤6)2-((2,6-二氟苄基)(乙氧羰酰基)氨基)-4-((二甲基氨基)甲基)-5-(4-硝基苯基)噻吩-3-羧酸乙酯的合Step 6) 2-((2,6-Difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene- Synthesis of ethyl 3-carboxylate 成become
在25℃下将4-(溴甲基)-2-((2,6-二氟苄基)(乙氧羰酰基)氨基)-5-(4-硝基苯基)噻吩-3-羧酸乙酯(23g,39.4mmol)、二甲胺盐酸盐(9.74g,118mmol)和DMF(100mL)加入到500mL单口圆底烧瓶中，然后加入三乙胺(22.1mL,158mmol)，继续搅拌反应2小时；停止反应，加入水(250mL)，乙酸乙酯萃取(200mL)，分液，收集有机相，减压旋干，将得到的固体柱层析纯化(石油醚/乙酸乙酯(v/v)＝1/1)得到标题化合物为淡黄色固体(20.22g,93.7％)。4-(Bromomethyl)-2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-5-(4-nitrophenyl)thiophene-3-carboxylate at 25°C Ethyl acid (23g, 39.4mmol), dimethylamine hydrochloride (9.74g, 118mmol) and DMF (100mL) were added to a 500mL single-neck round bottom flask, then triethylamine (22.1mL, 158mmol) was added, and stirring was continued React for 2 hours; stop the reaction, add water (250 mL), extract with ethyl acetate (200 mL), separate the layers, collect the organic phase, spin dry under reduced pressure, and purify the obtained solid by column chromatography (petroleum ether/ethyl acetate (v /v)=1/1) to give the title compound as a pale yellow solid (20.22 g, 93.7%).
MS(ESI,pos.ion)m/z:548.2[M+H] +； MS(ESI, pos.ion) m/z: 548.2[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm):8.23(d,J＝8.8Hz,2H),7.65(d,J＝8.8Hz,2H),7.29–7.23(m,1H),6.84(dd,J＝13.7,5.8Hz,2H),5.01(s,2H),4.22(dd,J＝14.2,7.1Hz,4H),3.51(s,2H),2.05(s,6H),1.29(t,J＝7.1Hz,3H),1.26(t,J＝7.1Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.23 (d, J=8.8 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.29-7.23 (m, 1H), 6.84 (dd , J=13.7, 5.8Hz, 2H), 5.01(s, 2H), 4.22(dd, J=14.2, 7.1Hz, 4H), 3.51(s, 2H), 2.05(s, 6H), 1.29(t, J=7.1Hz, 3H), 1.26(t, J=7.1Hz, 3H).
步骤7)2-((2,6-二氟苄基)(乙氧羰酰基)氨基)-4-((二甲基氨基)甲基)-5-(4-硝基苯基)噻吩-3-羧酸的合成Step 7) 2-((2,6-Difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene- Synthesis of 3-Carboxylic Acid
将2-((2,6-二氟苄基)(乙氧羰酰基)氨基)-4-((二甲基氨基)甲基)-5-(4-硝基苯基)噻吩-3-羧酸乙酯(4.0g,7.3mmol)、乙醇(38mL)和水(10mL)加入到250mL单口圆底烧瓶中，加入氢氧化钾(0.723g,12.9mmol)，油浴65℃反应5小时；停止反应，冷却至室温后，加入浓硫酸(0.548g,5.48mmol,98％)淬灭，减压旋干溶剂，柱层析纯化(二氯甲烷/甲醇(v/v)＝40/1)得到标题化合物为淡黄色固体(3.05g,80.4％)。2-((2,6-Difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3- Ethyl carboxylate (4.0g, 7.3mmol), ethanol (38mL) and water (10mL) were added to a 250mL single-neck round-bottomed flask, potassium hydroxide (0.723g, 12.9mmol) was added, and the reaction was performed at 65°C in an oil bath for 5 hours; The reaction was stopped, cooled to room temperature, quenched by adding concentrated sulfuric acid (0.548g, 5.48mmol, 98%), the solvent was spin-dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v)=40/1) The title compound was obtained as a pale yellow solid (3.05 g, 80.4%).
MS(ESI,pos.ion)m/z:520.0[M+H] +. MS(ESI,pos.ion)m/z:520.0[M+H] + .
步骤8)(2,6-二氟苄基)(4-((二甲基氨基)甲基)-5-(4-硝基苯基)-3-((5-(氧杂环丁-3-基氧基)吡啶-2-基)氨甲酰Step 8) (2,6-Difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrophenyl)-3-((5-(oxetine- 3-yloxy)pyridin-2-yl)carbamoyl 基)噻吩-2-基)氨基甲酸乙酯的合成Synthesis of ethyl)thiophen-2-yl)carbamate
将2-((2,6-二氟苄基)(乙氧羰酰基)氨基)-4-((二甲基氨基)甲基)-5-(4-硝基苯基)噻吩-3-羧酸(1.0g,1.93mmol)、5-(氧杂环丁-3-基氧基)吡啶-2-胺(0.5g,3.0mmol)、N,N-二异丙基乙胺(1.0mL,6.0mmol)和DMF(10mL)加入到100mL单口圆底烧瓶中，然后加入1-丙基磷酸酐乙酸乙酯溶液(1.9mL,3.2mmol,50％)，油浴60℃搅拌反应1小时；停止反应，冷却至室温后，加入水(50mL)淬灭，然后加入碳酸氢钠固体调节pH＝8-9，加入二氯甲烷萃取(50mL)，分液，收集有机相，减压旋干，将得到的固体柱层析分离纯化(石 油醚/乙酸乙酯(v/v)＝1/1)得到标题化合物为黄色固体(1.06g,82％)。2-((2,6-Difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3- Carboxylic acid (1.0 g, 1.93 mmol), 5-(oxetan-3-yloxy)pyridin-2-amine (0.5 g, 3.0 mmol), N,N-diisopropylethylamine (1.0 mL) , 6.0mmol) and DMF (10mL) were added in the 100mL single-neck round-bottomed flask, then 1-propyl phosphoric anhydride ethyl acetate solution (1.9mL, 3.2mmol, 50%) was added, and the oil bath was stirred at 60 ° C for 1 hour; The reaction was stopped, cooled to room temperature, quenched by adding water (50 mL), then adding solid sodium bicarbonate to adjust pH=8-9, adding dichloromethane for extraction (50 mL), separating the layers, collecting the organic phase, and spin-dried under reduced pressure, The obtained solid was separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a yellow solid (1.06 g, 82%).
MS(ESI,pos.ion)m/z:668.2[M+H] +. MS(ESI,pos.ion)m/z:668.2[M+H] + .
步骤9)1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-6-(4-硝基苯基)-3-(5-(氧杂环丁基-3-基氧基)吡啶-2-基)噻Step 9) 1-(2,6-Difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-3-(5-(oxetine) yl-3-yloxy)pyridin-2-yl)thio 吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成Synthesis of pheno[2,3-d]pyrimidine-2,4(1H,3H)-dione
将(2,6-二氟苄基)(4-((二甲基氨基)甲基)-5-(4-硝基苯基)-3-((5-(氧杂环丁-3-基氧基)吡啶-2-基)氨甲酰基)噻吩-2-基)氨基甲酸乙酯(1.06g,1.59mmol)和四氢呋喃(30mL)加入到100mL单口圆底烧瓶中，然后加入碳酸铯(1.14g,3.5mmol)，油浴70℃下继续搅拌反应2.5小时；停止反应，冷却至室温后，减压旋干除去溶剂，柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)得到标题化合物为黄色固体(0.879g,89％)。(2,6-Difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrophenyl)-3-((5-(oxetane-3- yloxy)pyridin-2-yl)carbamoyl)thiophen-2-yl)carbamate (1.06g, 1.59mmol) and tetrahydrofuran (30mL) were added to a 100mL single-neck round bottom flask, followed by cesium carbonate ( 1.14g, 3.5mmol), continue to stir the reaction at 70 ℃ of oil bath for 2.5 hours; stop the reaction, after cooling to room temperature, spin dry under reduced pressure to remove the solvent, and separate and purify by column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a yellow solid (0.879 g, 89%).
MS(ESI,pos.ion)m/z:622.1[M+H] +. MS(ESI,pos.ion)m/z:622.1[M+H] + .
步骤10)6-(4-氨基苯基)-1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(5-(氧杂环丁-3-基氧基)吡啶-2-基)噻吩Step 10) 6-(4-Aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(5-(oxetine- 3-yloxy)pyridin-2-yl)thiophene 并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成Synthesis of [2,3-d]pyrimidine-2,4(1H,3H)-dione
将1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-6-(4-硝基苯基)-3-(5-(氧杂环丁基-3-基氧基)吡啶-2-基)噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮(362mg,0.58mmol)、四氢呋喃(4mL)、乙醇(4mL)和水(2mL)加入到50mL单口圆底烧瓶中，然后加入铁粉(162mg,2.9mmol)和氯化铵(65mg,1.15mmol)，油浴70℃下反应14小时；停止反应，冷却至室温后，过滤，滤液减压旋干除去大部分溶剂，加入二氯甲烷(40mL)和水(20mL)，分液，收集有机相，减压旋干后柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)得到标题化合物为淡黄色固体(269mg,78.1％)。1-(2,6-Difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-3-(5-(oxetanyl)- 3-yloxy)pyridin-2-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (362 mg, 0.58 mmol), tetrahydrofuran (4 mL), ethanol (4 mL) and water (2mL) were added to a 50mL single-neck round-bottomed flask, then iron powder (162mg, 2.9mmol) and ammonium chloride (65mg, 1.15mmol) were added, and the reaction was carried out at 70°C in an oil bath for 14 hours; the reaction was stopped and cooled to room temperature After filtration, the filtrate was spin-dried under reduced pressure to remove most of the solvent, dichloromethane (40 mL) and water (20 mL) were added, the layers were separated, and the organic phase was collected. (v/v)=20/1) to give the title compound as a pale yellow solid (269 mg, 78.1%).
MS(ESI,pos.ion)m/z:592.1[M+H] +； MS(ESI, pos.ion) m/z: 592.1[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.17(d,J＝2.8Hz,1H),7.50–7.42(m,2H),7.38(d,J＝8.6Hz,1H),7.21(d,J＝7.8Hz,2H),7.14(t,J＝8.2Hz,2H),6.64(d,J＝8.3Hz,2H),5.49(s,2H),5.46–5.41(m,1H),5.20(s,2H),4.98(t,J＝6.7Hz,2H),4.61(dd,J＝7.1,5.0Hz,2H),2.19(s,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 8.17 (d, J=2.8 Hz, 1H), 7.50-7.42 (m, 2H), 7.38 (d, J=8.6 Hz, 1H), 7.21 (d, J=7.8Hz, 2H), 7.14 (t, J=8.2Hz, 2H), 6.64 (d, J=8.3Hz, 2H), 5.49 (s, 2H), 5.46–5.41 (m, 1H) ,5.20(s,2H),4.98(t,J＝6.7Hz,2H),4.61(dd,J＝7.1,5.0Hz,2H),2.19(s,6H).
步骤11)1-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(5-(氧杂环丁-3-基氧基)吡啶-2-基)-2,4-二氧代Step 11) 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(5-(oxetan-3-yloxy) yl)pyridin-2-yl)-2,4-dioxo -1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲的合成-Synthesis of 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea
将6-(4-氨基苯基)-1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(5-(氧杂环丁-3-基氧基)吡啶-2-基)噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮(269mg,0.45mmol)、苯基N-甲氧基氨基甲酸酯(304mg,1.82mmol)和DMF(5mL)加入到50mL单口圆底烧瓶中，然后加入三乙胺(0.27mL,1.8mmol)和4-二甲氨基吡啶(5mg,0.04mmol)，油浴60℃下反应14小时；停止反应，冷却至室温后，加入水(30mL)，析出固体，过滤，收集得到固体，柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)得到标题化合物为淡黄色固体(0.262g,86.7％)。6-(4-Aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(5-(oxetane-3- yloxy)pyridin-2-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (269 mg, 0.45 mmol), phenyl N-methoxycarbamate (304mg, 1.82mmol) and DMF (5mL) were added to a 50mL single-neck round bottom flask, then triethylamine (0.27mL, 1.8mmol) and 4-dimethylaminopyridine (5mg, 0.04mmol) were added, and the oil bath was 60°C. The reaction was continued for 14 hours; the reaction was stopped, and after cooling to room temperature, water (30 mL) was added to precipitate a solid, which was filtered and collected to obtain a solid, which was separated and purified by column chromatography (dichloromethane/methanol (v/v)=20/1) to obtain The title compound was a pale yellow solid (0.262 g, 86.7%).
MS(ESI,pos.ion)m/z:665.1[M+H] +； MS(ESI, pos.ion) m/z: 665.1[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ(ppm):9.64(s,1H),9.09(s,1H),8.17(d,J＝2.8Hz,1H),7.72(d,J＝8.6Hz,2H),7.52(d,J＝8.6Hz,2H),7.49–7.42(m,2H),7.38(d,J＝8.6Hz,1H),7.14(t,J＝8.2Hz,2H),5.48–5.41(m,1H),5.21(s,2H),4.98(t,J＝6.7Hz,2H),4.62(dd,J＝7.0,5.1Hz,2H),3.64(s,3H),2.08(s,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 9.64 (s, 1H), 9.09 (s, 1H), 8.17 (d, J=2.8 Hz, 1H), 7.72 (d, J=8.6 Hz) ,2H),7.52(d,J＝8.6Hz,2H),7.49–7.42(m,2H),7.38(d,J＝8.6Hz,1H),7.14(t,J＝8.2Hz,2H),5.48 –5.41(m, 1H), 5.21(s, 2H), 4.98(t, J=6.7Hz, 2H), 4.62(dd, J=7.0, 5.1Hz, 2H), 3.64(s, 3H), 2.08( s, 6H).
实施例2 1-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基氧基)吡啶-3-基)-2,4-二氧代-1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲的合成Example 2 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-yloxy) yl)pyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxy Synthesis of base urea
Figure PCTCN2020119029-appb-000015
Figure PCTCN2020119029-appb-000015
步骤1)(2,6-二氟苄基)(4-((二甲基氨基)甲基)-5-(4-硝基苯基)-3-((6-(氧杂环丁-3-基氧基)吡啶-3-基)氨甲酰Step 1) (2,6-Difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrophenyl)-3-((6-(oxetine- 3-yloxy)pyridin-3-yl)carbamoyl 基)噻吩-2-基)氨基甲酸乙酯的合成Synthesis of ethyl)thiophen-2-yl)carbamate
本步骤标题化合物参照实施例1步骤8所描述的方法制备得到，即将2-((2,6-二氟苄基)(乙氧羰酰基)氨基)-4-((二甲基氨基)甲基)-5-(4-硝基苯基)噻吩-3-羧酸(3.0g,5.8mmol)、6-(氧杂环丁-3-基氧基)吡啶-3-胺(1.2g,7.2mmol)、N,N-二异丙基乙胺(2.9mL,16.6mmol)和1-丙基磷酸酐乙酸乙酯溶液(6.9mL,11.6mmol,50％)在DMF(30mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50/1)，得到标题化合物为淡黄色固体(3.55g,92％)。The title compound in this step was prepared according to the method described in Example 1, Step 8, namely 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methane yl)-5-(4-nitrophenyl)thiophene-3-carboxylic acid (3.0 g, 5.8 mmol), 6-(oxetan-3-yloxy)pyridin-3-amine (1.2 g, 7.2 mmol), N,N-diisopropylethylamine (2.9 mL, 16.6 mmol) and ethyl acetate solution of 1-propylphosphoric anhydride (6.9 mL, 11.6 mmol, 50%) in DMF (30 mL) prepared by reaction , the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=50/1) to obtain the title compound as a pale yellow solid (3.55 g, 92%).
MS(ESI,pos.ion)m/z:668.1[M+H] +. MS(ESI,pos.ion)m/z:668.1[M+H] + .
步骤2)1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-6-(4-硝基苯基)-3-(6-(氧杂环丁基-3-基氧基)吡啶-3-基)噻Step 2) 1-(2,6-Difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-3-(6-(oxetine) yl-3-yloxy)pyridin-3-yl)thio 吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成Synthesis of pheno[2,3-d]pyrimidine-2,4(1H,3H)-dione
本步骤标题化合物参照实施例1步骤9所描述的方法制备得到，即将(2,6-二氟苄基)(4-((二甲基氨基)甲基)-5-(4-硝基苯基)-3-((6-(氧杂环丁-3-基氧基)吡啶-3-基)氨甲酰基)噻吩-2-基)氨基甲酸乙酯(3.5g,5.24mmol)、甲醇钠(0.584g,10.5mmol)在甲醇(35mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为淡黄色固体(1.95g,59.8％)。The title compound in this step was prepared according to the method described in Example 1, Step 9, namely (2,6-difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrobenzene) yl)-3-((6-(oxetan-3-yloxy)pyridin-3-yl)carbamoyl)thiophen-2-yl)carbamate (3.5 g, 5.24 mmol), methanol Sodium (0.584 g, 10.5 mmol) was prepared by reaction in methanol (35 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to obtain the title compound as a pale yellow solid (1.95 g, 59.8%).
MS(ESI,pos.ion)m/z:622.1[M+H] +； MS(ESI, pos.ion) m/z: 622.1[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm):8.28(d,J＝8.8Hz,2H),8.01(d,J＝2.4Hz,1H),7.86(d,J＝8.8Hz,2H),7.54(dd,J＝8.7,2.6Hz,1H),7.38–7.30(m,1H),6.98–6.88(m,3H),5.67–5.59(m,1H),5.38(s,2H),4.99(t,J＝7.0Hz,2H),4.79–4.73(m,2H),3.73(s,2H),2.19(s,6H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.28 (d, J=8.8 Hz, 2H), 8.01 (d, J=2.4 Hz, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.54(dd,J=8.7,2.6Hz,1H),7.38-7.30(m,1H),6.98-6.88(m,3H),5.67-5.59(m,1H),5.38(s,2H),4.99( t, J=7.0Hz, 2H), 4.79–4.73(m, 2H), 3.73(s, 2H), 2.19(s, 6H).
步骤3)6-(4-氨基苯基)-1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基氧基)吡啶-3-基)噻吩Step 3) 6-(4-Aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetine- 3-yloxy)pyridin-3-yl)thiophene 并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成Synthesis of [2,3-d]pyrimidine-2,4(1H,3H)-dione
在25℃下将1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-6-(4-硝基苯基)-3-(6-(氧杂环丁基-3-基氧基)吡啶-3-基)噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮(1.9g,3.06mmol)、氯化氢乙酸乙酯溶液(2mL,2M)和甲醇(10mL)加入到100mL单口圆底烧瓶中，然后加入Pd/C(0.57g)，氢气下反应6小时；停止反应，减压旋干除去大部分溶剂，加入甲醇(10mL)，然后加入碳酸氢钠固体调节至pH＝8，直接硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50/1)得到标题化合物为淡黄色固体(0.95g,53％)。1-(2,6-Difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-3-(6-(oxa) at 25°C Cyclobutyl-3-yloxy)pyridin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.9 g, 3.06 mmol), ethyl hydrogen chloride The solution (2mL, 2M) and methanol (10mL) were added to a 100mL single-neck round-bottomed flask, then Pd/C (0.57g) was added, and the reaction was carried out under hydrogen for 6 hours; the reaction was stopped, and most of the solvent was removed by spin-drying under reduced pressure, and methanol was added. (10 mL), then added sodium bicarbonate solid to adjust to pH=8, and directly separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=50/1) to obtain the title compound as a pale yellow solid (0.95 g, 53%).
MS(ESI,pos.ion)m/z:592.1[M+H] +； MS(ESI, pos.ion) m/z: 592.1[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm):8.01(d,J＝2.3Hz,1H),7.55(dd,J＝8.6,2.1Hz,1H),7.37–7.29(m,1H),7.28(s,2H),6.91(t,J＝8.1Hz,3H),6.70(d,J＝8.4Hz,2H),5.64–5.57(m,1H),5.34(s,2H),4.99(t,J＝7.0Hz,2H),4.79–4.73(m,2H),3.67(s,2H),2.13(s,6H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.01 (d, J=2.3 Hz, 1H), 7.55 (dd, J=8.6, 2.1 Hz, 1H), 7.37-7.29 (m, 1H), 7.28 (s, 2H), 6.91(t, J=8.1Hz, 3H), 6.70(d, J=8.4Hz, 2H), 5.64–5.57(m, 1H), 5.34(s, 2H), 4.99(t, J=7.0Hz, 2H), 4.79–4.73(m, 2H), 3.67(s, 2H), 2.13(s, 6H).
步骤4)1-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基氧基)吡啶-3-基)-2,4-二氧代Step 4) 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-yloxy) yl)pyridin-3-yl)-2,4-dioxo -1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲的合成-Synthesis of 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea
本步骤标题化合物参照实施例1步骤11所描述的方法制备得到，即将6-(4-氨基苯基)-1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基氧基)吡啶-3-基)噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮(0.9g, 1.52mmol)、苯基N-甲氧基氨基甲酸酯(0.763g,4.56mmol)、三乙胺(0.634mL,4.56mmol)和4-二甲基氨基吡啶(19mg,0.15mmol)在DMF(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)，得到标题化合物为淡黄色固体(0.55g,54.4％)。The title compound of this step was prepared according to the method described in step 11 of Example 1, namely 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino) Methyl)-3-(6-(oxetan-3-yloxy)pyridin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 0.9 g, 1.52 mmol), phenyl N-methoxycarbamate (0.763 g, 4.56 mmol), triethylamine (0.634 mL, 4.56 mmol) and 4-dimethylaminopyridine (19 mg, 0.15 mmol) The reaction was prepared in DMF (10 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1) to give the title compound as a pale yellow solid (0.55 g, 54.4%).
MS(ESI,pos.ion)m/z:665.1[M+H] +； MS(ESI, pos.ion) m/z: 665.1[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ(ppm):9.62(s,1H),9.07(s,1H),8.02(d,J＝2.3Hz,1H),7.70(d,J＝8.4Hz,3H),7.51(d,J＝8.5Hz,2H),7.45(dd,J＝14.7,7.7Hz,1H),7.13(t,J＝8.2Hz,2H),7.03(d,J＝8.7Hz,1H),5.63–5.55(m,1H),5.27(s,2H),4.91(t,J＝6.8Hz,2H),4.64–4.57(m,2H),3.63(s,3H),3.59(s,2H),2.03(s,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 9.62 (s, 1H), 9.07 (s, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.70 (d, J=8.4 Hz ,3H),7.51(d,J＝8.5Hz,2H),7.45(dd,J＝14.7,7.7Hz,1H),7.13(t,J＝8.2Hz,2H),7.03(d,J＝8.7Hz ,1H),5.63–5.55(m,1H),5.27(s,2H),4.91(t,J=6.8Hz,2H),4.64–4.57(m,2H),3.63(s,3H),3.59( s,2H),2.03(s,6H).
实施例3 1-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基氧基)哒嗪-3-基)-2,4-二氧代-1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲的合成Example 3 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-yloxy) yl)pyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methyl Synthesis of Oxyurea
Figure PCTCN2020119029-appb-000016
Figure PCTCN2020119029-appb-000016
步骤1)(2,6-二氟苄基)(4-((二甲基氨基)甲基)-5-(4-硝基苯基)-3-((6-(氧杂环丁-3-基氧基)哒嗪-3-基)氨甲酰Step 1) (2,6-Difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrophenyl)-3-((6-(oxetine- 3-yloxy)pyridazin-3-yl)carbamoyl 基)噻吩-2-基)氨基甲酸乙酯的合成Synthesis of ethyl)thiophen-2-yl)carbamate
本步骤标题化合物参照实施例1步骤8所描述的方法制备得到，即将2-((2,6-二氟苄基)(乙氧羰酰基)氨基)-4-((二甲基氨基)甲基)-5-(4-硝基苯基)噻吩-3-羧酸(2.18g,4.2mmol)、6-(氧杂环丁-3-基氧基)哒嗪-3-胺(0.7g,4.19mmol)、N,N-二异丙基乙胺(2.9mL,16.6mmol)和1-丙基磷酸酐乙酸乙酯溶液(3.6mL,6.1mmol,50％)在DMF(25mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50/1)，得到标题化合物为黄色固体(2.3g,82％)。The title compound in this step was prepared according to the method described in Example 1, Step 8, namely 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methane yl)-5-(4-nitrophenyl)thiophene-3-carboxylic acid (2.18g, 4.2mmol), 6-(oxetan-3-yloxy)pyridazin-3-amine (0.7g) , 4.19 mmol), N,N-diisopropylethylamine (2.9 mL, 16.6 mmol) and ethyl acetate solution of 1-propylphosphoric anhydride (3.6 mL, 6.1 mmol, 50%) were reacted in DMF (25 mL) Preparation, the crude product was isolated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=50/1) to give the title compound as a yellow solid (2.3 g, 82%).
MS(ESI,pos.ion)m/z:669.2[M+H] +； MS(ESI, pos.ion) m/z: 669.2[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm):8.61(d,J＝9.5Hz,1H),8.30(d,J＝8.6Hz,2H),7.49(d,J＝8.7Hz,2H),7.20–7.12(m,1H),7.08(d,J＝9.5Hz,1H),6.77(t,J＝7.6Hz,2H),5.84–5.78(m,1H),5.10–5.03(m,4H),4.81–4.77(m,2H),4.24(s,2H),3.52(s,2H),2.97(s,3H),2.90(s,3H),1.40–1.28(m,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.61 (d, J=9.5 Hz, 1H), 8.30 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H), 7.20–7.12 (m, 1H), 7.08 (d, J=9.5Hz, 1H), 6.77 (t, J=7.6Hz, 2H), 5.84–5.78 (m, 1H), 5.10–5.03 (m, 4H) ,4.81–4.77(m,2H),4.24(s,2H),3.52(s,2H),2.97(s,3H),2.90(s,3H),1.40–1.28(m,3H).
步骤2)1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-6-(4-硝基苯基)-3-(6-(氧杂环丁基-3-基氧基)哒嗪-3-基)噻Step 2) 1-(2,6-Difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-3-(6-(oxetine) yl-3-yloxy)pyridazin-3-yl)thio 吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成Synthesis of pheno[2,3-d]pyrimidine-2,4(1H,3H)-dione
本步骤标题化合物参照实施例1步骤9所描述的方法制备得到，即将(2,6-二氟苄基)(4-((二甲基氨基)甲基)-5-(4-硝基苯基)-3-((6-(氧杂环丁-3-基氧基)哒嗪-3-基)氨甲酰基)噻吩-2-基)氨基甲酸乙酯(2.6g,3.9mmol)、碳酸铯(2.5g,7.7mmol)在DMF(30mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为淡黄色固体(1.2g,50％)。The title compound in this step was prepared according to the method described in Example 1, Step 9, namely (2,6-difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrobenzene) yl)-3-((6-(oxetan-3-yloxy)pyridazin-3-yl)carbamoyl)thiophen-2-yl)carbamate (2.6 g, 3.9 mmol), Cesium carbonate (2.5 g, 7.7 mmol) was prepared by reaction in DMF (30 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to obtain the title compound as pale yellow Solid (1.2 g, 50%).
MS(ESI,pos.ion)m/z:623.1[M+H] +； MS(ESI, pos.ion) m/z: 623.1[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm):8.31(d,J＝8.7Hz,2H),7.90(d,J＝8.8Hz,2H),7.51(d,J＝9.1Hz,1H),7.36(dt,J＝14.7,7.4Hz,1H),7.24(d,J＝9.1Hz,1H),6.97(t,J＝8.1Hz,2H),5.91–5.85(m,1H),5.39(s,2H),5.08(t,J＝7.0Hz,2H),4.84(dd,J＝7.5,5.5Hz,2H),3.73(s,2H),2.21(s,6H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.31 (d, J=8.7 Hz, 2H), 7.90 (d, J=8.8 Hz, 2H), 7.51 (d, J=9.1 Hz, 1H), 7.36(dt,J=14.7,7.4Hz,1H),7.24(d,J=9.1Hz,1H),6.97(t,J=8.1Hz,2H),5.91-5.85(m,1H),5.39(s ,2H),5.08(t,J＝7.0Hz,2H),4.84(dd,J＝7.5,5.5Hz,2H),3.73(s,2H),2.21(s,6H).
步骤3)6-(4-氨基苯基)-1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基氧基)哒嗪-3-基)噻吩Step 3) 6-(4-Aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetine- 3-yloxy)pyridazin-3-yl)thiophene 并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成Synthesis of [2,3-d]pyrimidine-2,4(1H,3H)-dione
本步骤标题化合物参照实施例1步骤10所描述的方法制备得到，即将1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-6-(4-硝基苯基)-3-(6-(氧杂环丁基-3-基氧基)哒嗪-3-基)噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮(1.0g,1.6mmol)、铁粉(0.44g,7.9mmol)、氯化铵(0.17g,3.2mmol)在四氢呋喃(20mL)、乙醇(20mL)、水(5mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为黄色固体(0.79g,83％)。The title compound in this step was prepared according to the method described in step 10 of Example 1, namely 1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitro phenyl)-3-(6-(oxetan-3-yloxy)pyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)- Diketone (1.0g, 1.6mmol), iron powder (0.44g, 7.9mmol), ammonium chloride (0.17g, 3.2mmol) in tetrahydrofuran (20mL), ethanol (20mL), water (5mL) were prepared by reaction, crude The product was isolated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to give the title compound as a yellow solid (0.79 g, 83%).
MS(ESI,pos.ion)m/z:593.1[M+H] +. MS(ESI,pos.ion)m/z:593.1[M+H] + .
步骤4)1-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基氧基)哒嗪-3-基)-2,4-二氧代Step 4) 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-yloxy) yl)pyridazin-3-yl)-2,4-dioxo -1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲的合成-Synthesis of 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea
本步骤标题化合物参照实施例1步骤11所描述的方法制备得到，即将6-(4-氨基苯基)-1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基氧基)哒嗪-3-基)噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮(0.71g,1.2mmol)、苯基N-甲氧基氨基甲酸酯(0.801g,4.8mmol)、三乙胺(0.7mL,5.0mmol)在DMF(20mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)，得到标题化合物为淡黄色固体(0.42g,52.7％)。The title compound of this step was prepared according to the method described in step 11 of Example 1, namely 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino) Methyl)-3-(6-(oxetan-3-yloxy)pyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.71 g, 1.2 mmol), phenyl N-methoxycarbamate (0.801 g, 4.8 mmol), triethylamine (0.7 mL, 5.0 mmol) in DMF (20 mL) prepared by reacting the crude product on silica gel Separation and purification by column chromatography (dichloromethane/methanol (v/v)=20/1) gave the title compound as a pale yellow solid (0.42 g, 52.7%).
MS(ESI,pos.ion)m/z:666.1[M+H] +； MS(ESI, pos.ion) m/z: 666.1[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm):7.71(s,1H),7.57(t,J＝8.5Hz,2H),7.50(d,J＝8.2Hz,2H),7.39–7.29(m,1H),7.22(d,J＝9.1Hz,1H),6.94(t,J＝8.1Hz,2H),5.92–5.82(m,1H),5.33(d,J＝14.8Hz,2H),5.08(t,J＝7.0Hz,2H),4.87–4.79(m,2H),3.82(s,3H),3.78–3.45(m,2H),2.14(s,6H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.71 (s, 1H), 7.57 (t, J=8.5 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 7.39-7.29 (m ,1H),7.22(d,J＝9.1Hz,1H),6.94(t,J＝8.1Hz,2H),5.92–5.82(m,1H),5.33(d,J＝14.8Hz,2H),5.08 (t, J=7.0Hz, 2H), 4.87–4.79 (m, 2H), 3.82 (s, 3H), 3.78–3.45 (m, 2H), 2.14 (s, 6H).
实施例4 1-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基氧基)吡啶-2-基)-2,4-二氧代-1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲的合成Example 4 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-yloxy) yl)pyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxy Synthesis of base urea
Figure PCTCN2020119029-appb-000017
Figure PCTCN2020119029-appb-000017
步骤1)(2,6-二氟苄基)(4-((二甲基氨基)甲基)-5-(4-硝基苯基)-3-((6-(氧杂环丁-3-基氧基)吡啶-2-基)氨甲酰Step 1) (2,6-Difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrophenyl)-3-((6-(oxetine- 3-yloxy)pyridin-2-yl)carbamoyl 基)噻吩-2-基)氨基甲酸乙酯的合成Synthesis of ethyl)thiophen-2-yl)carbamate
本步骤标题化合物参照实施例1步骤8所描述的方法制备得到，即将2-((2,6-二氟苄基)(乙氧羰酰基)氨基)-4-((二甲基氨基)甲基)-5-(4-硝基苯基)噻吩-3-羧酸(3.3g,6.4mmol)、6-(氧杂环丁-3-基氧基)吡啶-2-胺(0.89g,5.4mmol)、N,N-二异丙基乙胺(2.8mL,16.0mmol)和1-丙基磷酸酐乙酸乙酯溶液(6.9mL,11.7mmol,50％)在DMF(15mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50/1)，得到标题化合物为黄色固体(3.8g,98％)。The title compound in this step was prepared according to the method described in Example 1, Step 8, namely 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methane yl)-5-(4-nitrophenyl)thiophene-3-carboxylic acid (3.3g, 6.4mmol), 6-(oxetan-3-yloxy)pyridin-2-amine (0.89g, 5.4mmol), N,N-diisopropylethylamine (2.8mL, 16.0mmol) and ethyl acetate solution of 1-propylphosphoric anhydride (6.9mL, 11.7mmol, 50%) in DMF (15mL) prepared by reaction , the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=50/1) to obtain the title compound as a yellow solid (3.8 g, 98%).
MS(ESI,pos.ion)m/z:668.1[M+H] +. MS(ESI,pos.ion)m/z:668.1[M+H] + .
步骤2)1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-6-(4-硝基苯基)-3-(6-(氧杂环丁基-3-基氧基)吡啶-2-基)噻Step 2) 1-(2,6-Difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-3-(6-(oxetine) yl-3-yloxy)pyridin-2-yl)thio 吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成Synthesis of pheno[2,3-d]pyrimidine-2,4(1H,3H)-dione
本步骤标题化合物参照实施例1步骤9所描述的方法制备得到，即将(2,6-二氟苄基)(4-((二甲基氨基)甲基)-5-(4-硝基苯基)-3-((6-(氧杂环丁-3-基氧基)吡啶-2-基)氨甲酰基)噻吩-2-基)氨基甲酸乙酯(3.3g,4.9mmol)、甲醇钠(0.53g,9.8mmol)在甲醇(25mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为淡黄色固体(0.55g,18％)。The title compound in this step was prepared according to the method described in Example 1, Step 9, namely (2,6-difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrobenzene) yl)-3-((6-(oxetan-3-yloxy)pyridin-2-yl)carbamoyl)thiophen-2-yl)carbamate (3.3 g, 4.9 mmol), methanol Sodium (0.53 g, 9.8 mmol) was prepared by reaction in methanol (25 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to give the title compound as a pale yellow solid (0.55 g, 18%).
MS(ESI,pos.ion)m/z:622.1[M+H] +； MS(ESI, pos.ion) m/z: 622.1[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm):8.28(d,J＝8.8Hz,2H),8.01(s,1H),7.85(d,J＝8.8Hz,2H),7.79(t,J＝7.6Hz,1H),7.37–7.31(m,1H),6.98(d,J＝3.2Hz,1H),6.96(d,J＝3.6Hz,1H),6.89(d,J＝8.4Hz,1H),5.62–5.54(m,1H),5.38(s,2H),4.89(t,J＝6.8Hz,2H),4.77–4.70(m,2H),3.73(s,2H),2.95(s,3H),2.88(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.28 (d, J=8.8 Hz, 2H), 8.01 (s, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.79 (t, J =7.6Hz,1H),7.37-7.31(m,1H),6.98(d,J=3.2Hz,1H),6.96(d,J=3.6Hz,1H),6.89(d,J=8.4Hz,1H) ), 5.62–5.54(m, 1H), 5.38(s, 2H), 4.89(t, J=6.8Hz, 2H), 4.77–4.70(m, 2H), 3.73(s, 2H), 2.95(s, 3H), 2.88(s, 3H).
步骤3)6-(4-氨基苯基)-1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基氧基)吡啶-2-基)噻吩Step 3) 6-(4-Aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetine- 3-yloxy)pyridin-2-yl)thiophene 并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成Synthesis of [2,3-d]pyrimidine-2,4(1H,3H)-dione
本步骤标题化合物参照实施例1步骤10所描述的方法制备得到，即将1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-6-(4-硝基苯基)-3-(6-(氧杂环丁基-3-基氧基)吡啶-2-基)噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮(2.5g,4.0mmol)、铁粉(1.1g,19.6mmol)、氯化铵(0.43g,8.0mmol)在四氢呋喃(10mL)、乙醇(10mL)、水(5mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为黄色固体(1.2g,50％)。The title compound in this step was prepared according to the method described in step 10 of Example 1, namely 1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitro phenyl)-3-(6-(oxetan-3-yloxy)pyridin-2-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-di Ketone (2.5g, 4.0mmol), iron powder (1.1g, 19.6mmol), ammonium chloride (0.43g, 8.0mmol) in tetrahydrofuran (10mL), ethanol (10mL), water (5mL) were prepared by reaction, crude product Separation and purification by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) gave the title compound as a yellow solid (1.2 g, 50%).
MS(ESI,pos.ion)m/z:592.1[M+H] +. MS(ESI,pos.ion)m/z:592.1[M+H] + .
步骤4)1-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基氧基)吡啶-2-基)-2,4-二氧代Step 4) 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-yloxy) yl)pyridin-2-yl)-2,4-dioxo -1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲的合成-Synthesis of 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea
本步骤标题化合物参照实施例1步骤11所描述的方法制备得到，即将6-(4-氨基苯基)-1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基氧基)吡啶-2-基)噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮(1.1g,1.9mmol)、苯基N-甲氧基氨基甲酸酯(1.2g,7.2mmol)、三乙胺(0.78mL,5.6mmol)和4-二甲基氨基吡啶(11mg,0.1mmol)在DMF(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)，得到标题化合物为淡黄色固体(0.38g,30％)。The title compound of this step was prepared according to the method described in step 11 of Example 1, namely 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino) Methyl)-3-(6-(oxetan-3-yloxy)pyridin-2-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 1.1 g, 1.9 mmol), phenyl N-methoxycarbamate (1.2 g, 7.2 mmol), triethylamine (0.78 mL, 5.6 mmol) and 4-dimethylaminopyridine (11 mg, 0.1 mmol) The reaction was prepared in DMF (10 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1) to give the title compound as a pale yellow solid (0.38 g, 30%).
MS(ESI,pos.ion)m/z:665.1[M+H] +； MS(ESI, pos.ion) m/z: 665.1[M+H] + ;
1H NMR(600MHz,CDCl 3)δ(ppm):7.77(t,J＝7.8Hz,1H),7.55(d,J＝8.4Hz,2H),7.47(d,J＝8.4Hz,2H),7.33–7.29(m,1H),6.99(d,J＝7.2Hz,1H),6.92(t,J＝7.8Hz,2H),6.86(d,J＝8.4Hz,1H),5.61–5.55(m,1H),5.34(s,2H),4.89(t,J＝6.6Hz,2H),4.72(s,2H),3.80(s,3H),3.71(s,2H),3.02(s,6H). 1 H NMR (600 MHz, CDCl 3 ) δ (ppm): 7.77 (t, J=7.8 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.33–7.29 (m, 1H), 6.99 (d, J=7.2Hz, 1H), 6.92 (t, J=7.8Hz, 2H), 6.86 (d, J=8.4Hz, 1H), 5.61–5.55 (m ,1H),5.34(s,2H),4.89(t,J＝6.6Hz,2H),4.72(s,2H),3.80(s,3H),3.71(s,2H),3.02(s,6H) .
实施例5 1-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(5-(氧杂环丁-3-基甲氧基)吡啶-2-基)-2,4-二氧代-1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲的合成Example 5 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(5-(oxetan-3-ylmethyl) oxy)pyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methyl Synthesis of Oxyurea
Figure PCTCN2020119029-appb-000018
Figure PCTCN2020119029-appb-000018
步骤1)(2,6-二氟苄基)(4-((二甲基氨基)甲基)-5-(4-硝基苯基)-3-((5-(氧杂环丁-3-基甲氧基)吡啶-2-基)氨Step 1) (2,6-Difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrophenyl)-3-((5-(oxetine- 3-ylmethoxy)pyridin-2-yl)amino 甲酰基)噻吩-2-基)氨基甲酸乙酯的合成Synthesis of ethyl formyl)thiophen-2-yl)carbamate
本步骤标题化合物参照实施例1步骤8所描述的方法制备得到，即将2-((2,6-二氟苄基)(乙氧羰酰基)氨基)-4-((二甲基氨基)甲基)-5-(4-硝基苯基)噻吩-3-羧酸(3.03g,5.83mmol)、5-(氧杂环丁-3-基甲氧基)吡啶-2-胺(1.26g,6.99mmol)、N,N-二异丙基乙胺(2.0mL,12.0mmol)和1-丙基磷酸酐乙酸乙酯溶液(5.3mL,9.0mmol,50％)在DMF(30mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50/1)，得到标题化合物为黄色固体(3.9g,98％)。The title compound in this step was prepared according to the method described in Example 1, Step 8, namely 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methane yl)-5-(4-nitrophenyl)thiophene-3-carboxylic acid (3.03g, 5.83mmol), 5-(oxetan-3-ylmethoxy)pyridin-2-amine (1.26g) , 6.99 mmol), N,N-diisopropylethylamine (2.0 mL, 12.0 mmol) and ethyl acetate solution of 1-propylphosphoric anhydride (5.3 mL, 9.0 mmol, 50%) were reacted in DMF (30 mL) Preparation, the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=50/1) to give the title compound as a yellow solid (3.9 g, 98%).
MS(ESI,pos.ion)m/z:682.2[M+H] +. MS(ESI,pos.ion)m/z:682.2[M+H] + .
步骤2)1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-6-(4-硝基苯基)-3-(5-(氧杂环丁基-3-基甲氧基)吡啶-2-基)Step 2) 1-(2,6-Difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-3-(5-(oxetine) yl-3-ylmethoxy)pyridin-2-yl) 噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成Synthesis of Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
本步骤标题化合物参照实施例1步骤9所描述的方法制备得到，即将(2,6-二氟苄基)(4-((二甲基氨基)甲基)-5-(4-硝基苯基)-3-((5-(氧杂环丁-3-基甲氧基)吡啶-2-基)氨甲酰基)噻吩-2-基)氨基甲酸乙酯(3.9g,5.72mmol)、碳酸铯(3.73g,11.4mmol)在四氢呋喃(60mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为淡黄色固体(3.6g,99％)。The title compound in this step was prepared according to the method described in Example 1, Step 9, namely (2,6-difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrobenzene) yl)-3-((5-(oxetan-3-ylmethoxy)pyridin-2-yl)carbamoyl)thiophen-2-yl)carbamate (3.9 g, 5.72 mmol), Cesium carbonate (3.73 g, 11.4 mmol) was prepared by reaction in tetrahydrofuran (60 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to obtain the title compound as pale yellow Solid (3.6 g, 99%).
MS(ESI,pos.ion)m/z:636.2[M+H] +； MS(ESI, pos.ion) m/z: 636.2[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm):8.34(d,J＝2.8Hz,1H),8.27(d,J＝8.8Hz,2H),7.89(d,J＝8.8Hz,2H),7.40(dd,J＝8.6,3.0Hz,1H),7.36–7.27(m,2H),6.93(t,J＝8.1Hz,2H),5.42(s,2H),4.90(dd,J＝7.7,6.4Hz,2H),4.57(t,J＝6.1Hz,2H),4.28(d,J＝6.6Hz,2H),3.73(s,2H),3.52–3.43(m,1H),2.19(s,6H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.34 (d, J=2.8 Hz, 1H), 8.27 (d, J=8.8 Hz, 2H), 7.89 (d, J=8.8 Hz, 2H), 7.40(dd,J=8.6,3.0Hz,1H),7.36-7.27(m,2H),6.93(t,J=8.1Hz,2H),5.42(s,2H),4.90(dd,J=7.7, 6.4Hz, 2H), 4.57(t, J=6.1Hz, 2H), 4.28(d, J=6.6Hz, 2H), 3.73(s, 2H), 3.52–3.43(m, 1H), 2.19(s, 6H).
步骤3)6-(4-氨基苯基)-1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(5-(氧杂环丁-3-基甲氧基)吡啶-2-基)噻Step 3) 6-(4-Aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(5-(oxetine- 3-ylmethoxy)pyridin-2-yl)thio 吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成Synthesis of pheno[2,3-d]pyrimidine-2,4(1H,3H)-dione
本步骤标题化合物参照实施例1步骤10所描述的方法制备得到，即将1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-6-(4-硝基苯基)-3-(5-(氧杂环丁基-3-基甲氧基)吡啶-2-基)噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮(3.6g,5.66mmol)、铁粉(1.86g,28.3mmol)、氯化铵(0.61g,11mmol)在四氢呋喃(20mL)、乙醇(20mL)、水(5mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为淡黄色固体(2.86g,83％)。The title compound in this step was prepared according to the method described in step 10 of Example 1, namely 1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitro phenyl)-3-(5-(oxetan-3-ylmethoxy)pyridin-2-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)- Diketone (3.6g, 5.66mmol), iron powder (1.86g, 28.3mmol), ammonium chloride (0.61g, 11mmol) in tetrahydrofuran (20mL), ethanol (20mL), water (5mL) were prepared by reaction, crude product Separation and purification by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) gave the title compound as a pale yellow solid (2.86 g, 83%).
MS(ESI,pos.ion)m/z:606.2[M+H] +. MS(ESI,pos.ion)m/z:606.2[M+H] + .
步骤4)1-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(5-(氧杂环丁-3-基甲氧基)吡啶-2-基)-2,4-二氧代Step 4) 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(5-(oxetan-3-ylmethyl) oxy)pyridin-2-yl)-2,4-dioxo -1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲的合成-Synthesis of 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea
本步骤标题化合物参照实施例1步骤11所描述的方法制备得到，即将6-(4-氨基苯基)-1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(5-(氧杂环丁-3-基甲氧基)吡啶-2-基)噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮(2.0g,3.3mmol)、苯基N-甲氧基氨基甲酸酯(2.21g,13.2mmol)、三乙胺(1.9mL,14.0mmol)和4-二甲基氨基吡啶(40mg,0.32mmol)在DMF(40mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)，得到标题化合物为类白色固体(1.52g,68％)。The title compound of this step was prepared according to the method described in step 11 of Example 1, namely 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino) Methyl)-3-(5-(oxetan-3-ylmethoxy)pyridin-2-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.0 g, 3.3 mmol), phenyl N-methoxycarbamate (2.21 g, 13.2 mmol), triethylamine (1.9 mL, 14.0 mmol) and 4-dimethylaminopyridine (40 mg, 0.32 mmol) ) was prepared by reaction in DMF (40 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1) to obtain the title compound as an off-white solid (1.52 g, 68%) .
MS(ESI,pos.ion)m/z:679.2[M+H] +； MS(ESI, pos.ion) m/z: 679.2[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ(ppm):9.63(s,1H),9.07(s,1H),8.29(d,J＝2.8Hz,1H),7.71(d,J＝8.6Hz,2H),7.60(dd,J＝8.7,2.9Hz,1H),7.52(d,J＝8.6Hz,2H),7.45(dt,J＝14.8,7.3Hz,1H),7.36(d,J＝8.7Hz,1H),7.13(t,J＝8.2Hz,2H),5.35(s,2H),4.74(dd,J＝7.7,6.3Hz,2H),4.46(t,J＝6.0Hz,2H),4.36(d,J＝6.6Hz,2H),3.64(s,3H),3.54(s,2H),3.48–3.40(m,1H),2.03(s,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 9.63 (s, 1H), 9.07 (s, 1H), 8.29 (d, J=2.8 Hz, 1H), 7.71 (d, J=8.6 Hz) ,2H),7.60(dd,J＝8.7,2.9Hz,1H),7.52(d,J＝8.6Hz,2H),7.45(dt,J＝14.8,7.3Hz,1H),7.36(d,J＝ 8.7Hz, 1H), 7.13 (t, J=8.2Hz, 2H), 5.35 (s, 2H), 4.74 (dd, J=7.7, 6.3Hz, 2H), 4.46 (t, J=6.0Hz, 2H) ,4.36(d,J=6.6Hz,2H),3.64(s,3H),3.54(s,2H),3.48–3.40(m,1H),2.03(s,6H).
实施例6 1-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基甲氧基)吡啶-3-基)-2,4-二氧代-1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲的合成Example 6 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-ylmethyl) oxy)pyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methyl Synthesis of Oxyurea
Figure PCTCN2020119029-appb-000019
Figure PCTCN2020119029-appb-000019
步骤1)(2,6-二氟苄基)(4-((二甲基氨基)甲基)-5-(4-硝基苯基)-3-((6-(氧杂环丁-3-基甲氧基)吡啶-3-基)氨甲Step 1) (2,6-Difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrophenyl)-3-((6-(oxetine- 3-ylmethoxy)pyridin-3-yl)carbamate 酰基)噻吩-2-基)氨基甲酸乙酯的合成Synthesis of Acyl)thiophen-2-yl)carbamate
本步骤标题化合物参照实施例1步骤8所描述的方法制备得到，即将2-((2,6-二氟苄基)(乙氧羰酰基)氨基)-4-((二甲基氨基)甲基)-5-(4-硝基苯基)噻吩-3-羧酸(2.0g,3.85mmol)、6-(氧杂环丁-3-基甲氧基)吡啶-3-胺(1.2g,6.7mmol)、N,N-二异丙基乙胺(2.0mL,12.0mmol)和1-丙基磷酸酐乙酸乙酯溶液(4.6mL,7.7mmol,50％)在DMF(20mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50/1)，得到标题化合物为砖红色固体(2.46g,93.7％)。The title compound in this step was prepared according to the method described in Example 1, Step 8, namely 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methane yl)-5-(4-nitrophenyl)thiophene-3-carboxylic acid (2.0g, 3.85mmol), 6-(oxetan-3-ylmethoxy)pyridin-3-amine (1.2g) , 6.7 mmol), N,N-diisopropylethylamine (2.0 mL, 12.0 mmol) and ethyl acetate solution of 1-propylphosphoric anhydride (4.6 mL, 7.7 mmol, 50%) were reacted in DMF (20 mL) Preparation, the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=50/1) to obtain the title compound as a brick red solid (2.46g, 93.7%).
MS(ESI,pos.ion)m/z:682.2[M+H] +. MS(ESI,pos.ion)m/z:682.2[M+H] + .
步骤2)1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-6-(4-硝基苯基)-3-(6-(氧杂环丁基-3-基甲氧基)吡啶-3-基)Step 2) 1-(2,6-Difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-3-(6-(oxetine) yl-3-ylmethoxy)pyridin-3-yl) 噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成Synthesis of Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
本步骤标题化合物参照实施例1步骤9所描述的方法制备得到，即将(2,6-二氟苄基)(4-((二甲基氨基)甲基)-5-(4-硝基苯基)-3-((6-(氧杂环丁-3-基甲氧基)吡啶-3-基)氨甲酰基)噻吩-2-基)氨基甲酸乙酯(2.46g,3.61mmol)、甲醇钠(0.5g,9.26mmol)在甲醇(30mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为黄色固体(1.62g,70.6％)。The title compound in this step was prepared according to the method described in Example 1, Step 9, namely (2,6-difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrobenzene) yl)-3-((6-(oxetan-3-ylmethoxy)pyridin-3-yl)carbamoyl)thiophen-2-yl)carbamate (2.46 g, 3.61 mmol), Sodium methoxide (0.5 g, 9.26 mmol) was prepared by reaction in methanol (30 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to obtain the title compound as a yellow solid (1.62 g, 70.6%).
MS(ESI,pos.ion)m/z:636.1[M+H] +. MS(ESI,pos.ion)m/z:636.1[M+H] + .
步骤3)6-(4-氨基苯基)-1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基甲氧基)吡啶-3-基)噻Step 3) 6-(4-Aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetine- 3-ylmethoxy)pyridin-3-yl)thio 吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成Synthesis of pheno[2,3-d]pyrimidine-2,4(1H,3H)-dione
本步骤标题化合物参照实施例1步骤10所描述的方法制备得到，即将1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-6-(4-硝基苯基)-3-(6-(氧杂环丁基-3-基甲氧基)吡啶-3-基)噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮(1.6g,2.5mmol)、铁粉(0.9g,16.1mmol)、氯化铵(0.5g,9.3mmol)在四氢呋喃(10mL)、乙醇(10mL)、水(5mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为白色固体(0.8g,58％)。The title compound in this step was prepared according to the method described in step 10 of Example 1, namely 1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitro phenyl)-3-(6-(oxetan-3-ylmethoxy)pyridin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)- Diketone (1.6g, 2.5mmol), iron powder (0.9g, 16.1mmol), ammonium chloride (0.5g, 9.3mmol) in tetrahydrofuran (10mL), ethanol (10mL), water (5mL) were prepared by reaction, crude The product was isolated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to obtain the title compound as a white solid (0.8 g, 58%).
MS(ESI,pos.ion)m/z:606.2[M+H] +. MS(ESI,pos.ion)m/z:606.2[M+H] + .
步骤4)1-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基甲氧基)吡啶-3-基)-2,4-二氧代Step 4) 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-ylmethyl) oxy)pyridin-3-yl)-2,4-dioxo -1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲的合成-Synthesis of 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea
本步骤标题化合物参照实施例1步骤11所描述的方法制备得到，即将6-(4-氨基苯基)-1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基甲氧基)吡啶-3-基)噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮(0.88g,1.45mmol)、苯基N-甲氧基氨基甲酸酯(1.0g,5.98mmol)、三乙胺(0.6mL,4.28mmol)和4-二甲基氨基吡啶(20mg,0.16mmol)在DMF(15mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)，得到标题化合物为白色固体(0.33g,33.5％)。The title compound of this step was prepared according to the method described in step 11 of Example 1, namely 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino) Methyl)-3-(6-(oxetan-3-ylmethoxy)pyridin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.88 g, 1.45 mmol), phenyl N-methoxycarbamate (1.0 g, 5.98 mmol), triethylamine (0.6 mL, 4.28 mmol) and 4-dimethylaminopyridine (20 mg, 0.16 mmol) ) in DMF (15 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1) to give the title compound as a white solid (0.33 g, 33.5%).
MS(ESI,pos.ion)m/z:679.2[M+H] +； MS(ESI, pos.ion) m/z: 679.2[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm):8.08(d,J＝2.3Hz,1H),7.63(s,1H),7.56(d,J＝8.6Hz,2H),7.50(dd,J＝12.8,5.6Hz,2H),6.97–6.83(m,4H),5.36(s,2H),4.90–4.83(m,2H),4.58(t,J＝6.4Hz,4H),3.82(s,3H),3.69(s,2H),3.48–3.44(m,1H),2.13(s,6H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.08 (d, J=2.3 Hz, 1H), 7.63 (s, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.50 (dd, J =12.8,5.6Hz,2H),6.97–6.83(m,4H),5.36(s,2H),4.90–4.83(m,2H),4.58(t,J=6.4Hz,4H),3.82(s, 3H), 3.69(s, 2H), 3.48–3.44(m, 1H), 2.13(s, 6H).
实施例7 1-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基甲氧基)哒嗪-3-基)-2,4-二氧代-1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲的合成Example 7 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-ylmethyl) oxy)pyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3- Synthesis of Methoxyurea
Figure PCTCN2020119029-appb-000020
Figure PCTCN2020119029-appb-000020
步骤1)(2,6-二氟苄基)(4-((二甲基氨基)甲基)-5-(4-硝基苯基)-3-((6-(氧杂环丁-3-基甲氧基)哒嗪-3-基)氨甲Step 1) (2,6-Difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrophenyl)-3-((6-(oxetine- 3-ylmethoxy)pyridazin-3-yl)carbamate 酰基)噻吩-2-基)氨基甲酸乙酯的合成Synthesis of Acyl)thiophen-2-yl)carbamate
本步骤标题化合物参照实施例1步骤8所描述的方法制备得到，即将2-((2,6-二氟苄基)(乙氧羰酰基)氨基)-4-((二甲基氨基)甲基)-5-(4-硝基苯基)噻吩-3-羧酸(2.5g,4.8mmol)、6-(氧杂环丁-3-基甲氧基)哒嗪-3-胺(1.0g,5.5mmol)、N,N-二异丙基乙胺(4.5mL,25.8mmol)和1-丙基磷酸酐乙酸乙酯溶液(4.5mL,7.6mmol,50％)在DMF(30mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50/1)，得到标题化合物为黄色固体(2.3g,69.7％)。The title compound in this step was prepared according to the method described in Example 1, Step 8, namely 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methane yl)-5-(4-nitrophenyl)thiophene-3-carboxylic acid (2.5 g, 4.8 mmol), 6-(oxetan-3-ylmethoxy)pyridazin-3-amine (1.0 g, 5.5 mmol), N,N-diisopropylethylamine (4.5 mL, 25.8 mmol) and a solution of 1-propylphosphoric anhydride in ethyl acetate (4.5 mL, 7.6 mmol, 50%) in DMF (30 mL) The reaction was prepared, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=50/1) to obtain the title compound as a yellow solid (2.3 g, 69.7%).
MS(ESI,pos.ion)m/z:683.1[M+H] +； MS(ESI, pos.ion) m/z: 683.1[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm):8.58(d,J＝9.5Hz,1H),8.30(d,J＝8.6Hz,2H),7.50(d,J＝8.7Hz,2H),7.21–7.11(m,1H),7.02(d,J＝9.5Hz,1H),6.77(t,J＝7.4Hz,2H),5.04(s,2H),4.90(dd,J＝7.8,6.3Hz,2H),4.73(d,J＝6.8Hz,2H),4.61(t,J＝6.1Hz,2H),4.28(s,2H),3.56–3.47(m,3H),2.22(s,6H),1.27(t,J＝7.1Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.58 (d, J=9.5 Hz, 1H), 8.30 (d, J=8.6 Hz, 2H), 7.50 (d, J=8.7 Hz, 2H), 7.21–7.11(m, 1H), 7.02(d, J=9.5Hz, 1H), 6.77(t, J=7.4Hz, 2H), 5.04(s, 2H), 4.90(dd, J=7.8, 6.3Hz ,2H),4.73(d,J＝6.8Hz,2H),4.61(t,J＝6.1Hz,2H),4.28(s,2H),3.56–3.47(m,3H),2.22(s,6H) ,1.27(t,J=7.1Hz,3H).
步骤2)1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-6-(4-硝基苯基)-3-(6-(氧杂环丁基-3-基甲氧基)哒嗪-3-基)Step 2) 1-(2,6-Difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-3-(6-(oxetine) yl-3-ylmethoxy)pyridazin-3-yl) 噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成Synthesis of Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
本步骤标题化合物参照实施例1步骤9所描述的方法制备得到，即将(2,6-二氟苄基)(4-((二甲基氨基)甲基)-5-(4-硝基苯基)-3-((6-(氧杂环丁-3-基甲氧基)哒嗪-3-基)氨甲酰基)噻吩-2-基)氨基甲酸乙酯(2.3g,3.4mmol)、碳酸铯(3.3g,10.1mmol)在四氢呋喃(50mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为淡黄色固体(1.6g,76.2％)。The title compound in this step was prepared according to the method described in Example 1, Step 9, namely (2,6-difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrobenzene) yl)-3-((6-(oxetan-3-ylmethoxy)pyridazin-3-yl)carbamoyl)thiophen-2-yl)carbamate (2.3 g, 3.4 mmol) , cesium carbonate (3.3 g, 10.1 mmol) were prepared by reaction in tetrahydrofuran (50 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to obtain the title compound as pale Yellow solid (1.6 g, 76.2%).
MS(ESI,pos.ion)m/z:637.1[M+H] +. MS(ESI,pos.ion)m/z:637.1[M+H] + .
步骤3)6-(4-氨基苯基)-1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基甲氧基)哒嗪-3-基)噻Step 3) 6-(4-Aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetine- 3-ylmethoxy)pyridazin-3-yl)thio 吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成Synthesis of pheno[2,3-d]pyrimidine-2,4(1H,3H)-dione
本步骤标题化合物参照实施例1步骤10所描述的方法制备得到，即将1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-6-(4-硝基苯基)-3-(6-(氧杂环丁基-3-基甲氧基)哒嗪-3-基)噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮(1.6g,2.5mmol)、铁粉(0.7g,12.5mmol)、氯化铵(0.27g,5mmol)在四氢呋喃(20mL)、乙醇(20mL)、水(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为淡黄色固体(1.1g,73.3％)。The title compound in this step was prepared according to the method described in step 10 of Example 1, namely 1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitro phenyl)-3-(6-(oxetan-3-ylmethoxy)pyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H) -Diketone (1.6g, 2.5mmol), iron powder (0.7g, 12.5mmol), ammonium chloride (0.27g, 5mmol) in tetrahydrofuran (20mL), ethanol (20mL), water (10mL) reaction preparation, crude The product was isolated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to obtain the title compound as a pale yellow solid (1.1 g, 73.3%).
MS(ESI,pos.ion)m/z:607.2[M+H] +. MS(ESI,pos.ion)m/z:607.2[M+H] + .
步骤4)1-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基甲氧基)哒嗪-3-基)-2,4-二氧代Step 4) 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-ylmethyl) oxy)pyridazin-3-yl)-2,4-dioxo -1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲的合成-Synthesis of 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea
本步骤标题化合物参照实施例1步骤11所描述的方法制备得到，即将6-(4-氨基苯基)-1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基甲氧基)哒嗪-3-基)噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮(0.7g,1.2mmol)、苯基N-甲氧基氨基甲酸酯(0.77g,4.6mmol)、三乙胺(0.65mL,4.7mmol)在DMF(20mL)中 反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)，得到标题化合物为白色固体(0.54g,69.4％)。The title compound of this step was prepared according to the method described in step 11 of Example 1, namely 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino) Methyl)-3-(6-(oxetan-3-ylmethoxy)pyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-di Ketone (0.7 g, 1.2 mmol), phenyl N-methoxycarbamate (0.77 g, 4.6 mmol), triethylamine (0.65 mL, 4.7 mmol) were prepared by reaction in DMF (20 mL), the crude product was Separation and purification by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1) gave the title compound as a white solid (0.54 g, 69.4%).
MS(ESI,pos.ion)m/z:680.2[M+H] +； MS(ESI, pos.ion) m/z: 680.2[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm):7.92(s,1H),7.80(s,1H),7.55(d,J＝8.0Hz,2H),7.50–7.45(m,1H),7.43(d,J＝8.0Hz,2H),7.29(dd,J＝13.2,5.7Hz,1H),7.14(d,J＝9.0Hz,1H),6.91(t,J＝7.8Hz,2H),5.29(s,2H),4.88(t,J＝6.8Hz,2H),4.79(d,J＝6.4Hz,2H),4.60(t,J＝5.8Hz,2H),3.77(s,3H),3.65–3.63(m,1H),3.61–3.45(m,2H),2.11(s,6H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.92 (s, 1H), 7.80 (s, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.50-7.45 (m, 1H), 7.43 (d, J=8.0Hz, 2H), 7.29 (dd, J=13.2, 5.7Hz, 1H), 7.14 (d, J=9.0Hz, 1H), 6.91 (t, J=7.8Hz, 2H), 5.29 (s, 2H), 4.88(t, J＝6.8Hz, 2H), 4.79(d, J＝6.4Hz, 2H), 4.60(t, J＝5.8Hz, 2H), 3.77(s, 3H), 3.65 –3.63(m,1H),3.61–3.45(m,2H),2.11(s,6H).
实施例8 1-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基甲氧基)吡啶-2-基)-2,4-二氧代-1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲的合成Example 8 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-ylmethyl) oxy)pyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methyl Synthesis of Oxyurea
Figure PCTCN2020119029-appb-000021
Figure PCTCN2020119029-appb-000021
步骤1)(2,6-二氟苄基)(4-((二甲基氨基)甲基)-5-(4-硝基苯基)-3-((6-(氧杂环丁-3-基甲氧基)吡啶-2-基)氨甲Step 1) (2,6-Difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrophenyl)-3-((6-(oxetine- 3-ylmethoxy)pyridin-2-yl)carbamate 酰基)噻吩-2-基)氨基甲酸乙酯的合成Synthesis of Acyl)thiophen-2-yl)carbamate
本步骤标题化合物参照实施例1步骤8所描述的方法制备得到，即将2-((2,6-二氟苄基)(乙氧羰酰基)氨基)-4-((二甲基氨基)甲基)-5-(4-硝基苯基)噻吩-3-羧酸(1.6g,3.1mmol)、6-(氧杂环丁-3-基甲氧基)吡啶-2-胺(0.5g,2.77mmol)、N,N-二异丙基乙胺(1.2mL,8.1mmol)和1-丙基磷酸酐乙酸乙酯溶液(3.6mL,6.1mmol,50％)在DMF(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50/1)，得到标题化合物为黄色固体(1.2g,63％)。The title compound in this step was prepared according to the method described in Example 1, Step 8, namely 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methane yl)-5-(4-nitrophenyl)thiophene-3-carboxylic acid (1.6g, 3.1mmol), 6-(oxetan-3-ylmethoxy)pyridin-2-amine (0.5g) , 2.77 mmol), N,N-diisopropylethylamine (1.2 mL, 8.1 mmol) and ethyl acetate solution of 1-propylphosphoric anhydride (3.6 mL, 6.1 mmol, 50%) were reacted in DMF (10 mL) Preparation, the crude product was isolated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 50/1) to give the title compound as a yellow solid (1.2 g, 63%).
MS(ESI,pos.ion)m/z:682.2[M+H] +； MS(ESI, pos.ion) m/z: 682.2[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm):8.28(d,J＝8.8Hz,2H),7.97(d,J＝7.6Hz,1H),7.59(t,J＝8.0Hz,1H),7.48(d,J＝8.8Hz,2H),7.15(s,1H),6.78(d,J＝7.2Hz,2H),6.47(d,J＝7.6Hz,1H),5.04(s,2H),4.85(dd,J＝7.6,6.4Hz,2H),4.52(t,J＝6.0Hz,2H),4.44(d,J＝6.8Hz,2H),4.22(s,2H),3.51(brs,2H),3.39(dt,J＝13.6,6.8Hz,1H),2.18(s,6H),1.25(t,J＝7.2Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.28 (d, J=8.8 Hz, 2H), 7.97 (d, J=7.6 Hz, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.48(d,J＝8.8Hz,2H),7.15(s,1H),6.78(d,J＝7.2Hz,2H),6.47(d,J＝7.6Hz,1H),5.04(s,2H), 4.85(dd,J＝7.6,6.4Hz,2H),4.52(t,J＝6.0Hz,2H),4.44(d,J＝6.8Hz,2H),4.22(s,2H),3.51(brs,2H ),3.39(dt,J=13.6,6.8Hz,1H),2.18(s,6H),1.25(t,J=7.2Hz,3H).
步骤2)1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-6-(4-硝基苯基)-3-(6-(氧杂环丁基-3-基甲氧基)吡啶-2-基)Step 2) 1-(2,6-Difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-3-(6-(oxetine) yl-3-ylmethoxy)pyridin-2-yl) 噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成Synthesis of Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
本步骤标题化合物参照实施例1步骤9所描述的方法制备得到，即将(2,6-二氟苄基)(4-((二甲基氨基)甲基)-5-(4-硝基苯基)-3-((6-(氧杂环丁-3-基甲氧基)吡啶-2-基)氨甲酰基)噻吩-2-基)氨基甲酸乙酯(1.2g,1.8mmol)、碳酸铯(1.1g,3.4mmol)在四氢呋喃(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为淡黄色固体(1.0g,89％)。The title compound in this step was prepared according to the method described in Example 1, Step 9, namely (2,6-difluorobenzyl)(4-((dimethylamino)methyl)-5-(4-nitrobenzene) yl)-3-((6-(oxetan-3-ylmethoxy)pyridin-2-yl)carbamoyl)thiophen-2-yl)carbamic acid ethyl ester (1.2 g, 1.8 mmol), Cesium carbonate (1.1 g, 3.4 mmol) was prepared by reaction in tetrahydrofuran (10 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to obtain the title compound as pale yellow Solid (1.0 g, 89%).
MS(ESI,pos.ion)m/z:636.2[M+H] +； MS(ESI, pos.ion) m/z: 636.2[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm):8.28(d,J＝8.8Hz,2H),7.87(d,J＝8.8Hz,2H),7.79–7.73(m,1H),7.37–7.31(m,1H),6.98–6.92(m,3H),6.84(d,J＝8.0Hz,1H),5.41(s,2H),4.82(dd,J＝7.4,6.4Hz,2H),4.56(t,J＝6.0Hz,2H),4.50(d,J＝6.8Hz,2H),3.74(s,2H),3.46–3.38(m,1H),2.20(s,6H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.28 (d, J=8.8 Hz, 2H), 7.87 (d, J=8.8 Hz, 2H), 7.79-7.73 (m, 1H), 7.37-7.31 (m,1H),6.98–6.92(m,3H),6.84(d,J=8.0Hz,1H),5.41(s,2H),4.82(dd,J=7.4,6.4Hz,2H),4.56( t, J=6.0Hz, 2H), 4.50(d, J=6.8Hz, 2H), 3.74(s, 2H), 3.46–3.38(m, 1H), 2.20(s, 6H).
步骤3)6-(4-氨基苯基)-1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基甲氧基)吡啶-2-基)噻Step 3) 6-(4-Aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetine- 3-ylmethoxy)pyridin-2-yl)thio 吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成Synthesis of pheno[2,3-d]pyrimidine-2,4(1H,3H)-dione
本步骤标题化合物参照实施例1步骤10所描述的方法制备得到，即将1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-6-(4-硝基苯基)-3-(6-(氧杂环丁基-3-基甲氧基)吡啶-2-基)噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮(1.0g,1.57mmol)、铁粉(0.53g,9.49mmol)、氯化铵(0.25g,4.67mmol)在四氢呋喃(5mL)、乙醇(5mL)、水(1mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为淡黄色固体(0.95g,99.7％)。The title compound in this step was prepared according to the method described in step 10 of Example 1, namely 1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitro phenyl)-3-(6-(oxetan-3-ylmethoxy)pyridin-2-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)- Diketone (1.0g, 1.57mmol), iron powder (0.53g, 9.49mmol), ammonium chloride (0.25g, 4.67mmol) in tetrahydrofuran (5mL), ethanol (5mL), water (1mL) were prepared by reaction, crude The product was isolated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to obtain the title compound as a pale yellow solid (0.95 g, 99.7%).
MS(ESI,pos.ion)m/z:606.2[M+H] +. MS(ESI,pos.ion)m/z:606.2[M+H] + .
步骤4)1-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基甲氧基)吡啶-2-基)-2,4-二氧代Step 4) 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-(oxetan-3-ylmethyl) oxy)pyridin-2-yl)-2,4-dioxo -1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲的合成-Synthesis of 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea
本步骤标题化合物参照实施例1步骤11所描述的方法制备得到，即将6-(4-氨基苯基)-1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-(氧杂环丁-3-基甲氧基)吡啶-2-基)噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮(0.95g,1.57mmol)、苯基N-甲氧基氨基甲酸酯(1.0g,5.98mmol)、三乙胺(0.65mL,4.7mmol)在DMF(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)得到标题化合物为白色固体(0.2g,18.8％)。The title compound of this step was prepared according to the method described in step 11 of Example 1, namely 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino) Methyl)-3-(6-(oxetan-3-ylmethoxy)pyridin-2-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.95 g, 1.57 mmol), phenyl N-methoxycarbamate (1.0 g, 5.98 mmol), triethylamine (0.65 mL, 4.7 mmol) in DMF (10 mL) prepared by reacting the crude product on silica gel Separation and purification by column chromatography (dichloromethane/methanol (v/v)=20/1) gave the title compound as a white solid (0.2 g, 18.8%).
MS(ESI,pos.ion)m/z:679.2[M+H] +； MS(ESI, pos.ion) m/z: 679.2[M+H] + ;
1H NMR(400MHz,CD 3OD)δ(ppm):7.75(t,J＝7.6Hz,1H),7.57(d,J＝8.4Hz,2H),7.30(d,J＝8.8Hz,3H),7.02(d,J＝7.2Hz,1H),6.90(t,J＝8.0Hz,2H),6.82(d,J＝8.4Hz,1H),5.31(s,2H),4.80(dd,J＝7.6,6.4Hz,2H),4.53(t,J＝6.0Hz,2H),4.44(brs,2H),4.19(s,2H),3.39(dd,J＝13.6,7.2Hz,1H),3.34(s,3H),2.40(s,6H). 1 H NMR (400 MHz, CD 3 OD) δ (ppm): 7.75 (t, J=7.6 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.8 Hz, 3H) ,7.02(d,J＝7.2Hz,1H),6.90(t,J＝8.0Hz,2H),6.82(d,J＝8.4Hz,1H),5.31(s,2H),4.80(dd,J＝ 7.6,6.4Hz,2H),4.53(t,J=6.0Hz,2H),4.44(brs,2H),4.19(s,2H),3.39(dd,J=13.6,7.2Hz,1H),3.34( s,3H),2.40(s,6H).
生物试验biological test
实施例A：本发明化合物对人源化GnRH受体的拮抗作用Example A: Antagonism of Compounds of the Invention on Humanized GnRH Receptors
实验目的Purpose
运用荧光法检测胞质钙流法，评价本发明化合物对RBL-1细胞(大鼠嗜碱性粒细胞性白血病细胞)中转染的人源化GnRH受体的拮抗作用。The antagonism of the compounds of the present invention on the transfected humanized GnRH receptors in RBL-1 cells (rat basophilic leukemia cells) was evaluated by using fluorescence method to detect cytoplasmic calcium flux.
实验流程experiment process
将细胞悬浮于HBSS缓冲液(美国英杰生命技术有限公司(Invitrogen))中，加入20mM HEPES缓冲液(美国英杰生命技术有限公司(Invitrogen))，然后以1.186×10 4细胞/孔的密度平均加入微孔反应板中。荧光探针(Fluo8Direct,AAT Bioquest)与HBSS缓冲液(加入20mM HEPES缓冲液，PH＝7.4)，混合后，加入每孔，将细胞置于30℃孵育60min。然后将反应板置于酶标仪中(FlipR Tetra,Molecular Device)测试，加入待测化合物或HBSS缓冲液(空白对照)，5min后加入8nM LH-RH，测量与胞质内钙离子浓度成正比的荧光强度变化。以未加入化合物的空白对照组的荧光强度为100％(抑制率为0％)，计算化合物的抑制率。测定化合物不同浓度下的抑制率，计算其IC 50值。实验结果如下表A所示。 The cells were suspended in HBSS buffer (Invitrogen, USA), 20 mM HEPES buffer (Invitrogen, USA) was added, and then added at a density of 1.186×10 4 cells/well on average in a microwell reaction plate. Fluorescent probe (Fluo8Direct, AAT Bioquest) and HBSS buffer (adding 20mM HEPES buffer, pH=7.4) were mixed, added to each well, and the cells were incubated at 30°C for 60min. Then put the reaction plate in a microplate reader (FlipR Tetra, Molecular Device) to test, add the compound to be tested or HBSS buffer (blank control), and add 8nM LH-RH after 5min, the measurement is proportional to the calcium ion concentration in the cytoplasm changes in fluorescence intensity. The inhibition rate of the compound was calculated by taking the fluorescence intensity of the blank control group to which no compound was added as 100% (the inhibition rate was 0%). The inhibition rates of the compounds at different concentrations were determined, and their IC 50 values were calculated. The experimental results are shown in Table A below.
表A 本发明化合物对人源化GnRH受体的拮抗作用Table A Antagonism of compounds of the present invention on humanized GnRH receptors
实施例号Example number IC 50(nM) IC50 (nM)
实施例2Example 2 15.3515.35
实施例4Example 4 21.8321.83
实施例5Example 5 3.6653.665
实施例6Example 6 2.4752.475
实施例7Example 7 2.012.01
实验结果显示，本发明化合物对人源化GnRH受体具有良好的拮抗作用。The experimental results show that the compounds of the present invention have a good antagonistic effect on the humanized GnRH receptor.
实施例B：大鼠、犬静注或灌胃定量本发明化合物后的药代动力学评价Example B: Pharmacokinetic evaluation of the compounds of the present invention after intravenous or gavage quantification in rats and dogs
本发明对本发明化合物在大鼠和/或犬体内的药代动力学研究进行了评估，动物信息详见表B。The present invention evaluates the pharmacokinetic studies of the compounds of the present invention in rats and/or dogs, and the animal information is shown in Table B.
表B 本发明受试动物信息表Table B Test animal information table of the present invention
Figure PCTCN2020119029-appb-000022
Figure PCTCN2020119029-appb-000022
试验方法experiment method
将本发明化合物以10％DMSO+10％Kolliphor HS15+78％Saline+2％(2％HCl)溶液或78％Saline+2％(2％HCl)+20％PEG400溶液形式，对受试动物进行给药，给药前动物禁食12h，自由饮水。对于静脉注射给药组，给药剂量为1mg/kg(大鼠)或者0.5mg/kg(犬)，给药后在以下时间点静脉取血(取血量约0.2mL)：0.083、0.25、0.5、1.0、2.0、4.0、6.0、8.0和24h(犬)或0.083、0.25、0.5、1.0、2.0、5.0、7.0和24h(大鼠)，采血管内预先加入EDTA-K 2作为抗凝剂。对于灌胃给药组，给药剂量为5mg/kg(大鼠)或者2.5mg/kg(犬)，给药后在以下时间点进行静脉取血(取血量约0.2mL)：0.25、0.5、1.0、2.0、4.0、6.0、8.0和24h(犬)或0.25、0.5、1.0、2.0、5.0、7.0和24h(大鼠)，采血管内预先加入EDTA-K 2作为抗凝剂。血样在12,000rpm下离心2分钟，收集血浆，并于-20℃或-70℃下保存。。 The compounds of the present invention were administered to test animals in the form of 10% DMSO+10% Kolliphor HS15+78% Saline+2% (2% HCl) solution or 78% Saline+2% (2% HCl)+20% PEG400 solution. Before administration, animals were fasted for 12 hours and had free access to water. For the intravenous injection group, the dose was 1 mg/kg (rats) or 0.5 mg/kg (dogs), and blood was collected at the following time points after administration (about 0.2 mL of blood): 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h (dog) or 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h (rat), EDTA-K 2 was pre-added in the blood collection tube as an anticoagulant. For the intragastric administration group, the administration dose was 5 mg/kg (rats) or 2.5 mg/kg (dogs), and intravenous blood was collected at the following time points after administration (about 0.2 mL of blood): 0.25, 0.5 , 1.0, 2.0, 4.0, 6.0, 8.0 and 24h (dog) or 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h (rat), EDTA-K 2 was pre-added into the blood collection tube as an anticoagulant. Blood samples were centrifuged at 12,000 rpm for 2 minutes, and plasma was collected and stored at -20°C or -70°C. .
对上述收集的血浆样品进行处理(冰冻血浆于室温下融化后，涡旋15s混匀，取10-20μL血浆，加入含内标的乙腈溶液120-150μL，涡旋5min混匀，4,000rpm下离心5分钟，取上清液100μL，加入120-150μL甲醇/水(v/v＝1/1)混匀)后采用LC/MS/MS分析血浆中化合物的浓度。The plasma samples collected above were processed (after the frozen plasma was thawed at room temperature, vortexed for 15s to mix, take 10-20μL of plasma, add 120-150μL of acetonitrile solution containing internal standard, vortex for 5min to mix, and centrifuge at 4,000rpm for 5 minutes. minutes, take 100 μL of the supernatant, add 120-150 μL methanol/water (v/v=1/1) and mix well), and analyze the concentration of compounds in plasma by LC/MS/MS.
分析结果表明，本发明化合物在大鼠和/或犬体内具有较好的药代动力学性质。说明本发明化合物成药性好，具有良好的临床应用前景。The analysis results show that the compounds of the present invention have good pharmacokinetic properties in rats and/or dogs. It shows that the compound of the present invention has good drug-forming property and good clinical application prospect.
在本说明书的描述中，参考术语“一个实施例”、“一实施方案”、“一些实施例”、“示例”、“具体示例”或“一些示例”等的描述意指结合该实施例、实施方案或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例、实施方案或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例、实施方案或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例、实施方案或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例、实施方案或示例以及不同实施例、实施方案或示例的特征进行结合和组合。In the description of this specification, reference to the terms "one embodiment", "an embodiment", "some embodiments", "example", "specific example" or "some examples", etc. A particular feature, structure, material or characteristic described by an embodiment or example is included in at least one embodiment, implementation or example of the invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment, implementation or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations or examples. Furthermore, those skilled in the art may combine and combine the different embodiments, implementations or examples described in this specification and the features of the different embodiments, implementations or examples without conflicting each other.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described above, it should be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Embodiments are subject to variations, modifications, substitutions and variations.

Claims (10)

  1. 一种化合物，其为式(I)所示的化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，A compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite of the compound represented by formula (I) product, a pharmaceutically acceptable salt or a prodrug thereof,
    Figure PCTCN2020119029-appb-100001
    Figure PCTCN2020119029-appb-100001
    其中：in:
    Z为NH、O或S；Z is NH, O or S;
    R为
    Figure PCTCN2020119029-appb-100002
    R is
    Figure PCTCN2020119029-appb-100002
    X为CH或N；X is CH or N;
    Y为CH或N；Y is CH or N;
    U为CH或N；U is CH or N;
    R 6为3-8个原子组成的饱和含氧杂环基； R 6 is a saturated oxygen-containing heterocyclic group consisting of 3-8 atoms;
    m为0、1、2或3；m is 0, 1, 2 or 3;
    R 1为C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、羟基取代的C 1-C 6烷基、氰基取代的C 1-C 6烷基、氨基取代的C 1-C 6烷基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基； R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkane oxy, hydroxy substituted C 1 -C 6 alkyl, cyano substituted C 1 -C 6 alkyl, amino substituted C 1 -C 6 alkyl, C 3-6 cycloalkyl, 3-8 atoms composed of a heterocyclic group, a C 6-10 aryl group or a heteroaryl group composed of 5-10 atoms;
    各R 2a、R 2b、R 2c和R 2d独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 6烷基)、-C(＝O)-(C 1-C 6烷氧基)、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烷硫基、C 1-C 6烷氨基或羟基取代的C 1-C 6烷基； Each of R 2a , R 2b , R 2c and R 2d is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C ( =O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 -C 6 alkyl), -C(=O )-(C 1 -C 6 alkoxy), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino or hydroxy substituted C 1 -C 6 alkyl;
    R 3和R 4各自独立地为H、D、-OH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基、5-10个原子组成的杂芳基、C 3-6环烷基-C 1-6亚烷基、(3-8个原子组成的杂环基)-C 1-6亚烷基、C 6-10芳基-C 1-6亚烷基或(5-10个原子组成的杂芳基)-C 1-6亚烷基； R 3 and R 4 are each independently H, D, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3-6 cycloalkyl, heterocyclic group consisting of 3-8 atoms, C 6-10 aryl group, heterocyclic group consisting of 5-10 atoms Aryl, C 3-6 cycloalkyl-C 1-6 alkylene, (heterocyclyl consisting of 3-8 atoms)-C 1-6 alkylene, C 6-10 aryl-C 1- 6 alkylene groups or (heteroaryl groups consisting of 5-10 atoms)-C 1-6 alkylene groups;
    R 5a、R 5b、R 5c、R 5d和R 5e各自独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 6烷基)、-C(＝O)-(C 1-C 6烷氧基)、-NHS(＝O) 2-(C 1-C 6烷基)、-N(C 1-6烷基)S(＝O) 2-(C 1-C 6烷基)、-S(＝O) 2-(C 1-C 6烷基)、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烷硫基、C 1-C 6烷氨基、羟基取代的C 1-C 6烷基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基。 R 5a , R 5b , R 5c , R 5d and R 5e are each independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 -C 6 alkyl), -C (=O)-(C 1 -C 6 alkoxy), -NHS(=O) 2 -(C 1 -C 6 alkyl), -N(C 1-6 alkyl)S(=O) 2 -(C 1 -C 6 alkyl), -S(=O) 2 -(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, hydroxy substituted C 1 -C 6 alkyl group, C 3-6 cycloalkyl group, heterocyclic group consisting of 3-8 atoms, C 6-10 aryl group or heteroaryl group consisting of 5-10 atoms.
  2. 根据权利要求1所述的化合物，其中，R 6为3-6个原子组成的饱和含氧杂环基。 The compound of claim 1, wherein R 6 is a saturated oxygen-containing heterocyclic group consisting of 3-6 atoms.
  3. 根据权利要求1或2所述的化合物，其中，R 6为
    Figure PCTCN2020119029-appb-100003
    Figure PCTCN2020119029-appb-100004
    The compound of claim 1 or 2, wherein R 6 is
    Figure PCTCN2020119029-appb-100003
    Figure PCTCN2020119029-appb-100004
  4. 根据权利要求1所述的化合物，其中，R 1为C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、羟基取代的C 1-C 4烷基、氰基取代的C 1-C 4烷基、氨基取代的C 1-C 4烷基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基。 The compound of claim 1, wherein R 1 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, hydroxy substituted C 1 -C 4 alkyl, cyano substituted C 1 -C 4 alkyl, amino substituted C 1 -C 4 alkyl, C 3 -6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 aryl group or heteroaryl group consisting of 5-6 atoms.
  5. 根据权利要求1或4所述的化合物，其中，R 1为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、2-甲基丙基、1-甲基丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、异丙氧基、-OCF 3、羟甲基、2-羟基乙基、-CH 2CN、-CH 2CH 2CN、-CH 2CH 2CH 2CN、-CH 2NH 2、-CH 2CH 2NH 2、-CH 2CH 2CH 2NH 2、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、茚基、萘基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基。 The compound according to claim 1 or 4, wherein R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl, 1-methylpropyl radical, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, isopropoxy, -OCF 3 , hydroxymethyl, 2-hydroxyethyl, -CH 2 CN, -CH 2 CH 2 CN , -CH2CH2CH2CN , -CH2NH2 , -CH2CH2NH2 , -CH2CH2CH2NH2 , cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , nitrogen Heterocyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazo azolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
  6. 根据权利要求1所述的化合物，其中，R 3和R 4各自独立地为H、D、-OH、C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基、5-6个原子组成的杂芳基、C 3-6环烷基-C 1-4亚烷基、(3-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基-C 1-4亚烷基或(5-6个原子组成的杂芳基)-C 1-4亚烷基； The compound of claim 1, wherein R 3 and R 4 are each independently H, D, -OH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl , C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 Aryl, heteroaryl consisting of 5-6 atoms, C 3-6 cycloalkyl-C 1-4 alkylene, (heterocyclyl consisting of 3-6 atoms)-C 1-4 alkylene , C 6-10 aryl-C 1-4 alkylene or (heteroaryl consisting of 5-6 atoms)-C 1-4 alkylene;
    R 5a、R 5b、R 5c、R 5d和R 5e各自独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 4烷基)、-C(＝O)-(C 1-C 4烷氧基)、-S(＝O) 2-(C 1-C 4烷基)、C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 1-C 4烷硫基、C 1-C 4烷氨基或羟基取代的C 1-C 4烷基。 R 5a , R 5b , R 5c , R 5d and R 5e are each independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 -C 4 alkyl), -C (=O)-(C 1 -C 4 alkoxy), -S(=O) 2 -(C 1 -C 4 alkyl), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4alkynyl , C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylamino or hydroxy substituted C 1 -C 4 alkyl.
  7. 根据权利要求1或6所述的化合物，其中，R 3和R 4各自独立地为H、D、-OH、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、2-甲基丙基、1-甲基丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、-CHF 2、-CF 3、甲氧基、乙氧基、异丙氧基、-OCF 3、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、茚基、萘基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、C 3-6环烷基-亚甲基、C 3-6环烷基-亚乙基、C 3-6环烷基-亚丙基、(3-6个原子组成的杂环基)-亚甲基、(3-6个原子组成的杂环基)-亚乙基、苯基-亚甲基、苯基-亚乙基、苯基-亚丙基、吡啶基-亚甲基、嘧啶基-亚甲基、吡咯基-亚甲基、吡唑基-亚甲基、三氮唑基-亚甲基或四氮唑基-亚甲基； The compound of claim 1 or 6, wherein R 3 and R 4 are each independently H, D, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl , 2-methylpropyl, 1-methylpropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, -CHF 2 , -CF 3 , methoxy, ethoxy radical, isopropoxy, -OCF 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl , phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridine Azinyl, pyridazinyl, C 3-6 cycloalkyl-methylene, C 3-6 cycloalkyl-ethylene, C 3-6 cycloalkyl-propylene, (composed of 3-6 atoms of heterocyclyl)-methylene, (heterocyclyl composed of 3-6 atoms)-ethylene, phenyl-methylene, phenyl-ethylene, phenyl-propylene, pyridyl - methylene, pyrimidinyl-methylene, pyrrolyl-methylene, pyrazolyl-methylene, triazolyl-methylene or tetrazolyl-methylene;
    R 5a、R 5b、R 5c、R 5d和R 5e各自独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-OCH 3、-S(＝O) 2-CH 3、甲基、乙基、正丙基、异丙基、叔丁基、乙烯基、-CHF 2、-CF 3、甲氧基、-OCF 3、甲氨基、二甲氨基或羟甲基。 R 5a , R 5b , R 5c , R 5d and R 5e are each independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-CH 3 , -C(=O)-OCH 3 , -S(=O) 2 -CH 3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, -CHF 2 , -CF 3 , methoxy, -OCF 3 , methyl amino, dimethylamino or hydroxymethyl.
  8. 根据权利要求1所述的化合物，其为具有下列之一结构的化合物或具有下列之一结构的化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药：The compound according to claim 1, which is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, Solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:
    Figure PCTCN2020119029-appb-100005
    Figure PCTCN2020119029-appb-100005
  9. 一种药物组合物，包含权利要求1-8任意一项所述的化合物；和A pharmaceutical composition comprising the compound of any one of claims 1-8; and
    所述药物组合物任选地进一步包含药学上可接受的赋形剂、载体、佐剂或它们的任意组合。The pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.
  10. 权利要求1-8任意一项所述的化合物或权利要求9所述的药物组合物在制备药物中的用途，其中，所述药物用于预防或治疗性激素依赖性疾病；Use of the compound of any one of claims 1-8 or the pharmaceutical composition of claim 9 in the preparation of a medicament, wherein the medicament is used to prevent or treat a sex hormone-dependent disease;
    其中，所述性激素依赖性疾病为性激素依赖性癌症、性激素依赖性癌症的骨质转移、前列腺肥大、子 宫肌瘤、子宫内膜异位症、子宫纤维瘤、性早熟、闭经、月经前期综合症、痛经、多房性卵巢综合症、多囊性卵巢综合症、痤疮、脱毛症、不育症或过敏性肠综合症。Wherein, the sex hormone-dependent disease is sex hormone-dependent cancer, bone metastasis of sex hormone-dependent cancer, prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, and premenstrual syndrome , dysmenorrhea, polylocular ovary syndrome, polycystic ovary syndrome, acne, alopecia, infertility or irritable bowel syndrome.
PCT/CN2020/119029 2020-09-29 2020-09-29 Pyrimidinedione compound containing saturated oxygen-containing heterocyclic group and use thereof WO2022067566A1 (en)

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Citations (6)

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CN1146206A (en) * 1994-04-19 1997-03-26 武田药品工业株式会社 Bicyclic thiophene derivatives and use as gonadotropin releasing hormone antagonists
CN1173868A (en) * 1995-02-08 1998-02-18 武田药品工业株式会社 Thienopyrimidine derivatives, their production and use
EP1479684A1 (en) * 2002-01-30 2004-11-24 Takeda Chemical Industries, Ltd. Thienopyrimidines, process for preparing the same and use thereof
EP1495768A1 (en) * 2002-04-12 2005-01-12 Takeda Pharmaceutical Company Limited Preventives/remedies for hotflash
EP2329823A1 (en) * 2008-09-03 2011-06-08 Takeda Pharmaceutical Company Limited Method for improving absorbability of preparation, and preparation having improved absorbability
WO2019020102A1 (en) * 2017-07-28 2019-01-31 江苏恒瑞医药股份有限公司 Method for preparing pyrimidone heteroaryl derivative and intermediate of pyrimidone heteroaryl derivative

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1146206A (en) * 1994-04-19 1997-03-26 武田药品工业株式会社 Bicyclic thiophene derivatives and use as gonadotropin releasing hormone antagonists
CN1173868A (en) * 1995-02-08 1998-02-18 武田药品工业株式会社 Thienopyrimidine derivatives, their production and use
EP1479684A1 (en) * 2002-01-30 2004-11-24 Takeda Chemical Industries, Ltd. Thienopyrimidines, process for preparing the same and use thereof
EP1495768A1 (en) * 2002-04-12 2005-01-12 Takeda Pharmaceutical Company Limited Preventives/remedies for hotflash
EP2329823A1 (en) * 2008-09-03 2011-06-08 Takeda Pharmaceutical Company Limited Method for improving absorbability of preparation, and preparation having improved absorbability
WO2019020102A1 (en) * 2017-07-28 2019-01-31 江苏恒瑞医药股份有限公司 Method for preparing pyrimidone heteroaryl derivative and intermediate of pyrimidone heteroaryl derivative

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