WO2020088442A1 - 三氟甲基取代的磺酰胺类选择性bcl-2抑制剂 - Google Patents

三氟甲基取代的磺酰胺类选择性bcl-2抑制剂 Download PDF

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Publication number
WO2020088442A1
WO2020088442A1 PCT/CN2019/113963 CN2019113963W WO2020088442A1 WO 2020088442 A1 WO2020088442 A1 WO 2020088442A1 CN 2019113963 W CN2019113963 W CN 2019113963W WO 2020088442 A1 WO2020088442 A1 WO 2020088442A1
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Prior art keywords
compound
preparation
methyl
alkyl
pharmaceutically acceptable
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PCT/CN2019/113963
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English (en)
French (fr)
Inventor
刘飞
丰巍伟
王斌
徐宏江
汪纪楠
张喜全
王善春
刘彦龙
张健青
姚绎炎
唐旭静
施伟
张洪英
李洋
汤松
朱益忠
刘利民
顾红梅
杨玲
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正大天晴药业集团股份有限公司
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Priority to IL282632A priority Critical patent/IL282632B1/en
Priority to CA3117849A priority patent/CA3117849A1/en
Priority to EP19878278.1A priority patent/EP3858832A4/en
Priority to SG11202104322YA priority patent/SG11202104322YA/en
Priority to MX2021004856A priority patent/MX2021004856A/es
Priority to AU2019372640A priority patent/AU2019372640B2/en
Priority to US17/289,406 priority patent/US20220002290A1/en
Priority to CN202310104396.3A priority patent/CN116199686A/zh
Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN201980067260.1A priority patent/CN112888687B/zh
Priority to BR112021008323-5A priority patent/BR112021008323A2/pt
Priority to JP2021523829A priority patent/JP7473545B2/ja
Priority to KR1020217016174A priority patent/KR20210086680A/ko
Publication of WO2020088442A1 publication Critical patent/WO2020088442A1/zh
Priority to PH12021550958A priority patent/PH12021550958A1/en

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    • 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
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • BCL-2 protein is divided into three families: BCL-2 family (the family members include BCL-2, BCL-XL, etc.), BAX family and BH3-only family, of which BCL-2 family plays an anti-apoptotic role , Members of the latter two families play a role in promoting apoptosis.
  • Anti-apoptotic BCL-2 family proteins are involved in many diseases and are being studied as potential therapeutic drug targets. These targets for interventional therapy include, for example, BCL-2 family proteins BCL-2 and BCL-XL. Recently, inhibitors of BCL-2 family proteins have been reported in WO2012071374, WO2010138588, and WO2010065865. Although inhibitors with high binding to target proteins are taught, compound binding affinity is only one of many parameters to be considered. One goal is to produce compounds that preferentially bind to one protein over another, that is, their selectivity. To show this selectivity, it is well known that the compound shows a high binding affinity for a specific protein, and a lower binding affinity for another member.
  • the disclosed BCL-2 inhibitors are not highly selective relative to the anti-apoptotic BCL-XL protein and the anti-apoptotic BCL-2 protein, and thus have a greater possibility of side effects.
  • Apoptosis BCL-XL protein causing side effects such as thrombocytopenia.
  • This application includes a series of compounds, which show higher selectivity than anti-apoptotic BCL-2 protein and anti-apoptotic BCL-XL protein, and also have activity in inhibiting anti-apoptotic BCL-2 protein activity Better performance. At the same time, it also has better liver microsome stability, and optimized pharmacokinetic parameters, and has better prospects for drug preparation.
  • R 1 is selected from halogen
  • R 1 is selected from fluorine or chlorine. In some embodiments, R 1 is selected from chlorine.
  • R 2 is selected from -R 3 or -C 1-6 alkylene-R 3 . In some embodiments, R 2 is selected from -C 1-4 alkylene-R 3 .
  • R 3 is selected from 5-6 membered heterocycloalkyl, the 5-6 membered heterocycloalkyl is optionally substituted with one or two groups, the substitution site is an N atom on the ring .
  • R 3 is selected from 5-6 membered heterocycloalkyl, which is optionally substituted with one or two groups selected from: 3-6 membered hetero Cycloalkyl, C 3-6 cycloalkyl, -COR a , -SO 2 R b , or C 1-6 alkyl optionally substituted with halogen.
  • R 3 is selected from 5-6 membered heterocycloalkyl, which is optionally substituted with 3-6 membered heterocycloalkyl.
  • R 3 is selected from 5-6 membered heterocycloalkyl, which is optionally substituted with —SO 2 R b .
  • R 3 is selected from 5-6 membered heterocycloalkyl, which is optionally substituted with -COOC 1-6 alkyl. In some embodiments, R 3 is selected from 5-6 membered heterocycloalkyl, which is optionally substituted with -COOC 1-4 alkyl.
  • R a or R b is independently selected from H, 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl, or C 1-4 alkyl, the C 1-4 alkyl The group is optionally substituted with halogen, -CN, -N (C 1-4 alkyl) 2 , -NHC 1-4 alkyl, or -OC 1-4 alkyl.
  • R a is selected from H, 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl, or C 1-4 alkyl, the C 1-4 alkyl is optionally halogenated , -CN, -N (C 1-4 alkyl) 2 , or -OC 1-4 alkyl substitution.
  • R b is selected from 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl, or C 1-4 alkyl, the C 1-4 alkyl is optionally halogen or- CN replaced.
  • R a or R b are independently selected from H, C 3-6 cycloalkyl, or C 1-4 alkyl, the C 1-4 alkyl is optionally halogen, -CN , -N (C 1-4 alkyl) 2 , -NHC 1-4 alkyl, or -OC 1-4 alkyl substitution.
  • R a is selected from H, C 3-6 cycloalkyl, or C 1-4 alkyl, said C 1-4 alkyl optionally substituted with halogen, -CN, -N (C 1 -4 alkyl) 2 or -OC 1-4 alkyl substitution.
  • R b is selected from C 3-6 cycloalkyl, or C 1-4 alkyl, said C 1-4 alkyl is optionally substituted with halogen, or -CN.
  • R a or R b are each independently selected from H, methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, -CH 2 OCH 3, -CH 2 CN, -CH 2 N (CH 3 ) 2 , cyclopropyl, or cyclobutyl.
  • R a is selected from H, methyl, isopropyl, t-butyl, trifluoromethyl, -CH 2 OCH 3, -CH 2 CN, -CH 2 N (CH 3) 2, or Cyclopropyl.
  • R b is selected from methyl, ethyl, trifluoromethyl, cyclopropyl, or cyclobutyl.
  • R a or R b are each independently selected from optionally substituted -OC 1-4 alkyl C 1-4 alkyl.
  • R a or R b are each independently selected from methyl, isopropyl, or -CH 2 OCH 3.
  • R a is selected from methyl, isopropyl, or -CH 2 OCH 3.
  • R b is selected from C 1-4 alkyl.
  • R b is selected from methyl.
  • R 3 is selected from 5-6 membered heterocycloalkyl, which is optionally substituted by the following groups: -C (O) H, -COCH 3 ,- COCH (CH 3 ) 2 , -COC (CH 3 ) 3 , -COCF 3 , -COCH 2 CN, -COCH 2 OCH 3 , -COCH 2 N (CH 3 ) 2 , -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -SO 2 CF 3 , -SO 2 C 2 F 5 , methyl, ethyl, -CF 3 , -CH 2 CH 2 F, -C 2 F 5 , tetrahydropyran, monooxe Butane, -SO 2 -cyclopropane, -CO-cyclopropane, -CO-monooxetane, -SO 2 -monooxetane, -SO 2 -cyclobutan
  • R 3 is selected from 5-6 membered heterocycloalkyl, the 5-6 membered heterocycloalkyl is optionally substituted with the following groups: -C (O) H, -COC (CH 3 ) 3 , -COCF 3 , -COCH 2 CN, -COCH 2 N (CH 3 ) 2 , -SO 2 CH 2 CH 3 , -SO 2 CF 3 , -SO 2 C 2 F 5 , -CF 3 , -C 2 F 5 , tetrahydropyran, monooxetane, -SO 2 -cyclopropane, -CO-cyclopropane, -CO-monooxetane, -SO 2 -monooxetane, -SO 2 -cyclobutane.
  • R 3 is selected from 5-6 membered heterocycloalkyl, which is optionally substituted with the following groups: -COOCH 2 CH 3 , or -COOCH 3 .
  • R 3 is selected from 5-6 membered heterocycloalkyl, which is optionally substituted by the following groups: -C (O) H, -COCH 3 ,- COCH (CH 3 ) 2 , -COC (CH 3 ) 3 , -COCF 3 , -COCH 2 CN, -COCH 2 OCH 3 , -COCH 2 N (CH 3 ) 2 , -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -SO 2 CF 3 , methyl, ethyl, -CH 2 CH 2 F, tetrahydropyran, -SO 2 -cyclopropane, -CO-cyclopropane, -SO 2 -cyclobutane.
  • R 3 is selected from 5-6 membered heterocycloalkyl, the 5-6 membered heterocycloalkyl is optionally substituted with the following groups: -C (O) H, -COC (CH 3 ) 3 , -COCF 3 , -COCH 2 CN, -COCH 2 N (CH 3 ) 2 , -SO 2 CH 2 CH 3 , -SO 2 CF 3 , -SO 2 C 2 F 5 , -CF 3 , -C 2 F 5 , tetrahydropyran, -SO 2 -cyclopropane, -CO-cyclopropane, -SO 2 -cyclobutane.
  • R 3 is selected from tetrahydropyran, piperidine, morpholine or dioxane, the tetrahydropyran, piperidine, morpholine or dioxane is optionally Substitution: -C (O) H, -COCH 3 , -COCH 2 OCH 3 , -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -CO-cyclopropane, -COCH 2 CN, -COCF 3 , -COCH 2 N (CH 3 ) 2 , or methyl.
  • R 3 is selected from tetrahydropyran, piperidine, morpholine or dioxane, the tetrahydropyran, piperidine, morpholine or dioxane is optionally Substitution: -COCH 3 , -COCH (CH 3 ) 2 , -COCH 2 OCH 3 , -SO 2 CH 3 , methyl, ethyl, or -CH 2 CH 2 F.
  • R 3 is selected from tetrahydropyran, piperidine, morpholine, or dioxane, the tetrahydropyran, piperidine, morpholine, or dioxane is optionally substituted by Substitution: -COOCH 2 CH 3 or -COOCH 3 .
  • R 3 is selected from tetrahydropyran or dioxane.
  • R 3 is selected from piperidine or morpholine, which is optionally substituted with the following groups: -C (O) H, -COCH 3 , -COCH 2 OCH 3 ,- SO 2 CH 3 , -SO 2 CH 2 CH 3 , -CO-cyclopropane, -COCH 2 CN, -COCF 3 , -COCH 2 N (CH 3 ) 2 , or methyl.
  • R 3 is selected from piperidine or morpholine, which is optionally substituted with -COCH 3 , -COCH (CH 3 ) 2 , -COCH 2 OCH 3 , -SO 2 CH 3 , methyl, ethyl, or -CH 2 CH 2 F.
  • R 3 is selected from
  • R 3 is selected from In some embodiments, R 3 is selected from
  • R 3 is selected from
  • R 3 is selected from
  • R 3 is selected from
  • R 3 is selected from
  • R 3 is selected from
  • R 3 is selected from
  • the hetero atom in the 5-6 membered heterocycloalkyl is selected from N or O, and the number of hetero atoms is selected from 1 or 2.
  • the 5-6 membered heterocycloalkyl is selected from dioxane, morpholinyl, tetrahydropyranyl, or piperidinyl.
  • the 5-6 membered heterocycloalkyl is selected from dioxane.
  • the hetero atom in the 3-6 membered heterocycloalkyl is selected from N or O, and the number of hetero atoms is selected from 1 or 2. In some embodiments, the hetero atom in the 3-6 membered heterocycloalkyl is selected from O, and the number of hetero atoms is 1 or 2. In some embodiments, the 3-6 membered heterocycloalkyl is selected from 4-6 membered heterocycloalkyl. In some embodiments, the 3-6 membered heterocycloalkyl is selected from 4-membered heterocycloalkyl or 6-membered heterocycloalkyl.
  • the 3-6 membered heterocycloalkyl is selected from monooxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.
  • the present application relates to a compound of formula II, its stereoisomers or pharmaceutically acceptable salts thereof:
  • R 2 is defined as the compound of formula I.
  • R is independently the following groups:
  • the present application describes the above formula I, formula II or specific compounds, their stereoisomers or pharmaceutically acceptable salts thereof, for preventing or treating diseases associated with the anti-apoptotic protein BCL-2, or Pharmaceutical composition.
  • the disease related to anti-apoptotic protein BCL-2 is selected from cancer.
  • the cancer is selected from acute lymphocytic leukemia.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced with a substituent, as long as the valence state of the specific atom is normal and the compound after substitution is stable.
  • alkyl refers to a hydrocarbon group of the formula C n H 2n +.
  • the alkyl group may be linear or branched.
  • C 1 - 6 alkyl refers to (e.g., methyl, ethyl, n-propyl, isopropyl, alkyl containing 1 to 6 carbon atoms, n-butyl, isobutyl, sec-butyl, Tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkyl portion ie, alkyl
  • alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.
  • C 1 - 4 alkyl refers to alkyl groups containing 4 (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-1 to carbon atoms, Tert-butyl, etc.).
  • alkylene refers to a divalent group formed by removing one hydrogen at any position of an alkyl group.
  • C 0-6 alkylene include, but are not limited to, methylene, ethylene, methylmethylene, dimethylmethylene, 1,3-propylene, etc. .
  • C 0 means the key.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and can exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 3 to 10 membered ring.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, Adamantyl, etc.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the heterocycle is usually a 3 to 7 membered ring containing 1 to 3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen and / or nitrogen.
  • treatment means the administration of a compound or formulation described herein to prevent, ameliorate or eliminate one or more symptoms associated with the disease or diseases, and includes:
  • terapéuticaally effective amount means (i) treatment or prevention of a specific disease, condition or disorder, (ii) reduction, improvement or elimination of one or more symptoms of a specific disease, condition or disorder, or (iii) prevention or delay
  • the amount of the compound of the present application constituting the “therapeutically effective amount” depends on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art It is determined by its own knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and / or dosage forms, which are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without Excessive toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit / risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like can be mentioned .
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant stimulating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can be interconverted via a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • proton migration such as keto-enol and imine-enamine isomerization.
  • proton tautomers is an imidazole moiety, where protons can migrate between two ring nitrogens.
  • Valence tautomers include interconversion through the recombination of some bonding electrons.
  • the present application also includes compounds of the present application that are the same as those described herein, but one or more atoms are replaced by an isotope labeled with an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature.
  • isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, 36 Cl, etc.
  • Certain isotopically-labeled compounds of the present application can be used in the analysis of compound and / or substrate tissue distribution. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emission isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • PET positron emission tomography
  • the isotopically labeled compounds of the present application can generally be prepared by isotopically labeled reagents instead of unisotopically labeled reagents by the following procedures similar to those disclosed in the schemes and / or examples below.
  • substitution with heavier isotopes can provide certain therapeutic advantages resulting from higher metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations
  • deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.
  • the compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included in this application, such as enantiomers and diastereomers.
  • the compounds containing asymmetric carbon atoms of the present application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral raw materials or chiral reagents.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes for administering the compounds of the present application or pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compound of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • the solid oral composition can be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by mixing the active compound with solid auxiliary materials, optionally grinding the resulting mixture, adding other suitable auxiliary materials if necessary, and then processing the mixture into granules to obtain tablets Or the core of sugar coating.
  • suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • the daily dose is 0.01 mg / kg to 200 mg / kg body weight, either in separate or divided doses.
  • the compounds of the present application can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination with other chemical synthetic methods, and equivalents well known to those skilled in the art Alternatively, preferred embodiments include but are not limited to the examples of the present application.
  • the chemical reaction of the specific embodiment of the present application is completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the present application and the reagents and materials required. In order to obtain the compound of the present application, it is sometimes necessary for a person skilled in the art to modify or select a synthesis step or a reaction scheme based on existing embodiments.
  • the compound of formula I of the present application may be prepared by a person skilled in the art of organic synthesis by the following route method:
  • X is selected from leaving groups, preferably from fluorine, chlorine, bromine or iodine;
  • R 4 is selected from C 1-6 alkyl or C 1-4 alkyl, preferably from tert-butyl, methyl or ethyl
  • R 5 is selected from amino protecting groups, preferably Boc or Cbz (benzyloxycarbonyl);
  • R 6 is selected from amino protecting groups, preferably from silane-based protecting groups, more preferably from TBS (tert-butyl dimethyl silicon) , TBDPS (tert-butyl diphenyl silicon) or TMS (trimethyl silicon), TES (triethyl silicon), TIPS (triisopropyl silicon) protecting groups.
  • the present application also provides a method for preparing the compound of formula A-4, including the following steps:
  • X is selected from leaving groups, preferably from fluorine, chlorine, bromine or iodine;
  • R 4 is selected from C 1-6 alkyl or C 1-4 alkyl, preferably from tert-butyl, methyl or ethyl
  • R 6 is selected from amino protecting groups, preferably from silane-based protecting groups, more preferably from TBS (tert-butyl dimethyl silicon), TBDPS (tert-butyl diphenyl silicon) or TMS (trimethyl silicon), TES (triethyl silicon), TIPS (triisopropyl silicon) protecting group.
  • the present application also provides a method for preparing the compound of formula A-3, including the following steps:
  • R 1 is selected from amino protecting groups, preferably Boc or Cbz (benzyloxycarbonyl).
  • the present application also provides a method for preparing the compound of formula A-2, including the following steps:
  • R 1 is selected from amino protecting groups, preferably Boc or Cbz (benzyloxycarbonyl).
  • the present application also provides a method for preparing a compound of formula A-5, including the following steps:
  • R 1 The definition is the same as above, R 4 is selected from C 1-6 alkyl or C 1-4 alkyl, preferably from tert-butyl, methyl or ethyl; R 6 is selected from an amino protecting group, preferably from a silane protecting group, more Preferably from TBS (tert-butyl dimethyl silicon), TBDPS (tert-butyl diphenyl silicon) or TMS (trimethyl silicon), TES (triethyl silicon), TIPS (triisopropyl silicon) protecting group group.
  • TBS tert-butyl dimethyl silicon
  • TBDPS tert-butyl diphenyl silicon
  • TMS trimethyl silicon
  • TES triethyl silicon
  • TIPS triisopropyl silicon
  • the present application also provides a method for preparing a compound of formula I, including the following steps:
  • R 1 , R 2 or The definition is the same as above.
  • R 1 is selected from C 1-6 alkyl or C 1-4 alkyl, preferably from tert-butyl, methyl or ethyl;
  • R 5 is selected from amino protecting groups, preferably Boc or Cbz (benzyloxy Carbonyl);
  • R 6 is selected from amino protecting groups, preferably from silane-based protecting groups, more preferably from TBS (tert-butyl dimethyl silicon), TBDPS (tert-butyl diphenyl silicon) or TMS (trimethyl silicon ), TES (triethyl silicon), TIPS (triisopropyl silicon) protecting groups.
  • the salt may be selected from hydrochloride and the like.
  • the above compounds are selected from the following compounds or salts thereof: Wherein the salt may be selected from hydrochloride and the like.
  • DMF stands for N, N-dimethylformamide
  • Boc stands for tert-butoxycarbonyl
  • NaOAc stands for sodium acetate
  • tBu stands for tert-butyl
  • TBS stands for tert-butyldimethylsilyl
  • THF stands for tetrahydrofuran
  • DMSO Represents dimethyl sulfoxide.
  • Example 1 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2, 3-b) pyridin-5-yloxy) -benzamide
  • Example 2 4- (4- ⁇ [2- (3-trifluoromethyl4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1- Group) -N-( ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3 -b) pyridin-5-yloxy) -benzamide
  • Example 3 4- (4- ⁇ [2- (4-chloro-2-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2, 3-b) pyridin-5-yloxy) -benzamide
  • Example 4 4- (4- ⁇ [2- (3-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2, 3-b) pyridin-5-yloxy) -benzamide
  • Example 5 4- (4- ⁇ [2- (2-fluoro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2, 3-b) pyridin-5-yloxy) -benzamide
  • Example 6 4- (4- ⁇ [2- (3-fluoro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2, 3-b) pyridin-5-yloxy) -benzamide
  • Example 9 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(4-acetylmorpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2, 3-b) pyridin-5-yloxy) -benzamide
  • Example 10 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(4-isobutyrylmorpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2 , 3-b] pyridin-5-yloxy) -benzamide
  • Example 11 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(R)-(4-methoxyacetylmorpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H -Pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 12 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(4-methylsulfonylmorpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2 , 3-b] pyridin-5-yloxy) -benzamide
  • Example 13 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-3-ylmethyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2, 3-b) pyridin-5-yloxy) -benzamide
  • Example 14 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(4-tetrahydro-2H-pyran-2-ylmethyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [ 2,3-b] pyridin-5-yloxy) -benzamide
  • Example 15 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(1- (methylsulfonyl) piperidin-3-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrole Benzo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 16 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(2- (4-acetylmorpholin-2-yl) ethyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 17 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(3- (1-methylpiperidin-4-yl) propyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 18 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(2- (1-methylpiperidin-4-yl) ethyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 19 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(2- (1-ethylpiperidin-4-yl) ethyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 20 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(2- (1- (2-fluoroethyl) piperidin-4-yl) ethyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 21 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(2- (4- (methylsulfonyl) morpholin-2-yl) ethyl) amino] phenyl ⁇ sulfonyl) -2- ( 1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 22 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(2- (4-isobutyrylmorpholin-2-yl) ethyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrole Benzo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 23 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(1-isobutyrylpiperidin-4-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2 , 3-b] pyridin-5-yloxy) -benzamide
  • Example 24 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(4-ethylmorpholin-3-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2, 3-b) pyridin-5-yloxy) -benzamide
  • Example 25 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 26 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[((4- (3-oxetane) morpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • step 1) for the preparation of compound 25-k and replace 4-aminomethyl-1- (tetrahydro-2H-) with 4- (3-oxetane) -2-aminomethylmorpholine Pyran) piperidine to prepare compound 26-k.
  • Example 27 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[((4- (tetrahydropyran-4-yl) morpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2 -(1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • step 1) for the preparation of compound 25-k and replace 4-aminomethyl-1- (tetrahydro-2H) with 4- (tetrahydropyran-4-yl) -2-aminomethylmorpholine -Pyran) piperidine to prepare compound 27-k.
  • Example 28 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[((4-cyclopropanesulfonylmorpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 29 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[((4-cyclopropanoylmorpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • step 1) for the preparation of compound 25-k and replace 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine with 4-cyclopropanoyl-2-aminomethylmorpholine
  • step 2) for the preparation of compound 25-k and replace 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine with 4-cyclopropanoyl-2-aminomethylmorpholine
  • compound 29-k (0.85g).
  • Example 30 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[((4- (oxetan-3-yl) formylmorpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl ) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • step 1) for the preparation of compound 25-k and 4- (oxetan-3-yl) formyl-2-aminomethylmorpholine was substituted for 4-aminomethyl-1- (tetra Hydrogen-2H-pyran) piperidine to prepare compound 30-k (0.85g).
  • Example 31 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[((4-cyclobutanesulfonylmorpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • step 1) for the preparation of compound 25-k and replace 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine with 4-cyclobutanesulfonyl-2-aminomethylmorpholine To give compound 31-k (0.98g).
  • Example 32 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[((4- (oxetan-3-yl) sulfonylmorpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl ) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • step 1) for the preparation of compound 25-k and 4- (oxetan-3-yl) sulfonyl-2-aminomethylmorpholine was substituted for 4-aminomethyl-1- (tetra Hydrogen-2H-pyran) piperidine to give compound 32-k (1.01g).
  • step 1) for the preparation method of compound 25-k and replace 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine with (S) -4-aminotetrahydrofuran hydrochloride to obtain compound 33-k (1.72g).
  • step 1) the method for preparing compound 25-k, replacing (3-R) -tetrahydrofuran-3-methylamine with 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine to give compound 35 -k (1.10g).
  • step 1) for the preparation method of compound 25-k replacing (3-S) -tetrahydrofuran-3-methylamine (0.64g) with 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine To give compound 36-k (1.39g).
  • step 1) the method for preparing compound 25-k, replacing (S) -2-tetrahydrofurfurylamine with 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine to give compound 37 -k (1.35g).
  • step 1) the preparation method of compound 25-k, and replace 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine with (R) -2-tetrahydrofurfurylamine to obtain compound 38 -k (1.38g).
  • Example 39 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(tetrahydropyran-4-yl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridine -5-yloxy) -benzamide
  • step 1) the method for preparing compound 25-k, 4-aminotetrahydropyran was substituted for 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine to obtain compound 39-k ( 1.70g).
  • step 1) for the preparation of compound 25-k replacing (S) -3-aminotetrahydropyran hydrochloride with 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine To give compound 40-k (1.08g).
  • step 1) for the preparation of compound 25-k and replace 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine with (R) -3-aminotetrahydropyran hydrochloride To give compound 41-k (0.95g).
  • step 1) for the preparation method of compound 25-k and replace 4-aminomethyl-1- (tetrahydro-2H-pyran) with (R) -3-aminomethyltetrahydropyran hydrochloride Piperidine gave compound 42-k (0.36g).
  • step 1) for the preparation of compound 25-k replacing (S) -3-aminomethyltetrahydropyran hydrochloride with 4-aminomethyl-1- (tetrahydro-2H-pyran) Piperidine gives compound 43-k (0.39g).
  • Example 44 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(2- (tetrahydropyran-2-yl) ethyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2 , 3-b] pyridin-5-yloxy) -benzamide
  • step 1) for the preparation of compound 25-k and replace 4-aminomethyl-1- (tetrahydro-2H) with 2- (tetrahydro-2H-pyran-2-yl) ethylamine hydrochloride -Pyran) piperidine to give compound 44-k (1.18g).
  • Example 45 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(2- (tetrahydropyran-3-yl) ethyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2 , 3-b] pyridin-5-yloxy) -benzamide
  • Example 46 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(3- (N-ethylmorpholin-2-yl) propyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • step 1) for the preparation of compound 25-k and replace 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine with N-ethyl-2-propylaminomorpholine hydrochloride To give compound 46-k (2.03g).
  • Example 47 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(3- (N- (2-fluoroethyl) morpholin-2-yl) propyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • step 1) for the preparation of compound 25-k and replace N- (2-fluoroethyl) -2-propylaminomorpholine hydrochloride with 4-aminomethyl-1- (tetrahydro-2H- Pyran) piperidine to give compound 47-k (2.03g).
  • Example 48 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[((N-formylmorpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2 , 3-b] pyridin-5-yloxy) -benzamide
  • step 1) for the preparation of compound 25-k and replace 4-aminomethyl-1- (tetrahydro-2H-pyran) piper with N-formyl-2-aminomethylmorpholine hydrochloride Pyridine to give compound 48-k (0.50g).
  • Example 49 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[((N-methylsulfonylmorpholin-3-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [ 2,3-b] pyridin-5-yloxy) -benzamide
  • Example 50 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(4-pivaloylmorpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2 , 3-b] pyridin-5-yloxy) -benzamide
  • step 1) the method for preparing compound 25-k, 2-aminomethyl-4-pivaloylmorpholine was substituted for 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine, Compound 50-k (1.71 g) was obtained.
  • Example 51 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(4- (2-cyanoacetyl) morpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H -Pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • step 1) for the preparation of compound 25-k and replace 2-aminomethyl-1- (tetrahydro-2H-pyridine) with 2-aminomethyl-4- (2-cyanoacetyl) morpholine Furan) piperidine to give compound 51-k (1.61 g).
  • Example 52 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(4- (2,2,2-trifluoroacetyl) morpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl)- 2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 53 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(4- (trifluoromethyl) morpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrole Benzo [2,3-b] pyridin-5-yloxy) -benzamide
  • step 1) for the preparation of compound 25-k replacing 2-aminomethyl-1- (tetrahydro-2H-pyran) with 2-aminomethyl-4- (trifluoromethyl) morpholine Piperidine gives compound 53-k (1.64g).
  • Example 54 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(4- (perfluoroethyl) morpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrole Benzo [2,3-b] pyridin-5-yloxy) -benzamide
  • step 1) for the preparation of compound 25-k replacing 2-aminomethyl-1- (tetrahydro-2H-pyran) with 2-aminomethyl-4- (perfluoroethyl) morpholine Piperidine gives compound 54-k (1.93g).
  • Example 55 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(4-((perfluoroethyl) sulfonyl) morpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • step 1) for the preparation of compound 25-k and replace 2-aminomethyl-1- (tetrahydro-2H) with 2-aminomethyl-4-((perfluoroethyl) sulfonyl) morpholine -Pyran) piperidine to give compound 55-k (2.05g).
  • Example 56 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(4-((trifluoromethyl) sulfonyl) morpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • step 1) for the preparation of compound 25-k and replace 2-aminomethyl-1- (tetrahydro-2H) with 2-aminomethyl-4-((perfluoroethyl) sulfonyl) morpholine -Pyran) piperidine to give compound 56-k (1.75g).
  • Example 57 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(4- (ethylsulfonyl) morpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrole Benzo [2,3-b] pyridin-5-yloxy) -benzamide
  • step 1) for the preparation of compound 25-k and replace 2-aminomethyl-1- (tetrahydro-2H-pyran) with 2-aminomethyl-4- (ethylsulfonyl) morpholine Piperidine gives compound 57-k.
  • Example 58 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(1- (2-methoxyacetyl) piperidin-3-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- ( 1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 59 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(1- (methylglycyl) piperidin-4-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H- Pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 60 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(1- (methylglycyl) piperidin-3-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H- Pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 68 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(3- (4-acetylmorpholin-2-yl) propyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 69 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(3- (4-isobutyrylmorpholin-2-yl) propyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrole Benzo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 70 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(3- (4- (2-methoxyacetyl) morpholin-2-yl) propyl) amino] phenyl ⁇ sulfonyl)- 2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 71 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(3- (4- (2-methylsulfonyl) morpholin-2-yl) propyl) amino] phenyl ⁇ sulfonyl) -2 -(1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 72 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(2- (4- (2-methoxyacetyl) morpholin-2-yl) ethyl) amino] phenyl ⁇ sulfonyl)- 2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 73 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4- [1- (2-methoxyacetyl) piperidin-4-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H -Pyrrolo [2,3-b] pyridin-5-yloxy) -benzamide
  • Example 74 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(4- (ethoxyformyl) morpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrole Benzo [2,3-b] pyridin-5-yloxy) -benzamide (Compound 74-1)
  • Example 75 4- (4- ⁇ [2- (2-chloro-4-trifluoromethylphenyl) -4,4-dimethylcyclohex-1-enyl] methyl ⁇ -piperazine-1 -Yl) -N-( ⁇ 3-nitro-4-[(4- (methoxyformyl) morpholin-2-yl) methyl) amino] phenyl ⁇ sulfonyl) -2- (1H-pyrrole Benzo [2,3-b] pyridin-5-yloxy) -benzamide (Compound 75-1)
  • dilution buffer in the kit (model: BCL-2 / BAK (BH3) BINDING ASSAY KITS, from cisbio) to dilute 500nM of Tag1-BCL-2 protein mother liquor to 5nM, and at the same time, 20 ⁇ M of Tag2-BAK protein mother liquor Dilute to 120nM, first add 5 ⁇ L of Tag1-BCL-2 protein dilution to each well, then use a nanoliter sampler to add different compounds dissolved in DMSO to the wells, so that the final concentration of the compound is 200nM-0.0488nM, 4 times gradient , A total of 7 concentrations, set blank control wells (without enzymes) and negative control wells (with enzymes, plus solvent DMSO), set up 2 duplicate wells, and finally add 5 ⁇ L of Tag2-BAK protein dilution per well, centrifuge Mix well and incubate at 25 ° C for 15 minutes.
  • kit model: BCL-2 / BAK (BH3) BINDING ASSAY KITS, from c
  • the PE Envision multi-functional microplate reader reads the plate (excitation 620nm, emission 665nm), using four-parameter fitting to calculate the IC 50 (shown in Table 1).
  • dilution buffer in the kit (model: BCL-XL / BAK (BH3) BINDING ASSAY KITS, from cisbio) to dilute the 300nM Tag1-BCL-XL protein mother liquor to 2nM, and at the same time, 10 ⁇ M Tag2-BAK protein mother liquor Dilute to 80nM, first add 5 ⁇ L of Tag1-BCL-XL protein diluent to each well, then use a nanoliter sampler to add different compounds dissolved in DMSO to the wells, so that the final concentration of the compound is 2000nM-0.488nM, 4-fold gradient , A total of 7 concentrations, set blank control wells (without enzymes) and negative control wells (with enzymes, plus solvent DMSO), set up 2 duplicate wells, and finally add 5 ⁇ L of Tag2-BAK protein dilution per well, centrifuge Mix well and incubate at 25 ° C for 15 minutes.
  • kit model: BCL-XL / BAK (BH3) BINDING ASSA
  • the PE Envision multi-functional microplate reader reads the plate (excitation 620nm, emission 665nm), using four-parameter fitting to calculate the IC 50 (shown in Table 1).
  • Test Example 2 Compounds inhibit the proliferation of RS4; 11 cells
  • RS4 11 cells in good condition during the exponential growth phase (from Nanjing Kebai), collect the cells into a centrifuge tube, a low-speed benchtop centrifuge, 1500 rpm / min, centrifuge for 3 min, discard the supernatant, add 5 mL with a pipette
  • the medium RPMI basal medium + 10 wt% fetal bovine serum (FBS)
  • FBS fetal bovine serum
  • the final 300 ⁇ L incubation system contains 30 ⁇ L of liver microsomes (protein concentration: 5 mg / mL), 30 ⁇ L of NADPH + MgCl 2 , 3 ⁇ L of test compound (formulated with acetonitrile), and 237 ⁇ L of PBS buffer (PH7.4).
  • the ratio of organic solvent (acetonitrile) is 1% (volume ratio). Make 2 copies of each species (mouse, rat, human), 0.3 mL each.
  • Each tube is prepared with a total volume of 270 ⁇ L of substrate and enzyme mixture, and pre-incubated with NADPH at 37 ° C for 5min, then added 30 ⁇ L of NADPH + MgCl 2 to mix, and removed 50 ⁇ L at 0, 15, 30, 60min respectively The reaction was stopped with 300 ⁇ L of ice acetonitrile containing internal standard.
  • SD rats weighing 180-220g, were randomly divided into groups of 3 to 5 days after acclimatization. Each group of 3 rats was intragastrically administered with compound 1-1 and 8-1 at a dose of 5mg / kg.
  • test animals SD rats were fasted for 12 hours before administration and given food for 4 hours after administration. They were free to drink water before and after the experiment and during the experiment.
  • the oral exposure of the compound of the present invention was evaluated by pharmacokinetic experiments in rats.
  • the DAS3.2.5 software is used to fit the pharmacokinetic parameters of the compounds as shown in the table below.
  • test compound Three male beagle dogs, weighing 9-12 kg, were used to gavage the test compound at a dose of 2.5 mg / kg after a period of adaptation.
  • test animals male beagle dogs
  • Male beagle dogs were fasted for 12 hours before the administration and given food 4 hours after the administration. They were free to drink water before and after the experiment.
  • blood was collected from the veins of the forelimbs at 0.25h (15min), 0.5h (30min), 1h, 1.5h, 2h, 4h, 6h, 8h, 10h, 24h, 30h, 48h, 72h.
  • the plasma was transferred to 4 °C, 4000rpm, and centrifuged to separate the plasma under 10min within 30min. After collecting all the plasma, store it immediately at -20 °C.
  • Pipette 50 ⁇ L of the plasma sample to be tested add 300 ⁇ L of acetonitrile solution containing internal standard (diazepam 20ng / mL), mix by shaking for 5min, centrifuge at 13000rpm for 10min, take the supernatant of 75 ⁇ L, add 75 ⁇ L of ultrapure water to dilute, mix, and draw 1 ⁇ L Used for LC / MS / MS determination and recording chromatograms.
  • internal standard diazepam 20ng / mL
  • the oral exposure of the compound of the present invention was evaluated by pharmacokinetic experiments in beagle dogs.
  • the DAS 3.2.5 software was used to fit the pharmacokinetic parameters of the compounds as shown in Table 4-2 below.
  • Test Example 5 Pharmacodynamic evaluation of test substance in RS4; 11 human B-cell leukemia subcutaneous transplantation model
  • NOD / SCID mice female, 9-10 weeks (the age of mice when tumor cells were inoculated), weighing 16.3-22.0 g. Purchased from Ankai Yibo Biotechnology Co., Ltd., production license number: SCXK (Beijing) 2017-0006, animal certificate number: 11402400013155. Feeding environment: SPF level. 1 ⁇ 10 7 RS4; 11 cells were inoculated subcutaneously on the right anterior back of mice. The day of inoculation is defined as day 0. When the average tumor volume is 240 mm 3 , the tumors are randomly grouped according to tumor size. Dosing according to Table 5 below.
  • Group n G Dose (mg / kg) Mode of administration Administration time 1 6 Vehicle A p.o. single 2 6 1-1 25 p.o. single 3 6 1-1 50 p.o. single 4 6 8-1 25 p.o. single
  • n number of animals; the administration volume is 10 ⁇ L / g.
  • StudyDirector TM version number 3.1.399.19, supplier Studylog System, Inc., S. San Francisco, CA, USA
  • the original data is directly imported into the software after being measured by the balance and vernier caliper, and any changes in the data will be recorded in this software.
  • the relative tumor proliferation rate, T / C% is the percentage value of the tumor volume or tumor weight of the treatment group and the control group at a certain time point. Calculated as follows:
  • T and C are the relative tumor volume (RTV) or tumor weight (TW) of the treatment group and the control group at a specific time point, respectively).
  • Table 6 Analysis of the drug efficacy of each group in the human B-cell leukemia RS4; 11 subcutaneous model
  • heparin sodium anticoagulant tube draw 10 mL of human whole blood, mix upside down, centrifuge at 90 g for 10 min, collect the supernatant, and continue to centrifuge at 1950 g for 10 min. Discard the supernatant, resuspend and mix with 4mL PBS, centrifuge at 1190g for 5min, discard the supernatant, resuspend and mix with 4mL PBS, centrifuge at 1190g for 5min, discard the supernatant, resuspend the platelets with PBS and adjust the density to 2 ⁇ 3 ⁇ 10 8 pieces / mL.

Abstract

公开了包括三氟甲基取代的磺酰胺类选择性BCL-2抑制剂，具体而言公开式I化合物、其立体异构体或其药学上可接受的盐、其制备方法以及该化合物的药物组合物，还公开了该化合物以及包含该化合物的药物组合物在治疗与抗凋亡蛋白BCL-2相关疾病例如癌症中的用途。

Description

三氟甲基取代的磺酰胺类选择性BCL-2抑制剂
相关申请的引用
本申请要求于2018年10月29日向中华人民共和国国家知识产权局提交的第201811268572.2号中国专利申请的优先权和权益、于2019年3月29日向中华人民共和国国家知识产权局提交的第201910249783.X号中国专利申请的优先权和权益以及于2019年9月29日向中华人民共和国国家知识产权局提交的第201910933513.0号中国专利申请的优先权和权益，在此将其全部内容以援引的方式整体并入文本中。
技术领域
本申请涉及选择性抑制抗凋亡蛋白BCL-2的化合物、其制备方法、含有这些化合物的药物组合物、以及其在治疗与抗凋亡蛋白BCL-2相关疾病例如癌症中的用途。
背景技术
BCL-2蛋白分为三个家族：BCL-2家族(其家族成员包括BCL-2、BCL-XL等)、BAX家族和BH3-only家族，其中BCL-2家族起着抗细胞凋亡的作用，后两个家族的成员起着促细胞凋亡的作用。
抗细胞凋亡BCL-2族蛋白与许多疾病有关并且正研究作为潜在的治疗药物目标。用于介入疗法的这些目标包括，例如，BCL-2族蛋白BCL-2和BCL-XL等。最近，BCL-2族蛋白的抑制剂已经报道于WO2012071374、WO2010138588、WO2010065865。虽然其中教导了具有对靶蛋白高结合的抑制剂，但化合物结合亲合力仅仅是许多待考虑的参数之一。一个目标是产生这样的化合物：其相对于另一种蛋白，优先地结合到一种蛋白，即对其的选择性。为显示这种选择性，周知的是化合物显示对特定的蛋白的高结合亲合力，以及对另一成员的较低的结合亲合力。
已经公开的BCL-2抑制剂，它们相对于抗细胞凋亡BCL-XL蛋白及抗细胞凋亡BCL-2蛋白选择性不高，并且由此产生较大可能性的副作用，其特征为抑制抗细胞凋亡BCL-XL蛋白，产生如血小板减少等副作用。
本申请包括一系列化合物，相对于抗细胞凋亡BCL-2蛋白及抗细胞凋亡BCL-XL蛋白，其显示出较高的选择性，且抑制抗细胞凋亡BCL-2蛋白活性方面也具有较好性能。同时，还具有较好的肝微粒体稳定性，以及优化的药代动力学参数，具有更好的成药前景。
发明详述
一方面，本申请涉及式I化合物、其立体异构体或其药学上可接受的盐，
Figure PCTCN2019113963-appb-000001
其中，
R 1选自卤素；
R 2选自-C 0-6亚烷基-R 3；
R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个选自以下的基团取代：3-6元杂环烷基、C 3-6环烷基、-COR a、-SO 2R b、-COOC 1-6烷基、或任选地被卤素取代的C 1-6烷基；
R a或R b分别独立地选自H、3-6元杂环烷基、C 3-6环烷基、或C 1-6烷基，所述C 1-6烷基任选地被卤素、-CN、-N(C 1-6烷基) 2、-NHC 1-6烷基、或-OC 1-6烷基取代。
在一些实施方案中，结构片段
Figure PCTCN2019113963-appb-000002
选自
Figure PCTCN2019113963-appb-000003
在一些实施方案中，结构片段
Figure PCTCN2019113963-appb-000004
选自
Figure PCTCN2019113963-appb-000005
在一些实施方案中，结构片段
Figure PCTCN2019113963-appb-000006
选自
Figure PCTCN2019113963-appb-000007
在一些实施方案中，结构片段
Figure PCTCN2019113963-appb-000008
选自
Figure PCTCN2019113963-appb-000009
在一些实施方案中，结构片段
Figure PCTCN2019113963-appb-000010
选自
Figure PCTCN2019113963-appb-000011
在一些实施方案中，R 1选自氟或氯。在一些实施方案中，R 1选自氯。
在一些实施方案中，R 2选自-R 3或-C 1-6亚烷基-R 3。在一些实施方案中，R 2选自-C 1-4亚烷基-R 3。
在一些实施方案中，R 2选自-(CH 2) n-R 3，其中，n选自0、1、2、3或4；或者n选自1、2或3；或者n选自1或2。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个基团取代，取代位点为环上的N原子。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个选自以下的基团取代：3-6元杂环烷基、C 3-6环烷基、-COR a、-SO 2R b、或任选地被卤素取代的C 1-6烷基。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个选自以下的基团取代：3-6元杂环烷基、-COR a、-SO 2R b、-COOC 1-6烷基、或任选地被卤素取代的C 1-6烷基。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个选自以下的基团取代：3-6元杂环烷基、-COR a、-SO 2R b、或任选地被卤素取代的C 1-6烷基。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个选自以下的基团取代：-COR a、-SO 2R b、-COOC 1-6烷基、或任选地被卤素取代的C 1-6烷基。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个选自以下的基团取代：-COR a、-SO 2R b、或任选地被卤素取代的C 1-6烷基。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被3-6元杂环烷基取代。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被-COR a取代。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被-SO 2R b取代。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被-COOC 1-6烷基取代。在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被-COOC 1-4烷基取代。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被C 1-6烷基取代，所述C 1-6烷基任选地被卤素取代；在一些实施方案中，所述C 1-6烷基任选地被氟取代。在一些实施方案中，所述5-6元杂环烷基任选地被以下基团取代：甲基、乙基、被氟取代的甲基、或被氟取代的乙基。
在一些实施方案中，R a或R b分别独立地选自H、3-6元杂环烷基、C 3-6环烷基、或C 1-4烷基，所述C 1-4烷基任选地被卤素、-CN、-N(C 1-4烷基) 2、-NHC 1-4烷基、或-OC 1-4烷基取代。在一些实施方案中，R a选自H、3-6元杂环烷基、C 3-6环烷基、或C 1-4烷基，所述C 1-4烷基任选地被卤素、-CN、-N(C 1-4烷基) 2、或-OC 1-4烷基取代。在一些实施方案中，R b选自3-6元杂环烷基、C 3-6环烷基、或C 1-4烷基，所述C 1-4烷基任选地 被卤素或-CN取代。
在一些实施方案中，R a或R b分别独立地选自H、甲基、乙基、异丙基、叔丁基、环丙基、环丁基、或单氧杂环丁基，所述甲基或乙基任选地被氟、-CN、-OCH 3、或-N(CH 3) 2取代。在一些实施方案中，R a选自H、甲基、异丙基、叔丁基、环丙基、或单氧杂环丁基，所述甲基任选地被氟、-CN、-OCH 3、或-N(CH 3) 2取代。在一些实施方案中，R b选自甲基、乙基、环丙基、环丁基、或单氧杂环丁基，所述甲基或乙基任选的被氟取代。
在一些实施方案中，R a或R b分别独立地选自H、甲基、乙基、异丙基、叔丁基、三氟甲基、五氟乙基、-CH 2OCH 3、-CH 2CN、-CH 2N(CH 3) 2、环丙基、环丁基、或单氧杂环丁基。在一些实施方案中，R a选自H、甲基、异丙基、叔丁基、三氟甲基、-CH 2OCH 3、-CH 2CN、-CH 2N(CH 3) 2、环丙基、或单氧杂环丁基。在一些实施方案中，R b选自甲基、乙基、三氟甲基、五氟乙基、环丙基、环丁基、或单氧杂环丁基。
在一些实施方案中，R a或R b分别独立地选自H、C 3-6环烷基、或C 1-4烷基，所述C 1-4烷基任选地被卤素、-CN、-N(C 1-4烷基) 2、-NHC 1-4烷基、或-OC 1-4烷基取代。在一些实施方案中，R a选自H、C 3-6环烷基、或C 1-4烷基，所述C 1-4烷基任选地被卤素、-CN、-N(C 1-4烷基) 2、或-OC 1-4烷基取代。在一些实施方案中，R b选自C 3-6环烷基、或C 1-4烷基，所述C 1-4烷基任选地被卤素或-CN取代。
在一些实施方案中，R a或R b分别独立地选自H、甲基、乙基、异丙基、叔丁基、环丙基、或环丁基，所述甲基或乙基任选地被氟、-CN、-OCH 3、或-N(CH 3) 2取代。在一些实施方案中，R a选自H、甲基、异丙基、叔丁基、或环丙基，所述甲基任选地被氟、-CN、-OCH 3、或-N(CH 3) 2取代。在一些实施方案中，R b选自甲基、乙基、环丙基、或环丁基，所述甲基任选的被氟取代。
在一些实施方案中，R a或R b分别独立地选自H、甲基、乙基、异丙基、叔丁基、三氟甲基、-CH 2OCH 3、-CH 2CN、-CH 2N(CH 3) 2、环丙基、或环丁基。在一些实施方案中，R a选自H、甲基、异丙基、叔丁基、三氟甲基、-CH 2OCH 3、-CH 2CN、-CH 2N(CH 3) 2、或环丙基。在一些实施方案中，R b选自甲基、乙基、三氟甲基、环丙基、或环丁基。
在一些实施方案中，R a或R b分别独立地选自任选地被-OC 1-4烷基取代的C 1-4烷基。
在一些实施方案中，R a或R b分别独立地选自甲基、异丙基、或-CH 2OCH 3。
在一些实施方案中，R a选自任选地被-OC 1-4烷基取代的C 1-4烷基。
在一些实施方案中，R a选自甲基、异丙基、或-CH 2OCH 3。
在一些实施方案中，R b选自C 1-4烷基。
在一些实施方案中，R b选自甲基。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被以下基团取代：-C(O)H、-COCH 3、-COCH(CH 3) 2、-COC(CH 3) 3、-COCF 3、-COCH 2CN、-COCH 2OCH 3、-COCH 2N(CH 3) 2、-SO 2CH 3、-SO 2CH 2CH 3、-SO 2CF 3、-SO 2C 2F 5、甲基、乙基、-CF 3、-CH 2CH 2F、-C 2F 5、四氢吡喃、单氧杂环丁烷、-SO 2-环丙烷、-CO-环丙烷、-CO-单氧杂环丁烷、-SO 2-单氧杂环丁烷、-SO 2-环丁烷、-COOCH 2CH 3、或-COOCH 3。在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被以下基团取代：-COCH 3、-COCH(CH 3) 2、-COCH 2OCH 3、-SO 2CH 3、甲基、乙基、-CH 2CH 2F。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被以下基团取代：-C(O)H、-COC(CH 3) 3、-COCF 3、-COCH 2CN、-COCH 2N(CH 3) 2、-SO 2CH 2CH 3、-SO 2CF 3、-SO 2C 2F 5、-CF 3、-C 2F 5、四氢吡喃、单氧杂环丁烷、-SO 2-环丙烷、-CO-环丙烷、-CO-单氧杂环丁烷、-SO 2-单氧杂环丁烷、-SO 2-环丁烷。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被以下基团取代：-COOCH 2CH 3、或-COOCH 3。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被以下基团取代：-C(O)H、-COCH 3、-COCH(CH 3) 2、-COC(CH 3) 3、-COCF 3、-COCH 2CN、-COCH 2OCH 3、-COCH 2N(CH 3) 2、-SO 2CH 3、-SO 2CH 2CH 3、-SO 2CF 3、甲基、乙基、-CH 2CH 2F、四氢吡喃、-SO 2-环丙烷、-CO-环丙烷、-SO 2-环丁烷。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被以下基团取代：-C(O)H、-COC(CH 3) 3、-COCF 3、-COCH 2CN、-COCH 2N(CH 3) 2、-SO 2CH 2CH 3、-SO 2CF 3、-SO 2C 2F 5、-CF 3、-C 2F 5、四氢吡喃、-SO 2-环丙烷、-CO-环丙烷、-SO 2-环丁烷。
在一些实施方案中，R 3选自四氢吡喃、哌啶、吗啉或二氧六环，所述四氢吡喃、哌啶、吗啉或二氧六环任选地被以下基团取代：-C(O)H、-COCH 3、-COCH 2OCH 3、-SO 2CH 3、-SO 2CH 2CH 3、-CO-环丙烷、-COCH 2CN、-COCF 3、-COCH 2N(CH 3) 2、或甲基。
在一些实施方案中，R 3选自四氢吡喃、哌啶、吗啉或二氧六环，所述四氢吡喃、哌啶、吗啉或二氧六环任选地被以下基团取代：-COCH 3、-COCH(CH 3) 2、-COCH 2OCH 3、-SO 2CH 3、甲基、乙基、或-CH 2CH 2F。
在一些实施方案中，R 3选自四氢吡喃、哌啶、吗啉或二氧六环，所述四氢吡喃、哌啶、吗啉或二氧六环任选地被以下基团取代：-COOCH 2CH 3、或-COOCH 3。
在一些实施方案中，R 3选自四氢吡喃或二氧六环。
在一些实施方案中，R 3选自二氧六环。
在一些实施方案中，R 3选自哌啶或吗啉，所述哌啶或吗啉任选地被以下基团取代：-C(O)H、-COCH 3、-COCH 2OCH 3、-SO 2CH 3、-SO 2CH 2CH 3、-CO-环丙烷、-COCH 2CN、-COCF 3、-COCH 2N(CH 3) 2、或甲基。在一些实施方案中，R 3选自哌啶或吗啉，所述哌啶或吗啉任选地被以下基团取代：-COCH 3、-COCH(CH 3) 2、-COCH 2OCH 3、-SO 2CH 3、甲基、乙基、或-CH 2CH 2F。
在一些实施方案中，R 3选自哌啶或吗啉，所述哌啶或吗啉任选地被以下基团取代：-COOCH 2CH 3、或-COOCH 3。
在一些实施方案中，R 3选自
Figure PCTCN2019113963-appb-000012
Figure PCTCN2019113963-appb-000013
Figure PCTCN2019113963-appb-000014
在一些实施方案中，R 3选自
Figure PCTCN2019113963-appb-000015
Figure PCTCN2019113963-appb-000016
在一些实施方案中，R 3选自
Figure PCTCN2019113963-appb-000017
Figure PCTCN2019113963-appb-000018
Figure PCTCN2019113963-appb-000019
在一些实施方案中，R 3选自
Figure PCTCN2019113963-appb-000020
在一些实施方案中，R 3选自
Figure PCTCN2019113963-appb-000021
Figure PCTCN2019113963-appb-000022
在一些实施方案中，R 3选自
Figure PCTCN2019113963-appb-000023
Figure PCTCN2019113963-appb-000024
在一些实施方案中，R 3选自
Figure PCTCN2019113963-appb-000025
在一些实施方案中，R 3选自
Figure PCTCN2019113963-appb-000026
Figure PCTCN2019113963-appb-000027
Figure PCTCN2019113963-appb-000028
在一些实施方案中，R 3选自
Figure PCTCN2019113963-appb-000029
在一些实施方案中，R 3选自
Figure PCTCN2019113963-appb-000030
Figure PCTCN2019113963-appb-000031
在一些实施方案中，R 3选自
Figure PCTCN2019113963-appb-000032
在一些实施方案中，所述5-6元杂环烷基中的杂原子选自N或O，杂原子个数选自1或2。
在一些实施方案中，所述5-6元杂环烷基选自二氧六环基、吗啉基、四氢吡喃基、哌啶基、或四氢呋喃基。
在一些实施方案中，所述5-6元杂环烷基选自6元杂环烷基。
在一些实施方案中，所述5-6元杂环烷基选自二氧六环基、吗啉基、四氢吡喃基、或哌啶基。
在一些实施方案中，所述5-6元杂环烷基选自二氧六环基。
在一些实施方案中，所述5-6元杂环烷基选自吗啉基。
在一些实施方案中，所述5-6元杂环烷基选自四氢吡喃基。
在一些实施方案中，所述3-6元杂环烷基中杂原子选自N或O，杂原子个数选自1或2。在一些实施方案中，所述3-6元杂环烷基中杂原子选自O，杂原子个数为1或2。在一些实施方案中，所述3-6元杂环烷基选自4-6元杂环烷基。在一些实施方案中，所述3-6元杂环烷基选自4元杂环烷基或6元杂环烷基。
在一些实施方案中，所述3-6元杂环烷基选自单氧杂环丁烷基、四氢呋喃基、四氢吡喃基。
在一些实施方案中，所述C 3-6环烷基选自环丙烷基、环丁烷基、环戊烷基。在一些实施方案中，所述C 3-6环烷基选自C 3-4环烷基。
另一方面，本申请涉及一种式II化合物、其立体异构体或其药学上可接受的盐：
Figure PCTCN2019113963-appb-000033
其中，R 2的定义同式I化合物。
本申请涉及以下化合物、其立体异构体或其药学上可接受的盐，
Figure PCTCN2019113963-appb-000034
Figure PCTCN2019113963-appb-000035
或以下化合物、其立体异构体或其药学上可接受的盐，
Figure PCTCN2019113963-appb-000036
其中，R独立为以下基团：
Figure PCTCN2019113963-appb-000037
Figure PCTCN2019113963-appb-000038
Figure PCTCN2019113963-appb-000039
本申请涉及以下化合物或其药学上可接受的盐，
Figure PCTCN2019113963-appb-000040
Figure PCTCN2019113963-appb-000041
Figure PCTCN2019113963-appb-000042
Figure PCTCN2019113963-appb-000043
或以下化合物或其药学上可接受的盐：
Figure PCTCN2019113963-appb-000044
其中，R独立为以下基团：
Figure PCTCN2019113963-appb-000045
Figure PCTCN2019113963-appb-000046
Figure PCTCN2019113963-appb-000047
Figure PCTCN2019113963-appb-000048
Figure PCTCN2019113963-appb-000049
Figure PCTCN2019113963-appb-000050
另一方面，本申请涉及一种药物组合物，其包含本申请的上述式I、式II或具体化合物、其立体异构体或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包含药学上可接受的辅料。
另一方面，本申请描述了治疗哺乳动物与抗凋亡蛋白BCL-2相关疾病的方法，包括对需要该治疗的哺乳动物(优选人类)给予治疗有效量的上述式I、式II或具体化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。
另一方面，本申请描述了上述式I、式II或具体化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在制备预防或者治疗与抗凋亡蛋白BCL-2相关疾病的药物中的用途。
另一方面，本申请描述了上述式I、式II或具体化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在预防或者治疗与抗凋亡蛋白BCL-2相关疾病的用途。
另一方面，本申请描述了用于预防或者治疗与抗凋亡蛋白BCL-2相关疾病的上述式I、式II或具体化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。
其中，所述与抗凋亡蛋白BCL-2相关疾病选自癌症。所述癌症选自急性淋巴细胞白血病。
定义
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(-CH 2CH 3)、单取代的(如-CH 2CH 2F)、多取代的(如-CHFCH 2F、-CH 2CHF 2等)或完全被取代的(-CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文中的C m-n，是该部分具有给定范围中的整数个碳原子。例如“C 1-6”是指该基团可具有1个碳原 子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“烷基”是指通式为C nH 2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C 1- 6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。再例如术语“C 1- 4烷基”指含有1至4个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等)。
术语“亚烷基”是指烷基的任意位置除去1个氢而形成的二价基团。例如，术语“C 0-6亚烷基”的非限制性实例包括但不限于亚甲基、亚乙基、甲基亚甲基、二甲基亚甲基、1,3-亚丙基等。C 0则表示键。
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至10元环。环烷基的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基等。
术语“杂环烷基”是指完全饱和的并且可以以单环、桥环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至3个(优选1或2个)独立地选自硫、氧和/或氮的杂原子的3至7元环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。优选为具有5或6个环原子的单环杂环烷基。
术语“治疗”意为将本申请所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；
(ii)抑制疾病或疾病状态，即遏制其发展；
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“药学上可接受的”，是指针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising等应理解为开放的、非排他性的意义，即“包括但不限于”。
本申请的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
某些同位素标记的本申请化合物(例如用 3H及 14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素由于其易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括在本申请中，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品等。
本文所述的式I化合物的所有施用方法中，每天给药的剂量为0.01mg/kg到200mg/kg体重，以单独或分开剂量的形式。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其它化学合成方法的结合所形成的实施方式以及本领域技术人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的羟基)选择合适的保护 基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley & Sons,Inc.
在一些实施方案中，本申请式I的化合物可以由有机合成领域技术人员通过以下路线方法来制备：
路线1：
Figure PCTCN2019113963-appb-000051
路线2：
Figure PCTCN2019113963-appb-000052
Figure PCTCN2019113963-appb-000053
上述路线中，R 1、R 2或
Figure PCTCN2019113963-appb-000054
的定义同上，X选自离去基团，优选自氟、氯、溴或碘；R 4选自C 1-6烷基或者C 1-4烷基，优选自叔丁基、甲基或乙基；R 5选自氨基保护基，优选为Boc或Cbz(苄氧基羰基)；R 6选自氨基保护基，优选自硅烷类保护基，更优选自TBS(叔丁基二甲基硅)、TBDPS(叔丁基二苯基硅)或TMS(三甲基硅)、TES(三乙基硅)、TIPS(三异丙基硅)保护基团。
本申请还提供一种制备式A-4化合物的方法，包括以下步骤：
Figure PCTCN2019113963-appb-000055
其中，R 1或
Figure PCTCN2019113963-appb-000056
的定义同上；X选自离去基团，优选自氟、氯、溴或碘；R 4选自C 1-6烷基或者C 1-4烷基，优选自叔丁基、甲基或乙基；R 6选自氨基保护基，优选自硅烷类保护基，更优选自TBS(叔丁基二甲基硅)、TBDPS(叔丁基二苯基硅)或TMS(三甲基硅)、TES(三乙基硅)、TIPS(三异丙基硅)保护基团。
本申请还提供一种制备式A-3化合物的方法，包括以下步骤：
Figure PCTCN2019113963-appb-000057
其中，R 1、
Figure PCTCN2019113963-appb-000058
的定义同上，R 5选自氨基保护基，优选为Boc或Cbz(苄氧基羰基)。
本申请还提供一种制备式A-2化合物的方法，包括以下步骤：
Figure PCTCN2019113963-appb-000059
其中，R 1、
Figure PCTCN2019113963-appb-000060
的定义同上，R 5选自氨基保护基，优选为Boc或Cbz(苄氧基羰基)。
本申请还提供一种制备式A-5化合物的方法，包括以下步骤：
Figure PCTCN2019113963-appb-000061
其中，R 1、
Figure PCTCN2019113963-appb-000062
的定义同上，R 4选自C 1-6烷基或者C 1-4烷基，优选自叔丁基、甲基或乙基；R 6选自氨基保护基，优选自硅烷类保护基，更优选自TBS(叔丁基二甲基硅)、TBDPS(叔丁基二苯基硅)或TMS(三甲基硅)、TES(三乙基硅)、TIPS(三异丙基硅)保护基团。
本申请还提供一种制备式I化合物的方法，包括以下步骤：
Figure PCTCN2019113963-appb-000063
其中，R 1、R 2或
Figure PCTCN2019113963-appb-000064
的定义同上。
本申请还提供了以下中间体化合物或其盐：
Figure PCTCN2019113963-appb-000065
Figure PCTCN2019113963-appb-000066
其中，R 1、
Figure PCTCN2019113963-appb-000067
的定义同上，R 4选自C 1-6烷基或者C 1-4烷基，优选自叔丁基、甲基或乙基；R 5选自氨基保护基，优选为Boc或Cbz(苄氧基羰基)；R 6选自氨基保护基，优选自硅烷类保护基，更优选自TBS(叔丁基二甲基硅)、TBDPS(叔丁基二苯基硅)或TMS(三甲基硅)、TES(三乙基硅)、TIPS(三异丙基硅)保护基团。其中所述盐可以选自盐酸盐等。
在更具体的在一些实施方案中，上述化合物分别选自以下化合物或其盐：
Figure PCTCN2019113963-appb-000068
Figure PCTCN2019113963-appb-000069
其中所述盐可以选自盐酸盐等。
具体实施方式
缩略词：DMF代表N,N-二甲基甲酰胺；Boc代表叔丁氧羰基；NaOAc代表乙酸钠；tBu代表叔丁基；TBS代表叔丁基二甲基硅基；THF代表四氢呋喃；DMSO代表二甲基亚砜。
为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。
实施例1 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000070
1)化合物1-b的制备
0℃条件下，向DMF(173.7g)及二氯甲烷(460mL)溶液中，滴加三氯氧磷，滴加完毕，升温至20℃ 搅拌1h后，降温至0℃，滴加3,3-二甲基环己酮(1-a)(200g)，滴加完毕，加热回流过夜。搅拌条件下将反应液滴加至含有NaOAc(86.7g)、NaCl(80g)、水(1.2L)及二氯甲烷(600mL)的溶液中，室温搅拌20min，分液，水相用二氯甲烷(500mL)萃取，合并有机相，用含有K 3PO 4(40g)、NaCl(90g)的水(1L)溶液再洗涤一次，无水硫酸钠干燥，过滤，浓缩，得化合物1-b(249g)。
2)化合物1-c的制备
将化合物1-b(5.36g)、4-三苯基膦钯(0.18g)、K 3PO 4(16.5g)、DMF(60mL)、水(60mL)混合搅拌10min，进一步加入2-氯-4-三氟甲基苯硼酸(6.96g)，N 2保护，100℃反应6h，反应完全。将30mL(含有5wt％NaHCO 3+2wt％L-半胱氨酸)水溶液和50mL乙酸乙酯加入反应液，搅拌0.5h，过滤，分液，水相用乙酸乙酯60mL×2萃取，合并有机相，所得有机相用饱和NaCl水溶液洗涤，无水Na 2SO 4干燥，过滤，浓缩，柱层析得化合物1-c(2g)。
3)化合物1-e的制备
将2-[(1H-吡咯并[2,3-b]吡啶-5-基)氧基]-4-溴苯甲酸叔丁酯(化合物1-d)(77.8g)、Boc-哌嗪(55.8g)、三(二亚苄基丙酮)二钯(9g)、[(4-(N,N-二甲氨基)苯基]二叔丁基膦(5.2g)、叔丁醇钠(96.1g)、甲苯(800mL)、四氢呋喃(300mL)混合，搅拌，氮气保护，加热至60℃反应24h。用含有L-半胱氨酸(100g)和NaHCO 3(150g)的水溶液(1.5L)洗涤反应液2次(750mL×2)，饱和NaCl水溶液洗涤，无水Na 2SO 4干燥，过滤，浓缩，得化合物1-e(40g)。ESI-MS:m/z＝495.4[M+H]+.
4)化合物1-f的制备
将化合物1-e(40g)、800mL四氢呋喃、270mL乙醇及15mL水混合，搅拌，加入KOH(45.3g)固体，升温至80℃搅拌回流8h，反应完全。加入500mL水搅拌，用稀盐酸调节pH至5～6，过滤，用水(1L)打浆2次(500mL×2)，干燥得化合物1-f(35g)。
5)化合物1-h的制备
将化合物1-f(35g)和二氯甲烷(100mL)混合，室温搅拌，加入4-二甲氨基吡啶(38.5g)及1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(65.8g)，搅拌溶解，加入3-硝基-4-[[(四氢吡喃-4-基)甲基]氨基]苯磺酰胺(化合物1-g)(25.2g)，室温反应3h。依次用5wt％盐酸、饱和碳酸氢钠水溶液、饱和氯化钠水溶液洗涤，无水Na 2SO 4干燥，过滤，浓缩，加二氯甲烷(200mL)室温搅拌2h，过滤，干燥，得化合物1-h(40g)。
6)化合物1-i的制备
将化合物1-h加入500mL异丙醇中搅拌，加入50mL浓HCl，升温至65℃搅拌8h，反应完全。过滤，将滤饼溶于300mL水中，滴加饱和碳酸氢钠调pH6～7，过滤，干燥，所得固体用200mL乙酸乙酯打浆，过滤烘干得化合物1-i(27g)。
7)化合物1-1的制备
将化合物1-c(1g)及化合物1-i(2g)溶于20mL甲醇中，搅拌，加入硼氢化钠(0.24g)，搅拌6h，反应完全。加入10mL饱和氯化铵水溶液淬灭，20mL乙酸乙酯萃取两次，饱和氯化钠水溶液洗涤，无水Na 2SO 4干燥，过滤，浓缩滤液，柱层析得化合物1-1(200mg)。
化合物1-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.68(s,1H),8.62(m,1H),8.58(d,1H),8.04(d,1H),7.83(s,1H),7.81(dd,1H),7.70(d,1H),7.54(m,3H),7.40(d,1H),7.12(d,1H),6.74(d,1H),6.40(s,1H),6.29(s,1H),3.87(m,4H),3.55(d,2H),3.37(d,2H),3.32(m,4H),2.27(d,1H),2.19(m,1H),2.09(s,1H),1.96(s,2H),1.89(m,1H),1.63(d,2H),1.50(m,2H),1.28(m,4H),0.98(d,6H).
13C NMR(125MHz,DMSO-d6),δ:163.9,158.8,153.9,147.9,142.9,132.5,130.1,128.3,125.6,124.7,120.3,118.4,115.5,114.1,109.6,103.4,100.4,67.0,58.3,50.9,48.4,46.9,44.1,34.6,30.6,29.1,25.2.ESI-MS:m/z＝936.5[M+H]+.
实施例2 4-(4-{[2-(3-三氟甲基4-氯苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000071
1)化合物2-c的制备
将化合物1-b(5.16g)、4-三苯基膦钯(0.17g)、K 3PO 4(12.74g)、DMF(60mL)、水(60mL)混合搅拌10min，进一步加入3-三氟甲基4-氯苯硼酸(6.72g)，N 2保护，100℃反应6h，反应完全。将30mL(含有5wt％NaHCO 3+2wt％L-半胱氨酸)水溶液和50mL乙酸乙酯加入反应液，搅拌0.5h，过滤，分液，水相用乙酸乙酯60mL×2萃取，合并有机相，所得有机相用饱和NaCl水溶液洗涤，无水Na 2SO 4干燥，过滤，浓缩，柱层析得化合物2-c(1.2g)。
2)化合物2-1的制备
将化合物2-c(1g)及化合物1-i(2.01g)溶于20mL甲醇中，搅拌，加入硼氢化钠(0.27g)，搅拌6h，反应完全。加入10mL饱和氯化铵水溶液淬灭，20mL乙酸乙酯萃取两次，饱和氯化钠水溶液洗涤，无水Na 2SO 4干燥，过滤，浓缩滤液，柱层析得化合物2-1(80mg)。
化合物2-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.66(s,1H),8.61(m,1H),8.57(d,1H),8.04(d,1H),7.81(dd,1H),7.67(d,1H),7.54(m,4H),7.40(d,1H),7.12(d,1H),6.74(d,1H),6.40(s,1H),6.29(s,1H),3.87(m,4H),3.55(d,2H),3.32(m,6H),3.01(s，2H)2.21(d,2H),1.98(m,2H),1.87(m,1H),1.60(d,2H),1.45(m,2H),1.28(m,4H),0.98(d,6H).
13C NMR(125MHz,DMSO-d6),δ:163.9,158.7,158.4,158.2,153.9,147.9,146.8,145.9,141.5,135.6,134.3,134.2,132.5,132.4,130.1,130.0,129.8,128.3,127.6,127.4,124.7,122.1,120.2,118.4,115.5,114.0,109.5,103.4,100.4,67.0,58.3,50.8,48.4,46.7,44.3,34.6,34.3,30.6,29.2,28.3,25.2,14.4.ESI-MS:m/z＝936.5[M+H] +.
实施例3 4-(4-{[2-(4-氯-2-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000072
1)化合物3-c的制备
将化合物1-b(5.16g)、4-三苯基膦钯(0.17g)、K 3PO 4(12.74g)、DMF(60mL)、水(60mL)混合搅拌10min，进一步加入2-三氟甲基4-氯苯硼酸(6.72g)，N 2保护，100℃反应6h，反应完全。将30mL(含有5wt％NaHCO 3+2wt％L-半胱氨酸)水溶液和50mL乙酸乙酯加入反应液，搅拌0.5h，过滤，分液，水相用乙酸乙酯60mL×2萃取，合并有机相，所得有机相用饱和NaCl水溶液洗涤，无水Na 2SO 4干燥，过滤，浓缩，柱层析得化合物3-c(1.6g)。
2)化合物3-1的制备
将化合物3-c(1g)及化合物1-i(2.01g)溶于20mL甲醇中，搅拌，加入硼氢化钠(0.27g)，搅拌6h，反应完全。加入10mL饱和氯化铵水溶液淬灭，20mL乙酸乙酯萃取两次，饱和氯化钠水溶液洗涤，无水Na 2SO 4干燥，过滤，浓缩滤液，柱层析得化合物3-1(110mg)。
化合物3-1： 1H NMR(500MHz,DMSO-d6),δ:11.73(s,1H),11.67(s,1H),8.61(m,1H),8.58(d,1H),8.05(d,1H),7.79(m,2H),7.71(d,1H),7.52(m,3H),7.29(d,1H),7.13(d,1H),6.74(d,1H),6.41(s,1H),6.26(s,1H),3.84(d,2H),3.61(d,2H),3.18(m,4H),3.05(s,3H),231(d,1H),1.89(m,5H),1.61(d,2H),1.51(m,1H),1.41(m,1H),1.24(d,6H),0.91(m,6H).
13C NMR(125MHz,DMSO-d6),δ:163.9,158.8,158.5,158.2,153.9,147.9,146.7,145.9,139.1,135.6,134.3,133.4,133.1,133.0,132.6,130.0,128.3,126.7,124.7,120.3,118.5,115.5,114.1,109.6,103.3,100.4,67.0,58.7,48.4,46.8,44.3,34.5,34.3,30.6,29.4,29.0,28.9,27.5,27.0,24.6,22.5.ESI-MS:m/z＝936.5[M+H] +.
实施例4 4-(4-{[2-(3-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000073
1)化合物4-c的制备
将化合物1-b(5.16g)、4-三苯基膦钯(0.17g)、K 3PO 4(12.74g)、DMF(60mL)、水(60mL)混合搅拌10min，进一步加入3-氯-4-三氟甲基苯硼酸(6.72g)，N 2保护，100℃反应6h，反应完全。将30mL(含有5wt％NaHCO 3+2wt％L-半胱氨酸)水溶液和50mL乙酸乙酯加入反应液，搅拌0.5h，过滤，分液，水相用乙酸乙酯60mL×2萃取，合并有机相，所得有机相用饱和NaCl水溶液洗涤，无水Na 2SO 4干燥，过滤，浓缩，柱层析得化合物4-c(1.5g)。
2)化合物4-1的制备
将化合物4-c(1g)及化合物1-i(2.01g)溶于20mL甲醇中，搅拌，加入硼氢化钠(0.27g)，搅拌6h，反应完全。加入10mL饱和氯化铵水溶液淬灭，20mL乙酸乙酯萃取两次，饱和氯化钠水溶液洗涤，无水Na 2SO 4干燥，过滤，浓缩滤液，柱层析得化合物4-1(120mg)。
化合物4-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,1H),11.62(s,1H),8.61(m,1H),8.57(d,1H),8.04(d,1H),7.79(m,2H),7.50(m,3H),7.43(s,1H),7.23(d,1H),7.12(d,1H),6.71(dd,1H),6.39(m,1H),6.25(d,1H),3.84(dd,2H),3.29(m,4H),3.24(m,2H),2.21(d,3H),2.03(d,3H),1.88(m,1H),1.60(m,2H),1.43(m,3H),1.22(m,4H),0.94(d,9H).
13C NMR(125MHz,DMSO-d6),δ:163.9,158.8,158.6,158.3,154.1,147.9,146.8,145.9,135.7,134.7,134.3,132.5,131.4,130.0,128.3,127.8,125.7,124.7,124.5,120.2,118.4,115.5,114.0,109.5,103.3,100.4,67.0,64.6,51.0,48.4,46.4,45.2,44.6,34.6,34.3,30.6,29.3,29.1,28.2,28.1,25.2,24.8.ESI-MS:m/z＝936.5[M+H] +.
实施例5 4-(4-{[2-(2-氟-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000074
1)化合物5-c的制备
将化合物1-b(5.16g)、4-三苯基膦钯(0.17g)、K 3PO 4(12.74g)、DMF(60mL)、水(60mL)混合搅拌10min，进一步加入2-氟-4-三氟甲基苯硼酸(6.24g)，N 2保护，100℃反应6h，反应完全。将30mL(含有5wt％NaHCO 3+2wt％L-半胱氨酸)水溶液和50mL乙酸乙酯加入反应液，搅拌0.5h，过滤，分液，水相用乙酸乙酯60mL×2萃取，合并有机相，所得有机相用饱和NaCl水溶液洗涤，无水Na 2SO 4干燥，过滤，浓缩，柱层析得化合物5-c(1.8g)。
2)化合物5-1的制备
将化合物5-c(1g)及化合物1-i(2.12g)溶于20mL甲醇中，搅拌，加入硼氢化钠(0.27g)，搅拌6h，反应完全。加入10mL饱和氯化铵水溶液淬灭，20mL乙酸乙酯萃取两次，饱和氯化钠水溶液洗涤，无水Na 2SO 4干燥，过滤，浓缩滤液，柱层析得化合物5-1(90mg)。
化合物5-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,2H),8.61(m,1H),8.57(d,1H),8.03(d,1H),7.80(dd,1H),7.66(d,1H),7.56(d,1H),7.51(dd,3H),7.35(m,1H),7.12(d,1H),6.73(dd,1H),6.39(m,1H),6.29(d,1H),3.84(m,3H),3.55(d,5H),3.24(d,6H),2.25(s,2H),1.98(m,2H),1.88(m,1H),1.60(d,2H),1.47(m,2H),1.24(m,4H),0.95(d,6H).
13C NMR(125MHz,DMSO-d6),δ:163.9,159.6,158.7,158.5,158.1,157.7,154.0,147.9,146.9,145.9,135.6,134.3,133.2,132.5,132.1,130.0,128.3,124.9,124.7,122.7,122.1,120.2,118.2,115.5,114.1,109.6,103.5,100.4,67.0,58.6,50.8,48.4,45.7,44.3,34.5,34.3,30.6,29.1,28.6,27.6,25.1.ESI-MS:m/z＝920.6[M+H] +.
实施例6 4-(4-{[2-(3-氟-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000075
1)化合物6-c的制备
将化合物1-b(5.16g)、4-三苯基膦钯(0.17g)、K 3PO 4(12.74g)、DMF(60mL)、水(60mL)混合搅拌10min，进一步加入3-氟-4-三氟甲基苯硼酸(6.24g)，N 2保护，100℃反应6h，反应完全。将30mL(含有5wt％NaHCO 3+2wt％L-半胱氨酸)水溶液和50mL乙酸乙酯加入反应液，搅拌0.5h，过滤，分液，水相用乙酸乙酯60mL×2萃取，合并有机相，所得有机相用饱和NaCl水溶液洗涤，无水Na 2SO 4干燥，过滤，浓缩，柱层析得化合物6-c(1.6g)。
2)化合物6-1的制备
将化合物6-c(1g)及化合物1-i(2.12g)溶于20mL甲醇中，搅拌，加入硼氢化钠(0.27g)，搅拌6h，反应完全。加入10mL饱和氯化铵水溶液淬灭，20mL乙酸乙酯萃取两次，饱和氯化钠水溶液洗涤，无水Na 2SO 4干燥，过滤，浓缩滤液，柱层析得化合物6-1(150mg)。
化合物6-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.67(s,1H),8.61(m,1H),8.57(d,1H),8.04(d,1H),7.81(dd,1H),7.72(m,1H),7.52(dd,3H),7.24(d,1H),7.09(m,2H),6.72(dd,1H),6.39(m,1H),6.27(d,1H),3.87(m,4H),3.55(d,2H),3.37(d,2H),3.32(m,4H),2.27(d,1H),2.19(m,2H),2.09(s,1H),1.96(s,2H),1.89(m,1H),1.63(d,2H),1.50(m,2H),1.28(m,4H),0.98(d,6H).
13C NMR(125MHz,DMSO-d6),δ:163.9,158.8,158.5,158.2,154.0,149.2,147.9,146.8,145.9,135.6,134.3,132.5,132.4,130.1,130.0,128.3,128.1,125.1,120.3,118.4,117.6,117.2,117.1,115.5,115.3,109.6,103.4,100.4,67.0,58.3,50.9,48.4,46.4,44.3,34.5,34.3,31.7,30.6,29.0,28.2,25.5,25.1.ESI-MS:m/z＝920.6[M+H] +.
实施例7 (R)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(1,4-二噁烷-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000076
1)化合物7-d的制备
将化合物1-c(198.6g)、1-Boc-哌嗪(175.5g)溶于乙腈(800mL)中，搅拌，降温至0℃，缓慢加入三乙酰氧基硼氢化钠(532.6g)，室温搅拌5h。反应完全，加水(1L)和乙酸乙酯(300mL)萃取，收 集有机相，无水Na 2SO 4干燥，过滤，浓缩，得化合物7-d(269.8g)。
2)化合物7-e的制备
将化合物7-d(269.8g)、异丙醇(800mL)、盐酸(浓度36～38wt％，169mL)混合，加热至65℃，反应3h。冷却析出固体，过滤，干燥，得化合物7-e(151.2g)。
化合物7-e： 1H NMR(500MHz,DMSO-d6),δ:7.82(s,1H),7.68(d,1H),7.36(d,1H),7.10(dd,1H),2.98(s,4H),2.63(d,2H),2.23(m,6H),1.89(m,2H),1.43(s,2H),0.94(s,6H).
13C NMR(125MHz,DMSO-d6),δ:133.1,132.6,131.9,130.9,129.3,128.6,126.5,125.7,124.9,124.6,122.7,60.2,49.4,44.7,35.2,29.4,28.4,27.1,25.2,21.4.ESI-MS:m/z＝387.1[M+H] +.
3)化合物7-g的制备
将NaH(21.1g)溶于THF(100mL)中降温至-20℃搅拌10min，将2-[(1H-吡咯并[2,3-b]吡啶-5-基)氧基]-4-溴苯甲酸叔丁酯(化合物1-d，128.3g)溶于200mL THF中，缓慢滴加至反应液中，滴加过程中控制内温0℃以下，滴加完毕后搅拌30min，向反应液中滴加TBSCl(64.7g)的THF(200mL)溶液，滴加过程中控制内温-10℃左右，滴毕反应30min，反应完全后加入500mL饱和碳酸氢钠和乙酸乙酯萃取，收集有机相，无水Na 2SO 4干燥，过滤，浓缩，柱层析纯化得化合物7-f(150g)。ESI-MS:m/z＝503.1[M+H] +。
将化合物7-e(151.2g)、2-[(1-叔丁基二甲基硅基吡咯并[2,3-b]吡啶-5-基)氧基]-4-溴苯甲酸叔丁酯(化合物7-f，197.1g)、三(二亚苄基丙酮)二钯(2.7g)、[(4-(N,N-二甲氨基)苯基]二叔丁基膦(1.6g)、叔丁醇钠(187.4g)、甲苯(800mL)混合，搅拌，氮气保护，加热至100℃反应24h。反应结束，加水(1L)和乙酸乙酯(300mL)萃取，收集有机相，无水Na 2SO 4干燥，过滤，浓缩，得化合物7-g(181.9g)。
化合物7-g： 1H NMR(500MHz,DMSO-d6),δ:7.95(s,1H),7.82(s,1H),7.65(t,2H),7.37(m,4H),6.76(d,1H),6.47(s,1H),3.14(s,2H),2.64(d,1H),2.55(d,1H),2.19(m,5H),1.92(m,2H),1.42(t,2H),1.31(t,2H),1.22(m,9H),0.95(d,6H),0.84(s,10H),0.60(s,6H).
13C NMR(125MHz,DMSO-d6),δ:164.4 156.8,155.1,150.3,149.8,146.2,133.6,133.4,133.2,132.0,131.9,131.5,129.5,129.0,128.8,126.4,126.1,124.4,122.8,114.4,113.8,110.2,106.8,103.3,80.1,60.6,52.6,47.1,44.7,35.2,29.4,27.9,27.2,26.7,25.4,19.0.ESI-MS:m/z＝809.4[M+H] +
4)化合物7-h的制备
将化合物7-g(181.9g)、甲苯(1.8L)、三氟乙酸(107mL)的混合物加热至45℃，反应5h。浓缩反应液，加乙酸乙酯1.5L，饱和NaHCO 3水溶液、饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，浓缩，加1L甲苯和200mL乙酸乙酯，加热溶清后，降温析出固体，过滤，干燥，得化合物7-h(83.4g)。
化合物7-h： 1H NMR(500MHz,DMSO-d6),δ:7.98(s,1H),7.82(s,1H),7.73(d,1H),7.64(d,1H),7.46(s,1H),7.40(s,1H),7.32(d,1H),6.73(d,1H),6.36(d,1H),6.34(s,1H),3.09(s,4H),2.64(d,1H),2.55(d,1H),2.19(m,6H),1.88(m,2H),1.42(m,2H),1.25(m,2H),0.95(m,6H).
13C NMR(125MHz,DMSO-d6),δ:166.3,158.9,155.1,148.9,146.2,145.3,135.0,133.8,133.2,132.0,131.9,131.4,129.5,129.2,127.8,126.4,124.9,124.4,122.7,120.2,116.6,112.0,109.5,105.3,100.2,60.5,55.3,52.7,47.0,44.7,35.2,29.4,27.2,25.4.ESI-MS:m/z＝639.2[M+H] +.
5)化合物7-k的制备
将3-硝基-4-氯苯磺酰胺(0.64g)、(R)-(1,4-二噁烷)-2-甲胺盐酸盐(0.5g)和N,N-二异丙基乙胺(1.58g)溶于乙腈(10mL)中，加热至85℃，反应6.5h，室温冷却，静置过夜，过滤，得化合物7-k(0.65g)。ESI-MS:m/z＝316.2[M-H] -.
6)化合物7-1的制备
将化合物7-h(1g)和二氯甲烷(10mL)混合，室温搅拌，加入4-二甲氨基吡啶(0.28g)及1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(0.44g)，搅拌溶解，加入化合物7-k(0.5g)和三乙胺(0.44g)，室温反应3h。依次用5wt％盐酸、饱和碳酸氢钠水溶液、饱和氯化钠水溶液洗涤，无水Na 2SO 4干燥，过滤，浓缩，经柱层析分离纯化得化合物7-1(0.8g)。
化合物7-1： 1H NMR(500MHz,DMSO-d6),δ:11.66(s,1H),11.37(s,1H),8.59(t,1H),8.57(d,1H),8.05(d,1H),7.88(d,1H),7.83(dd,1H),7.70(d,1H),7.53(d,1H),7.52(m,2H),7.40(m,1H),7.12(d,1H),6.75(dd,1H),6.40(dd,1H),6.30(d,1H),3.80(m,3H),3.62(m,2H),3.51(m,2H),3.42(m,2H),3.03(m,4H),2.67(d,1H),2.54(d,1H),2.17(m,6H),1.88(dd,2H),1.42(t,2H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,159.2,159.0,158.7,158.4,158.2,154.0,147.8,146.9,145.8,144.2,139.0,135.5,134.3,132.8,132.6,131.7,130.1,130.0,128.3,128.2,127.0,125.1,124.9,124.4,122.75,120.3,118.3,117.5,115.7,115.2,114.2,122.8,109.7,103.6,100.4,58.5,45.2,44.3,43.8,34.6,29.2,29.1,27.1,24.8.ESI-MS:m/z＝938.5[M+H] +.
实施例8 (S)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(1,4-二噁烷-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000077
1)化合物8-k的制备
将3-硝基-4-氟苯磺酰胺(3.58g)、(S)-2-(氨甲基)-1,4-二氧六环盐酸盐(3.0g)和N,N-二异丙基乙胺(9.47g)溶于乙腈(50mL)中，加热至85℃，反应5h，室温冷却，静置过夜，抽滤，得化合物8-k(4.70g)。ESI-MS:m/z＝316.1[M-H]-.
2)化合物8-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物8-k，得到化合物8-1。
化合物8-1： 1H NMR(500MHz,DMSO-d6),δ:11.66(s,1H),11.37(s,1H),8.59(t,1H),8.57(d,1H),8.04(d,1H),7.89(d,1H),7.84(dd,1H),7.70(d,1H),7.54(d,1H),7.52(m,2H),7.40(m,1H),7.11(d,1H),6.75(dd,1H),6.40(dd,1H),6.29(d,1H),3.79(m,3H),3.65(m,2H),3.51(m,2H),3.42(m,2H),3.03(m,4H),2.67(d,1H),2.54(d,1H),2.17(m,6H),1.88(dd,2H),1.42(t,2H),0.96(s,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,158.2,154.0,147.9,146.9,145.9,144.3,135.6,134.3,132.9,132.6,131.8,130.2,130.0,128.3,128.2,127.0,125.2,125.0,122.8,120.3,118.3,115.7,114.1,109.7,103.6,100.4,73.4,68.5,66.4,66.2,58.6,45.1,44.4,43.9,34.6,29.3,29.1,27.2,24.8.ESI-MS:m/z＝939.4[M+H] +.
实施例9 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-乙酰基吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000078
1)化合物9-k的制备
将3-硝基-4-氟苯磺酰胺(0.56g)、[(4-乙酰基吗啉-2-基)甲基]胺(0.48g)和N,N-二异丙基乙胺(0.65g)溶于乙腈(10mL)中，加热至85℃，反应5h，室温冷却，静置过夜，抽滤，得化合物9-k(1.2g)。ESI-MS:m/z＝359.0[M+H] +.
2)化合物9-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物9-k，得到化合物9-1。
化合物9-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,2H),8.63(t,1H),8.57(d,1H),8.04(d,1H),7.89(s,1H),7.84(dd,1H),7.70(d,1H),7.53(d,3H),7.39(m,1H),7.15(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.87(m,3H),3.68(m,2H),3.60(m,3H),3.48(m,2H),3.40(m,2H),3.30(m,2H),3.18(m,1H),3.02(m,2H),2.29(m,1H),2.19(m,1H),1.96(d,2H),1.49(t,2H),1.24(m,1H),0.97(s,9H).
13C NMR(125MHz,DMSO-d6),δ:169.1,164.0,158.9,158.6,158.2,154.0,147.9,146.9,145.9,144.2,135.5,134.3,132.8,132.6,131.7,130.2,128.3,128.2,127.0,125.2,124.9,122.8,120.3,118.3,117.4,115.8,115.1,114.2,109.7,103.6,100.4,73.8,66.4,58.5,48.5,46.0,45.1,44.9,44.3,43.8,34.6,29.3,29.1,27.2,24.8,21.6,21.6.ESI-MS:m/z＝979.3[M+H] +.
实施例10 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-异丁酰基吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000079
1)化合物10-k的制备
将3-硝基-4-氟苯磺酰胺(1.48g)、[(4-异丁酰基吗啉-2-基)甲基]胺(1.5g)和N,N-二异丙基乙胺(2.2g)溶于乙腈(10mL)中，加热至85℃，反应5h，室温冷却，静置过夜，抽滤，得化合物10-k(1.8g)。ESI-MS:m/z＝387.0[M+H] +.
2)化合物10-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物10-k，得到化合物10-1。
化合物10-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,2H),8.64(t,1H),8.58(s,1H),8.04(d,1H),7.89 (s,1H),7.84(t,1H),7.70(d,1H),7.53(d,3H),7.40(d,1H),7.16(t,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),4.36(m,1H),3.86(m,2H),3.58(m,4H),3.47(t,2H),3.39(m,2H),3.19(m,1H),3.02(m,2H),2.87(m,2H),2.71(m,1H),2.57(m,1H),2.29(m,1H),2.20(m,1H),1.96(s,2H),1.49(m,2H),1.24(m,1H),0.97(s,12H).
13C NMR(125MHz,DMSO-d6),δ:175.2,164.0,158.8,158.6,158.2,154.0,147.9,146.9,145.9,144.2,135.6,134.3,132.8,132.6,131.8,130.2,130.0,128.3,128.2,127.0,125.2,124.9,122.8,120.3,118.3,117.9,115.8,115.6,114.1,109.7,103.6,100.4,74.2,74.0,66.6,58.5,47.8,45.2,45.1,44.3,44.1,34.6,29.5,29.3,29.1,27.2,24.8,20.0,19.5.ESI-MS:m/z＝1007.3[M+H] +.
实施例11 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(R)-(4-甲氧乙酰基吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000080
1)化合物11-k的制备
将3-硝基-4-氟苯磺酰胺(0.36g)、(R)-2-(氨甲基)-4-甲氧乙酰基吗啉盐酸盐(0.45g)和N,N-二异丙基乙胺(0.97g)溶于乙腈(20mL)中，加热至85℃，反应5h，室温冷却，静置过夜，抽滤，得化合物11-k(0.39g)。ESI-MS:m/z＝387.1[M-H] -。
2)化合物11-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物11-k，得到化合物11-1。
化合物11-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,2H),8.64(m,1H),8.57(d,1H),8.04(d,1H),7.89(d,1H),7.84(dd,1H),7.70(d,1H),7.54(d,1H),7.52(m,2H),7.38(m,1H),7.21(d,1H),6.75(dd,1H),6.38(dd,1H),6.29(d,1H),3.47(m,3H),3.42(m,1H),3.27(m,5H),2.27(m,3H),2.21(m,1H),2.01(m,2H),1.98(d,2H),1.48(t,3H),1.24(m,7H),0.97(s,9H).
ESI-MS:m/z＝1010.4[M+H] +.
实施例12 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-甲磺酰基吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000081
1)化合物12-k的制备
将3-硝基-4-氟苯磺酰胺(0.66g)、[(4-甲磺酰基吗啉-2-基)甲基]胺(0.7g)和N,N-二异丙基乙胺(0.97g)溶于乙腈(10mL)中，加热至85℃，反应5h，室温冷却，静置过夜，抽滤，得化合物12-k(1.2g)。ESI-MS:m/z＝395.0[M+H] +.
2)化合物12-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物12-k，得到化合物12-1。
化合物12-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,2H),8.64(t,1H),8.58(d,1H),8.05(d,1H),7.89(s,1H),7.84(d,1H),7.70(d,1H),7.54(d,3H),7.39(d,1H),7.17(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.99(d,1H),3.79(d,2H),3.63(m,5H),3.50(m,1H),3.38(m,3H),2.92(s,3H),2.86(m,2H),2.70(m,2H),2.29(m,1H),2.19(m,1H),1.96(s,3H),1.50(m,2H),1.24(m,1H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,158.9,158.6,158.3,154.0,147.8,146.9,145.9,144.2,139.0,135.6,134.3,132.8,132.6,131.8,130.3,128.3,128.2,127.0,125.2,124.4,122.8,120.3,118.3,117.6,115.8,115.2,114.1,109.7,103.6,100.4,73.7,66.0,58.5,47.8,45.4,45.2,45.0,44.3,34.6,34.3,29.3,29.3,29.1,27.2,24.8.
ESI-MS:m/z＝1015.3[M+H] +.
实施例13 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-3-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000082
1)化合物13-k的制备
将3-硝基-4-氯苯磺酰胺(1.0g)、3-氨甲基四氢吡喃盐酸盐(0.77g)和N,N-二异丙基乙胺(2.18g)溶于乙腈(20mL)中，加热至85℃，反应5h，室温冷却，静置过夜，抽滤，得化合物13-k(1.3g)。ESI-MS:m/z＝314.1[M-H] -。
2)化合物13-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物13-k，得到化合物13-1。
化合物13-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,1H),11.69(s,1H),8.59(t,1H),8.57(d,1H),8.05(d,1H),7.88(d,1H),7.82(dd,1H),7.70(d,1H),7.55(d,1H),7.52(m,2H),7.39(m,1H),7.10(d,1H),6.75(dd,1H),6.40(dd,1H),6.30(d,1H),3.79(m,1H),3.72(m,2H),3.59(m,1H),3.33(m,5H),3.18(m,2H),3.05(m,4H),2.28(m,1H),2.20(m,1H),2.08(m,1H),1.96(d,3H),1.62(m,1H),1.49(t,3H),1.24(m,2H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:158.2,154.0,147.8,146.9,145.9,144.2,139.0,135.6,134.3,132.8,132.6,131.7,130.2,130.1,130.0,128.3,127.0,124.9,124.8,124.4,122.8,120.3,118.3,117.6,115.5,115.3,114.2,109.7,103.6,100.4,70.5,68.0,58.5,45.1,44.9,44.3,35.3,34.6,29.3,29.1,27.2,27.1,25.0,24.8.
ESI-MS:m/z＝937.4[M+H] +.
实施例14 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-四氢-2H-吡喃-2-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000083
1)化合物14-k的制备
将3-硝基-4-氯苯磺酰胺(1.2g)、2-氨甲基四氢吡喃(0.7g)和N,N-二异丙基乙胺(1.64g)溶于乙腈(10mL)中，加热至85℃，反应8h，室温冷却，静置过夜，抽滤，得化合物14-k(1.92g)。ESI-MS:m/z＝316.0[M+H] +.
2)化合物14-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物14-k，得到化合物14-1。
化合物14-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,2H),8.62(t,1H),8.57(d,1H),8.05(d,1H),7.89(s,1H),7.83(d,1H),7.70(d,1H),7.54(d,3H),7.39(d,1H),7.11(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.92(d,1H),3.56(t,2H),3.48(m,1H),3.37(m,5H),2.85(m,4H),2.23(m,1H),2.20(m,1H),1.96(s,2H),1.80(m,1H),1.65(d,1H),1.50(m,5H),1.28(m,2H),0.97(d,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,158.9,158.6,158.2,154.0,147.9,146.9,145.9,144.2,139.0,135.6,134.3,132.8,132.6,131.8,130.2,130.0,128.3,128.2,127.0,125.0,124.4,122.8,120.3,118.3,115.8,114.2,109.7,103.6,100.4,75.6,68.0,58.5,47.9,45.2,44.3,34.6,29.3,29.2,29.1,27.2,26.0,24.8,22.9.
ESI-MS:m/z＝936.4[M+H] +.
实施例15 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(1-(甲基磺酰基)哌啶-3-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000084
1)化合物15-k的制备
将3-硝基-4-氟苯磺酰胺(1.57g)、3-氨甲基-1-甲基磺酰基哌啶(1.65g)和N,N-二异丙基乙胺(2.31g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，抽滤，得化合物15-k(2.40g)。ESI-MS:m/z＝393.1[M+H] +.
2)化合物15-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物15-k，得到化合物15-1。
化合物15-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(d,2H),8.64(t,1H),8.58(s,1H),8.05(s,1H),7.89(s,1H),7.84(d,1H),7.70(d,1H),7.54(t,3H),7.39(d,1H),7.15(d,1H),6.75(d,1H),6.41(s,1H),6.29(s,1H),3.54(d,2H),3.36(m,6H),2.85(s,4H),2.76(t,2H),2.59(t,1H),2.29(m,1H),2.19(m,1H),1.96(s,4H),1.79(m,2H),1.49(m,4H),1.24(m,3H),0.97(d,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,158.8,158.2,154.0,147.8,146.9,145.9,144.2,135.6,134.4,132.8,132.6,131.8,130.2,128.3,127.0,125.0,122.8,120.3,118.3,115.6,114.1,109.7,103.5,100.4,58.5,49.3,46.4,45.7,45.2,44.4,35.0,34.6,34.5,29.3,29.1,27.4,27.2,24.8,24.1.
ESI-MS:m/z＝1013.3[M+H] +.
实施例16 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(2-(4-乙酰基吗啉-2-基)乙基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000085
1)化合物16-k的制备
将3-硝基-4-氟苯磺酰胺(2.13g)、2-氨乙基-4-乙酰基吗啉(2g)和N,N-二异丙基乙胺(3.13g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，抽滤，得化合物16-k(3.40g)。ESI-MS:m/z＝373.1[M+H] +.
2)化合物16-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物16-k，得到化合物16-1。
化合物16-1： 1H NMR(500MHz,DMSO-d6),δ:11.70(s,2H),8.78(s,1H),8.57(s,1H),8.04(s,1H),7.82(m,2H),7.69(d,1H),7.52(s,1H),7.44(m,2H),7.38(d,1H),7.23(m,1H),6.75(d,1H),6.39(s,1H),6.29(s,1H),4.87(m,2H),3.89(d,2H),3.43(m,8H),3.03(m,4H),2.90(m,2H),2.67(m,2H),2.20(m,4H),1.96(m,3H),1.47(m,2H),1.24(m,1H),0.96(s,6H).
13C NMR(125MHz,DMSO-d6),δ:168.9,163.9,163.5,153.9,147.6,145.9,135.5,134.4,133.2,132.8,131.7,130.1,129.6,128.3,127.5,124.9,120.2,115.2,109.3,100.4,74.3,66.6,66.4,58.5,49.8,50.4,45.7,45.3,44.2,41.2,34.6,31.6,31.4,29.3,29.1,27.2,24.8,21.6.ESI-MS:m/z＝993.3[M+H] +.
实施例17 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(3-(1-甲基哌啶-4-基)丙基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000086
1)化合物17-k的制备
将3-硝基-4-氟苯磺酰胺(2.34g)、4-氨丙基-1-甲基哌啶(2g)和N,N-二异丙基乙胺(3.56g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，抽滤，得化合物17-k(3.56g)。ESI-MS:m/z＝357.2[M+H] +.
2)化合物17-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物17-k，得到化合物17-1。
化合物17-1： 1H NMR(500MHz,DMSO-d6),δ:11.54(s,2H),8.43(s,1H),8.30(t,1H),8.19(s,1H),7.94(s,1H),7.82(s,1H),7.67(t,2H),7.58(d,1H),7.33(m,2H),6.82(d,1H),6.63(d,1H),6.31(s,1H),6.24(s,1H),3.34(m,3H),2.98(m,6H),2.75(t,2H),2.65(d,1H),2.54(s,1H),2.20(m,6H),1.90(t,4H),1.56(s,3H),1.35(m,4H),1.23(s,1H),1.17(t,3H),0.96(d,6H).
13C NMR(125MHz,DMSO-d6),δ:169.2,164.0,156.9,153.4,149.3,146.2,145.2,135.3,135.1,133.2,132.5,132.0,131.5,129.8,129.5,129.2,127.5,126.5,126.2,125.0,124.4,122.8,121.5,120.1,116.6,114.1,109.7,105.8,100.1,60.6,52.8,51.4,51.3,47.7,44.7,35.3,34.3,31.3,29.4,29.3,27.3,25.4,9.8.
ESI-MS:m/z＝977.6[M+H] +.
实施例18 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(2-(1-甲基哌啶-4-基)乙基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000087
1)化合物18-k的制备
将3-硝基-4-氟苯磺酰胺(2.58g)、4-氨乙基-1-甲基哌啶(2g)和N,N-二异丙基乙胺(3.78g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，抽滤，得化合物18-k(3.68g)。ESI-MS:m/z＝343.1[M+H] +.
2)化合物18-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物18-k，得到化合物18-1。
化合物18-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(d,2H),8.58(s,2H),8.04(s,1H),7.88(s,1H),7.84 (d,1H),7.70(d,1H),7.53(m,3H),7.40(d,1H),7.08(d,1H),6.75(d,1H),6.40(s,1H),6.29(s,1H),3.56(d,1H),3.42(m,6H),3.10(m,1H),2.91(m,3H),2.77(m,4H),2.21(m,2H),1.94(d,4H),1.53(m,4H),1.36(m,2H),1.24(m,2H),0.97(d,9H).
13C NMR(125MHz,DMSO-d6),δ:164.0,158.9,158.6,158.2,154.0,147.6,146.9,145.9,144.3,135.6,134.4,132.9,132.5,131.8,130.1,128.3,125.0,124.8,120.3,118.3,115.6,115.4,114.2,109.7,103.6,100.4,58.5,53.9,45.2,44.3,43.1,34.6,34.3,30.8,29.4,29.3,29.1,28.0,24.8.ESI-MS:m/z＝963.8[M+H] +.
实施例19 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(2-(1-乙基哌啶-4-基)乙基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000088
1)化合物19-k的制备
将3-硝基-4-氟苯磺酰胺(2.34g)、4-氨乙基-1-乙基哌啶(2g)和N,N-二异丙基乙胺(3.43g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，抽滤，得化合物19-k(3.35g)。ESI-MS:m/z＝357.2[M+H] +.
2)化合物19-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物19-k，得到化合物19-1。
化合物19-1： 1H NMR(500MHz,DMSO-d6),δ:11.61(s,1H),11.57(s,1H),8.45(s,1H),8.37(t,1H),8.17(s,1H),7.96(s,1H),7.82(s,1H),7.70(d,1H),7.65(d,1H),7.55(d,1H),7.36(s,1H),7.33(d,1H),6.87(d,1H),6.64(d,1H),6.33(s,1H),6.23(s,1H),3.31(m,3H),3.01(s,6H),2.81(t,1H),2.66(m,3H),2.54(s,1H),2.15(m,5H),1.90(d,2H),1.81(d,2H),1.59(m,1H),1.43(m,2H),1.27(m,8H),0.95(d,6H).
13C NMR(125MHz,DMSO-d6),δ:168.1,157.2,153.8,148.7,146.6,146.2,145.3,135.4,135.0,133.2,132.5,132.0,131.5,129.7,129.5,127.7,126.6,126.5,125.0,124.7,124.5,122.8,120.1,117.0,114.3,109.6,105.1,100.2,53.8,52.8,47.6,44.7,43.1,42.8,35.3,32.6,31.8,31.6,30.3,29.4,29.2,27.3,25.7,25.4,22.6,14.4.ESI-MS:m/z＝977.7[M+H] +.
实施例20 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(2-(1-(2-氟乙基)哌啶-4-基)乙基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000089
1)化合物20-k的制备
将3-硝基-4-氟苯磺酰胺(2.11g)、4-氨乙基-1-(2-氟乙基)哌啶(2g)和N,N-二异丙基乙胺(3.09g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，抽滤，得化合物20-k(3.29g)。ESI-MS:m/z＝375.1[M+H] +.
2)化合物20-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物20-k，得到化合物20-1。
化合物20-1： 1H NMR(500MHz,DMSO-d6),δ:11.62(s,2H),8.51(s,1H),8.43(t,1H),8.16(s,1H),8.00(s,1H),7.82(s,1H),7.76(d,1H),7.65(d,1H),7.52(d,1H),7.47(s,1H),7.33(d,1H),6.95(d,1H),6.66(d,1H),6.36(s,1H),6.21(s,1H),4.69(s,1H),4.60(s,1H),3.39(m,2H),3.12(d,2H),3.03(s,3H),2.98(s,1H),2.92(s,1H),2.64(d,1H),2.54(s,1H),2.42(t,2H),2.15(m,6H),1.89(d,2H),1.78(d,2H),1.56(m,2H),1.43(m,3H),1.29(m,3H),0.96(d,6H).
13C NMR(125MHz,DMSO-d6),δ:163.6,157.7,154.4,148.0,147.0,146.2,145.6,135.6,134.8,133.2,132.5,132.0,131.4,129.9,129.5,129.3,128.2,127.9,127.3,126.5,124.9,124.4,122.8,120.2,117.6,116.7,114.7,109.4,104.1,100.3,81.6,80.2,60.5,57.4,57.3,53.3,52.7,47.3,44.7,35.3,34.7,32.2,30.7,29.4,25.4.ESI-MS:m/z＝995.4[M+H] +.
实施例21 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(2-(4-(甲基磺酰基)吗啉-2-基)乙基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000090
1)化合物21-k的制备
将3-硝基-4-氟苯磺酰胺(2.2g)、2-氨乙基-4-甲基磺酰基吗啉(2.52g)和N,N-二异丙基乙胺(3.26g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物21-k(3.52g)。ESI-MS:m/z＝409.1[M+H] +.
2)化合物21-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物21-k，得到化合物21-1。
化合物21-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,2H),8.59(d,1H),8.18(d,1H),8.04(d,1H),7.89(m,2H),7.69(dd,1H),7.56(d,1H),7.52(m,2H),7.40(m,1H),7.27(m,1H),6.75(d,1H),6.40(m,1H),6.30(m,1H),4.00(m,3H),3.67(m,1H),3.59(m,3H),3.46(m,1H),3.35(m,5H),3.15(m,3H),2.28(m,3H),2.05(m,5H),1.84(m,1H),1.71(m,1H),1.60(m,1H),1.49(m,2H),1.24(m,1H),0.96(s,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,158.2,154.0,146.9,146.6,145.9,144.2,139.0,135.6,134.5,132.9,132.5,131.8,130.6,130.0,128.3,128.2,127.0,125.7,124.9,124.5,122.8,120.3,118.3,115.6,114.2,109.7,103.6,100.5,66.0,62.1,58.5,58.5,48.0,47.9,45.2,44.3,34.6,29.3,29.2,29.1,27.9,27.5,27.1,24.8.ESI-MS:m/z＝1029.4[M+H] +.
实施例22 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基 -4-[(2-(4-异丁酰基吗啉-2-基)乙基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000091
1)化合物22-k的制备
将3-硝基-4-氟苯磺酰胺(2.2g)、2-氨乙基-4-异丁酰基吗啉(2.42g)和N,N-二异丙基乙胺(3.26g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物22-k(3.42g)。ESI-MS:m/z＝401.1[M+H] +.
2)化合物22-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物22-k，得到化合物22-1。
化合物22-1： 1H NMR(500MHz,DMSO-d6),δ:11.69(s,2H),8.79(s,1H),8.58(s,1H),8.05(s,1H),7.82(m,2H),7.65(d,1H),7.55(s,1H),7.50(m,2H),7.33(d,1H),7.06(m,1H),6.69(d,1H),6.39(s,1H),6.20(s,1H),3.89(d,2H),3.42(m,8H),3.17(m,4H),2.88(m,2H),2.66(m,2H),2.22(m,4H),1.92(m,3H),1.42(m,2H),1.23(m,1H),0.96(s,12H).
13C NMR(125MHz,DMSO-d6),δ:174.9,163.9,163.5,158.3,155.0,147.6,146.9,145.9,135.7,134.4,133.2,132.6,131.9,130.1,129.6,129.3,128.2,126.5,124.9,124.5,122.8,120.2,118.3,115.2,112.8,109.3,102.8,100.4,74.5,74.4,66.6,66.4,60.3,52.4,49.8,46.7,46.0,45.3,44.8,41.5,35.2,31.6,31.4,29.4,29.2,27.3,25.3,20.1,19.5.ESI-MS:m/z＝1021.4[M+H] +.
实施例23 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(1-异丁酰基哌啶-4-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000092
1)化合物23-k的制备
将3-硝基-4-氟苯磺酰胺(1.99g)、4-氨甲基-1-异丁酰基哌啶(2.0g)和N,N-二异丙基乙胺(2.91g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物23-k(3.24g)。ESI-MS:m/z＝385.2[M+H] +.
2)化合物23-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物23-k，得到化合物 23-1。
化合物23-1： 1H NMR(500MHz,DMSO-d6),δ:11.73(s,1H),11.68(s,1H),8.64(t,1H),8.58(s,1H),8.05(s,1H),7.89(s,1H),7.82(d,1H),7.70(d,1H),7.54(m,3H),7.39(d,1H),7.14(d,1H),6.75(d,1H),6.40(s,1H),6.29(s,1H),4.42(d,1H),3.96(d,2H),3.74(m,1H),3.58(d,1H),3.40(d,1H),3.32(t,4H),2.98(t,3H),2.86(m,2H),2.47(s,1H),2.29(m,1H),2.20(m,1H),1.93(m,4H),1.74(m,2H),1.49(m,2H),1.24(m,1H),1.14(m,1H),0.97(s,12H).
13C NMR(125MHz,DMSO-d6),δ:174.5,164.0,159.2,158.9,158.6,154.0,147.9,146.9,145.9,144.2,139.0,135.6,134.3,132.8,132.6,131.7,130.2,130.1,130.0,128.3,127.0,124.8,124.4,122.8,120.3,118.4,117.5,115.6,115.2,114.2,109.7,103.5,100.4,58.5,48.0,45.2,45.0,44.3,41.4,35.5,34.6,30.7,29.7,29.5,29.3,29.1,27.2,24.8,20.0,19.9.ESI-MS:m/z＝1005.4[M+H] +.
实施例24 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-乙基吗啉-3-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000093
1)化合物24-k的制备
将3-硝基-4-氟苯磺酰胺(2.54g)、3-氨甲基-4-乙基吗啉(2.0g)和N,N-二异丙基乙胺(3.72g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物24-k(3.51g)。ESI-MS:m/z＝345.1[M+H] +.
2)化合物24-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物24-k，得到化合物24-1。
化合物24-1： 1H NMR(500MHz,DMSO-d6),δ:11.73(s,2H),8.68(t,1H),8.61(s,1H),8.05(s,1H),7.92(d,1H),7.88(s,1H),7.70(d,1H),7.58(s,1H),7.53(m,2H),7.40(d,1H),6.75(d,2H),6.41(s,1H),6.29(s,1H),4.05(d,3H),3.61(m,8H),3.35(m,6H),3.12(m,3H),2.25(m,2H),2.00(s,2H),1.49(m,2H),1.23(m,4H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:159.0,158.7,158.4,158.3,154.0,146.8,145.9,144.2,139.0,135.6,134.6,132.8,132.6,131.8,131.3,130.2,128.4,128.1,127.0,125.9,125.0,124.4,122.8,120.3,118.5,117.5,115.4,115.2,114.0,109.6,103.5,100.5,58.5,47.9,45.2,44.3,34.6,29.5,29.3,29.1,27.1,24.8.
ESI-MS:m/z＝965.4[M+H] +.
实施例25 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(1-(四氢-2H-吡喃-4-基)哌啶-4-基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000094
1)化合物25-k的制备
将3-硝基-4-氟苯磺酰胺(1.67g)、4-氨甲基-1-(四氢-2H-吡喃)哌啶(2.0g)和N,N-二异丙基乙胺(2.91g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物25-k(2.91g)。ESI-MS:m/z＝385.2[M+H] +.
2)化合物25-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物25-k，得到化合物25-1。
化合物25-1： 1H NMR(500MHz,DMSO-d6),δ:11.62(s,1H),11.58(s,1H),8.66(s,1H),8.50(s,1H),7.99(s,1H),7.82(s,1H),7.75(d,1H),7.66(d,1H),7.52(d,1H),7.47(s,1H),7.43(s,1H),7.34(d,1H),6.95(d,1H),6.66(d,1H),6.35(s,1H),6.22(s,1H),3.97(d,1H),3.61(t,1H),3.50(m,4H),3.36(d,1H),3.03(s,4H),3.90(s,2H),2.83(t,1H),2.61(m,2H),2.54(s,1H),2.16(m,6H),1.90(m,4H),1.74(m,1H),1.42(t,2H),1.24(m,4H),0.96(s,6H).
13C NMR(125MHz,DMSO-d6),δ:146.2,145.6,135.5,134.7,133.2,132.5,132.1,132.0,131.4,130.1,130.0,127.9,126.5,125.0,124.5,122.8,120.2,109.4,100.3,74.0,65.9,60.5,52.7,49.8,47.3,45.4,44.7,35.6,35.3,34.2,31.5,29.5,29.4,29.2,29.0,27.3,25.4,22.6,14.4.ESI-MS:m/z＝1005.4[M+H] +.
实施例26 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[((4-(3-氧杂环丁烷)吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000095
1)化合物26-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以4-(3-氧杂环丁烷)-2-氨甲基吗啉替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，制备得化合物26-k。
2)化合物26-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物26-k，得到化合物26-1。
实施例27 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[((4-(四氢吡喃-4-基)吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000096
1)化合物27-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以4-(四氢吡喃-4-基)-2-氨甲基吗啉替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，制备得化合物27-k。
2)化合物27-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物27-k，得到化合物27-1。
实施例28 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[((4-环丙磺酰基吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000097
1)化合物28-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以4-环丙磺酰基-2-氨甲基吗啉替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，制备得化合物28-k(1.01g)。
2)化合物28-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物28-k，得到化合物28-1。
化合物28-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,1H),11.67(s,1H),8.64(m,1H),8.58(s,1H),8.05(d,1H),7.89(s,1H),7.84(d,1H),7.70(d,1H),7.55(m,3H),7.38(d,1H),7.17(d,1H),6.76(d,1H),6.40(s,1H),6.29(s,1H),3.55(m,7H),3.42(m,4H),2.99(m,4H),2.83(m,2H),2.65(m,1H),2.27(m,2H),1.96(m,2H),1.50(s,2H),1.24(s,1H),0.98(m,10H).
13C NMR(125MHz,DMSO-d6),δ:164.0,158.9,158.6,158.2,154.0,147.9,146.9,145.9,144.2,139.0,135.6,134.3,132.8,132.6,131.7,130.3,128.3,128.2,125.2,124.9,124.4,120.3,118.4,117.4,115.8,115.1,114.1,109.7,103.5,100.4,73.8,66.1,58.5,48.3,45.8,45.1,44.9,44.3,34.6,29.3,29.1,27.2,25.1,24.8,4.4,4.3.
实施例29 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[((4-环丙甲酰基吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000098
1)化合物29-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以4-环丙甲酰基-2-氨甲基吗啉替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，制备得化合物29-k(0.85g)。
2)化合物29-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物29-k，得到化合物29-1。
化合物29-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.70(s,1H),8.62(m,2H),8.05(s,1H),7.89(s,1H),7.84(d,1H),7.70(d,1H),7.55(m,3H),7.39(d,1H),7.16(d,1H),6.76(d,1H),6.40(s,1H),6.30(s,1H),3.95(d,2H),3.62(m,4H),3.49(m,3H),3.39(m,3H),2.91(m,2H),2.75(m,2H),2.33(m,6H),2.02(m,1H),1.50(s,2H),1.24(s,1H),0.97(s,6H),0.78(d,4H).
实施例30 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[((4-(氧杂环丁烷-3-基)甲酰基吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000099
1)化合物30-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以4-(氧杂环丁烷-3-基)甲酰基-2-氨甲基吗啉替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，制备得化合物30-k(0.85g)。
2)化合物30-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物30-k，得到化合物30-1。
实施例31 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[((4-环丁磺酰基吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000100
1)化合物31-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以4-环丁磺酰基-2-氨甲基吗啉替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物31-k(0.98g)。
2)化合物31-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物31-k，得到化合物31-1。
化合物31-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,1H),11.69(s,1H),8.61(m,2H),8.05(s,1H),7.89(s,1H),7.83(d,1H),7.71(d,1H),7.54(m,3H),7.39(d,1H),7.17(d,1H),6.76(d,1H),6.40(s,1H),6.29(s,1H),3.95(d,2H),3.62(m,6H),3.49(m,3H),3.39(m,3H),2.91(m,2H),2.75(m,2H),2.33(m,6H),2.02(m,4H),1.50(s,2H),1.24(s,1H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:163.9,158.2,154.0,147.8,146.9,145.9,144.2,135.6,134.3,132.8,132.6,131.8,130.3,128.3,128.2,127.0,125.2,124.9,122.8,120.3,118.3,115.8,114.1,109.7,103.5,100.4,74.0,66.3,58.5,50.9,48.0,45.6,45.1,44.9,44.3,34.6,29.3,29.1,27.2,24.8.
实施例32 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[((4-(氧杂环丁烷-3-基)磺酰基吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000101
1)化合物32-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以4-(氧杂环丁烷-3-基)磺酰基-2-氨甲基吗啉替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物32-k(1.01g)。
2)化合物32-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物32-k，得到化合物32-1。
实施例33 (S)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基 -4-[(四氢呋喃-3-基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000102
1)化合物33-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以(S)-4-氨基四氢呋喃盐酸盐替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物33-k(1.72g)。
2)化合物33-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物33-k，得到化合物33-1。
化合物33-1： 1H NMR(500MHz,DMSO-d6),δ:11.70(s,1H),11.68(s,1H),8.57(s,1H),8.32(d,1H),8.03(s,1H),7.87(t,2H),7.70(d,1H),7.54(d,3H),7.40(d,1H),7.13(d 1H),6.76(d,1H),6.39(s,1H),6.31(s,1H),3.93(m,3H),3.78(m,2H),3.73(d,2H),3.58(d,1H),3.41(d,1H),3.04(m,3H),2.78(s,1H),2.34(m,2H),2.28(m,1H),2.08(s,1H),1.96(s,2H),1.90(m,1H),1.49(m,2H),1.24(s,1H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,159.1,158.9,158.6,158.3,158.1,154.0,147.0,146.9,145.9,144.2,135.5,134.5,132.8,132.5,131.8,130.5,128.3,128.1,127.0,125.6,125.0,122.8,120.2,118.1,115.8,114.3,109.7,103.7,100.4,72.7,66.9,58.5,53.7,45.2,44.3,34.6,33.0,29.3,29.1,27.1,24.8.
实施例34 (R)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(四氢呋喃-3-基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000103
1)化合物34-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以(R)-4-氨基四氢呋喃盐酸盐替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物34-k(1.65g)。
2)化合物34-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物34-k，得到化合物34-1。
化合物34-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,1H),11.68(s,1H),8.57(s,1H),8.32(d,1H),8.03(s,1H),7.87(t,2H),7.71(d,1H),7.54(d,3H),7.40(d,1H),7.13(s,1H),6.76(d,1H),6.39(s,1H),6.31(s,1H),3.95(m, 1H),3.89(m,1H),3.79(m,2H),3.73(d,2H),3.60(d,1H),3.42(d,1H),3.29(m,2H),3.05(m,3H),2.78(m,1H),2.33(m,2H),2.21(m,1H),1.96(s,2H),1.91(m,1H),1.49(m,2H),1.23(s,1H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:159.2,158.9,158.7,158.4,158.1,154.0,147.0,146.9,145.8,144.2,139.0,135.4,134.5,132.8,132.5,131.7,130.5,128.3,128.1,127.1,125.6,124.9,124.4,120.3,118.1,117.3,115.8,114.9,114.4,109.8,103.7,100.4,72.7,66.9,58.5,53.7,45.1,44.3,34.6,33.0,29.2,29.1,27.1,24.8.
实施例35 (R)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[((四氢呋喃-3-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000104
1)化合物35-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以(3R)-四氢呋喃-3-甲胺替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物35-k(1.10g)。
2)化合物35-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物35-k，得到化合物35-1。
化合物35-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.69(s,1H),8.64(m,1H),8.58(d,1H),8.05(d,1H),7.88(s,1H),7.82(d,1H),7.70(d,1H),7.54(d,3H),7.39(d,1H),7.12(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.80(m,2H),3.71(m,2H),3.63(m,2H),3.52(m,2H),3.40(m,4H),2.58(m,1H),2.28(m,2H),2.08(s,2H),1.98(m,4H),1.67(m,1H),1.50(m,2H),1.24(m,1H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:163.9,158.9,158.6,158.2,154.0,147.8,146.9,145.9,144.2,138.9,135.6,134.3,132.9,132.5,131.8,130.2,130.1,128.3,127.0,124.9,124.5,122.8,120.3,118.5,118.3,117.8,115.5,114.2,109.7,103.6,100.4,70.8,67.3,58.5,45.8,45.2,44.3,38.1,34.6,29.8,29.3,29.1,27.2,24.8,1.6.
实施例36 (S)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[((四氢呋喃-3-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000105
1)化合物36-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以(3S)-四氢呋喃-3-甲胺(0.64g)替换4-氨甲基-1-(四 氢-2H-吡喃)哌啶，得化合物36-k(1.39g)。
2)化合物36-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物36-k，得到化合物36-1。
化合物36-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.69(s,1H),8.65(s,1H),8.58(s,1H),8.05(s,1H),7.89(s,1H),7.83(d,1H),7.71(d,1H),7.54(d,3H),7.40(d,1H),7.12(d,1H),6.76(d,1H),6.40(s,1H),6.30(s,1H),3.81(m,1H),3.73(m,2H),3.61(m,3H),3.53(m,1H),3.41(m,4H),3.05(m,3H),2.58(m,1H),2.31(m,1H),2.27(m,1H),2.08(s,1H),1.96(m,3H),1.65(m,1H),1.49(s,2H),1.24(s,1H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:159.2,158.9,158.6,158.4,158.1,154.0,147.7,146.9,145.9,144.2,139.0,135.5,134.3,132.8,132.5,131.7,130.1,128.3,128.2,127.0,124.9,124.4,122.7,120.3,118.3,117.5,115.4,115.1,114.2,109.7,103.6,100.4,70.8,67.3,58.5,45.8,45.1,44.3,38.1,34.6,29.8,29.3,29.1,27.1,24.8.
实施例37 (S)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[((四氢呋喃-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000106
1)化合物37-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以(S)-2-四氢糠胺替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物37-k(1.35g)。
2)化合物37-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物37-k，得到化合物37-1。
化合物37-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,2H),8.62(s,1H),8.58(m,1H),8.04(s,1H),7.89(d,1H),7.81(m,1H),7.70(d,1H),7.52(m,3H),7.40(m,1H),7.13(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.83(m,2H),3.69(m,2H),3.55(m,2H),3.40(m,2H),3.29(m,2H),3.04(m,3H),2.77(m,1H),2.27(m,1H),2.21(m,1H),2.00(m,1H),1.96(m,2H),1.87(m,2H),1.66(m,2H),1.50(m,2H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,159.2,158.9,158.1,154.0,148.0,146.2,145.9,144.2,139.0,135.5,134.3,132.8,130.2,130.0,128.3,127.0,125.0,122.8,118.3,117.5,115.8,115.2,114.2,109.7,100.4,76.9,67.9,58.5,46.9,45.2,44.3,34.6,29.3,27.1,24.8.
实施例38 (R)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[((四氢呋喃-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000107
1)化合物38-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以(R)-2-四氢糠胺替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物38-k(1.38g)。
2)化合物38-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物38-k，得到化合物38-1。
化合物38-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.69(s,1H),8.61(m,2H),8.04(d,1H),7.88(s,1H),7.82(d,1H),7.70(d,1H),7.54(m,3H),7.39(d,1H),7.13(d,1H),6.76(d,1H),6.39(s,1H),6.29(s,1H),3.82(m,2H),3.70(m,2H),3.56(m,2H),3.41(m,2H),3.38(m,1H),3.04(m,3H),2.79(m,1H),2.31(m,2H),2.18(s,1H),1.98(m,3H),1.89(m,2H),1.65(m,1H),1.49(m,2H),1.24(s,1H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,158.9,158.7,158.1,154.0,147.9,146.9,145.9,144.2,139.0,135.5,134.3,132.6,131.7,130.0,128.3,127.0,125.0,124.9,124.4,122.7,120.3,118.3,117.5,115.8,114.2,109.7,103.6,100.4,76.9,67.9,58.5,46.9,45.1,44.3,34.6,29.2,27.1,25.7,24.8.
实施例39 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(四氢吡喃-4-基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000108
1)化合物39-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以4-氨基四氢吡喃替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物39-k(1.70g)。
2)化合物39-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物39-k，得到化合物39-1。
化合物39-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,2H),8.58(m,1H),8.26(m,1H),8.04(s,1H),7.88(d,1H),7.82(m,1H),7.70(d,1H),7.52(m,3H),7.40(m,1H),7.20(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.88(m,3H),3.58(m,2H),3.47(m,2H),3.39(m,2H),3.30(m,2H),3.04(m,3H),2.77(m,1H),2.27(m,1H), 2.21(m,1H),1.96(m,2H),1.90(m,2H),1.65(m,2H),1.50(m,2H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,159.2,158.9,158.1,154.0,146.9,146.7,145.8,144.2,139.0,135.5,134.4,132.8,131.7,130.1,128.4,127.1,125.1,122.8,118.3,117.3,115.7,115.0,114.3,109.7,103.6,100.4,66.0,58.5,49.0,45.1,44.3,34.6,29.3,27.1,24.8.
实施例40 (S)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(四氢吡喃-3-基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000109
1)化合物40-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以(S)-3-氨基四氢吡喃盐酸盐替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物40-k(1.08g)。
2)化合物40-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物40-k，得到化合物40-1。
化合物40-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.69(s,1H),8.59(s,1H),8.52(d,1H),8.05(s,1H),7.85(m,2H),7.70(s,1H),7.53(m,3H),7.40(d,1H),7.16(d,1H),6.74(d,1H),6.40(s,1H),6.29(s,1H),3.85(m,3H),3.59(m,4H),3.41(d,1H),3.05(m,5H),2.28(m,2H),2.08(s,1H),1.96(s,3H),1.74(m,2H),1.52(m,3H),1.24(s,1H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,158.9,158.6,158.2,154.0,146.9,145.9,144.2,135.6,134.6,132.8,131.8,130.2,130.0,128.4,127.0,125.3,124.9,124.4,120.3,118.3,117.6,115.7,115.3,114.2,109.7,103.5,100.4,70.1,67.8,58.5,48.1,45.2,44.3,34.6,29.3,29.1,27.7,27.1,24.8,23.0,1.6.
实施例41 (R)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(四氢吡喃-3-基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000110
1)化合物41-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以(R)-3-氨基四氢吡喃盐酸盐替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物41-k(0.95g)。
2)化合物41-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物41-k，得到化合物41-1。
化合物41-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,2H),8.59(m,1H),8.53(m,1H),8.05(s,1H),7.88(d,1H),7.83(m,1H),7.70(d,1H),7.53(m,3H),7.40(m,1H),7.17(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.85(m,3H),3.59(m,2H),3.47(m,2H),3.39(m,2H),3.30(m,2H),3.04(m,2H),2.27(m,1H),2.21(m,1H),2.08(m,2H),1.96(m,2H),1.90(m,2H),1.69(m,2H),1.50(m,2H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,158.9,158.6,158.2,154.0,146.9,145.9,144.2,135.6,134.6,132.8,131.8,130.2,128.4,127.0,125.3,125.0,120.3,118.5,118.3,115.7,114.2,109.7,103.5,100.4,70.1,67.8,58.5,48.2,45.2,44.3,34.6,29.3,27.7,24.8,23.0.
实施例42 (R)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[((四氢吡喃-3-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000111
1)化合物42-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以(R)-3-氨甲基四氢吡喃盐酸盐替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物42-k(0.36g)。
2)化合物42-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物42-k，得到化合物42-1。
化合物42-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.68(s,1H),8.57(m,2H),8.05(d,1H),7.88(s,1H),7.81(d,1H),7.70(d,1H),7.53(d,3H),7.40(d,1H),7.10(d,1H),6.75(d,1H),6.40(s,1H),6.29(s,1H),3.78(m,3H),3.59(m,1H),3.32(m,7H),2.92(m,3H),2.28(m,2H),2.08(s,1H),1.95(m,4H),1.63(m,1H),1.49(m,3H),1.31(m,2H),0.98(s,6H).
13C NMR(125MHz,DMSO-d6),δ:163.9,158.9,158.6,158.2,154.0,147.8,146.9,145.9,144.2,139.0,135.6,134.3,132.9,132.6,131.8,130.2,130.0,128.3,127.0,124.9,124.8,122.8,120.3,118.3,117.7,115.5,115.4,114.2,109.7,103.6,100.4,70.6,68.0,58.5,45.2,44.9,44.3,35.3,34.6,29.3,29.1,27.2,27.1,25.0,24.8,1.6.
实施例43 (S)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[((四氢吡喃-3-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000112
1)化合物43-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以(S)-3-氨甲基四氢吡喃盐酸盐替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物43-k(0.39g)。
2)化合物43-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物43-k，得到化合物43-1。
化合物43-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,1H),11.68(s,1H),8.58(m,2H),8.05(s,1H),7.87(s,1H),7.83(d,1H),7.69(d,1H),7.53(m,3H),7.39(d,1H),7.11(d,1H),6.75(d,1H),6.40(s,1H),6.28(s,1H),3.78(m,4H),3.34(m,6H),3.15(m,2H),2.30(m,1H),2.20(m,1H),2.08(s,2H),1.95(m,4H),1.84(m,1H),1.63(m,1H),1.48(s,3H),1.31(m,2H),0.98(d,6H).
13C NMR(125MHz,DMSO-d6),δ:163.9,158.7,158.2,154.2,147.8,146.9,146.0,135.7,134.3,132.9,132.6,131.8,130.2,128.3,127.0,124.9,124.8,122.8,120.3,118.5,118.3,115.5,109.6,103.4,100.4,70.5,68.0,44.9,35.3,29.3,29.2,27.2,27.1,25.0,1.6.
实施例44 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(2-(四氢吡喃-2-基)乙基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000113
1)化合物44-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以2-(四氢-2H-吡喃-2-基)乙胺盐酸盐替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物44-k(1.18g)。
2)化合物44-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物44-k，得到化合物44-1。
化合物44-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.68(s,1H),8.86(s,1H),8.58(s,1H),8.05(s,1H),7.88(s,1H),7.83(d,1H),7.71(m,1H),7.54(m,3H),7.40(m,1H),7.03(m,1H),6.76(d,1H),6.40(s,1H), 6.29(s,1H),3.93(m,1H),3.78(m,1H),3.59(d,1H),3.41(m,7H),3.05(m,4H),2.55(s,2H),2.31(m,1H),2.21(m,1H),1.96(s,2H),1.76(m,3H),1.59(d,1H),1.49(m,4H),1.29(m,1H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:163.9,158.9,158.6,158.4,158.2,154.0,147.7,146.9,145.9,144.2,139.0,135.5,134.4,132.8,132.6,131.7,130.2,130.0,128.3,127.0,124.9,124.6,124.4,122.8,120.3,118.3,117.5,115.2,114.2,109.7,103.6,100.4,76.3,67.9,58.5,45.2,44.3,34.7,34.6,31.8,29.3,29.1,27.1,26.0,24.8,23.4.
实施例45 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(2-(四氢吡喃-3-基)乙基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000114
1)化合物45-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以2-(四氢-2H-吡喃-3-基)乙胺替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物45-k(1.06g)。
2)化合物45-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物45-k，得到化合物45-1。
化合物45-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,2H),8.56(m,2H),8.05(s,1H),7.84(t,2H),7.68(d,1H),7.52(m,3H),7.37(d,1H),7.05(d,1H),6.72(d,1H),6.40(s,1H),6.25(s,1H),3.37(m,10H),3.28(m,2H),3.03(m,2H),2.28(d,1H),2.17(d,1H),1.93(s,2H),1.85(d,1H),1.51(m,8H),1.23(m,2H),0.96(s,6H).
13C NMR(125MHz,DMSO-d6),δ:163.9,158.4,158.3,154.5,147.6,146.9,146.0,135.7,134.4,133.0,132.5,131.8,130.0,128.3,128.2,126.8,124.9,124.8,122.8,120.3,118.3,115.4,109.5,103.2,100.4,72.5,67.9,51.6,45.0,34.9,33.9,31.2,29.7,29.3,29.2,27.2,25.7,25.1.
实施例46 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(3-(N-乙基吗啉-2-基)丙基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000115
1)化合物46-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以N-乙基-2-丙氨基吗啉盐酸盐替换4-氨甲基-1-(四 氢-2H-吡喃)哌啶，得化合物46-k(2.03g)。
2)化合物46-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物46-k，得到化合物46-1。
实施例47 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(3-(N-(2-氟乙基)吗啉-2-基)丙基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000116
1)化合物47-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以N-(2-氟乙基)-2-丙氨基吗啉盐酸盐替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物47-k(2.03g)。
2)化合物47-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物47-k，得到化合物47-1。
实施例48 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[((N-甲酰基吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000117
1)化合物48-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以N-甲酰基-2-氨甲基吗啉盐酸盐替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物48-k(0.50g)。
2)化合物48-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物48-k，得到化合物48-1。
化合物48-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,2H),8.65(s,1H),8.57(m,1H),8.04(s,1H),7.88(d,1H),7.83(m,1H),7.70(d,1H),7.54(m,3H),7.39(m,1H),7.16(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.90(m,1H),3.75(m,2H),3.60(m,4H),3.51(m,1H),3.45(m,1H),3.21(m,1H),3.06(m,2H),2.81(m,1H),2.67(m,1H),2.27(m,2H),2.07(m,4H),1.96(m,2H),1.50(m,2H),1.24(m,2H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:162.4,160.1,157.4,156.6,152.4,146.3,145.3,144.2,142.6,137.5,133.9,132.7,131.2,130.2,130.1,128.7,126.8,123.6,122.8,118.8,116.8,115.6,114.1,108.1,98.7,72.8,65.4,56.9,46.1,43.6,42.7,33.0,27.5,23.2.
实施例49 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[((N-甲磺酰基吗啉-3-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000118
1)化合物49-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以N-甲磺酰基-3-氨甲基吗啉替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物49-k(0.63g)。
2)化合物49-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物49-k，得到化合物49-1。
实施例50 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-新戊酰吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000119
1)化合物50-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以2-氨甲基-4-新戊酰吗啉替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物50-k(1.71g)。
2)化合物50-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物50-k，得到化合物50-1。
化合物50-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.67(s,1H),8.78(m,1H),8.57(s,1H),8.04(s,1H),7.88(s,1H),7.83(t,1H),7.70(d,1H),7.52(d,3H),7.39(d,1H),7.06(t,1H),6.74(d,1H),6.39(s,1H),6.30(s,1H),4.25(d,1H),4.10(d,1H),3.88(d,1H),3.59(m,6H),3.50(m,6H),3.02(m,2H),2.82(m,2H),2.21(m,2H),1.98(s,2H),1.49(m,2H),1.18(s,9H),0.87(s,6H).
13C NMR(125MHz,DMSO-d6),δ:175.8,163.9,159.2,158.9,158.6,158.3,158.2,154.0,147.9,146.9, 145.9,144.2,139.0,135.6,134.3,132.8,132.6,131.8,130.2,129.9,128.3,128.2,127.0,125.2,124.9,124.5,122.8,120.3,118.4,117.7,115.8,115.4,114.1,113.0,109.7,103.5,100.4,74.1,66.5,58.5,45.2,45.0,44.3,34.6,29.3,29.1.
实施例51 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-(2-氰基乙酰基)吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000120
1)化合物51-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以2-氨甲基-4-(2-氰基乙酰基)吗啉替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物51-k(1.61g)。
2)化合物51-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物51-k，得到化合物51-1。
化合物51-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.69(s,1H),8.05(s,1H),7.87(s,1H),7.83(d,1H),7.70(d,1H),7.54(m,4H),7.39(m,2H),7.15(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.90(m,1H),3.60(m,9H),3.31(m,2H),3.18(m,1H),3.03(m,3H),2.83(t,1H),2.66(m,1H),2.27(m,2H),2.07(s,1H),1.96(m,2H),1.50(m,2H),1.24(t,2H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:163.9,162.3,159.0,154.0,146.9,145.8,139.1,135.4,134.3,132.8,132.6,131.7,130.3,130.2,128.2,127.0,125.2,124.9,124.3,120.4,117.1,109.7,103.6,100.5,73.7,66.0,58.5,48.2,45.7,44.9,44.5,34.6,29.3,29.1,27.1,25.3,24.8.
实施例52 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-(2,2,2-三氟乙酰基)吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000121
1)化合物52-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以2-氨甲基-4-(2,2,2-三氟乙酰基)吗啉替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物52-k(1.75g)。
2)化合物52-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物52-k，得到化合物52-1。
化合物52-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,2H),8.65(s,1H),8.58(m,1H),8.05(s,1H),7.85(d,1H),7.83(m,1H),7.70(d,1H),7.54(m,3H),7.39(m,1H),7.17(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.79(m,4H),3.58(m,3H),3.32(m,4H),3.05(m,4H),2.66(m,1H),2.27(m,2H),1.96(m,3H),1.50(m,2H),1.24(t,2H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,158.6,154.0,147.9,145.9,144.2,139.0,135.6,134.3,132.8,132.6,131.8,130.3,130.0,128.3,127.0,125.3,125.0,120.3,118.3,117.5,115.8,109.7,103.5,100.4,73.9,66.0,58.5,51.1,48.0,45.5,44.6,43.1,40.3,34.6,29.3.
实施例53 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-(三氟甲基)吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000122
1)化合物53-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以2-氨甲基-4-(三氟甲基)吗啉替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物53-k(1.64g)。
2)化合物53-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物53-k，得到化合物53-1。
实施例54 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-(全氟乙基)吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000123
1)化合物54-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以2-氨甲基-4-(全氟乙基)吗啉替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物54-k(1.93g)。
2)化合物54-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物54-k，得到化合物 54-1。
实施例55 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-((全氟乙基)磺酰基)吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000124
1)化合物55-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以2-氨甲基-4-((全氟乙基)磺酰基)吗啉替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物55-k(2.05g)。
2)化合物55-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物55-k，得到化合物55-1。
实施例56 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-((三氟甲基)磺酰基)吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000125
1)化合物56-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以2-氨甲基-4-((全氟乙基)磺酰基)吗啉替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物56-k(1.75g)。
2)化合物56-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物56-k，得到化合物56-1。
化合物56-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,2H),8.64(t,1H),8.59(d,1H),8.05(d,1H),7.89(s,1H),7.84(d,1H),7.71(d,1H),7.55(d,3H),7.40(d,1H),7.16(d,1H),6.75(d,1H),6.40(s,1H),6.29(s,1H),3.80(d,2H),3.64(m,5H),3.52(m,1H),3.38(m,3H),2.91(s,3H),2.86(m,2H),2.72(m,2H),2.27(m,1H),2.21(m,1H),1.96(s,2H),1.50(m,2H),1.24(m,1H),0.96(s,6H).
实施例57 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-(乙基磺酰基)吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000126
1)化合物57-k的制备
参照实施例25步骤1)化合物25-k的制备方法，以2-氨甲基-4-(乙基磺酰基)吗啉替换4-氨甲基-1-(四氢-2H-吡喃)哌啶，得化合物57-k。
2)化合物57-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物57-k，得到化合物57-1。
化合物57-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,2H),8.64(s,1H),8.58(m,1H),8.05(s,1H),7.89(d,1H),7.83(m,1H),7.70(d,1H),7.54(m,3H),7.39(m,1H),7.16(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.95(m,1H),3.75(m,2H),3.52(m,6H),3.42(m,2H),3.39(m,2H),3.12(m,3H),2.96(m,2H),2.77(m,1H),2.28(m,2H),2.08(m,1H),1.96(m,2H),1.50(m,2H),1.24(t,4H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,158.9,154.0,147.9,145.9,144.2,139.0,135.5,134.3,132.8,132.6,131.7,130.3,130.0,128.3,127.0,125.2,124.9,120.3,118.5,117.3,115.8,109.7,103.6,100.5,73.9,66.3,58.5,47.7,45.3,44.9,42.9,34.6,29.3,27.4,24.8.
实施例58 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(1-(2-甲氧基乙酰基)哌啶-3-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000127
1)化合物58-k的制备
将3-硝基-4-氟苯磺酰胺(1.03g)、3-氨甲基-1-(2-甲氧基乙酰基)哌啶(1.04g)和N,N-二异丙基乙胺(1.51g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物58-k(1.51g)。ESI-MS:m/z＝387.0[M+H] +.
2)化合物58-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物58-k，得到化合物58-1。
化合物58-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,1H),11.68(s,1H),8.64(m,1H),8.58(d,1H),8.05(d,1H),7.88(s,1H),7.83(m,1H),7.71(d,1H),7.55(m,3H),7.40(d,1H),7.16(d,1H),6.76(m,1H),6.40(m,1H), 6.30(d,1H),3.93(m,2H),3.76(m,8H),3.39(m,4H),3.05(m,4H),2.79(m,2H),2.27(m,2H),2.09(s,1H),1.96(s,2H),1.62(m,2H),1.50(m,2H),1.37(m,2H),1.24(s,1H),0.97(s,6H).ESI-MS:m/z＝1007.4[M+H] +.
实施例59 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(1-(甲基甘氨酰)哌啶-4-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000128
1)化合物59-k的制备
将3-硝基-4-氟苯磺酰胺(0.91g)、4-氨甲基-1-(甲基甘氨酰)哌啶(0.99g)和N,N-二异丙基乙胺(1.34g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物59-k(1.62g)。ESI-MS:m/z＝400.1[M+H] +.
2)化合物59-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物59-k，得到化合物59-1。
ESI-MS:m/z＝1020.4[M+H] +.
化合物59-1： 1H NMR(500MHz,DMSO-d6),δ:11.74(s,2H),8.67(s,1H),8.59(m,1H),8.05(s,1H),7.88(d,1H),7.83(m,1H),7.69(d,1H),7.54(m,3H),7.39(m,1H),7.16(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.61(m,4H),3.38(m,5H),3.02(m,4H),2.81(m,7H),2.67(m,2H),2.28(m,2H),2.02(m,3H),1.78(m,2H),1.49(m,2H),1.20(m,4H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:158.9,154.0,147.9,145.9,144.2,139.0,135.6,134.3,132.8,132.6,131.8,130.2,130.1,128.3,127.0,124.9,124.5,120.3,118.4,117.6,115.6,114.2,109.7,103.5,100.4,58.5,47.7,45.3,44.9,41.7,34.6,29.4,27.1,24.8.
实施例60 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(1-(甲基甘氨酰)哌啶-3-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000129
1)化合物60-k的制备
将3-硝基-4-氟苯磺酰胺(0.90g)、3-氨甲基-1-(甲基甘氨酰)哌啶(0.98g)和N,N-二异丙基乙胺(1.32g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物60-k(1.58g)。 ESI-MS:m/z＝400.0[M+H] +.
2)化合物60-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物60-k，得到化合物60-1。
化合物60-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,2H),8.63(m,1H),8.59(d,1H),8.04(d,1H),7.88(s,1H),7.84(m,1H),7.70(d,1H),7.54(m,3H),7.40(d,1H),7.17(d,1H),6.76(m,1H),6.40(m,1H),6.29(d,1H),3.89(m,2H),3.66(m,7H),3.33(m,4H),3.04(m,4H),2.89(s,6H),2.27(m,3H),2.09(s,1H),1.96(s,2H),1.62(m,2H),1.50(m,2H),1.24(s,2H),0.97(s,6H).ESI-MS:m/z＝1020.4[M+H] +.
实施例61 (S)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-乙酰基吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000130
1)化合物61-k的制备
将3-硝基-4-氟苯磺酰胺(0.68g)、(S)-2-氨甲基-4-乙酰基吗啉(0.59g)和N,N-二异丙基乙胺(2.59g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物61-k(0.89g)。ESI-MS:m/z＝359.0[M+H] +.
2)化合物61-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物61-k，得到化合物61-1。
化合物61-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,2H),8.64(s,1H),8.58(m,1H),8.05(s,1H),7.87(d,1H),7.84(m,1H),7.70(d,1H),7.54(m,3H),7.39(m,1H),7.15(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.91(m,1H),3.67(m,2H),3.60(m,4H),3.47(m,2H),3.42(m,2H),3.30(m,2H),3.17(m,1H),3.02(m,2H),2.72(m,1H),2.55(m,1H),2.27(m,1H),2.21(m,2H),2.01(m,3H),1.96(m,2H),1.50(m,2H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:169.1,164.0,158.9,158.6,154.0,147.9,146.9,145.9,144.2,135.5,132.8,131.7,130.2,128.3,128.2,125.2,120.3,118.3,117.4,115.8,114.2,109.7,103.6,100.4,73.8,66.4,58.5,48.5,45.2,44.3,41.2,34.6,29.3,27.1,24.8,21.6.ESI-MS:m/z＝979.4[M+H] +.
实施例62 (S)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-异丁酰基吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000131
1)化合物62-k的制备
将3-硝基-4-氟苯磺酰胺(0.68g)、(S)-2-氨甲基-4-异丁酰基吗啉(0.69g)和N,N-二异丙基乙胺(2.59g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物62-k(0.87g)。ESI-MS:m/z＝387.0[M+H] +.
2)化合物62-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物62-k，得到化合物62-1。
化合物62-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.69(s,1H),8.64(s,1H),8.58(m,1H),8.05(s,1H),7.88(d,1H),7.83(m,1H),7.70(d,1H),7.54(m,3H),7.39(m,1H),7.16(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.92(m,1H),3.80(m,1H),3.60(m,4H),3.47(m,2H),3.39(m,2H),3.30(m,2H),3.19(m,1H),2.86(m,5H),2.72(m,1H),2.57(m,1H),2.27(m,2H),1.96(m,2H),1.50(m,2H),1.00(s,6H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:158.9,154.0,147.9,145.6,144.2,139.0,135.5,134.3,132.8,132.6,131.7,130.2,130.0,128.3,127.0,125.2,125.0,120.3,118.4,117.3,115.8,109.7,103.6,100.4,74.0,66.6,58.5,45.3,44.3,42.9,34.6,29.3,27.1,24.8,20.0.ESI-MS:m/z＝1007.4[M+H] +.
实施例63 (S)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-(甲磺酰基)吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000132
1)化合物63-k的制备
将3-硝基-4-氟苯磺酰胺(0.68g)、(S)-2-氨甲基-4-(甲磺酰基)吗啉(0.72g)和N,N-二异丙基乙胺(2.59g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物63-k(0.68g)。ESI-MS:m/z＝395.0[M+H] +.
2)化合物63-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物63-k，得到化合物63-1。
化合物63-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,1H),11.69(s,1H),8.65(s,1H),8.58(m,1H),8.05(s,1H),7.89(d,1H),7.84(m,1H),7.70(d,1H),7.54(m,3H),7.39(m,1H),7.16(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.98(m,1H),3.79(m,3H),3.66(m,2H),3.58(m,3H),3.49(m,1H),3.44(m,1H),3.35(m,2H),2.92(m,4H),2.85(m,2H),2.69(m,2H),2.27(m,1H),2.21(m,1H),1.96(m,3H),1.50(m,2H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,158.9,158.6,154.0,147.8,146.9,145.9,144.2,135.6,132.8,131.7,130.3,128.3,128.2,125.2,120.3,118.3,115.8,115.1,114.1,109.7,103.6,100.4,73.7,66.0,58.5,47.9,45.4,44.3,34.6,29.3,27.2,24.8.ESI-MS:m/z＝1015.3[M+H] +.
实施例64 (S)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-(2-甲氧基乙酰基)吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000133
1)化合物64-k的制备
将3-硝基-4-氟苯磺酰胺(0.68g)、(S)-2-氨甲基-4-(2-甲氧基乙酰基)吗啉(0.70g)和N,N-二异丙基乙胺(2.59g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物64-k(0.68g)。ESI-MS:m/z＝389.0[M+H] +.
2)化合物64-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物64-k，得到化合物64-1。
化合物64-1： 1H NMR(500MHz,DMSO-d6),δ:11.76(s,1H),11.73(s,1H),8.65(s,1H),8.58(m,1H),8.05(s,1H),7.88(d,1H),7.85(m,1H),7.70(d,1H),7.54(m,3H),7.40(m,1H),7.15(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.67(m,5H),3.36(m,7H),2.99(m,5H),2.78(m,1H),2.28(m,3H),1.96(m,3H),1.50(m,3H),0.97(s,9H).
13C NMR(125MHz,DMSO-d6),δ:164.9,159.3,158.9,158.7,158.4,153.0,147.9,145.9,144.2,139.1,135.5,134.3,132.8,131.7,130.2,128.4,127.1,125.0,124.9,124.4,122.8,120.5,119.4,117.0,115.1,114.8,112.4,109.6,100.5,76.7,66.6,58.5,45.2,44.7,40.9,34.6,29.3,29.1,27.2,24.9.ESI-MS:m/z＝1009.4[M+H] +.
实施例65 (R)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[((4-乙酰基吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000134
1)化合物65-k的制备
将3-硝基-4-氟苯磺酰胺(0.68g)、(R)-2-氨甲基-4-乙酰基吗啉(0.59g)和N,N-二异丙基乙胺(2.59g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物65-k(0.89g)。ESI-MS:m/z＝359.0[M+H] +.
2)化合物65-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物65-k，得到化合物65-1。
化合物65-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,1H),11.69(s,1H),8.64(s,1H),8.58(m,1H),8.05(s,1H),7.88(d,1H),7.84(m,1H),7.70(d,1H),7.55(m,3H),7.39(m,1H),7.15(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.89(m,2H),3.67(m,2H),3.58(m,3H),3.49(m,3H),3.30(m,2H),3.17(m,2H),3.02(m,2H),2.72(m,1H),2.56(m,1H),2.27(m,2H),2.21(m,1H),2.02(m,3H),1.96(m,2H),1.50(m,2H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:169.1,164.0,158.9,158.6,158.2,154.0,147.8,146.9,145.8,144.2,139.0,135.5,132.8,131.7,130.2,128.3,128.2,124.4,120.3,118.3,115.8,114.9,114.1,109.7,103.6,100.4,73.8,66.4,58.5,48.5,45.4,44.3,41.2,34.6,29.3,29.1,27.1,24.8,21.6.ESI-MS:m/z＝979.4[M+H] +.
实施例66 (R)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-异丁酰基吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000135
1)化合物66-k的制备
将3-硝基-4-氟苯磺酰胺(0.68g)、(R)-2-氨甲基-4-乙酰基吗啉(0.69g)和N,N-二异丙基乙胺(2.59g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物66-k(0.87g)。ESI-MS:m/z＝387.0[M+H] +.
2)化合物66-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物66-k，得到化合物66-1。
化合物66-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.69(s,1H),8.64(s,1H),8.58(m,1H),8.05(s,1H),7.88(d,1H),7.84(m,1H),7.70(d,1H),7.56(m,3H),7.40(m,1H),7.16(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.91(m,2H),3.81(m,1H),3.60(m,4H),3.45(m,2H),3.39(m,2H),3.30(m,2H),3.18(m,1H),3.03(m,2H),2.87(m,2H),2.72(m,1H),2.57(m,1H),2.27(m,1H),2.21(m,1H),1.96(m,2H),1.50(m,2H),1.00(s,6H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:175.2,164.0,158.2,154.0,147.8,146.9,145.9,144.2,139.0,135.5,134.3,132.8,132.6,131.7,130.2,128.3,125.2,124.4,120.3,118.3,115.8,114.1,109.7,103.6,100.4,74.0,66.6,58.5,56.5,45.3,44.3,41.5,34.6,29.4,29.3,27.1,24.3,20.0.ESI-MS:m/z＝1007.4[M+H] +.
实施例67 (R)-4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-(甲磺酰基)吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000136
1)化合物67-k的制备
将3-硝基-4-氟苯磺酰胺(0.68g)、(R)-2-氨甲基-4-(甲磺酰基)吗啉(0.72g)和N,N-二异丙基乙胺(2.59g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物67-k(0.68g)。ESI-MS:m/z＝395.0[M+H] +.
2)化合物67-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物67-k，得到化合物67-1。
化合物67-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.69(s,1H),8.64(s,1H),8.58(m,1H),8.05(s,1H),7.88(d,1H),7.85(m,1H),7.70(d,1H),7.54(m,3H),7.39(m,1H),7.16(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.98(m,2H),3.79(m,2H),3.66(m,2H),3.56(m,3H),3.49(m,2H),3.38(m,3H),2.92(m,3H),2.88(m,2H),2.70(m,2H),2.27(m,1H),2.21(m,1H),1.96(m,2H),1.50(m,2H),1.24(t,1H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:159.3,159.0,158.7,158.2,154.0,147.8,146.9,145.8,144.2,139.0,135.5,132.8,131.7,130.2,128.3,128.2,124.3,120.4,118.4,115.8,114.8,114.1,109.7,103.6,100.5,73.7,66.0,58.5,47.8,45.4,44.3,34.6,29.3,29.1,27.1,24.8.ESI-MS:m/z＝1015.3[M+H] +.
实施例68 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(3-(4-乙酰基吗啉-2-基)丙基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000137
1)化合物68-k的制备
将3-硝基-4-氟苯磺酰胺(1.20g)、2-氨丙基-3-(4-乙酰基)吗啉(1.22g)和N,N-二异丙基乙胺(4.59g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物68-k(1.67g)。ESI-MS:m/z＝387.0[M+H] +.
2)化合物68-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物68-k，得到化合物68-1。
化合物68-1： 1H NMR(500MHz,DMSO-d6),δ:11.74(s,2H),8.61(s,1H),8.58(m,1H),8.05(s,1H),7.88(d,1H),7.85(m,1H),7.70(d,1H),7.54(m,3H),7.39(m,1H),7.07(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.83(m,1H),3.66(m,2H),3.59(m,1H),3.40(m,4H),3.32(m,2H),3.10(m,2H),3.05(m,2H),2.83(m,1H),2.63(m,1H),2.27(m,2H),2.21(m,1H),2.00(m,3H),1.71(m,3H),1.96(m,2H),1.50(m,4H),1.24(t,1H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:168.8,164.0,159.3,159.0,158.7,154.0,147.7,145.8,144.2,139.0,135.5,132.8,131.7,130.1,128.3,124.4,120.4,117.3,115.4,114.9,109.7,100.5,75.1,66.3,58.5,46.1,45.1,44.3,42.8,41.3,34.6,29.3,29.1,27.1,24.8,21.6.ESI-MS:m/z＝1007.4[M+H] +.
实施例69 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(3-(4-异丁酰基吗啉-2-基)丙基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000138
1)化合物69-k的制备
将3-硝基-4-氟苯磺酰胺(1.20g)、2-氨丙基-3-(4-异丁酰基)吗啉(1.40g)和N,N-二异丙基乙胺(4.59g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物69-k(1.69g)。ESI-MS:m/z＝415.1[M+H] +.
2)化合物69-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物69-k，得到化合物69-1。
化合物69-1： 1H NMR(500MHz,DMSO-d6),δ:11.73(s,1H),11.67(s,1H),8.60(s,1H),8.58(m,1H),8.05(s,1H),7.88(d,1H),7.83(m,1H),7.70(d,1H),7.54(m,3H),7.39(m,1H),7.07(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.83(m,3H),3.58(m,2H),3.40(m,5H),3.32(m,3H),3.15(m,1H),3.05(m,3H),2.85(m,1H),2.64(m,1H),2.40(m,1H),2.27(m,1H),2.21(m,1H),1.96(m,2H),1.70(m,2H),1.50(m,4H),1.01(s,6H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:174.9,164.0,159.0,158.7,158.2,154.0,147.7,146.9,145.8,144.2,139.0,135.5,132.8,131.7,130.0,128.3,124.9,124.4,120.3,118.4,115.4,109.7,100.4,75.2,66.6,58.5,46.3,45.2,44.3,42.9,34.6,29.4,29.1,27.1,24.8,24.3,20.6.ESI-MS:m/z＝1035.3[M+H] +.
实施例70 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(3-(4-(2-甲氧基乙酰基)吗啉-2-基)丙基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000139
1)化合物70-k的制备
将3-硝基-4-氟苯磺酰胺(1.20g)、2-氨丙基-3-(4-(2-甲氧基乙酰基)吗啉(1.42g)和N,N-二异丙基乙胺(4.59g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物70-k(1.71g)。ESI-MS:m/z＝417.1[M+H] +.
2)化合物70-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物70-k，得到化合物70-1。
化合物70-1： 1H NMR(500MHz,DMSO-d6),δ:11.73(s,1H),11.69(s,1H),8.64(m,1H),8.58(d,1H),8.05(d,1H),7.89(s,1H),7.83(m,1H),7.71(d,1H),7.54(m,3H),7.40(d,1H),7.18(d,1H),6.76(m,1H),6.39(m,1H),6.30(d,1H),4.26(m,2H),3.64(m,6H),3.54(m,2H),3.49(m,2H),3.39(m,4H),3.05(m,4H),2.79(m,2H),2.27(m,1H),2.21(m,1H),2.09(s,1H),1.96(s,2H),1.62(m,2H),1.50(m,2H),1.37(m,2H),1.24(s,1H),0.97(s,6H).
ESI-MS:m/z＝1037.2[M+H] +.
实施例71 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(3-(4-(2-甲基磺酰基)吗啉-2-基)丙基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000140
1)化合物71-k的制备
将3-硝基-4-氟苯磺酰胺(1.13g)、2-氨丙基-3-(4-(2-甲磺酰基)吗啉(1.36g)和N,N-二异丙基乙胺(4.59g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物71-k(1.51g)。ESI-MS:m/z＝423.0[M+H] +.
2)化合物71-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物71-k，得到化合物71-1。
化合物71-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,2H),8.62(s,1H),8.57(m,1H),8.05(s,1H),7.89(d,1H),7.83(m,1H),7.70(d,1H),7.54(m,3H),7.39(m,1H),7.07(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),3.92(m,1H),3.78(m,2H),3.53(m,4H),3.35(m,7H),2.89(m,7H),2.55(m,1H),2.21(m,2H),1.96(m,2H),1.70(m,2H),1.52(m,4H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,158.9,154.0,147.7,145.9,144.2,136.0,134.3,132.9,132.6,131.8,130.2,130.0,128.4,127.0,125.0,124.7,122.8,120.3,118.3,115.4,114.2,109.7,103.6,100.4,74.7,65.9,58.5,50.1,45.1,44.3,42.8,34.6,29.3,27.2,24.8.ESI-MS:m/z＝1043.2[M+H] +.
实施例72 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(2-(4-(2-甲氧基乙酰基)吗啉-2-基)乙基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000141
1)化合物72-k的制备
将3-硝基-4-氟苯磺酰胺(1.20g)、2-氨乙基-2-(4-(2-甲氧基乙酰基)吗啉(1.33g)和N,N-二异丙基乙胺(4.59g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物72-k(1.56g)。ESI-MS:m/z＝403.0[M+H] +.
2)化合物72-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物72-k，得到化合物72-1。
化合物72-1： 1H NMR(500MHz,DMSO-d6),δ:11.72(s,2H),8.64(m,1H),8.58(d,1H),8.04(d,1H),7.88(s,1H),7.84(m,1H),7.70(d,1H),7.55(m,3H),7.39(d,1H),7.16(d,1H),6.76(m,1H),6.39(m,1H),6.29(d,1H),3.89(m,2H),3.70(m,6H),3.55(m,2H),3.51(m,2H),3.40(m,4H),3.04(m,4H),2.79(m,2H),2.28(m,1H),2.21(m,1H),2.11(s,1H),1.96(s,2H),1.62(m,2H),1.35(m,2H),1.24(s,1H),0.97(s,6H).ESI-MS:m/z＝1023.3[M+H] +.
实施例73 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[1-(2-甲氧基乙酰基)哌啶-4-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺
Figure PCTCN2019113963-appb-000142
1)化合物73-k的制备
将3-硝基-4-氟苯磺酰胺(1.56g)、4-氨甲基-1-(2-甲氧基乙酰基)哌啶(1.59g)和N,N-二异丙基乙胺(2.30g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物73-k(2.58g)。ESI-MS:m/z＝387.0[M+H] +.
2)化合物73-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物73-k，得到化合物73-1。
化合物73-1： 1H NMR(500MHz,DMSO-d6),δ:11.74(s,1H),11.69(s,1H),8.64(s,1H),8.58(m,1H),8.05(s,1H),7.89(d,1H),7.82(m,1H),7.70(d,1H),7.54(m,3H),7.39(m,1H),7.14(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),4.08(m,2H),3.76(m,3H),3.58(m,1H),3.31(m,6H),2.93(m,4H),2.54(m,2H),2.27(m,2H),1.96(m,4H),1.74(m,2H),1.50(m,2H),1.24(m,4H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:164.0,158.9,154.0,147.9,146.9,145.8,144.2,139.0,135.5,134.3,132.8,132.6,131.7,130.2,130.1,128.3,127.0,124.8,120.4,118.5,117.2,115.8,114.9,109.7,103.6,100.5,71.2,58.7,48.0,45.2,44.4,41.3,35.3,30.3,29.6,27.4.ESI-MS:m/z＝1007.3[M+H] +.
实施例74 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-(乙氧甲酰基)吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺(化合物74-1)
Figure PCTCN2019113963-appb-000143
1)化合物74-k的制备
将3-硝基-4-氟苯磺酰胺(1.20g)、2-氨甲基-4-(乙氧甲酰基)吗啉(1.23g)和N,N-二异丙基乙胺(4.59g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物74-k(1.80g)。ESI-MS:m/z＝387.1[M-H] -.
2)化合物74-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物74-k，得到化合物74-1。
化合物74-1： 1H NMR(500MHz,DMSO-d6),δ:11.70(s,2H),8.64(s,1H),8.57(m,1H),8.04(s,1H),7.88(d,1H),7.83(m,1H),7.70(d,1H),7.53(m,3H),7.39(m,1H),7.15(d,1H),6.75(d,1H),6.40(s,1H),6.30(s,1H),4.08(m,2H),3.89(m,3H),3.65(m,2H),3.51(m,7H),2.96(m,3H),2.79(m,2H),2.21(m,2H),2.02(m,1H),1.95(m,2H),1.50(m,2H),1.23(m,1H),1.18(m,3H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:162.4,156.0,153.6,152.5,146.3,145.3,144.3,142.8,134.0,132.7,131.3,131.0,130.2,128.6,126.7,126.6,125.4,123.6,123.3,118.7,116.7,114.2,108.1,101.9,98.8,72.1,64.5,59.8,56.9,43.5,42.8,33.1,27.5,25.6,23.3.ESI-MS:m/z＝1009.3[M+H] +.
实施例75 4-(4-{[2-(2-氯-4-三氟甲基苯基)-4,4-二甲基环己-1-烯基]甲基}-哌嗪-1-基)-N-({3-硝基-4-[(4-(甲氧甲酰基)吗啉-2-基)甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酰胺(化合物75-1)
Figure PCTCN2019113963-appb-000144
1)化合物75-k的制备
将3-硝基-4-氟苯磺酰胺(1.20g)、2-氨甲基-4-(甲氧甲酰基)吗啉(1.14g)和N,N-二异丙基乙胺(4.59g)溶于乙腈(10mL)中，加热至85℃，反应6h，室温冷却，静置过夜，浓缩干燥，得化合物75-k(1.73g)。ESI-MS:m/z＝373.1[M-H] -.
2)化合物75-1的制备
参考实施例7步骤6)中化合物7-1的制备方法，将其中的化合物7-k换成化合物75-k，得到化合物75-1。
化合物75-1： 1H NMR(500MHz,DMSO-d6),δ:11.71(s,1H),11.68(s,1H),8.64(m,1H),8.58(d,1H),8.05(d,1H),7.88(s,1H),7.83(m,1H),7.71(d,1H),7.55(m,3H),7.40(d,1H),7.16(d,1H),6.76(m,1H),6.40(m,1H),6.30(d,1H),3.93(m,2H),3.76(m,8H),3.49(m,4H),3.02(m,4H),2.79(m,2H),2.28(m,2H),2.08(s,1H),1.96(s,2H),1.51(m,2H),1.24(s,1H),0.97(s,6H).
13C NMR(125MHz,DMSO-d6),δ:162.4,157.6,157.3,157.0,156.6,154.0,152.4,146.3,145.3,144.3,142.6,137.4,133.9,132.7,131.2,131.0,130.1,128.6,126.7,126.6,123.6,123.4,122.8,118.7,116.7,115.9,114.2,113.6,112.6,108.1,102.0,98.8,72.1,64.5,56.9,51.3,43.6,43.4,42.7,33.0,27.7,27.5,25.5,23.2.
ESI-MS:m/z＝995.3[M+H] +.
实施例76-实施例82
参照实施例7的制备过程，得到以下化合物：
Figure PCTCN2019113963-appb-000145
Figure PCTCN2019113963-appb-000146
Figure PCTCN2019113963-appb-000147
Figure PCTCN2019113963-appb-000148
试验例1 体外蛋白结合抑制活性
1.1 BCL-2/BAK结合抑制活性筛选
用试剂盒(型号：BCL-2/BAK(BH3)BINDING ASSAY KITS，来源于cisbio)中的稀释缓冲液将500nM的Tag1-BCL-2蛋白母液稀释成5nM，同时将20μM的Tag2-BAK蛋白母液稀释成120nM，先每孔加入5μL的Tag1-BCL-2蛋白稀释液，然后用纳升加样仪将DMSO溶解的不同化合物加入到孔中，使化合物终浓度为200nM-0.0488nM，4倍梯度，共7个浓度，同时设空白对照孔(不含酶)与阴性对照孔(含酶，加溶媒DMSO)，设2个复孔，最后再每孔加入5μL的Tag2-BAK蛋白稀释液，离心混匀，25℃孵育15min。用试剂盒中的检测缓冲液将100×的anti-Tag1-Eu 3+稀释成1×的使用浓度，同时将100X的anti-Tag2-XL665稀释成1×的使用浓度。将anti-Tag1-Eu 3+和anti-Tag2-XL665按1：1混匀，每孔加入5μL的混合液，25℃反应2h及以上。PE Envision多功能酶标仪进行读板(激发620nm，发射665nm)，采用四参数拟合，计算IC 50(表1所示)。
1.2 BCL-XL/BAK结合抑制活性筛选
用试剂盒(型号：BCL-XL/BAK(BH3)BINDING ASSAY KITS，来源于cisbio)中的稀释缓冲液将300nM的Tag1-BCL-XL蛋白母液稀释成2nM，同时将10μM的Tag2-BAK蛋白母液稀释成80nM，先每孔加入5μL的Tag1-BCL-XL蛋白稀释液，然后用纳升加样仪将DMSO溶解的不同化合物加入到孔中，使化合物终浓度为2000nM-0.488nM，4倍梯度，共7个浓度，同时设空白对照孔(不含酶)与阴性对照孔(含酶，加溶媒DMSO)，设2个复孔，最后再每孔加入5μL的Tag2-BAK蛋白稀释液，离心混匀，25℃孵育15min。用试剂盒中的检测缓冲液将100×的anti-Tag1-Eu 3+稀释成1×的使用浓度，同时将100X的anti-Tag2-XL665稀释成1×的使用浓度。将anti-Tag1-Eu 3+和anti-Tag2-XL665按1：1混匀，每孔加入5μL的混合液，25℃反应2h及以上。PE Envision多功能酶标仪进行读板(激发620nm，发射665nm)，采用四参数拟合，计算IC 50(表1所示)。
表1 化合物抑制BCL-2/BAK和BCL-XL/BAK结合活性
Figure PCTCN2019113963-appb-000149
Figure PCTCN2019113963-appb-000150
试验例2 化合物对RS4；11细胞的增殖抑制作用
取处于指数生长期状态良好的RS4；11细胞(来源于南京科佰)，收集细胞至离心管，低速台式离心机，1500转/min，离心3min，弃上清，用移液器加入5mL完全培养基(RPMI基础培养基+10wt％胎牛血清(FBS))进行细胞重悬。使用细胞计数仪计数，用完全培养基进行稀释，调整细胞密度至2×10 5个/mL，在加入等量的RPMI基础培养基调整血清浓度为5％，细胞密度为1×10 5个/mL种板。使用排枪接种于96孔板上，100μL/孔，置于37℃、含5％CO 2饱和湿度的细胞培养箱中培养。培养24h后，使用纳升加样仪进行化合物加样，每一浓度设置2个复孔，以不加化合物的细胞作为阴性对照，72小时后加CCK-8试剂，10μL/孔，4小时后Envision酶标仪450nm处检测其吸光值，计算抑制率，抑制率(％)＝(阴性对照组平均值—实验组平均值)/(阴性对照组平均值—空白组平均值)×100％，以化合物浓度对数为横坐标，抑制率为纵坐标，四参数分析，拟合量效曲线，计算IC 50(见表2)。
表2 化合物对RS4；11细胞的增殖抑制作用
Figure PCTCN2019113963-appb-000151
Figure PCTCN2019113963-appb-000152
试验例3 体外肝微位体稳定性评价
300μL最终的温孵体系中，含30μL肝微粒体(蛋白浓度：5mg/mL)，30μL NADPH+MgCl 2，3μL受试化合物(乙腈配制)，237μL PBS缓冲液(PH7.4)。其中有机溶剂(乙腈)的比例为1％(体积比)。每个种属(小鼠、大鼠、人)做2份，每份0.3mL。每管先配好总体积为270μL的底物及酶的混匀液，和NADPH分别在37℃预温孵5min后，加入30μL NADPH+MgCl 2混合，分别于0、15、30、60min取出50μL用含内标的冰乙腈300μL终止反应。
50μL温孵样品，加入300μL含内标(地西泮20ng/mL)的冰乙腈沉淀，涡旋震荡5min后，离心(13000rpm，20℃)10min。吸取上清液70μL，加入70μL超纯水稀释混匀，1μL进样分析。化合物在人、大鼠和小鼠肝微粒体中消除参数见表3。
表3 化合物体外肝微粒体代谢稳定性(1μM)
Figure PCTCN2019113963-appb-000153
试验例4 体内药代动力学评价
4.1大鼠体内药代动力学评价
SD大鼠，体重180～220g，适应3～5天后，随机分组，每组3只，按5mg/kg剂量灌胃化合物1-1及 8-1。
受试动物(SD大鼠)给药前禁食12h，给药后4h给食物，实验前后和实验过程中均自由饮水。
灌胃给药后，于0min、15min、30min、1h、2h、4h、6h、8h、10h、24h于眼眶取血0.2mL左右，EDTA-K2抗凝后，30min内转移到4℃，4000rpm，10min条件下离心分离血浆。收集全部血浆后立即于-20℃保存待测。
吸取50μL待测血浆样品，加入300μL含内标(地西泮20mg/mL)的乙腈溶液，振荡混匀5min，13000rpm离心10min，取上清75μL，加入75μL超纯水稀释，混匀，吸取2μL用于LC/MS/MS测定，记录色谱图。
通过大鼠体内药物动力学实验评估本发明化合物的口服暴露量。采用DAS3.2.5软件拟合化合物的药代参数如下表所示。
化合物1-1及8-1药代数据如下表4-1所示。
表4-1 化合物的药代参数
Figure PCTCN2019113963-appb-000154
4.2比格犬体内药代动力学评价
雄性比格犬3只，体重9～12kg，适应一段时间后，按2.5mg/kg剂量分别灌胃受试化合物。
受试动物(雄性比格犬)给药前禁食12h，给药后4h给食物，实验前后和实验过程中均自由饮水。
灌胃给药后，于0.25h(15min)、0.5h(30min)、1h、1.5h、2h、4h、6h、8h、10h、24h、30h、48h、72h于前肢静脉取血约0.5mL置于EDTA-K2抗凝真空采血管中，血浆于30min内转移到4℃，4000rpm，10min条件下离心分离血浆。收集全部血浆后立即于-20℃保存待测。
吸取50μL待测血浆样品，加入300μL含内标(地西泮20ng/mL)的乙腈溶液，振荡混匀5min，13000rpm离心10min，取上清75μL，加入75μL超纯水稀释，混匀，吸取1μL用于LC/MS/MS测定，记录色谱图。
通过比格犬体内药物动力学实验评估本发明化合物的口服暴露量。采用DAS3.2.5软件拟合化合物的药代参数如下表4-2所示。
表4-2 化合物的比格犬体内药代参数
Figure PCTCN2019113963-appb-000155
Figure PCTCN2019113963-appb-000156
试验例5 受试物在RS4；11人类B细胞白血病皮下移植模型中的药效学评价
NOD/SCID小鼠，雌性，9-10周(肿瘤细胞接种时的小鼠周龄)，体重16.3-22.0g。购自安凯毅博生物技术有限公司，生产许可证号：SCXK(京)2017-0006，动物合格证编号：11402400013155。饲养环境：SPF级。小鼠右侧前背部皮下接种1×10 7RS4；11细胞。接种当天定义为第0天。待肿瘤平均体积240mm 3时，根据肿瘤大小随机分组。按下表5进行给药。
表5 人源B细胞白血病RS4；11皮下动物模型中的给药途径、剂量及方案
组别 n 给药组 剂量(mg/kg) 给药方式 给药时间
1 6 Vehicle   p.o. 单次
2 6 1-1 25 p.o. 单次
3 6 1-1 50 p.o. 单次
4 6 8-1 25 p.o. 单次
注：n：动物只数；给药体积为10μL/g。
实验过程中观察到的临床症状均记录在原始数据中。肿瘤体积计算公式：肿瘤体积(mm 3)＝1/2×(a×b 2)(其中a表示长径，b表示短径)。实验中使用StudyDirector TM(版本号3.1.399.19，供应商Studylog System,Inc.,S.San Francisco,CA,USA)软件收集数据，包括肿瘤的长短径的测量和动物体重的称量。原始数据由天平和游标卡尺测量后直接导入软件，数据的任何变动都将被记录在此软件中。相对肿瘤增殖率，T/C％，即在某一时间点，治疗组和对照组相对肿瘤体积或瘤重的百分比值。计算公式如下：
T/C％＝T RTV/C RTV×100％(T RTV：治疗组平均RTV；C RTV：溶媒对照组平均RTV；RTV＝V t/V 0，V 0为分组时该动物的瘤体积，V t为治疗后该动物的瘤体积)。
相对肿瘤抑制率，TGI(％)，计算公式如下：TGI％＝(1-T/C)×100％。(T和C分别为治疗组和对照组在某一特定时间点的相对肿瘤体积(RTV)或瘤重(TW))。
所有实验结果以平均瘤体积±SEM(平均标准误差)表示。用独立样本T检验方法比较治疗组相对肿瘤体积与对照组相比有无显著性差异。所有的数据均用SPSS 18.0进行分析。p<0.05为具有显著性差异。结果见表6。
表6 在人源B细胞白血病RS4；11皮下模型中各组药效分析表
Figure PCTCN2019113963-appb-000157
注：1.数据以“平均值±标准误差”表示；
2.T/C％＝T RTV/C RTV×100％；TGI％＝(1-T/C)×100％。
试验例6 人血小板毒性实验(Caspase3活性测定)
使用肝素钠抗凝管抽取10mL人全血，上下颠倒混匀，90g离心10min，收集上清，继续1950g离心10min。弃上清，用4mL PBS重悬混匀后，1190g离心5min，弃上清，再用4mL PBS重悬混匀，1190g离心5min，弃上清，用PBS重悬血小板并调整密度为2～3×10 8个/mL。按2～3×10 7个/mL的密度接种于96孔板，100μL/孔，阴性对照孔加50μL对照缓冲液，化合物孔每孔加入50μL对应浓度的化合物，使化合物 终浓度为2.5μM，2μM，1μM或0.5μM，37℃培养箱中孵育90min。将96孔板中的液体分别转移到1.5mL离心管中。4℃6000g离心5min，弃上清，置于冰上待用。用试剂盒中提供的水将5×的裂解液稀释成1×的裂解液，同时按1:200的比例加蛋白酶抑制剂cocktail，配制成待用裂解混合液。每个离心管中加入40μL裂解混合液，用移液器将底部的血小板重悬，冰上裂解15～20min，4℃14000g离心10min，样品分装待用。用试剂盒中提供的水将10×的检测液稀释成1×的检测液，同时按1:600的比例加底物Ac-DEVD-AMC，配置成反应混合液。空白对照孔加入5μL检测缓冲液，40μL反应混合液。样品阴性对照孔，加入5μL对照血小板裂解液，40μL反应混合液。化合物组，加入5μL血小板裂解液，40μL反应混合液。其中40μL的反应混合液最后加入，轻轻混合，PE Envision多功能酶标仪进行读板(激发360nm，发射46nm)，每10min检测一次，检测6次。根据释放的AMC荧光强度的大小，可以测定Caspase-3的活性，即每个孔所对应拟合直线的斜率代表Caspase活性大小(所有数据做了归一化处理，基准为ABT-199)。结果见表7及表8。
表7 化合物对人血小板Caspase3活性作用
Figure PCTCN2019113963-appb-000158
注：数据做了归一化处理。
表8 化合物对人血小板Caspase3活性作用
Figure PCTCN2019113963-appb-000159
注：数据做了归一化处理。

Claims (15)

  1. 式I化合物、其立体异构体或其药学上可接受的盐，
    Figure PCTCN2019113963-appb-100001
    其中，
    R 1选自卤素；
    R 2选自-C 0-6亚烷基-R 3；
    R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个选自以下的基团取代：3-6元杂环烷基、C 3-6环烷基、-COR a、-SO 2R b、-COOC 1-6烷基、或任选地被卤素取代的C 1-6烷基；
    R a或R b分别独立地选自H、3-6元杂环烷基、C 3-6环烷基、或C 1-6烷基，所述C 1-6烷基任选地被卤素、-CN、-N(C 1-6烷基) 2、-NHC 1-6烷基、或-OC 1-6烷基取代。
  2. 如权利要求1所述的式I化合物、其立体异构体或其药学上可以接受的盐，其中，结构片段
    Figure PCTCN2019113963-appb-100002
    选自
    Figure PCTCN2019113963-appb-100003
  3. 如权利要求1或2所述的式I化合物、其立体异构体或其药学上可以接受的盐，其中，R 1选自氟或氯。
  4. 如权利要求1-3任一项所述的式I化合物、其立体异构体或其药学上可以接受的盐，其中，R 2选自-(CH 2) n-R 3，其中，n选自0、1、2、3或4。
  5. 如权利要求1-4任一项所述的式I化合物、其立体异构体或其药学上可以接受的盐，其中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个基团取代，取代位点为环上的N原子。
  6. 如权利要求1-5任一项所述的式I化合物、其立体异构体或其药学上可以接受的盐，其中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个选自以下的基团取代：3-6元杂环烷基、-COR a、-SO 2R b、-COOC 1-4烷基取代、或任选地被卤素取代的C 1-6烷基。
  7. 如权利要求1-6任一项所述的式I化合物、其立体异构体或其药学上可以接受的盐，其中，R a或R b分别独立地选自H、3-6元杂环烷基、C 3-6环烷基、或C 1-4烷基，所述C 1-4烷基任选地被卤素、-CN、-N(C 1-4烷基) 2、-NHC 1-4烷基、或-OC 1-4烷基取代；或者，R a或R b分别独立地选自H、甲基、乙基、异丙基、叔丁基、环丙基、环丁基、或单氧杂环丁基，所述甲基或乙基任选地被氟、-CN、-OCH 3、或-N(CH 3) 2取代；或者，R a或R b分别独立地选自H、甲基、乙基、异丙基、叔丁基、三氟甲基、五氟乙基、-CH 2OCH 3、-CH 2CN、或-CH 2N(CH 3) 2、环丙基、环丁基、或单氧杂环丁基。
  8. 如权利要求7所述的式I化合物、其立体异构体或其药学上可以接受的盐，其中，R a或R b分别独立地选自任选地被-OC 1-4烷基取代的C 1-4烷基；或者，R a或R b分别独立地选自甲基、异丙基、或-CH 2OCH 3。
  9. 如权利要求1-6任一项所述的式I化合物、其立体异构体或其药学上可以接受的盐，其中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被以下基团取代：-C(O)H、-COCH 3、-COCH(CH 3) 2、-COC(CH 3) 3、-COCF 3、-COCH 2CN、-COCH 2OCH 3、-COCH 2N(CH 3) 2、-SO 2CH 3、-SO 2CH 2CH 3、-SO 2CF 3、-SO 2C 2F 5、甲基、乙基、-CF 3、-CH 2CH 2F、-C 2F 5、四氢吡喃、单氧杂环丁烷、-SO 2-环丙烷、-CO-环丙烷、-CO-单氧杂环丁烷、-SO 2-单氧杂环丁烷、-SO 2-环丁烷、-COOCH 2CH 3、或-COOCH 3；或者，R 3选自四氢吡喃、哌啶、吗啉或二氧六环，所述四氢吡喃、哌啶、吗啉或二氧六环任选地被以下基团取代：-COCH 3、-COCH(CH 3) 2、-COCH 2OCH 3、-SO 2CH 3、-SO 2CH 2CH 3、-CO-环丙烷、-COCH 2CN、-COCF 3、-COCH 2N(CH 3) 2、甲基、乙基、-CH 2CH 2F、-COOCH 2CH 3、或-COOCH 3；或者，R 3选自四氢吡喃、哌啶、吗啉或二氧六环，所述四氢吡喃、哌啶、吗啉或二氧六环任选地被以下基团取代：-COCH 3、-COCH(CH 3) 2、-COCH 2OCH 3、-SO 2CH 3、甲基、乙基、-CH 2CH 2F、-COOCH 2CH 3、或-COOCH 3。
  10. 如权利要求1所述式I化合物、其立体异构体或其药学上可以接受的盐，其中R 3选自
    Figure PCTCN2019113963-appb-100004
    Figure PCTCN2019113963-appb-100005
    Figure PCTCN2019113963-appb-100006
  11. 权利要求1所述的式I化合物、其立体异构体或其药学上可接受的盐选自式II化合物、其立体异构体或其药学上可接受的盐：
    Figure PCTCN2019113963-appb-100007
    其中R 2的定义如权利要求1中的定义。
  12. 以下化合物、其立体异构体或其药学上可接受的盐，
    Figure PCTCN2019113963-appb-100008
    Figure PCTCN2019113963-appb-100009
    Figure PCTCN2019113963-appb-100010
    ；或以下化合物：
    Figure PCTCN2019113963-appb-100011
    其中，R独立为以下基团：
    Figure PCTCN2019113963-appb-100012
    Figure PCTCN2019113963-appb-100013
    Figure PCTCN2019113963-appb-100014
  13. 以下化合物或其药学上可接受的盐，
    Figure PCTCN2019113963-appb-100015
    Figure PCTCN2019113963-appb-100016
    Figure PCTCN2019113963-appb-100017
    Figure PCTCN2019113963-appb-100018
    或以下化合物：
    Figure PCTCN2019113963-appb-100019
    其中，R独立为以下基团：
    Figure PCTCN2019113963-appb-100020
    Figure PCTCN2019113963-appb-100021
    Figure PCTCN2019113963-appb-100022
    Figure PCTCN2019113963-appb-100023
    Figure PCTCN2019113963-appb-100024
    Figure PCTCN2019113963-appb-100025
  14. 一种药物组合物，其包含权利要求1-13中任一项所述的化合物、其立体异构体或其药学上可接受的盐。
  15. 权利要求1-13中任一项所述化合物、其立体异构体或其药学上可接受的盐、或权利要求14所述的药物组合物在制备预防或者治疗与抗凋亡蛋白BCL-2相关疾病的药物中的用途。
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