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WO2023060489A1 - 10-取代-1-氮杂吩噻嗪衍生物及其应用 - Google Patents

10-取代-1-氮杂吩噻嗪衍生物及其应用 Download PDF

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WO2023060489A1
WO2023060489A1 PCT/CN2021/123627 CN2021123627W WO2023060489A1 WO 2023060489 A1 WO2023060489 A1 WO 2023060489A1 CN 2021123627 W CN2021123627 W CN 2021123627W WO 2023060489 A1 WO2023060489 A1 WO 2023060489A1
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pharmaceutical composition
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alkyl
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aryl
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PCT/CN2021/123627
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French (fr)
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毛斐
王玉东
伍慧雯
孙笑
刘小虎
李丽娟
宋鸰沂
李剑
李晓康
朱进
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华东理工大学
中国福利会国际和平妇幼保健院
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Priority to PCT/CN2021/123627 priority Critical patent/WO2023060489A1/zh
Priority to CN202180098067.1A priority patent/CN117715907A/zh
Publication of WO2023060489A1 publication Critical patent/WO2023060489A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to 10-substituted-1-azaphenothiazine derivatives and their preparation methods and applications.
  • Endometrial cancer is a group of epithelial malignant tumors that occur in the endometrium. It is one of the most common gynecological malignancies in the world, and its morbidity and mortality are increasing. Although EC is more common in postmenopausal women, the incidence of EC in young women has increased dramatically over the past decade, with younger and younger women being diagnosed with endometrial cancer, and the underlying cause of the increase is obesity The prevalence and resulting hyperinsulinemia, and endometrial cancer rates have risen along with obesity rates. In 2015, there were about 63,400 new EC cases and about 21,800 new EC deaths in China.
  • EC is usually divided into type I and type II.
  • type I EC is positive for progesterone receptor expression
  • type II EC is negative for progesterone receptor expression.
  • surgical treatment is a common method for the treatment of EC, but conservative treatment is required for patients who need to preserve fertility function, and the main method of conservative treatment is hormone therapy with progesterone drugs.
  • hormone therapy has limitations. It is only effective for patients with positive progesterone receptor expression and has a high recurrence rate, which is prone to drug resistance. With the full liberalization of the two-child and three-child policy, the demand for conservative treatment for fertility preservation in young EC patients has increased. Therefore, the development of new EC therapeutic drugs is imminent.
  • the purpose of the present invention is to provide a class of EC therapeutic drugs.
  • Another object of the present invention is to provide the application of the above compounds in the preparation of drugs for treating and/or improving endometrial cancer.
  • the first aspect of the present invention provides a compound represented by formula I, or a stereoisomer or a pharmaceutically acceptable salt thereof,
  • n 2, 3, 4, 5 or 6;
  • R 1 is H, hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, nitro, nitroso, amino, formyl, acetyl or cyano base;
  • R 1 is H, hydroxyl, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, C 1 -C 4 fluoroalkyl, methoxy, ethoxy base.
  • the spiroheterocyclyl is s 1 , s 2 , s 3 and s 4 are each independently 1, 2 or 3; Z is CH 2 or NH.
  • the bridging heterocyclic group is n 1 , n 2 , n 3 and n 4 are each independently 0, 1, 2 or 3.
  • R 2 is formula I-2 or I-3
  • a 1 , A 2 , A 3 , and A 4 are each independently selected from: N, O, S, -CO(CH 2 ) p -, -(CH 2 ) m -, -(CH 2 ) m O-, - (CH 2 ) m S-; m, p are each independently 0, 1, 2 or 3;
  • X is CH, N or O
  • n 1 , n 2 , n 3 , n 4 are each independently 0, 1, 2 or 3;
  • R 3 is H, -COOC 1 -C 6 alkyl, -C 1 -C 6 alkylene, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, -COC 1 -C 6 alkyl, -C 1- C 6 alkylene 5-7 membered heteroaryl, C 6 -C 10 aryl, 5-7 Heteroaryl, -C 1 -C 6 alkylene halo C 6 -C 10 aryl, C 3 -C 8 cycloalkyl.
  • R 3 is H, tert-butoxycarbonyl, C 1 -C 4 alkyl, chlorobenzyl, benzyl, -CH 2 -6-membered nitrogen-containing heteroaryl, -COC 1 -C 4 alkyl or C 2 -C 4 alkynyl.
  • the compound is selected from the following group:
  • a second aspect of the present invention provides a pharmaceutical composition, comprising:
  • the pharmaceutical composition further includes other pharmaceutically acceptable ingredients which are anti-endometrial cancer drugs.
  • the anti-endometrial cancer drug is progesterone.
  • the progestogen is one or a combination of two or more of megestrol acetate, medroxyprogesterone acetate, or progesterone caproate.
  • the pharmaceutical composition is injection, tablet, capsule, pill, suspension or emulsion.
  • the pharmaceutical composition is in oral dosage form, transdermal dosage form, intravenous or intramuscular injection dosage form.
  • the third aspect of the present invention provides the use of the compound described in the first aspect or its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the second aspect, for the preparation of therapeutic and/or Medicines to prevent endometrial cancer.
  • the fourth aspect of the present invention provides a method for preparing the compound described in the first aspect or its stereoisomer, or a pharmaceutically acceptable salt thereof, and the specific synthesis strategy is as follows:
  • the fifth aspect of the present invention provides a method for treating endometrial cancer, comprising administering the compound described in the first aspect, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof to a subject in need.
  • Figure 1 is a schematic diagram of the effect of compound X32 on the clone formation of ISK and KLE cells.
  • A Crystal violet staining of ISK cells;
  • B Crystal violet staining of KLE cells;
  • C Quantification of crystal violet staining of ISK cells;
  • D Quantification of crystal violet staining of KLE cells; data are mean ⁇ SD, *p ⁇ 0.05, **p ⁇ 0.01,***p ⁇ 0.001,****p ⁇ 0.0001vs Ctrl,One-way ANOVA.
  • Fig. 2 is a schematic diagram showing the effect of compound X32 on the migration ability of ISK and KLE cells.
  • A ISK cell crystal violet staining
  • B ISK cell crystal violet staining quantification
  • C KLE cell crystal violet staining
  • D KLE cell crystal violet staining quantification
  • data are mean ⁇ SD, *p ⁇ 0.05, **p ⁇ 0.01,***p ⁇ 0.001,****p ⁇ 0.0001vs Ctrl,One-way ANOVA.
  • Fig. 3 is a schematic diagram showing the effect of compound X32 on the apoptosis of ISK and KLE cells.
  • A Effect on apoptosis of ISK cells;
  • B Effect on apoptosis of KLE cells;
  • C Quantification of apoptosis ratio of ISK cells;
  • D Quantification of apoptosis ratio of KLE cells; data are mean ⁇ SD, * p ⁇ 0.05,**p ⁇ 0.01,***p ⁇ 0.001,****p ⁇ 0.0001vs Ctrl,One-way ANOVA.
  • Fig. 4 is a schematic diagram of the effect of compound X32 on the central nervous system of mice.
  • the data are mean ⁇ SEM, *p ⁇ 0.05,**p ⁇ 0.01,***p ⁇ 0.001,****p ⁇ 0.0001vs Vehicle, one-way ANOVA.
  • Fig. 5 is a schematic diagram showing the inhibitory effect of compound X01 on the growth of subcutaneous KLE cell xenografts in mice.
  • A Change curve of mouse body weight with administration time;
  • B Tumor volume after administration for 14 days;
  • C Tumor pictures of mice after administration for 14 days;
  • D Tumor weight after administration for 14 days; data are average values ⁇ SEM,*p ⁇ 0.05,**p ⁇ 0.01,***p ⁇ 0.001,****p ⁇ 0.0001vs Vehicle, one-way ANOVA.
  • C 1 -C 6 means having 1, 2, 3, 4, 5 or 6 carbon atoms
  • C 1 -C 8 means having 1, 2, 3, 4, 5 , 6, 7 or 8 carbon atoms, and so on.
  • 5-7 membered means having 5, 6 or 7 ring atoms, and so on.
  • Alkyl refers to straight chain or branched chain alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and the like.
  • Alkylene refers to a straight or branched chain saturated aliphatic group, ie, a divalent hydrocarbon group, having the specified number of carbon atoms and linked to at least two other groups. Two groups attached to an alkylene group can be attached to the same or different atoms of the alkylene group.
  • a linear alkylene group can be a divalent group of -(CH 2 )q-, where q is 1, 2, 3, 4, 5, or 6.
  • Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene.
  • alkoxy denotes a -O-(C 1 -6 alkyl) group.
  • C 1 -C 6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, n-propoxy, iso Propoxy and Butoxy, etc.
  • alkenyl means a straight or branched chain hydrocarbon moiety containing at least one double bond
  • C2 - C6 alkenyl means a straight or branched chain having 2 to 6 carbon atoms containing a double bond.
  • Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.
  • alkynyl refers to a straight or branched chain alkynyl group containing a triple bond, including, but not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.
  • Cycloalkyl means a saturated cyclic hydrocarbon moiety, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • aryl denotes a hydrocarbyl moiety comprising one or more aromatic rings.
  • C 6 -C 10 aryl refers to an aromatic ring group having 6 to 10 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl and the like.
  • heteroaryl means an aromatic cyclic group containing at least one (such as 1, 2, 3 or 4) ring heteroatoms (such as N, O or S), such as pyrrolyl, Furyl, thienyl, pyrazolyl, oxazolyl, pyridyl, pyrimidyl, etc.
  • heterocyclyl means a saturated or unsaturated, non-aromatic cyclic group comprising at least one (eg 1, 2, 3 or 4) ring heteroatoms (eg N, O or S), eg tetra Hydropyridyl, pyrrolinyl, dihydropyridyl, dihydrofuryl, dihydrothienyl, morpholinyl.
  • the heterocyclic group can be a monocyclic heterocyclic ring, a polycyclic heterocyclic ring, and a polycyclic heterocyclic group includes a spiro ring, a condensed ring and a bridged ring.
  • Halogen is F, Cl, Br or I.
  • the present invention also includes the pharmaceutically acceptable salts of the above compounds.
  • the pharmaceutically acceptable salt of the 10-substituted-1-azaphenothiazine derivative of the present invention refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include but not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but not limited to formate, acetate, 2,2-dichloroacetate , Trifluoroacetate, Propionate, Caproate, Caprylate, Caprate, Undecylenate, Glycolate, Gluconate, Lactate, Sebacate, Hexanoate glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-amino salicylate, naphthalene disulfon
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 3-methyl-3,9-diazaspiro[5,5]undecane- tert-Butyl 3-carboxylate to give X02 as a yellow oil.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester to obtain Yellow oil X03.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester to obtain Yellow oil X04.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 1-oxa-4,9-diazaspiro[5.5]undecane-9- tert-Butyl formate affords X05 as a yellow oil.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 2,6-diazo-spiro[3.4]octane-2-tert-butyl carbonate to obtain Yellow oil X06.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, X07 was obtained as a yellow oil.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane to obtain Yellow oil X08.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester to obtain Yellow oil X09.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 2,9-diazaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester, X10 is obtained as a yellow oil.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 2,6-diazo-spiro[3.4]octane-2-carboxylic acid tert-butyl ester, A yellow oil X11 is obtained.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrogen spiro[5,5]undecane is replaced by 1,8-diaza-spiro[4.5]decane-1-carboxylic acid tert-butyl ester , to obtain yellow oil X12.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 1,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester to obtain Yellow oil X13.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 1,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester to obtain Yellow oil X14.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 2,6-diazaspiro[3.4]octane-6-carboxylic acid tert-butyl ester to obtain Yellow oil X15.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester to obtain Yellow oil X16.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 9-benzyl-3,9-diaza[5.5]undecane-2,4 - diketone, yielding X17 as a yellow oil.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride salt to give X18 as a yellow oil.
  • Example 25 The specific implementation steps are the same as in Example 25, except that the raw material 3-chloropropyne is replaced by acetyl chloride to obtain yellow oil X21.
  • Example 25 The specific implementation steps are the same as in Example 25, except that the raw material 3-chloropropyne is replaced by 1-chloropropane to obtain yellow oil X22.
  • Example 25 The specific implementation steps are the same as in Example 25, except that the raw material 3-chloropropyne is replaced by 2-chloromethylpyridine to obtain yellow oil X23.
  • Example 25 The specific implementation steps are the same as in Example 25, except that the raw material 3-chloropropyne is replaced by benzyl chloride to obtain yellow oil X25.
  • Example 25 The specific implementation steps are the same as in Example 25, except that the raw material 3-chloropropyne is replaced by 4-chlorobenzyl chloride to obtain yellow oil X26.
  • Example 7 The specific implementation steps are the same as in Example 7, except that the raw material VI A is replaced by VI C to obtain yellow oil X27.
  • Example 7 The specific implementation steps are the same as in Example 7, except that the raw material VI A is replaced by VI B to obtain yellow oil X28.
  • Example 7 The specific implementation steps are the same as in Example 7, except that the raw material VI A is replaced by VI D to obtain yellow oil X29.
  • Example 7 The specific implementation steps are the same as in Example 7, except that the raw material VI A is replaced by VI E to obtain yellow oil X30.
  • Example 7 The specific implementation steps are the same as in Example 7, except that the raw material VI A is replaced by VI F to obtain yellow oil X31.
  • Example 6 The specific implementation steps are the same as in Example 6, except that the raw material 3-nitrospiro[5,5]undecane is replaced by 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1] Heptane to give X34 as a yellow oil.
  • Example 41 Inhibitory effect of compounds of the present invention on proliferation of endometrial cancer cells
  • the invention evaluates the proliferation inhibitory activity of 10-substituted-1-azaphenothiazine derivatives on endometrium cancer cells by CCK-8 experiment.
  • Endometrial cancer cells ISK and KLE were purchased from the American Type Culture Collection (ATCC); phosphate buffered saline (PBS) was purchased from Bio-channel; DMEM/F12 medium was purchased from Biosharp; fetal calf Serum (FBS) and trypsin were purchased from Gibco; CCK-8 was purchased from Biyuntian Biotechnology Co., Ltd.
  • ATCC American Type Culture Collection
  • PBS phosphate buffered saline
  • DMEM/F12 medium was purchased from Biosharp
  • FBS fetal calf Serum
  • trypsin were purchased from Gibco
  • CCK-8 was purchased from Biyuntian Biotechnology Co., Ltd.
  • ISK and KLE cells were cultured in DMEM/F12 (containing 10% fetal bovine serum, 1% penicillin/streptomycin) medium and placed in an incubator at 37°C and 5% CO 2 .
  • the endometrial cancer cells basically covered the cell culture dish (10 cm)
  • the cells were digested with trypsin, and seeded in a 96-well plate at a cell density of 5000 cells/well, 100 ⁇ L per well.
  • DMEM/F12 medium containing different concentrations of derivatives were added, 200 ⁇ L per well, and 3 replicate wells were set up for each group. Incubate for 48h in a cell culture incubator.
  • Inhibition rate calculation formula: cell inhibition rate% [1-(administration group A value-blank group A value)/(control group A value-blank group A value)] ⁇ 100%, IC50 value through Graphpad Prism 8.0 software fit.
  • the inhibitory activity of 10-substituted-1-azaphenothiazine derivatives on the proliferation of endometrial cancer cells is shown in Table 1 and Table 2. The results show that the derivatives all have inhibitory effects on the proliferation of endometrial cancer cells ISK and KLE Significant inhibitory effect.
  • the present invention tests the effect of the compound X32 on the colony formation ability of endometrial cancer cells ISK and KLE by means of a plate colony formation experiment at the cell level. The results showed that compound X32 could inhibit the colony formation of endometrial cancer cells ISK and KLE in a concentration-dependent manner.
  • 0.5% crystal violet dye solution was purchased from Beyontian Biotechnology Co., Ltd. Methanol is a common reagent in the laboratory and was purchased commercially without any treatment. The source of other experimental materials is the same as in Example 41.
  • the EC cells in the logarithmic growth phase were digested with trypsin to prepare a single cell suspension, seeded into a 6-well plate at a density of about 1000 cells per well, and cultured overnight. After the cells adhered to the wall, they were divided into 4 groups, namely the control group and different drug administration groups, with 3 replicate wells in each group.
  • the treatment group received 2 mL of DMEM/F12 medium containing different concentrations of drugs, and the control group was added with drug-free medium for 48 hours, and then replaced with drug-free medium for about 8 days.
  • the cells grow into a cell group visible to the naked eye, place them on ice, and wash the cells twice with pre-cooled PBS for 3 minutes each time. Cells were then fixed with pre-cooled methanol for 10 min at -20°C. Suction methanol, add crystal violet staining solution 1mL, stain for 30min. Remove the crystal violet dye solution and wash with water until the dye solution is completely eluted. Invert the 6-well plate and wait for it to dry, take pictures with a gel imager, count manually with Image J software, and count the number of clones formed in each well.
  • the number of cell colonies in the administration group also decreased, and it decreased significantly with the increase of the concentration of compound X32, indicating that compound X32 has an inhibitory effect on the colony formation of KLE cells, and can inhibit the formation of KLE cells in a concentration-dependent manner.
  • the vertical axis of the histogram indicates the number of cell communities in each group, and the significant difference of data was analyzed by One-way ANOVA method (Graphpad Prism 8.0 software).
  • Example 43 Inhibition of the compound of the present invention on the migration ability of endometrial cancer cells
  • the present invention tested the effect of compound X32 on the migration ability of endometrial cancer cells ISK and KLE by Transwell experiment at the cell level. The results showed that X32 could inhibit the migration of endometrial cancer cells ISK and KLE.
  • the Transwell chamber was purchased from Costar Company; paraformaldehyde is a common laboratory reagent, commercially purchased without any treatment, and the sources of other experimental materials are the same as in Example 41.
  • the EC cells in the logarithmic growth phase were digested with trypsin, prepared into a single cell suspension using serum-free DMEM/F12 medium, and seeded on the top of the Transwell chamber at a density of about 100,000 cells per well. Add 600 ⁇ L of DMEM/F12 medium containing 20% FBS to the bottom of the small chamber, taking care to avoid the generation of air bubbles. They were divided into 4 groups, namely the control group and different drug administration groups, and each group had 3 replicate wells.
  • 150 ⁇ L of serum-free DMEM/F12 medium containing different drugs was added to the upper chamber of the treatment group, and 150 ⁇ L of serum-free DMEM/F12 medium without drug was added to the upper chamber of the control group. Place in an incubator at 37°C with 5% CO 2 for 24 hours. Then carefully remove the small chamber with tweezers, blot the liquid in the upper chamber, move it to a 24-well plate that has been added with about 800 ⁇ L of pre-cooled PBS, and wash it twice, 5 min each time. Take out the small chamber, move it to a 24-well plate pre-added with about 800 ⁇ L of paraformaldehyde solution, and fix it at room temperature for 30 minutes.
  • the present invention uses the Annexin V-FITC/PI cell apoptosis detection kit to test the effect of compound X32 on the apoptosis of endometrial cancer cells ISK and KLE at the cellular level.
  • the research results showed that compound X32 could induce apoptosis of endometrial cancer cells ISK and KLE.
  • the Annexin V-FITC/PI Cell Apoptosis Detection Kit was purchased from Beyotime Biotechnology Co., Ltd., in which Annexin V-FITC Conjugate Solution, Annexin V-FITC, and Propidium Iodide (PI) are all reagents in the kit.
  • the source of other experimental materials is the same as in Example 41.
  • the EC cells in the logarithmic growth phase were digested with trypsin to prepare a single cell suspension, seeded into a 6-well plate at a density of about 120,000 cells per well, and cultured overnight. After the cells adhered to the wall, they were divided into 4 groups, namely the control group and different drug administration groups, with 3 replicate wells in each group.
  • the administration group was added with 2 mL of DMEM/F12 medium containing different concentrations of derivatives, and the control group was added with 2 mL of drug-free DMEM/F12 medium. Incubate for 48 h at 37 °C in an incubator with 5% CO 2 . Then suck out the cell culture solution into a 10ml centrifuge tube, wash the adherent cells once with PBS, add 300 ⁇ L of trypsin to digest the cells for 2 minutes, blow the cells down gently, transfer them to the corresponding centrifuge tube, centrifuge at 1000rpm for 5 minutes, discard the supernatant, and collect the cells. Gently resuspend cells in PBS and count.
  • the influence of the compound X32 on the central nervous system of mice is tested through a rotarod test, that is, the side effects of the extrapyramidal system.
  • the research results show that the side effects of the central nervous system of compound X32 are relatively low, and the administration doses of 100mg/kg and 50mg/kg basically do not affect the grasping motor ability of mice, and have no extrapyramidal side effects.
  • the experimental animals were 7-8 week old female C57BL/6 nude mice, which were purchased from Shanghai Slack Co., Ltd.; cisplatin (DDP) was from the old drug library of the laboratory.
  • the compound preparation method is to weigh a certain amount of the compound, dissolve it in physiological saline, and give the corresponding solvent to the control group.
  • Compounds are formulated and used immediately prior to administration.
  • mice were randomly divided into 4 groups: control group, positive drug chlorpromazine 5mg/kg, X32 50mg/kg, X32 100mg/kg. 12 in each group. Train the mice three days in advance to adapt to the rotarod movement: train the mice to exercise at a rotational speed of 35 rpm/min for 3 minutes every day. On the fourth day, after intraperitoneal injection of 0.1 mL for 1 hour (the control group was injected with normal saline 0.1 mL), at a speed of 35 rpm/min, the time that the mice persisted on the rotarod within 5 min was recorded.
  • Example 46 Inhibitory effect of compounds of the present invention on growth of endometrial cancer tumor-bearing mice subcutaneously transplanted tumors
  • the effect of the compound X01 on the growth of endometrium cancer cell (KLE) xenografts is tested by subcutaneous tumor formation experiments in nude mice. The results of the study showed that compound X01 could significantly inhibit the growth of subcutaneous KLE cell xenografts in mice.
  • mice of SPF grade 5-6 weeks old female BALB/C nude mice of SPF grade were selected as experimental animals, which were purchased from Shanghai Slack Animal Experiment Co., Ltd.; cisplatin (DDP) was obtained from the old drug storehouse of the laboratory.
  • the compound preparation method is to weigh a certain amount of the compound, dissolve it in physiological salt and dilute it to the required concentration, and give the corresponding solvent to the control group.
  • Compounds are formulated and used immediately prior to administration.
  • mice were implanted subcutaneously in the right armpit of 5-6 week-old nude mice, and about 5 million cells were implanted in each mouse. After the tumor grew to 800-1000 mm 3 , the mice were sacrificed, and then the tumor tissue was cut into tumor tissue pieces of uniform size, which were transplanted into new 5-6 week-old nude mice under the skin of the right armpit. When the newly grown tumor volume reached an average of 300-400 mm 3 , the mice were randomly divided into 4 groups: control group, positive drug DDP 2 mg/kg, X01 2 mg/kg administration group, X01 5 mg/kg administration group, chlorine Promethazine 5mg/kg group.

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Abstract

一种10-取代-1-氮杂吩噻嗪衍生物及其应用，该衍生物结构如式（I）所示，各取代基的定义如说明书和权利要求书所述。本发明的10-取代-1-氮杂吩噻嗪衍生物对子宫内膜癌细胞具有显著增殖抑制作用，能够抑制子宫内膜癌细胞的克隆形成和迁移，诱导子宫内膜癌细胞凋亡，以及体内抑制裸鼠皮下移植瘤的生长。因此，本发明提供的10-取代-1-氮杂吩噻嗪衍生物有望被用于制备治疗和/或预防子宫内膜癌药物。

Description

10-取代-1-氮杂吩噻嗪衍生物及其应用 技术领域
本发明涉及药物化学和药物治疗学领域，具体涉及10-取代-1-氮杂吩噻嗪衍生物及其制备方法和用途。
背景技术
子宫内膜癌(Endometrial Cancer，EC)是发生于子宫内膜的一组上皮性恶性肿瘤，是世界上最常见的妇科恶性肿瘤之一，其发病率和死亡率都在上升。虽然EC在绝经后妇女中更常见，但在过去的十年，年轻女性EC的发病率急剧增加，有越来越年轻的女性被诊断出子宫内膜癌，发病率增加的根本原因是肥胖的流行和由此引起的高胰岛素血症，随着肥胖率的上升，子宫内膜癌的发病率也在上升。2015年中国新增EC病例约63400例，新增EC死亡病例约21,800例。
EC通常分为I型和II型，两者主要区别是在于I型EC孕激素受体表达呈阳性，II型EC孕激素受体表达呈阴性。目前手术治疗是治疗EC的常用方法，但是对于需要保留生育功能的患者需要采用保守治疗方法，保守治疗的主要方法是应用孕激素类药物的激素疗法。然而激素疗法存在局限性，它只对孕激素受体表达呈阳性的患者有效并且复发率高，易产生耐药性。随着二胎、三胎政策的全面开放，年轻EC患者对保留生育功能的保守治疗需求增加。因此，开发新的EC治疗药物迫在眉睫。
发明内容
本发明的目的在于，提供一类EC治疗药物。
本发明另一个目的在于提供上述化合物在制备治疗和/或改善子宫内膜癌药物中的应用。
本发明的第一方面，提供一种式I所示化合物、或其立体异构体或药学上可接受的盐，
Figure PCTCN2021123627-appb-000001
其中，n为2、3、4、5或6；
R 1为H、羟基、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、硝基、亚硝基、氨基、甲酰基、乙酰基或氰基；
R 2为取代或未取代的6-14元杂环基，所述杂环基含有选自下组的1、2、3或4个杂原子：N、O、S；所述取代是指具有一个或多个选自下组的取代基：-COOC 1-C 6烷基、-C 1-C 6亚烷基C 6-C 10芳基、氧代(＝O)、C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、-COC 1-C 6 烷基、-C 1-C 6亚烷基5-7元杂芳基、C 6-C 10芳基、5-7元杂芳基、-C 1-C 6亚烷基卤代C 6-C 10芳基、C 3-C 8环烷基。
在另一优选例中，R 1为H、羟基、F、Cl、Br、甲基、乙基、正丙基、异丙基、C 1-C 4氟代烷基、甲氧基、乙氧基。
在另一优选例中，R 2为取代或未取代的7-12元螺杂环基或桥杂环基，所述螺杂环基或桥杂环基含有选自下组的1、2或3个杂原子：N、O；所述取代是指具有1、2、3或4个选自下组的取代基：-COOC 1-C 4烷基、-C 1-C 2亚烷基苯基、氧代(＝O)、C 1-C 4烷基、C 1-C 4卤代烷基、C 2-C 4烯基、C 2-C 4炔基、-COC 1-C 4烷基、-C 1-C 2亚烷基5-7元杂芳基、C 6-C 10芳基、5-7元杂芳基、-C 1-C 2亚烷基卤代C 6-C 10芳基、C 3-C 6环烷基。
在另一优选例中，所述螺杂环基为
Figure PCTCN2021123627-appb-000002
s 1、s 2、s 3、s 4各自独立地为1、2或3；Z为CH 2或NH。
在另一优选例中，所述桥杂环基为
Figure PCTCN2021123627-appb-000003
n 1、n 2、n 3、n 4各自独立地为0、1、2或3。
在另一优选例中，R 2为式I-2或者I-3，
Figure PCTCN2021123627-appb-000004
A 1、A 2、A 3、A 4各自独立地选自：N、O、S、-CO(CH 2) p-、-(CH 2) m-、-(CH 2) mO-、-(CH 2) mS-；m、p各自独立地为0、1、2或3；
X为CH、N或O；
n 1、n 2、n 3、n 4各自独立地为0、1、2或3；
R 3为H、-COOC 1-C 6烷基、-C 1-C 6亚烷基C 6-C 10芳基、C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、-COC 1-C 6烷基、-C 1-C 6亚烷基5-7元杂芳基、C 6-C 10芳基、5-7元杂芳基、-C 1-C 6亚烷基卤代C 6-C 10芳基、C 3-C 8环烷基。
在另一优选例中，R 3为H、叔丁氧羰基、C 1-C 4烷基、氯代苄基、苄基、-CH 2-6元含 氮杂芳基、-COC 1-C 4烷基或C 2-C 4炔基。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2021123627-appb-000005
Figure PCTCN2021123627-appb-000006
Figure PCTCN2021123627-appb-000007
本发明的第二方面，提供一种药物组合物，包括：
(1)第一方面所述的化合物、或其药学上可接受的盐、或其立体异构体；和(2)药学上可接受的载体。
在另一优选例中，所述药物组合物还包括其他药学上可接受的成分为抗子宫内膜癌药物。在另一优选例中，所述抗子宫内膜癌药物为孕激素。在另一优选例中，所述孕激素为醋酸甲地孕酮、酸酸甲羟孕酮或己酸孕酮中的一种或两种以上的组合。
在另一优选例中，所述药物组合物为注射剂、片剂、胶囊剂、丸剂、悬浮剂或乳剂。
在另一优选例中，所述药物组合物为口服剂型、经皮剂型、静脉或肌肉注射剂型。
本发明的第三方面，提供第一方面所述的化合物或其立体异构体，或其药学上可接受的盐或第二方面所述的药物组合物的用途，用于制备治疗和/或预防子宫内膜癌的药物。
本发明第四方面提供了第一方面所述的化合物或其立体异构体，或其药学上可接受的盐的制备方法，具体合成策略如下：
Figure PCTCN2021123627-appb-000008
所述方法具体步骤如下：
1)将不同4位取代或未取代的2-氨基苯硫酚溶于乙腈中，冰浴下慢慢加入叔丁醇钾，搅拌30min后慢慢加入2-氯-3-硝基吡啶，移到室温反应2h，过滤，保留滤饼，滤液减压蒸除溶剂，剩余残渣用乙醇溶解，过滤，合并滤饼，在红外干燥箱中干燥过夜，得中间体II A(II B或II C)。
2)在圆底烧瓶中加入中间体II A(II B或II C)、醋酸酐和吡啶室温反应过液，过滤，保留滤饼，滤液加入水析出产物，过滤，合并滤饼，放入红外干燥箱，约90℃干燥过夜，得中间体III A(III B或III C)。
3)在圆底烧瓶中加入中间体III A(III B或III C)、丙酮、KOH和乙醇，60℃左右反应2h，柱层析纯化(石油醚：乙酸乙酯＝10:1)，得中间体Ⅳ A(Ⅳ B或Ⅳ C)。
4)在圆底烧瓶中加入中间体Ⅳ A(Ⅳ B或Ⅳ C)、浓盐酸和乙醇，80℃左右反应过夜，减压蒸除溶剂，加氨水过滤得淡黄色固体中间体Ⅴ A(Ⅴ B或Ⅴ C)。
5)中间体Ⅴ A(Ⅴ B或Ⅴ C或10H-吡啶并(3,2-b)(1,4)苯并噻嗪)分别与不同链长的二溴烷反应得中间体Ⅵ A(ⅤI B或ⅤI C或ⅤI D或ⅤI E或ⅤI F)。
6)关键中间体Ⅵ A(ⅤI B或ⅤI C或ⅤI D或ⅤI E或ⅤI F)分别与不同胺反应得到不同衍生物X01-19、X27-35。
7)在X02中加入三氟乙酸和二氯甲烷，室温反应2小时得X19，随后X19分别与不同的R 3Cl反应，加入K 2CO 3和乙腈，60℃回流过夜，得不同衍生物X20-26。
本发明的第五方面，提供一种治疗子宫内膜癌的方法，包括向有需要的对象施用第一方面所述的化合物、或其药学上可接受的盐、或其立体异构体。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。说明书中所揭示的各个特征，可以被任何提供相同、均等或相似目的的替代性特征取代。限于篇幅，在此不再一一累述。
附图说明
图1为化合物X32对ISK和KLE细胞克隆形成的影响示意图。(A)ISK细胞结晶紫染色；(B)KLE细胞结晶紫染色；(C)ISK细胞结晶紫染色定量；(D)KLE细胞结晶紫染色定量；数据为平均值±SD，*p<0.05,**p<0.01,***p<0.001,****p<0.0001vs Ctrl,One-way ANOVA.
图2为化合物X32对ISK和KLE细胞的迁移能力的影响示意图。(A)ISK细胞结晶紫染色；(B)ISK细胞结晶紫染色定量；(C)KLE细胞结晶紫染色；(D)KLE细胞结晶紫染色定量；数据为平均值±SD，*p<0.05,**p<0.01,***p<0.001,****p<0.0001vs Ctrl,One-way ANOVA.
图3为化合物X32对ISK和KLE细胞的凋亡的影响示意图。(A)对ISK细胞凋亡的影响；(B)对KLE细胞凋亡的影响；(C)ISK细胞凋亡比例定量；(D)KLE细胞凋亡比例定量；数据为平均值±SD，*p<0.05,**p<0.01,***p<0.001,****p<0.0001vs Ctrl,One-way ANOVA.
图4为化合物X32对小鼠中枢神经系统的影响示意图。数据为平均值±SEM，*p<0.05,**p<0.01,***p<0.001,****p<0.0001vs Vehicle,one-way ANOVA.
图5为化合物X01对小鼠皮下KLE细胞移植瘤的生长抑制作用示意图。(A)小鼠体重随给药时间的变化曲线；(B)给药14天后肿瘤体积；(C)给药14天后小鼠肿瘤图片；(D)给药14天后肿瘤重量；数据为平均值±SEM，*p<0.05,**p<0.01,***p<0.001,****p<0.0001vs Vehicle,one-way ANOVA.
具体实施方式
本申请的发明人经过广泛而深入的研究，发现了一类具有抗子宫内膜癌活性的10-取代-1-氮杂吩噻嗪衍生物，其对EC细胞具有显著增殖抑制作用，能够抑制EC细胞的克隆形成和迁移，诱导EC细胞凋亡，以及体内抑制裸鼠皮下移植瘤的生长。在此基础上，完成了本发明。
术语
在本发明中采用的术语具有以下含义。
在本发明中，术语“C 1-C 6”是指具有1、2、3、4、5或6个碳原子，“C 1-C 8”是指具有1、2、3、4、5、6、7或8个碳原子，依此类推。“5-7元”是指具有5、6或7个环原子，依此类推。
“烷基”是指直链或支链烷基，如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基等。
“亚烷基”是指具有指定的碳原子数并连接至少两个其他基团的直链或支链饱和脂肪族基团，即二价烃基团。连接到亚烷基的两个基团可以连接到亚烷基上相同的或不同原子。例如，直链亚烷基可以是-(CH 2)q-的二价基团，其中q是1、2、3、4、5或6。代表性的亚烷基包括但不限于亚甲基、亚乙基、亚丙基、亚异丙基、亚丁基、亚异丁基、亚仲丁基、亚戊基和亚己基。
术语“烷氧基”表示-O-(C 1- 6烷基)基团。例如术语“C 1-C 6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、正丙氧基、异丙氧基和丁氧基等。
术语“烯基”表示包含至少一个双键的直链或支链烃基部分，例如术语“C 2-C 6烯基”是指具有2至6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
术语“炔基”是指含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
“环烷基”是指表示饱和的环状烃基部分，如环丙基、环丁基、环戊基、环己基、环庚基等。
术语“芳基”表示包含一个或多个芳环的烃基部分。例如术语“C 6-C 10芳基”是指在环上不含杂原子的具有6至10个碳原子的芳香族环基，如苯基、萘基等。
在本发明中，术语“杂芳基”表示包含至少一个(如1、2、3或4个)环杂原子(例如N，O或S)的芳香性的环状基团，如吡咯基、呋喃基、噻吩基、吡唑基、恶唑基、吡啶基、嘧啶基等。
术语“杂环基”表示包含至少一个(如1、2、3或4个)环杂原子(例如N，O或S)的饱和或不饱和的、非芳香性的环状基团，例如四氢吡啶基、吡咯啉基、二氢吡啶基、二氢呋喃基、二氢噻吩基、吗啉基。杂环基可以是单环杂环、多环杂环，多环杂环基包括螺环、稠环和桥环。
“卤素”是F、Cl、Br或I。
本发明还包括上述化合物药学上可接受的盐。本发明10-取代-1-氮杂吩噻嗪衍生物的药用盐是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过已知的成盐方法由式I的化合物制备。
在以下的实施例中将进一步举例说明本发明。这些实施例仅用于说明本发明，但不以任何方式限制本发明的保护范围。以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例1中间体II A、Ⅱ B、Ⅱ C的制备
Figure PCTCN2021123627-appb-000009
向干净的500mL反应瓶中依次加入乙腈200mL，20.0g 2-氨基-4-氯苯硫酚，冰浴下慢慢加入14.1g叔丁醇钾，搅拌30min，慢慢加入19.8g 2-氯-3-硝基吡啶，加毕移到室温，反应2h，TLC板监测反应完全，过滤，保留滤饼，滤液减压蒸除溶剂，剩余残渣用乙醇打浆，过滤，合并滤饼，放入红外干燥箱，约50℃干燥过夜，得到棕黄色固体为Ⅱ A粗产品。
1H NMR(400MHz,Chloroform-d)δ8.55(dd,J＝3.9,1.9Hz,1H),8.51(dd,J＝8.2,1.8Hz,1H),7.38(d,J＝8.1Hz,1H),7.21(dd,J＝8.2,4.0Hz,1H),7.02(dd,J＝8.2,1.9 Hz,1H),6.96(d,J＝2.0Hz,1H).
Figure PCTCN2021123627-appb-000010
具体实施步骤同Ⅱ A的制备，不同之处在于原料2-氨基-4-氯苯硫酚换为2-氨基-4-甲氧基苯硫酚，得到土黄色絮状物为Ⅱ B粗产品。
1H NMR(400MHz,DMSO-d 6)δ8.63–8.55(m,2H),7.37(dd,J＝8.2,4.6Hz,1H),7.14(d,J＝8.4Hz,1H),6.31(d,J＝2.7Hz,1H),6.19(dd,J＝8.5,2.7Hz,1H),5.35(s,2H),3.72(s,3H).
Figure PCTCN2021123627-appb-000011
具体实施步骤同Ⅱ A的制备，不同之处在于原料2-氨基-4-氯苯硫酚换为2-氨基-4-三氟甲基苯硫酚，得到土黄色固体为Ⅱ C粗产品。
1H NMR(400MHz,DMSO-d6)δ8.66–8.54(m,2H),7.48(d,J＝7.9Hz,1H),7.42(dd,J＝8.2,4.7Hz,1H),7.02(d,J＝2.0Hz,1H),6.82(dd,J＝7.9,2.0Hz,1H),5.86(s,2H).
实施例2中间体Ⅲ A、Ⅲ B、Ⅲ C的制备
Figure PCTCN2021123627-appb-000012
向干净的250mL反应瓶中依次加入醋酸酐100mL，10.0g II A，2.0mL吡啶，室温反应过液，TLC板监测反应完全，过滤，保留滤饼，滤液加入500mL水析出产物，过滤，合并滤饼，放入红外干燥箱，约90℃干燥过夜，得到黄色固体为Ⅲ A粗产品。
1H NMR(400MHz,CDCl3)δ8.01(dd,J＝4.8,1.6Hz,1H),7.26(dd,J＝7.6,2.0Hz,1H),6.95(d,J＝8.0Hz,1H),6.90(dd,J＝8.4,2.0Hz,1H),6.83(d,J＝2.0Hz,1H),6.79–6.76(m,1H),4.11(t,J＝6.4Hz,2H),3.61(t,J＝6.4Hz,2H),1.97–1.91(m,4H).
Figure PCTCN2021123627-appb-000013
具体实施步骤同IⅡ A的制备，不同之处在于原料II A换为II B，得到黄色固体为IⅡ B 粗产品。
1H NMR(400MHz,DMSO-d 6)δ9.03(s,1H),8.62(dd,J＝8.3,1.6Hz,1H),8.55(dd,J＝4.7,1.6Hz,1H),7.64–7.57(m,1H),7.48–7.37(m,2H),6.80(dd,J＝8.6,2.8Hz,1H),3.80(s,3H),1.90(s,3H).
Figure PCTCN2021123627-appb-000014
具体实施步骤同IⅡ A的制备，不同之处在于原料II A换为II C，得到黄色固体为IⅡ C。
1H NMR(400MHz,DMSO-d 6)δ9.40(s,1H),8.66(dd,J＝8.2,1.6Hz,1H),8.55(dd,J＝4.7,1.6Hz,1H),8.30(d,J＝2.0Hz,1H),7.81(d,J＝8.1Hz,1H),7.55(dd,J＝8.0,2.0Hz,1H),7.47(dd,J＝8.3,4.6Hz,1H),1.90(s,3H).
实施例3中间体Ⅳ A、Ⅳ B、Ⅳ C的制备
Figure PCTCN2021123627-appb-000015
向干净的250mL反应瓶中依次加入丙酮100mL，10.0g IⅡ A，5.2g KOH和1mL乙醇，升温至60℃左右，反应2h，TLC板监测反应完全，将反应体系降至室温，减压蒸除溶剂，剩余残渣柱层析纯化(石油醚：乙酸乙酯＝10:1)，得到黄色固体粗产品Ⅳ A。
Figure PCTCN2021123627-appb-000016
具体实施步骤同IV A的制备，不同之处在于原料III A换为III B，得到黄色固体为Ⅳ B。
1H NMR(400MHz,DMSO-d 6)δ8.50(dd,J＝4.8,1.7Hz,1H),8.12(dd,J＝7.8,1.7Hz,1H),7.97(d,J＝2.0Hz,1H),7.82(d,J＝8.2Hz,1H),7.68(dd,J＝8.4,2.0Hz,1H),7.45(dd,J＝7.9,4.8Hz,1H),3.75(s,3H),2.26(s,3H).
Figure PCTCN2021123627-appb-000017
具体实施步骤同IV A的制备，不同之处在于原料III A换为III C，得到黄色固体为Ⅳ C。
1H NMR(400MHz,Chloroform-d)δ7.81(dd,J＝5.1,1.6Hz,1H),7.19(dd,J＝7.6,1.6Hz,1H),7.07(ddd,J＝8.1,1.8,0.8Hz,1H),7.00(d,J＝8.0Hz,1H),6.78–6.73(m,2H).
实施例4中间体Ⅴ A、Ⅴ B、Ⅴ C的制备
Figure PCTCN2021123627-appb-000018
向干净的250mL反应瓶中依次加入2gⅣ A，60ml乙醇，2ml浓盐酸，升温至80℃左右，反应过夜，TLC板监测反应完全，将反应体系降至室温，减压蒸除溶剂，加氨水过滤得淡黄色固体Ⅴ A。
1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),7.83(dd,J＝4.9,1.6Hz,1H),7.30(dd,J＝7.6,1.6Hz,1H),6.94(d,J＝8.2Hz,1H),6.86(d,J＝2.2Hz,1H),6.82(dd,J＝8.2,2.2Hz,1H),6.76(dd,J＝7.5,4.9Hz,1H).
Figure PCTCN2021123627-appb-000019
具体实施步骤同V A的制备，不同之处在于原料IV A换为IV B，得到黄色固体为V B。
1H NMR(400MHz,Chloroform-d)δ7.72(d,J＝5.3Hz,1H),7.66(s,1H),7.24–7.19(m,1H),6.82(d,J＝8.5Hz,1H),6.72(t,J＝6.4Hz,1H),6.46(d,J＝8.6Hz,1H),6.24(d,J＝2.5Hz,1H),3.75(s,3H).
Figure PCTCN2021123627-appb-000020
具体实施步骤同V A的制备，不同之处在于原料IV A换为IV C，得到黄色固体为V C。
1H NMR(400MHz,Chloroform-d)δ7.81(dd,J＝5.1,1.6Hz,1H),7.19(dd,J＝7.6,1.6Hz,1H),7.07(ddd,J＝8.1,1.8,0.8Hz,1H),7.00(d,J＝8.0Hz,1H),6.79–6.70(m,2H).
实施例5中间体ⅤI A、ⅤI B、ⅤI C、ⅤI D、ⅤI E、ⅤI F的制备
Figure PCTCN2021123627-appb-000021
向干净的100mL反应瓶中依次加入DMF 50mL，10.0g中间体V A，20.1g1,5-二溴戊烷，5.1g氢氧化钾，室温反应1h，TLC板监测反应完全，加入150mL的水淬灭反应，乙酸乙酯萃取多次至水相没有产物点，合并有机相，饱和食盐水洗一次，无水硫酸钠 干燥，减压蒸除溶剂，剩余残渣柱层析纯化(石油醚：乙酸乙酯＝100:1，v/v)，得到灰黄色固体Ⅵ A。
1H NMR(400MHz,CDCl3)δ8.01(dd,J＝4.8,1.6Hz,1H),7.24(dd,J＝7.2,1.6Hz,1H),6.93–6.85(m,3H),6.77(dd,J＝7.6,4.8Hz,1H),4.08(t,J＝7.6Hz,2H),2.34(t,J＝7.2Hz,2H),1.86–1.78(m,2H),1.65–1.58(m,4H).
Figure PCTCN2021123627-appb-000022
具体实施步骤同Ⅵ A的制备，不同之处在于原料V A换为V B，得到黄色固体为Ⅵ B。
1H NMR(600MHz,Chloroform-d)δ8.01(s,1H),7.35–7.27(m,1H),6.96(d,J＝8.4Hz,1H),6.78(s,1H),6.47(d,J＝2.3Hz,2H),4.12(p,J＝6.5,5.9Hz,2H),3.79(s,3H),3.42(t,J＝6.8Hz,2H),1.92(dt,J＝15.0,6.9Hz,2H),1.84(q,J＝7.6Hz,2H),1.63–1.56(m,2H).
Figure PCTCN2021123627-appb-000023
具体实施步骤同VI A的制备，不同之处在于原料V A换为V C，得到黄色固体为Ⅵ C。
1H NMR(400MHz,Chloroform-d)δ8.06(d,J＝4.9Hz,1H),7.34(d,J＝7.4Hz,1H),7.19(d,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H),7.04(s,1H),6.86(dd,J＝7.4,4.9Hz,1H),4.19(t,J＝7.2Hz,2H),3.42(t,J＝6.7Hz,2H),1.96–1.87(m,2H),1.83(q,J＝7.5Hz,2H),1.61(dd,J＝10.4,5.0Hz,2H).
Figure PCTCN2021123627-appb-000024
具体实施步骤同VI A的制备，不同之处在于原料V A换为10H-吡啶并(3,2-b)(1,4)苯并噻嗪，得到黄色固体为VI D。
1H NMR(400MHz,Chloroform-d)δ7.99(d,J＝4.9Hz,1H),7.24(dd,J＝7.5,1.8Hz, 1H),7.14(t,J＝7.8Hz,1H),7.05(dd,J＝7.6,1.6Hz,1H),6.91(t,J＝7.5Hz,1H),6.84(d,J＝8.2Hz,1H),6.78–6.68(m,1H),4.10(q,J＝8.3Hz,2H),3.42(t,J＝6.7Hz,2H),1.88(dp,J＝35.3,7.3Hz,4H),1.60(q,J＝8.0Hz,2H).
Figure PCTCN2021123627-appb-000025
具体实施步骤同Ⅵ A的制备，不同之处在于原料1,5-二溴戊烷换为1,4-二溴丁烷，得到黄色油状物为Ⅵ E。
1H NMR(400MHz,Chloroform-d)δ7.28(d,J＝3.5Hz,1H),6.98(d,J＝8.4Hz,2H),6.92(dd,J＝8.3,2.2Hz,1H),6.88–6.76(m,2H),4.13(t,J＝7.3Hz,2H),3.55–3.40(m,4H),2.04–1.95(m,2H).
Figure PCTCN2021123627-appb-000026
具体实施步骤同Ⅵ A的制备，不同之处在于原料1,5-二溴戊烷换为1,6-二溴已烷，得到黄色油状物为Ⅵ F。
1H NMR(400MHz,Chloroform-d)δ8.01(dd,J＝5.0,1.7Hz,1H),7.26–7.22(m,1H),6.94(d,J＝8.1Hz,1H),6.88(dd,J＝8.2,2.0Hz,1H),6.82–6.74(m,2H),4.11–4.01(m,2H),3.56–3.37(m,2H),1.91–1.75(m,4H),1.49(dt,J＝8.9,5.3Hz,4H).
实施例6 10-(5-(3-氮杂螺环[5.5]十一碳-3-基)戊基)-8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪(X01)的制备
Figure PCTCN2021123627-appb-000027
向干净的50mL单口圆底烧瓶中依次加入15mL乙腈，200mg的中间体VI A、87mg K 2CO 3，95mg 3-氮螺环[5,5]十一烷，60℃回流反应过夜，过滤减压蒸馏，柱层析 纯化(二氯甲醇：甲醇＝20：1，v/v)，得到黄色油状物X01。
1H NMR(400MHz,Chloroform-d)δ7.93(dd,J＝4.9,1.6Hz,1H),7.16(dd,J＝7.5,1.7Hz,1H),6.86(d,J＝8.1Hz,1H),6.80(dd,J＝8.2,1.9Hz,1H),6.74–6.67(m,2H),3.97(t,J＝7.3Hz,2H),2.36(t,6H),1.74(p,J＝7.4Hz,3H),1.46(m,6H),1.40–1.31(m,8H),1.25(m,J＝7.0Hz,4H).HRMS(ESI)m/z calcd for C 26H 34ClN 3S(M+H) +456.2162,found 456.2242.
实施例7 9-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-3,9-二氮螺环[5.5]十一碳-3-羧酸叔丁酯(X02)的制备
Figure PCTCN2021123627-appb-000028
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为3-甲基-3,9-二氮杂螺[5,5]十一烷-3-甲酸叔丁酯，得到黄色油状物X02。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝5.0,1.7Hz,1H),7.24(d,J＝1.7Hz,1H),6.95(d,J＝8.2Hz,1H),6.88(dd,J＝8.2,1.9Hz,1H),6.80–6.75(m,2H),4.05(t,J＝7.1Hz,2H),3.37(t,J＝5.9Hz,4H),2.75(m,4H),1.83(m,J＝7.6Hz,8H),1.45(m,17H).HRMS(EI)m/z calcd for C 30H 41ClN 4O 2S(M +)556.2639,found 556.2630.
实施例8 7-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-2,7-二氮螺环[4.4]壬烷-2-羧酸叔丁酯(X03)的制备
Figure PCTCN2021123627-appb-000029
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为2,7-二氮杂螺[4.4]壬烷-2-甲酸叔丁酯，得到黄色油状物X03。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.2,1.9Hz,1H),6.80–6.75(m,2H),4.05(t,J＝7.2Hz,2H),3.44–3.22(m,5H),2.58(m,4H),1.94–1.77(m,6H),1.68(m,4H),1.46(m,11H).HRMS(EI)m/z calcd forC 28H 37ClN 4O 2S(M +)528.2326,found 528.2322.
实施例9 8-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-2,8-二氮螺环[4.5]癸烷-2-羧酸叔丁酯(X04)的制备
Figure PCTCN2021123627-appb-000030
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为2,8-二氮杂螺[4.5]癸-2-羧酸叔丁酯，得到黄色油状物X04。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.1,2.0Hz,1H),6.81–6.74(m,2H),4.05(t,J＝7.2Hz,2H),3.38(dt,J＝21.4,7.1Hz,2H),3.17(d,J＝33.0Hz,2H),1.90–1.55(m,13H),1.46(s,14H).HRMS(EI)m/z calcd for C 29H 39ClN 4O 2S(M +)542.2842,found 542.2478.
实施例10 4-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-1-氧代-4,9-二氮螺环[5.5]十一碳-9-羧酸叔丁酯(X05)的制备
Figure PCTCN2021123627-appb-000031
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为1-氧杂-4,9-二氮杂螺[5.5]十一烷-9-甲酸叔丁酯，得到黄色油状物X05。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.25–7.21(m,1H),6.94(d,J＝8.1Hz,1H),6.88(dd,J＝8.2,1.9Hz,1H),6.81–6.74(m,2H),4.05(t,J＝7.2Hz,2H),3.70(m,4H),3.12(m,2H),2.43–2.07(m,6H),1.80(d,J＝7.5Hz,3H),1.62(m,3H),1.46(m,16H).HRMS(EI)m/z calcd for C 29H 39ClN 4O 3S(M +)558.2431,found 558.2429.
实施例11 6-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-2,6-二氮螺环[3.4]辛烷-2-羧酸叔丁酯(X06)的制备
Figure PCTCN2021123627-appb-000032
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为2,6-二氮-螺[3.4]辛烷-2-碳酸叔丁酯，得到黄色油状物X06。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.1Hz,1H),6.88(dd,J＝8.2,1.9Hz,1H),6.81–6.74(m,2H),4.04(t,J＝7.3Hz,2H),3.85(q,J＝8.6Hz,4H),2.70(d,J＝49.7Hz,4H),2.48(d,J＝7.8Hz,2H),2.07(t,J＝7.1Hz,2H),1.81(p,J＝7.4Hz,3H),1.60(t,J＝7.8Hz,3H),1.44(m,11H).HRMS(EI)m/z calcd for C 27H 35ClN 4O 2S(M +)514.2169,found 514.2171.
实施例12 2-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-2,8-二氮螺环[4.5]癸烷-8-羧酸叔丁酯(X07)的制备
Figure PCTCN2021123627-appb-000033
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为2,8-二氮杂螺[4.5]癸烷-8-羧酸叔丁酯，得到黄色油状物X07。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.2,2.0Hz,1H),6.81–6.74(m,2H),4.04(t,J＝7.2Hz,2H),3.41(dt,J＝11.3,5.4Hz,2H),3.35–3.26(m,2H),2.55(m,4H),1.81(p,J＝7.4Hz,12H),1.45(m,12H).HRMS(EI)m/z calcd for C 29H 39ClN 4O 2S(M +)542.2482,found 542.2483.
实施例13 7-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-2,7-二氮螺环[3.5]壬烷-2-羧酸叔丁酯(X08)的制备
Figure PCTCN2021123627-appb-000034
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为2-叔丁氧羰基-2,7-二氮杂螺[3.5]壬烷，得到黄色油状物X08。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.23(dd,J＝7.5,1.7Hz,1H),6.93(d,J＝8.1Hz,1H),6.87(dd,J＝8.2,1.9Hz,1H),6.80–6.74(m,2H),4.03(t,J＝7.3Hz,2H),3.60(m,4H),2.35(m,4H),1.80(p,J＝7.4Hz,7H),1.44(m,14H).HRMS(EI)m/z calcd for C 28H 37ClN 4O 2S(M +)528.2326,found 528.2323.
实施例14 2-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-2,7-二氮螺环[3.5]壬烷-7-羧酸叔丁酯(X09)的制备
Figure PCTCN2021123627-appb-000035
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯，得到黄色油状物X09。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.2,2.0Hz,1H),6.81–6.74(m,2H),4.04(t,J＝7.2Hz,2H),3.38–3.27(m,6H),2.77(t,J＝7.8Hz,2H),1.80(d,J＝7.1Hz,6H),1.60(q,J＝7.8Hz,2H),1.45(s,13H).HRMS(EI)m/z calcd for C 28H 37ClN 4O 2S(M +)528.2326,found 528.2324.
实施例15 2-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-2,9-二氮螺环[5.5]十一碳-9-羧酸叔丁酯(X10)的制备
Figure PCTCN2021123627-appb-000036
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为2,9-二氮杂螺[5.5]十一烷-2-甲酸叔丁酯，得到黄色油状物X10。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.23(dd,J＝7.4,1.7Hz,1H),6.93(d,J＝8.2Hz,1H),6.87(dd,J＝8.2,2.0Hz,1H),6.81–6.73(m,2H),4.04(t,J＝7.3Hz,2H),3.34(m,4H),2.25(m,4H),1.80(p,J＝7.4Hz,2H),1.45(m,21H),1.28(m,J＝18.4Hz,2H).HRMS(EI)m/z calcd for C 30H 41ClN 4O 2S(M +)556.2639,found 556.2635.
实施例16 6-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-2,6-二氮螺环[3.4]辛烷-2-羧酸叔丁酯(X11)的制备
Figure PCTCN2021123627-appb-000037
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为2,6-二氮-螺[3.4]辛烷-2-羧酸叔丁酯，得到黄色油状物X11。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.1,1.9Hz,1H),6.80–6.74(m,2H),4.05(t,J＝7.3Hz,2H),3.93–3.79(m,5H),2.85–2.38(m,6H),2.15–2.02(m,2H),1.81(p,J＝7.4Hz,3H),1.44(d,J＝4.2Hz,13H).HRMS(EI)m/z calcd for C 27H 35ClN 4O 2S(M +)514.2169,found 514.2163.
实施例17 8-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-1,8-二氮螺环[4.5]癸烷-1-羧酸叔丁酯(X12)的制备
Figure PCTCN2021123627-appb-000038
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为1,8-二氮杂-螺[4.5]癸烷-1-羧酸叔丁酯，得到黄色油状物X12。
1H NMR(400MHz,Chloroform-d)δ8.01(dd,J＝4.9,1.7Hz,1H),7.23(dd,J＝7.4,1.7Hz,1H),6.93(d,J＝8.2Hz,1H),6.87(dd,J＝8.2,2.0Hz,1H),6.82–6.72(m,2H),4.03(t,J＝7.3Hz,2H),3.42(m,2H),2.88(m,4H),1.92–1.67(m,8H),1.55–1.18(m,15H).HRMS(EI)m/z calcd for C 29H 39ClN 4O 2S(M +)542.2482,found 542.2457.
实施例18 1-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-1,8-二氮螺环[4.5]癸烷-8-羧酸叔丁酯(X13)的制备
Figure PCTCN2021123627-appb-000039
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为1,8-二氮杂螺[4.5]癸烷-8-甲酸叔丁酯，得到黄色油状物X13。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝5.0,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.1,1.9Hz,1H),6.81–6.74(m,2H),4.23–3.98(m,5H),2.74(s,4H),1.59(m,7H),1.46(m,13H),1.27(d,J＝12.4Hz,3H).HRMS(EI)m/z calcd for C 29H 39ClN 4O 2S(M +)542.2482,found 542.2488.
实施例19 1-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-1,7-二氮螺环[3.5]壬烷-7-羧酸叔丁酯(X14)的制备
Figure PCTCN2021123627-appb-000040
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为1,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯，得到黄色油状物X14。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝5.0,1.7Hz,1H),7.23(dd,J＝7.4,1.7Hz,1H),6.93(d,J＝8.2Hz,1H),6.87(dd,J＝8.2,2.0Hz,1H),6.81–6.73(m,2H),4.03(t,J＝7.3Hz,3H),2.67(d,J＝13.7Hz,3H),2.48(m,2H),1.97(m,3H),1.88–1.72(m,4H),1.59 (d,J＝17.8Hz,4H),1.45(m,15H).HRMS(EI)m/z calcd for C 28H 37ClN 4O 2S(M +)528.2326,found 528.2328.
实施例20 2-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-2,6-二氮螺环[3.4]辛烷-6-羧酸叔丁酯(X15)的制备
Figure PCTCN2021123627-appb-000041
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯，得到黄色油状物X15。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.1Hz,1H),6.88(dd,J＝8.2,2.0Hz,1H),6.80–6.75(m,2H),4.04(t,J＝7.2Hz,2H),3.45(s,4H),3.33(d,J＝14.6Hz,5H),1.80(p,J＝7.3Hz,3H),1.45(s,17H).HRMS(EI)m/z calcd for C 27H 35ClN 4O 2S(M +)514.2169,found 514.2164.
实施例21 6-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-2,6-二氮螺环[3.3]庚烷-2-羧酸叔丁酯(X16)的制备
Figure PCTCN2021123627-appb-000042
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯，得到黄色油状物X16。
1H NMR(400MHz,Chloroform-d)δ8.00(d,J＝4.9Hz,1H),7.24(d,J＝7.4Hz,1H),6.94(d,J＝8.1Hz,1H),6.90–6.85(m,1H),6.80–6.73(m,2H),4.00(d,J＝18.7Hz,6H),3.30(s,4H),2.40(t,J＝6.7Hz,2H),1.79(q,J＝7.2Hz,2H),1.43(s,14H).HRMS(EI)m/z calcd for C 26H 33ClN 4O 2S(M +)500.2013,found 500.2018.
实施例22 9-苄基-3-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-3,9-二氮螺环[5.5]十一烷-2,4-二酮(X17)的制备
Figure PCTCN2021123627-appb-000043
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为9-苄基-3,9-二杂氮[5.5]十一烷-2,4-二酮，得到黄色油状物X17。
1H NMR(400MHz,Chloroform-d)δ7.98(dd,J＝4.9,1.7Hz,1H),7.33(s,4H),7.21(dd,J＝7.5,1.7Hz,1H),6.91(d,J＝8.2Hz,1H),6.85(dd,J＝8.1,2.0Hz,1H),6.81–6.70(m,2H),4.01(t,J＝7.3Hz,2H),3.75(t,J＝7.5Hz,2H),3.57(m,2H),2.57(s,7H),1.79(p,J＝7.5Hz,2H),1.71–1.47(m,7H),1.45–1.21(m,4H).HRMS(EI)m/z calcd for C 32H 35ClN 4O 2S(M +)574.2169,found 574.2159.
实施例23 8-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-2,8-二氮螺环[4.5]癸烷-1,3-二酮(X18)的制备
Figure PCTCN2021123627-appb-000044
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为2,8-二氮杂螺[4.5]癸烷-1,3-二酮盐酸盐，得到黄色油状物X18。
1H NMR(400MHz,DMSO-d 6)δ11.10(s,1H),8.05(dd,J＝4.9,1.7Hz,1H),7.46(dd,J＝7.5,1.7Hz,1H),7.12(d,J＝7.9Hz,1H),7.01(d,J＝7.9Hz,2H),6.91(dd,J＝7.5,4.8Hz,1H),4.06(t,J＝7.1Hz,2H),2.71(m,2H),2.23(m,2H),1.90–1.62(m,6H),1.56–1.15(m,8H).HRMS(EI)m/z calcd for C 24H 27ClN 4O 2S(M +)470.1543,found 470.1541.
实施例24 10-(5-(3,9-二氮螺环[5.5]十一碳-3-基)戊基)-8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪(X19)的制备
Figure PCTCN2021123627-appb-000045
向干净的圆底烧瓶中加入200mg X02、10mL三氟乙酸和10mL二氯甲烷，室温反应2小时得黄色油状物X19。
1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),9.04(s,2H),8.07(dd,J＝4.9,1.5Hz,1H),7.49(dd,J＝7.6,1.6Hz,1H),7.14(d,J＝8.1Hz,1H),7.08–6.99(m,2H),6.93(dd,J＝7.5,4.9Hz,1H),4.06(d,J＝7.1Hz,3H),3.25(d,J＝12.5Hz,2H),3.00(dt,J＝12.0,5.7Hz,8H),1.86–1.61(m,10H),1.53(t,J＝5.8Hz,2H),1.40(p,J＝7.6Hz,2H).HRMS(ESI)m/z calcd for C 25H 33ClN 4S(M+H) +457.2114,found 457.2170.
实施例25 8-氯-10-(5-(9-(丙-2-炔-1-基)-3,9-二氮螺环[5.5]十一碳-3-基)戊基)-10H苯并[b]吡啶[2,3-e][1,4]噻嗪(X20)的制备
Figure PCTCN2021123627-appb-000046
向干净的圆底烧瓶中加入200mg X19、90mg 3-氯丙炔、120mg K 2CO 3和10mL乙腈，60℃回流过夜，得黄色油状物X20。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.4,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.87(dd,J＝8.2,1.9Hz,1H),6.81–6.73(m,2H),4.04(t,J＝7.3Hz,2H),3.31(d,J＝2.4Hz,2H),2.50(q,J＝12.4,9.0Hz,9H),2.24(t,J＝2.4Hz,1H),1.81(p,J＝7.5Hz,3H),1.55(d,J＝11.1Hz,10H),1.49–1.39(m,3H),1.34–1.18(m,3H).HRMS(EI)m/z calcd for C 28H 35ClN 4S(M +)494.2271,found 494.2275.
实施例26 1-(9-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-3,9-二氮螺环[5.5]十一碳-3-基)乙烷-1-酮(X21)的制备
Figure PCTCN2021123627-appb-000047
具体实施步骤同实施例25，不同之处在于原料3-氯丙炔换为乙酰氯，得到黄色油状物X21。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(d,J＝1.6Hz,1H),6.95(d,J＝8.2Hz,1H),6.89(dd,J＝8.2,1.9Hz,1H),6.81–6.76(m,2H),4.06(t,J＝7.0Hz,2H),3.56(t,J＝5.7Hz,2H),3.42(d,J＝7.7Hz,4H),2.95(s,2H),2.74(s,2H),2.09(s,4H),1.83(ddd,J＝24.2,16.8,12.2Hz,7H),1.27(d,J＝12.3Hz,2H).HRMS(EI)m/z calcd for C 27H 35ClN 4OS(M+H) +499.2220,found 499.2270.
实施例27 8-氯-10-(5-(9-丙基-3,9-二氮螺环[5.5]十一碳-3-基)戊基)-10H苯并[b]吡啶[2,3-e][1,4]噻嗪(X22)的制备
Figure PCTCN2021123627-appb-000048
具体实施步骤同实施例25，不同之处在于原料3-氯丙炔换为1-氯丙烷，得到黄色油状物X22。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.23(d,J＝1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.2,1.9Hz,1H),6.80–6.73(m,2H),4.04(t,J＝7.3Hz,2H),2.48(s,6H),1.81(p,J＝7.5Hz,4H),1.63(s,18H),1.46(q,J＝7.8Hz,3H),1.27(d,J＝12.3Hz,2H),0.92(t,J＝7.4Hz,3H).HRMS(EI)m/z calcd for C 28H 39ClN 4S(M +)498.2584,found 498.2578.
实施例28 8-氯-10-(5-(9-(吡啶-2-基甲基)-3,9-二氮螺环[5.5]十一碳-3-基)戊基)-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪(X23)的制备
Figure PCTCN2021123627-appb-000049
具体实施步骤同实施例25，不同之处在于原料3-氯丙炔换为2-氯甲基吡啶，得到黄色油状物X23。
1H NMR(400MHz,Chloroform-d)δ8.57(d,J＝4.4Hz,1H),8.00(d,J＝4.3Hz,1H),7.67(t,J＝7.5Hz,1H),7.44(s,1H),7.21(dd,J＝12.8,7.1Hz,3H),6.94(d,J＝8.2Hz,1H),6.88(d,J＝8.2Hz,1H),6.79(d,J＝9.2Hz,2H),4.05(t,J＝6.8Hz,2H),3.74(m,2H),2.89(m,4H),2.56(m,4H),1.85(dt,J＝14.7,6.9Hz,9H),1.65(s,4H),1.54–1.41(m,3H).HRMS(EI)m/z calcd for C 32H 39ClN 4S(M-H) -546.2536,found 546.2465.
实施例29 8-氯-10-(5-(9-甲基-3,9-二氮螺环[5.5]十一碳-3-基)戊基)-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪(X24)的制备
Figure PCTCN2021123627-appb-000050
向干净的圆底烧瓶中加入800mg X19、1g多聚甲醛、300mg硼氢化钠和10mL三氟乙醇，室温反应3小时，得黄色油状物X24。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.2,1.9Hz,1H),6.81–6.72(m,2H),4.04(t,J＝7.3Hz,2H),2.50(d,J＝18.2Hz,8H),2.39(s,3H),1.81(p,J＝7.4Hz,2H),1.64(t,J＝5.8Hz,10H),1.46(h,J＝7.5,6.4Hz,2H),1.33(t,J＝7.3Hz,2H).HRMS(EI)m/z calcd for C 26H 35ClN 4S(M +)470.2271,found 470.2263.
实施例30 10-(5-(9-苄基-3,9-二氮螺环[5.5]十一碳-3-基)戊基)-8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪(X25)的制备
Figure PCTCN2021123627-appb-000051
具体实施步骤同实施例25，不同之处在于原料3-氯丙炔换为苄氯，得到黄色油状物X25。
1H NMR(400MHz,Chloroform-d)δ7.99(dd,J＝4.9,1.7Hz,1H),7.31(d,J＝4.3Hz,4H),7.26–7.20(m,2H),6.93(d,J＝8.1Hz,1H),6.87(dd,J＝8.2,1.9Hz,1H),6.80–6.73(m,2H),4.03(t,J＝7.2Hz,2H),3.52(s,2H),2.66–2.46(m,6H),2.40(d,J＝5.7Hz,4H),1.82(q,J＝7.4Hz,2H),1.63(q,J＝7.7,5.6Hz,6H),1.52(t,J＝5.6Hz,4H),1.45(p,J＝7.8Hz,3H).HRMS(EI)m/z calcd for C 32H 39ClN 4S(M +)546.2584,found 546.2574.
实施例31 8-氯-10-(5-(9-(4-氯苄基)-3,9-二氮螺环[5.5]十一碳-3-基)戊基)-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪(X26)的制备
Figure PCTCN2021123627-appb-000052
具体实施步骤同实施例25，不同之处在于原料3-氯丙炔换为4-氯苄氯，得到黄色油状物X26。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝5.1,1.7Hz,1H),7.28(d,J＝2.4Hz,2H),7.26–7.19(m,3H),6.93(d,J＝8.1Hz,1H),6.87(dd,J＝8.3,1.9Hz,1H),6.81–6.72(m,2H),4.03(t,J＝7.3Hz,2H),3.45(s,2H),2.76(s,2H),2.46–2.31(m,8H),1.80(p,J＝7.5Hz,2H),1.47(td,J＝21.4,20.1,10.5Hz,14H).
实施例32 9-(5-(8-(三氟甲基)-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-3,9-二氮螺环[5.5]十一烷-3-羧酸叔丁酯(X27)的制备
Figure PCTCN2021123627-appb-000053
具体实施步骤同实施例7，不同之处在于原料Ⅵ A换为Ⅵ C，得到黄色油状物X27。
1H NMR(400MHz,Chloroform-d)δ8.01(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),7.16–7.08(m,2H),6.96(d,J＝1.5Hz,1H),6.79(dd,J＝7.5,4.9Hz,1H),4.10(q,J ＝7.5Hz,2H),3.37(t,J＝5.8Hz,4H),2.70(s,4H),1.83(p,J＝7.4Hz,5H),1.45(s,15H),1.31–1.21(m,2H).HRMS(EI)m/z calcd for C 31H 41F 3N 4O 2S(M +)590.2902,found 590.2897.
实施例33 9-(5-(8-甲氧基-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-3,9-二氮螺环[5.5]十一烷-3-羧酸叔丁酯(X28)的制备
Figure PCTCN2021123627-appb-000054
具体实施步骤同实施例7，不同之处在于原料Ⅵ A换为Ⅵ B，得到黄色油状物X28。
1H NMR(400MHz,Chloroform-d)δ7.99(dd,J＝5.0,1.7Hz,1H),7.25(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.3Hz,1H),6.74(dd,J＝7.5,4.9Hz,1H),6.51–6.43(m,2H),4.07(q,J＝7.1Hz,2H),3.78(s,3H),3.36(t,J＝5.8Hz,4H),1.83(p,J＝7.4Hz,2H),1.63(m,6H),1.45(m,15H).HRMS(EI)m/z calcd for C 31H 44N 4O 3S(M +)552.3134,found 552.3132.
实施例34 9-(5-(10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-3,9-二氮螺环[5.5]十一碳-3-羧酸叔丁酯(X29)的制备
Figure PCTCN2021123627-appb-000055
具体实施步骤同实施例7，不同之处在于原料Ⅵ A换为Ⅵ D，得到黄色油状物X29。
1H NMR(400MHz,Chloroform-d)δ7.98(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),7.13(ddd,J＝8.4,7.4,1.6Hz,1H),7.04(dd,J＝7.6,1.6Hz,1H),6.90(td,J＝7.5,1.1Hz,1H),6.84(dd,J＝8.2,1.1Hz,1H),6.74(dd,J＝7.4,4.9Hz,1H),4.12–4.03(m,2H),3.41–3.32(m,4H),3.02(q,J＝7.3Hz,2H),1.83(p,J＝7.4Hz,2H),1.66(m,6H),1.45(m,15H),1.36(t,J＝7.3Hz,2H).HRMS(ESI)m/z calcd for C 30H 42N 4O 2S(M+H) +523.3028,found 523.3075.
实施例35 9-(4-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)丁基)-3,9-二氮螺环[5.5]十一烷-3-羧酸叔丁酯(X30)的制备
Figure PCTCN2021123627-appb-000056
具体实施步骤同实施例7，不同之处在于原料Ⅵ A换为Ⅵ E，得到黄色油状物X30。
1H NMR(600MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.26–7.23(m,1H),6.95(d,J＝8.2Hz,1H),6.89(dd,J＝8.3,1.9Hz,1H),6.82–6.75(m,2H),4.10(dq,J＝23.5,6.2,5.3Hz,4H),3.36(t,J＝5.8Hz,4H),2.05(m,2H),1.84(m,2H),1.56(m,6H),1.45(m,13H),1.26(t,J＝7.1Hz,2H).HRMS(ESI)m/z calcd for C 29H 39ClN 4O 2S(M+H) +543.2482,found 543.2520.
实施例36 9-(6-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)己基)-3,9-二氮螺环[5.5]十一烷-3-羧酸叔丁酯(X31)的制备
Figure PCTCN2021123627-appb-000057
具体实施步骤同实施例7，不同之处在于原料Ⅵ A换为Ⅵ F，得到黄色油状物X31。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.2,2.0Hz,1H),6.80–6.74(m,2H),4.03(t,J＝7.3Hz,2H),3.37(dd,J＝7.0,4.5Hz,4H),2.60(m,4H),1.84–1.59(m,8H),1.45(m,19H).HRMS(ESI)m/z calcd for C 31H 43ClN 4O 2S(M+H) +571.2795,found 571.2843.
实施例37 8-甲氧基-10-(5-(9-甲基-3,9-二氮螺环[5.5]十一碳-3-基)戊基)-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪(X32)的制备
Figure PCTCN2021123627-appb-000058
向干净的圆底烧瓶中加入200mg X28、10mL三氟乙酸和10mL二氯甲烷，室温反应2小时后旋干，加入1g多聚甲醛、300mg硼氢化钠和10mL三氟乙醇，室温反应3小时，得黄色油状物X32。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.27(dd,J＝7.4,1.8Hz,1H),6.96(d,J＝8.4Hz,1H),6.76(dd,J＝7.4,4.9Hz,1H),6.53–6.42(m,2H),4.08(t,J＝7.1Hz,2H),3.80(s,3H),3.13(q,J＝7.3Hz,4H),2.72(d,J＝29.9Hz,8H),2.55(s,3H),1.85(p,J＝7.4Hz,2H),1.47(p,J＝7.4Hz,2H),1.34(t,J＝7.3Hz,6H).HRMS(ESI)m/z calcd for C 27H 38N 4OS(M+H) +467.2766,found 467.2810.
实施例38(1R，4R)-5-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(X33)的制备
Figure PCTCN2021123627-appb-000059
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为(1R,4R)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯，得到黄色油状物X33。
1H NMR(400MHz,Chloroform-d)δ7.92(dd,J＝4.9,1.7Hz,1H),7.14(dd,J＝7.5,1.7Hz,1H),6.84(d,J＝8.2Hz,1H),6.78(dd,J＝8.2,2.0Hz,1H),6.72–6.65(m,2H),4.18(d,J＝50.3Hz,1H),3.96(t,J＝7.3Hz,2H),3.48–3.34(m,2H),3.04(ddd,J＝10.2,7.8,2.2Hz,1H),2.84(ddd,J＝34.1,9.6,2.2Hz,1H),2.58–2.38(m,3H),1.73(q,J＝6.8Hz,3H),1.59(dd,J＝19.4,9.7Hz,1H),1.49–1.39(m,4H),1.38(d,J＝2.0Hz,9H).HRMS(ESI)m/z calcd for C 26H 33ClN 4O 2S(M+H) +501.2013,found 501.2105.
实施例39 3-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-3,6-二氮杂环[3.1.1]庚烷-6-羧酸叔丁酯(X34)的制备
Figure PCTCN2021123627-appb-000060
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷，得到黄色油状物X34。
1H NMR(400MHz,Chloroform-d)δ7.93(dd,J＝4.9,1.7Hz,1H),7.16(dd,J＝7.5,1.7Hz,1H),6.86(d,J＝8.1Hz,1H),6.80(dd,J＝8.2,2.0Hz,1H),6.74–6.67(m,2H),3.96(t,J ＝7.4Hz,4H),3.01(s,1H),2.87(s,1H),2.73(s,2H),2.44(t,J＝7.3Hz,2H),2.28(q,J＝6.6Hz,1H),1.72(q,J＝7.4Hz,2H),1.67–1.61(m,1H),1.48(p,J＝7.1Hz,2H),1.39(s,2H),1.37(s,9H).HRMS(ESI)m/z calcd for C 26H 33ClN 4O 2S(M+H) +501.2013,found 501.2147.
实施例40(1S，4S)-5-(5-(8-氯-10H-苯并[b]吡啶[2,3-e][1,4]噻嗪-10-基)戊基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(X35)的制备
Figure PCTCN2021123627-appb-000061
具体实施步骤同实施例6，不同之处在于原料3-氮螺环[5,5]十一烷换为(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯，得到黄色油状物X35。
1H NMR(400MHz,Chloroform-d)δ7.93(dd,J＝4.9,1.6Hz,1H),7.17(dd,J＝7.5,1.7Hz,1H),6.87(d,J＝8.1Hz,1H),6.80(dd,J＝8.2,1.9Hz,1H),6.74–6.67(m,2H),4.21(d,J＝50.8Hz,1H),3.97(t,J＝7.3Hz,2H),3.45(t,J＝12.4Hz,2H),3.06(t,J＝8.8Hz,1H),2.89(d,J＝37.7Hz,1H),2.56–2.35(m,3H),1.74(dd,J＝14.9,7.6Hz,3H),1.66–1.59(m,1H),1.51–1.39(m,4H),1.38(d,J＝2.0Hz,9H).HRMS(ESI)m/z calcd for C 26H 33ClN 4O 2S(M+H) +501.2013,found 501.2129.
实施例41本发明化合物对子宫内膜癌细胞的增殖抑制作用
本发明通过CCK-8实验评价10-取代-1-氮杂吩噻嗪衍生物对子宫内膜癌细胞的增殖抑制活性。
1、实验材料和方法
子宫内膜癌细胞ISK和KLE购自于美国模式菌种收集中心(ATCC)；磷酸盐缓冲盐溶液(PBS)购自于Bio-channel公司；DMEM/F12培养基购自于Biosharp公司；胎牛血清(FBS)和胰蛋白酶购自于Gibco公司；CCK-8购自于碧云天生物科技有限公司。
ISK和KLE细胞用DMEM/F12(含10％胎牛血清，1％青霉素/链霉素)培养基，并置于37℃，5％CO 2的培养箱中培养。待子宫内膜癌细胞基本长满细胞培养皿(10cm)后，用胰蛋白酶将细胞消化下来，并以5000个/孔的细胞密度种到96孔板中，每孔100μL。培养过夜，待细胞贴壁后，分别加入含不同浓度衍生物的DMEM/F12培养基，每孔200μL，每组设3个复孔。在细胞培养箱中孵育48h。随后去除培养基，每孔加入100μL含10％CCK-8的无血清培养基，在培养箱中37℃孵育1h后，使用Bio-Tek多功能酶标仪检测在450nm处的吸光值A，计算抑制率和IC 50值。抑制率计算公式：细胞抑制率％＝[1-(给药组A值-空白组A值)/(对照组A值-空白组A值)]×100％，IC 50值通过Graphpad Prism 8.0软件拟合。
2、实验结果
10-取代-1-氮杂吩噻嗪衍生物对子宫内膜癌细胞的增殖抑制活性如表1和表2所示， 结果表明，衍生物对子宫内膜癌细胞ISK和KLE的增殖均具有显著的抑制作用。
表1 10-取代-1-氮杂吩噻嗪类衍生物对ISK细胞的增殖抑制活性结果
Figure PCTCN2021123627-appb-000062
表2 10-取代-1-氮杂吩噻嗪类衍生物对KLE细胞的增殖抑制活性结果
Figure PCTCN2021123627-appb-000063
实施例42本发明化合物对子宫内膜癌细胞克隆形成的抑制作用
本发明在细胞水平上通过平皿克隆形成实验测试化合物X32对子宫内膜癌细胞ISK和KLE克隆形成能力的影响。研究结果表明，化合物X32能够浓度依赖性地抑制子宫内膜癌细胞ISK和KLE的克隆形成。
1、实验材料和方法
0.5％的结晶紫染液购自于碧云天生物科技有限公司；甲醇为实验室常用试剂，商业购买，未经任何处理。其余实验材料来源同实施例41。取对数生长期的EC细胞，用胰蛋白酶消化下来制备成单细胞混悬液，以每孔约1000个细胞的密度接种至6孔板，过夜培养。待细胞贴壁后，分成4组，分别为对照组和不同的给药组，每组设3个复孔。给药组用含不同浓度药物的DMEM/F12培养基2mL，对照组加不含药物的培养基，培养48h，之后换成无药的培养基继续培养8天左右。待细胞长成肉眼可见的细胞群落后，置于冰上，用预冷的PBS清洗细胞两次，每次3min。然后用预冷的甲醇，于-20℃固定细胞10min。吸除甲醇，加入结晶紫染液1mL，染色30min。移除结晶紫染液，清水清洗至染液被洗脱完毕。倒扣6孔板待其晾干，用凝胶成像仪拍照，Image J软件手动计数，统计各个孔的克隆形成数。
2、实验结果
实验结果如图1所示，图中Ctrl为对照组，照片中的每一个黑点表示一个细胞群落。结果表明，对于ISK细胞，与Ctrl相比，给药组的细胞群落数量减少，且随着化合物X32浓度的增加而明显减少，尤其是化合物X32的2μM组，说明化合物X32对ISK细胞的克隆形成具有抑制作用，并且能够浓度依赖性地抑制子宫内膜癌细胞ISK的克隆形成。对于KLE细胞，与对照组相比，给药组的细胞群落数量也有所减少，且随着化合物X32浓度的增加而明显减少，说明化合物X32对KLE细胞的克隆形成具有抑制作用，并且能够浓度依赖性地抑制子宫内膜癌细胞KLE的克隆形成。柱状图纵坐标表示各组细胞群落的数目，数据显著性差异采用One-way ANOVA法分析(Graphpad Prism 8.0软件)。
实施例43本发明化合物对子宫内膜癌细胞迁移能力的抑制作用
本发明在细胞水平上通过Transwell实验测试了化合物X32对子宫内膜癌细胞ISK和KLE迁移能力的影响。研究结果表明，X32能够抑制子宫内膜癌细胞ISK和KLE迁移。
1、实验材料和方法
Transwell小室购自于Costar公司；多聚甲醛为实验室常用试剂，商业购买，未经任何处理，其余实验材料来源同实施例41。取对数生长期的EC细胞，用胰蛋白酶消化下来，使用不含血清的DMEM/F12培养基制备成单细胞混悬液，以每孔约10万个细胞的密度接种至Transwell小室上方。小室下方加入600μL含20％FBS的DMEM/F12培养基，注意避免气泡产生。分成4组，分别为对照组和不同的给药组，每组设3个复孔。给药组的上室加入含不同药物的无血清DMEM/F12培养基150μL，对照组上室加入无药物无血清的DMEM/F12培养基150μL。置于37℃，5％CO 2的培养箱培养24h。随后用镊子小心取出小室，吸干上室液体，移到预先加入约800μL预冷PBS的24孔板中，清洗2次，每次5 min。取出小室，移到预先加入约800μL多聚甲醛溶液的24孔板中，室温固定30min。取出小室，吸干上室固定液，移到预先加入约800μL结晶紫染液的24孔板中，室温染色30min。轻轻用清水冲洗数次，用湿棉棒小心擦去上室膜表面上的细胞。200倍显微镜下随机取5个视野拍照，Image J软件手动计数，统计各个视野下的细胞数。
2、实验结果
结果如图2所示，图中Ctrl为对照组，照片中的每一个点表示一个穿过小室的细胞。结果表明，在ISK和KLE细胞中，与Ctrl组相比，给药组穿过小室的细胞数量减少，且随着化合物X32浓度的增加而明显减少，尤其是高剂量组，只有少量细胞穿过，说明化合物X32具有抑制ISK和KLE细胞迁移的能力，并且能够浓度依赖性地抑制子宫内膜癌细胞的迁移。柱状图纵坐标表示各组穿过小室细胞数目，数据显著性差异采用One-way ANOVA法分析(Graphpad Prism8.0软件)。
实施例44本发明化合物对子宫内膜癌细胞凋亡的影响
本发明在细胞水平上采用Annexin V-FITC/PI细胞凋亡检测试剂盒测试化合物X32对子宫内膜癌细胞ISK和KLE凋亡的影响。研究结果表明，化合物X32能够诱导子宫内膜癌细胞ISK和KLE凋亡。
1.实验材料和方法
Annexin V-FITC/PI细胞凋亡检测试剂盒购自于碧云天生物科技有限公司，其中Annexin V-FITC结合液、Annexin V-FITC、碘化丙啶(PI)均为试剂盒中试剂。其余实验材料来源同实施例41。取对数生长期的EC细胞，用胰蛋白酶消化下来制备成单细胞混悬液，以每孔约12万个细胞的密度接种至6孔板，过夜培养。待细胞贴壁后，分成4组，分别为对照组和不同的给药组，每组设3个复孔。给药组加入含不同浓度衍生物的DMEM/F12培养基2mL，对照组加入无药物DMEM/F12培养基2mL。在37℃，5％CO 2的培养箱孵育48h。随后将细胞培养液吸出至10ml离心管内，PBS清洗贴壁细胞一次，加入300μL胰酶消化细胞2min，将细胞轻轻吹打下来，转移到相应离心管内，1000rpm离心5min，弃上清，收集细胞，用PBS轻轻重悬细胞并计数。取5-10万重悬的细胞，1000rpm离心5min，弃上清，加入195μL Annexin V-FITC结合液轻轻重悬细胞，加入5μL Annexin V-FITC和10μL碘化丙啶(PI)染色液，轻轻混匀。室温避光孵育20min，立即用Beckman Coulter(cytoFLEX LX)流式细胞仪检测。
2、实验结果
结果如图3所示，图中Ctrl为对照组，在凋亡示意图中的第一象限为晚凋细胞，第四象限为早凋细胞，凋亡比例为第一、四象限比例之和。与对照组相比，化合物X32能够显著诱导ISK和KLE细胞凋亡，并且具有浓度依赖性。柱状图纵坐标表示各组细胞凋亡比例，数据显著性差异采用One-way ANOVA法分析(Graphpad Prism8.0软件)。
实施例45本发明化合物对小鼠中枢神经系统的影响
本发明通过转棒试验测试了化合物X32对小鼠中枢神经系统的影响，即锥体外系副作用。研究结果表明，化合物X32的中枢神经系统的副作用较低，100mg/kg和50mg/kg给 药剂量基本不影响小鼠抓握运动能力，无锥体外系副作用。
1、实验材料和方法
实验动物选择7-8周龄的雌性C57BL/6裸鼠，购自上海斯莱克有限公司；顺铂(DDP)来源于实验室老药库。化合物配制方法是称取一定量的化合物，溶于生理盐水中，对照组给予相应溶剂。化合物给药前现配现用。
小鼠随机分为4组：对照组、阳性药氯丙嗪5mg/kg、X32 50mg/kg、X32 100mg/kg。每组12只。先提前三天训练小鼠以适应转棒运动：每天以35rpm/min的转速训练小鼠运动3min。第四天在腹腔注射给药0.1mL 1小时后(对照组注射生理盐水0.1mL)，在35rpm/min的转速下，记录小鼠5min内在转棒上坚持的时间。
2、实验结果
实验结果如图4所示，图中Vehicle为对照组，纵坐标代表小鼠掉落时间，每个点代表一只小鼠掉落时间。可以看出，化合物X32 100mg/kg和50mg/kg给药剂量均对小鼠抓握运动能力无明显影响，小鼠随棒转动的平均时间为分别为255s和243s，和对照组无显著性差异；氯丙嗪5mg/kg给药剂量对小鼠抓握运动能力有很大影响，小鼠随棒转动的平均时间为142s(p＜0.001)。实验结果表明，X32 100mg/kg和50mg/kg给药剂量基本不影响小鼠抓握运动能力。数据显著性差异采用One-way ANOVA法分析(Graphpad Prism8.0软件)。
实施例46本发明化合物对子宫内膜癌荷瘤小鼠皮下移植瘤生长的抑制作用
本发明通过裸鼠体内皮下成瘤实验测试了化合物X01对子宫内膜癌细胞(KLE)移植瘤生长的影响。研究结果表明，化合物X01能够显著抑制小鼠皮下KLE细胞移植瘤的生长。
1、实验材料和方法
实验动物选择5-6周龄的SPF级的雌性BALB/C裸鼠，购自上海斯莱克动物实验有限公司；顺铂(DDP)来源于实验室老药库。化合物配制方法是称取一定量的化合物，溶于生理盐中稀释成所需浓度，对照组给予相应溶剂。化合物给药前现配现用。
首先在5-6周龄的裸鼠右侧腋下皮下植入KLE细胞，每只小鼠约植入500万个细胞。待肿瘤长至800-1000mm 3后处死小鼠，再将肿瘤组织切成大小均匀的肿瘤组织块，通过手术移植到新的5-6周龄裸鼠右侧腋下皮下。待新长出的肿瘤体积达到平均300-400mm 3时，将小鼠随机分4组：对照组、阳性药DDP 2mg/kg、X01 2mg/kg给药组、X01 5mg/kg给药组、氯丙嗪5mg/kg组。按不同的药物浓度腹腔注射0.1mL，对照组腹腔注射生理盐水0.1mL，每天称量小鼠体重，每天给药。连续给药2周后，处死小鼠，剥离肿瘤，拍照。解剖当天用游标卡尺测量肿瘤长L(mm)和宽W(mm)，肿瘤体积计算公式V(mm 3)＝0.5×L(mm)×W(mm) 2。
2、实验结果
实验结果如图5所示，图中Vehicle为对照组。其中图5中A为小鼠体重随给药时间的变化曲线，横坐标为给药天数，纵坐标为小鼠体重，从图中可以看到，X01给药组体重平稳，顺铂DDP组体重有明显下降。图5中B、C、D可以看出给药结束后，与对照组相 比，化合物X01给药组的肿瘤生长均受到抑制，X01 2mg/kg和X01 5mg/kg均能显著抑制小鼠肿瘤的生长，且与阳性药顺铂组效果相当甚至略优于顺铂。数据显著性差异采用One-way ANOVA法分析(Graphpad Prism8.0软件)。本实验证明化合物X01能够抑制小鼠皮下KLE细胞移植瘤的生长且对体重没有影响，其药效与阳性药顺铂相当，毒性小于顺铂。
以上所述仅是本发明的较佳实施例而已，并非对本发明作任何形式上的限制，虽然本发明已以较佳实施例揭露如上，然而并非用以限定本发明，任何熟悉本专利的技术人员在不脱离本发明技术方案范围内，当可利用上述提示的技术内容作出些许更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明方案的范围内。

Claims (13)

  1. 一种式I所示化合物、或其立体异构体或药学上可接受的盐，
    Figure PCTCN2021123627-appb-100001
    其中，n为2、3、4、5或6；
    R 1为H、羟基、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、硝基、亚硝基、氨基、甲酰基、乙酰基或氰基；
    R 2为取代或未取代的6-14元杂环基，所述杂环基含有选自下组的1、2、3或4个杂原子：N、O、S；所述取代是指具有一个或多个选自下组的取代基：-COOC 1-C 6烷基、-C 1-C 6亚烷基C 6-C 10芳基、氧代(＝O)、C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、-COC 1-C 6烷基、-C 1-C 6亚烷基5-7元杂芳基、C 6-C 10芳基、5-7元杂芳基、-C 1-C 6亚烷基卤代C 6-C 10芳基、C 3-C 8环烷基。
  2. 如权利要求1所述的化合物，其特征在于，R 1为H、羟基、F、Cl、Br、甲基、乙基、正丙基、异丙基、C 1-C 4氟代烷基、甲氧基、乙氧基。
  3. 如权利要求1所述的化合物，其特征在于，R 2为式I-2或者I-3，
    Figure PCTCN2021123627-appb-100002
    A 1、A 2、A 3、A 4各自独立地选自：N、O、S、-CO(CH 2) p-、-(CH 2) m-、-(CH 2) mO-、-(CH 2) mS-；m、p各自独立地为0、1、2或3；
    X为CH、N或O；
    n 1、n 2、n 3、n 4各自独立地为0、1、2或3；
    R 3为H、-COOC 1-C 6烷基、-C 1-C 6亚烷基C 6-C 10芳基、C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、-COC 1-C 6烷基、-C 1-C 6亚烷基5-7元杂芳基、C 6-C 10芳基、5-7元杂芳基、-C 1-C 6亚烷基卤代C 6-C 10芳基、C 3-C 8环烷基。
  4. 如权利要求1所述的化合物，其特征在于，R 3为H、叔丁氧羰基、C 1-C 4烷基、氯代苄基、苄基、-CH 2-6元含氮杂芳基、-COC 1-C 4烷基或C 2-C 4炔基。
  5. 如权利要求1所述的化合物，其特征在于，所述化合物选自下组：
    Figure PCTCN2021123627-appb-100003
    Figure PCTCN2021123627-appb-100004
    Figure PCTCN2021123627-appb-100005
  6. 一种药物组合物，其特征在于，所述药物组合物包括：
    (1)如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体；和(2)药学上可接受的载体。
  7. 如权利要求6所述的药物组合物，其特征在于，所述药物组合物还包括其他药学上可接受的成分为抗子宫内膜癌药物。
  8. 如权利要求7所述的药物组合物，其特征在于，所述抗子宫内膜癌药物为孕激素。
  9. 如权利要求8所述的药物组合物，其特征在于，所述孕激素为醋酸甲地孕酮、酸酸甲羟孕酮或己酸孕酮中的一种或两种以上的组合。
  10. 如权利要求6所述的药物组合物，其特征在于，所述药物组合物为注射剂、片剂、胶囊剂、丸剂、悬浮剂或乳剂。
  11. 如权利要求6所述的药物组合物，其特征在于，所述药物组合物为口服剂型、经皮剂型、静脉或肌肉注射剂型。
  12. 如权利要求1所述的化合物或其立体异构体，或其药学上可接受的盐或如权利要求6所述的药物组合物的用途，其特征在于，用于制备治疗和/或预防子宫内膜癌的药物。
  13. 如权利要求1所述的化合物或其立体异构体，或其药学上可接受的盐的制备方法，其特征在于，包括步骤：
    Figure PCTCN2021123627-appb-100006
    Figure PCTCN2021123627-appb-100007
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