WO2020221272A1 - 吲哚类大环衍生物、其制备方法及其在医药上的应用 - Google Patents

吲哚类大环衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2020221272A1
WO2020221272A1 PCT/CN2020/087671 CN2020087671W WO2020221272A1 WO 2020221272 A1 WO2020221272 A1 WO 2020221272A1 CN 2020087671 W CN2020087671 W CN 2020087671W WO 2020221272 A1 WO2020221272 A1 WO 2020221272A1
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general formula
cancer
pharmaceutically acceptable
compound represented
tautomer
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PCT/CN2020/087671
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English (en)
French (fr)
Inventor
张晓敏
费洪博
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN202080021819.XA priority Critical patent/CN113574058B/zh
Publication of WO2020221272A1 publication Critical patent/WO2020221272A1/zh

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present disclosure belongs to the field of medicine, and relates to an indole macrocyclic derivative represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a MCL-1 inhibitor
  • Apoptosis is inhibited, which gives them a greater survival advantage.
  • Apoptosis is also called programmed death, which can be divided into exogenous apoptosis and endogenous apoptosis.
  • endogenous apoptosis is an important barrier to the occurrence and development of cancer.
  • BCL-2 family proteins are important regulators of endogenous apoptosis.
  • the BCL-2 family proteins mainly exist on the mitochondrial membrane, and can be divided into anti-apoptotic proteins and pro-apoptotic proteins according to their functions.
  • Anti-apoptotic proteins include BCL-2, BCL-XL, BCL-w and MCL-1.
  • Pro-apoptotic proteins include Bax, Bak and BH3-only proteins. When Bax and Bak are activated, multimer cavities are formed, which increases the permeability of cell mitochondrial membranes and promotes the release of cytochrome C into the cytoplasm, leading to cell death.
  • the BH3-only protein contains only the BH3 domain. In the state of cell survival, BH3-only protein (such as Bim) binds to anti-apoptotic protein.
  • the balance of binding is broken, and the BH3-only protein is released to bind to Bax on the mitochondria, promote Bax/Bak to form multimers, promote the release of cytochrome C and SMAC into the cytoplasm, and activate downstream apoptosis path.
  • MCL-1 is overexpressed in a variety of tumors. For example, overexpression of MCL-1 is detected in 55% of breast cancer and 84% of lung cancer samples. In multiple myeloma samples, as the degree of cancer progression increased, the expression of MCL-1 increased significantly, but the expression of BCL-2 did not change. In addition, the expression of MCL-1 is negatively correlated with the survival rate of patients. Both breast cancer and multiple myeloma patients have observed high expression of MCL-1 accompanied by lower survival rates. This shows that MCL-1 is an important tumor treatment target.
  • the purpose of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or In the form of a mixture or its pharmaceutically acceptable salt,
  • R m , R n and R w are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro Group, cycloalkyl, cycloalkyloxy and heterocyclic group;
  • R m and R n together with the connected carbon atoms form a cycloalkyl group
  • R w is selected from hydrogen atom, halogen, deuterated alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, Nitro, cycloalkyl, cycloalkyloxy and heterocyclic groups;
  • R n and R w together with the connected carbon atoms form a cycloalkyl group
  • R m is selected from hydrogen atom, halogen, deuterated alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, Nitro, cycloalkyl, cycloalkyloxy and heterocyclic groups;
  • Z is S atom, O atom or -CH 2 -;
  • M is S atom, O atom or -NR 6 -;
  • R 1 is selected from hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, cycloalkyloxy and heterocycle base;
  • R 2 are the same or different, and are each selected from hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino and nitro;
  • R 3 is selected from hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino and nitro;
  • R 4 is selected from hydrogen atom, alkyl group, deuterated alkyl group and cycloalkyl group;
  • R 5 is selected from hydrogen atom, alkyl group, deuterated alkyl group and cycloalkyl group;
  • R 6 is selected from hydrogen atom, alkyl group and cycloalkyl group
  • n 0, 1, 2 or 3.
  • the compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers The structure, its mixture form or its pharmaceutically acceptable salt is the compound represented by general formula (I-1) and general formula (I-2) or its tautomer, meso, racemic Forms, enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
  • R m , R n , R w , Z, M, R 1 to R 5 and n are as defined in the compound of general formula (I).
  • the compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers A structure, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: R m , R n and R w are the same or different, and are each independently selected from a hydrogen atom, a halogen and an alkyl group; or R m and R n are the same as The connected carbon atoms together form a cycloalkyl group, and R w is selected from a hydrogen atom, a halogen and an alkyl group; or R n and R w together with the connected carbon atoms form a cycloalkyl group, and R m is selected from a hydrogen atom, a halogen and alkyl.
  • the compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers A structure, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: R m , R n and R w are the same or different, and are each independently selected from a hydrogen atom, a halogen and an alkyl group; or R m and R n are the same as The connected carbon atoms together form a C 4-6 cycloalkyl group, and R w is a hydrogen atom; or R n and R w together with the connected carbon atoms form a C 4-6 cycloalkyl group, and R m is a hydrogen atom.
  • the compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers A structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (II), general formula (III) or general formula (IV) or a tautomer or meso , Racemates, enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
  • p 0, 1 or 2;
  • q 0, 1 or 2;
  • R m , R n and R w are the same or different, and are each independently selected from a hydrogen atom, a halogen, and an alkyl group;
  • the compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the Z is an S atom or an O atom.
  • the compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the M is an S atom or -NR 6 -, and R 6 is a hydrogen atom or an alkyl group.
  • the compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the R 1 is a hydrogen atom or an alkyl group.
  • the compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 2 is halogen.
  • the compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each of R 3 and R 4 is an alkyl group.
  • the compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers The structure, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein said R 5 is an alkyl group.
  • Typical compounds of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its pharmaceutically acceptable salt:
  • R a is an alkyl group
  • R m , R n , R w , Z, M, R 1 to R 5 and n are as defined in the compound of the general formula (I).
  • the compound represented by the general formula (IA) or its tautomers, mesosomes, racemates, enantiomers, diastereomers Structure, or its mixture form or its pharmaceutically acceptable salt wherein Selected from: R m , R n and R w are the same or different, and are each independently selected from a hydrogen atom, a halogen, and an alkyl group; p is 0, 1, or 2; q is 0, 1, or 2.
  • Typical compounds of general formula (IA) of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I), the method comprising:
  • R a is an alkyl group
  • R m , R n , R w , Z, M, R 1 to R 5 and n are as defined in the compound of the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or general formula (I-2), the method comprising:
  • the compound of general formula (IA) is chirally prepared to obtain the compound of general formula (IA-1) or the compound of general formula (IA-2);
  • R a is an alkyl group
  • R m , R n , R w , Z, M, R 1 to R 5 and n are as defined in the compound of the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II), the method comprising:
  • R a is an alkyl group
  • R m , R n , Z, M and R 1 to R 5 are as defined in the compound of general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III), the method comprising:
  • R a is an alkyl group
  • R w , Z, M, R 1 to R 5 and p are as defined in the compound of general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV), the method comprising:
  • R a is an alkyl group
  • R m , Z, M, R 1 to R 5 and q are as defined in the compound of general formula (IV).
  • Another aspect of the present disclosure relates to a pharmaceutical composition containing a therapeutically effective amount of the compound represented by the general formula (I) of the present disclosure or its tautomer, mesosome, racemic Isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • a pharmaceutical composition containing a therapeutically effective amount of the compound represented by the general formula (I) of the present disclosure or its tautomer, mesosome, racemic Isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • Another aspect of the present disclosure relates to the compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or mixture thereof, Use of or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same in preparing a medicament for inhibiting MCL-1.
  • Another aspect of the present disclosure relates to the compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or mixture thereof, Use of or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same in the preparation of a medicament for treating or preventing MCL-1 mediated diseases.
  • tumors are preferably selected from bladder cancer, brain tumors, breast cancer Cancer, uterine cancer, cervical cancer, endometrial cancer, ovarian cancer, leukemia (such as chronic myelogenous leukemia, chronic lymphocytic leukemia, lymphoblastic leukemia or acute myeloid leukemia), kidney cancer, colon cancer, rectal cancer, colon Rectal cancer, esophageal cancer, liver cancer, stomach cancer, head and neck cancer, skin cancer, lymphoma, pancreatic cancer, melanoma, myeloma (such as multiple myeloma), bone cancer, neuroblastoma, gli
  • Another aspect of the present disclosure relates to a method for inhibiting MCL-1, which comprises administering to a patient a therapeutically effective amount of a compound represented by the general formula (I) or a tautomer, a mesoform, or a racemate thereof.
  • a compound represented by the general formula (I) or a tautomer, a mesoform, or a racemate thereof a compound represented by the general formula (I) or a tautomer, a mesoform, or a racemate thereof.
  • Another aspect of the present disclosure relates to a method for treating or preventing MCL-1 mediated diseases, which comprises administering to a patient a therapeutically effective amount of a compound represented by general formula (I) or a tautomer or internal elimination Rotate, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.
  • a compound represented by general formula (I) or a tautomer or internal elimination Rotate, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.
  • Another aspect of the present disclosure relates to a method for the treatment of tumors, autoimmune diseases or immune system diseases, which comprises administering to a desired patient a therapeutically effective amount of a compound represented by general formula (I) or a tautomer, internal Racemate, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same; wherein the tumor is preferably selected from the bladder Cancer, brain tumor, breast cancer, uterine cancer, cervical cancer, endometrial cancer, ovarian cancer, leukemia (such as chronic myelogenous leukemia, chronic lymphocytic leukemia, lymphoblastic leukemia or acute myeloid leukemia), kidney cancer, colon Cancer, rectal cancer, colorectal cancer, esophageal cancer, liver cancer, stomach cancer, head and neck cancer, skin cancer, lymphoma, pancreatic cancer, melanoma, myeloma (such as multiple myeloma), bone
  • Another aspect of the present disclosure relates to a compound represented by general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, it is used as a medicine.
  • Another aspect of the present disclosure relates to the compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or mixture thereof, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as an MCL-1 inhibitor.
  • Another aspect of the present disclosure relates to the compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or mixture thereof, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used for treating or preventing MCL-1 mediated diseases.
  • tumors are preferably selected from bladder cancer, brain tumor, breast cancer, uterine cancer, Cervical cancer, endometrial cancer, ovarian cancer, leukemia (such as chronic myeloid leukemia, chronic lymphocytic leukemia, lymphoblastic leukemia, or acute myeloid leukemia), kidney cancer, colon cancer, rectal cancer, colorectal cancer, esophageal cancer , Liver cancer, stomach cancer, head and neck cancer, skin cancer, lymphoma, pancreatic cancer, melanoma, myeloma (such as multiple myeloma), bone cancer, neuroblastoma, glioma,
  • the active compound can be prepared in a form suitable for administration by any appropriate route, and the active compound is preferably in a unit dose form, or a form in which the patient can self-administer in a single dose.
  • the expression mode of the unit dose of the compound or composition of the present disclosure can be tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, regenerating powder or liquid preparation.
  • the dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound.
  • a suitable unit dose can be 0.1-1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain 0.1 to 99% by weight of the active compound.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions. Such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, In order to provide pleasing and delicious medicinal preparations.
  • the tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
  • Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing.
  • the aqueous suspension may also contain one or more preservatives such as ethyl paraben or n-propyl paraben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents. Flavoring agent.
  • Oil suspensions can be formulated by suspending active ingredients in vegetable oils.
  • the oil suspension may contain thickening agents.
  • the above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation.
  • dispersible powders and granules suitable for preparing aqueous suspensions can be provided with active ingredients and dispersing or wetting agents for mixing, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweetening agents, flavoring agents and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.
  • composition of the present disclosure may also be in the form of an oil-in-water emulsion.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • Acceptable solvents or solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injection preparation may be a sterile oil-in-water injection microemulsion in which the active ingredient is dissolved in an oil phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is added to the mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the patient's bloodstream by local large injections.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
  • the pharmaceutical composition may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above.
  • the sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oil can be conveniently used as a solvent or suspension medium.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycol.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient , The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best mode of treatment such as the mode of treatment, the daily dosage of compound (I) or the amount of pharmaceutically acceptable salt
  • the type can be verified according to the traditional treatment plan.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing 1 to 6 carbon atoms An alkyl group of carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • a lower alkyl group containing 1 to 6 carbon atoms non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point.
  • the substituents are preferably independently selected from H atom, D atom, halogen, and alkane. Is substituted by one or more substituents in the group, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from H atom, D atom, halogen, alkyl, and alkoxy , Haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl substituted by one or more substituents.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 The carbon atom more preferably contains 4 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but none of the rings have complete conjugate ⁇ electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure
  • the ring together is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably phenylcyclopentyl, tetrahydronaphthyl.
  • Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl and so on.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between monocyclic rings of 5 to 20 members, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (where m is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclic groups include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the rest of the ring
  • the atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclic groups include:
  • the heterocyclyl ring includes the heterocyclic group (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the group is
  • the structures linked together are heterocyclic groups, non-limiting examples of which include:
  • the heterocyclyl ring includes the heterocyclic group (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the group is
  • the structures linked together are heterocyclic groups, non-limiting examples of which include:
  • the heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene Base and naphthyl.
  • the aryl ring includes the aryl ring as described above fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include :
  • the aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, and alkyl groups.
  • One or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl are substituted.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members, more preferably 5 members or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, Imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like.
  • the heteroaryl ring includes the aforementioned heteroaryl group fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include :
  • Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.
  • cycloalkyloxy refers to cycloalkyl-O-, where cycloalkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.
  • hydroxy refers to the -OH group.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to the -OH group.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • the present disclosure also includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the compound of formula (I) in deuterated form with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques using deuterated reagents. Deuterated reagents include but are not limited to deuterated borane and tri-deuterated. Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present disclosure. Such salt is safe and effective when used in the body of a mammal, and has due biological activity.
  • the compounds of the present disclosure may also include isotopic derivatives thereof.
  • isotopic derivative refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms.
  • 18 F-fluorine label 18 F isotope
  • 11 C-, 13 C-, or 14 C-rich Compounds in which collective carbons ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C- isotopes) replace carbon atoms are within the scope of the present disclosure.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies.
  • Deuterated compounds can generally retain activity comparable to that of non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements) ).
  • the term "therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.
  • the preparation method of medicinal salt includes the following steps:
  • R a is an alkyl group
  • R m , R n , R w , Z, M, R 1 to R 5 and n are as defined in the compound of the general formula (I).
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and lithium diisopropylamide.
  • the inorganic bases include but are not limited to sodium bicarbonate, potassium bicarbonate, hydrogenation Sodium, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide and their hydrates; preferably lithium hydroxide monohydrate;
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, methanol, ethanol, n-butanol, tert-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl Sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water and N,N-dimethylformamide and mixtures thereof.
  • the preparation method of the body, its mixture form, or its pharmaceutically acceptable salt includes the following steps:
  • the compound of general formula (IA) is chirally prepared to obtain the compound of general formula (IA-1) or the compound of general formula (IA-2);
  • R a is an alkyl group
  • R m , R n , R w , Z, M, R 1 to R 5 and n are as defined in the compound of the general formula (I).
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and lithium diisopropylamide.
  • the inorganic bases include but are not limited to sodium bicarbonate, potassium bicarbonate, hydrogenation Sodium, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide and their hydrates; preferably lithium hydroxide monohydrate;
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, methanol, ethanol, n-butanol, tert-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl Sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water and N,N-dimethylformamide and mixtures thereof.
  • the preparation method of medicinal salt includes the following steps:
  • R a is an alkyl group
  • R m , R n , Z, M and R 1 to R 5 are as defined in the compound of general formula (II).
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and lithium diisopropylamide.
  • the inorganic bases include but are not limited to sodium bicarbonate, potassium bicarbonate, hydrogenation Sodium, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide and their hydrates; preferably lithium hydroxide monohydrate;
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, methanol, ethanol, n-butanol, tert-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl Sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water and N,N-dimethylformamide and mixtures thereof.
  • the preparation method of medicinal salt includes the following steps:
  • R a is an alkyl group
  • R w , Z, M, R 1 to R 5 and p are as defined in the compound of general formula (III).
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and lithium diisopropylamide.
  • the inorganic bases include but are not limited to sodium bicarbonate, potassium bicarbonate, hydrogenation Sodium, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide and their hydrates; preferably lithium hydroxide monohydrate;
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, methanol, ethanol, n-butanol, tert-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl Sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water and N,N-dimethylformamide and mixtures thereof.
  • the preparation method of medicinal salt includes the following steps:
  • R a is an alkyl group
  • R m , Z, M, R 1 to R 5 and q are as defined in the compound of general formula (IV).
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and lithium diisopropylamide.
  • the inorganic bases include but are not limited to sodium bicarbonate, potassium bicarbonate, hydrogenation Sodium, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide and their hydrates; preferably lithium hydroxide monohydrate;
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, methanol, ethanol, n-butanol, tert-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl Sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water and N,N-dimethylformamide and mixtures thereof.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
  • HPLC High performance liquid chromatography analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.
  • HPLC preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • the silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Darui Chemicals and other companies.
  • reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere refers to the reaction flask connected to a hydrogen balloon with a volume of about 1L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
  • the microwave reaction uses the CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC).
  • the developing reagent used in the reaction, the eluent system of column chromatography used in the purification of the compound and the developing reagent system of thin-layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound.
  • a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • reaction solution was poured into ice water, extracted with dichloromethane (50mL ⁇ 2), the organic phases were combined, washed with water (30mL), saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate It was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1 g (2.20 g, yield: 86.8%).
  • reaction solution was diluted with ethyl acetate (50mL), washed successively with water (30mL ⁇ 3) and saturated sodium chloride solution (30mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and used a silica gel column
  • the resulting residue was purified by chromatography with eluent system A to obtain the title compound 1k (200 mg, yield: 100%).
  • the reaction solution was cooled to room temperature, diluted with ethyl acetate (300mL), washed with water (100mL ⁇ 2) and saturated sodium chloride solution (100mL ⁇ 2), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure
  • the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2d (5.0 g, yield: 70%).
  • reaction solution was diluted with ethyl acetate (50mL), washed successively with water (30mL ⁇ 3) and saturated sodium chloride solution (30mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and used a silica gel column
  • the resulting residue was purified by chromatography with eluent system A to obtain the title compound 2g (130mg, yield: 71.0%).
  • reaction solution was poured into ice water, extracted with dichloromethane (50mL ⁇ 2), the organic phases were combined, washed with water (30mL), saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate After concentration under reduced pressure, the residue obtained was purified by silica gel column chromatography with eluent system B to obtain the title compound 3b (620 mg, yield: 73.4%).
  • reaction solution was diluted with ethyl acetate (50mL), washed successively with water (30mL ⁇ 3) and saturated sodium chloride solution (30mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and used a silica gel column
  • the resulting residue was purified by chromatography with eluent system A to obtain the title compound 3e (150 mg, yield: 82.0%).
  • reaction solution was diluted with ethyl acetate (50mL), washed successively with water (30mL ⁇ 3) and saturated sodium chloride solution (30mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and used a silica gel column
  • the residue obtained was purified by chromatography with eluent system A to obtain the title compound 4a (150 mg, yield: 82.0%).
  • reaction solution was cooled to 0-5°C, quenched with methanol (6mL), added water (12mL), stirred for 30 minutes, extracted with ethyl acetate (50mL ⁇ 3), combined the organic phases, and used saturated sodium chloride solution (30mL) Washed, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 5b (4.71 g, yield: 100%).
  • the crude product 5e (3.60g, 12.54mmol) was dissolved in methanol (30mL), tetrahydrofuran (30mL) and water (30mL) at room temperature, lithium hydroxide monohydrate (2.63g, 62.67mmol) was added, and the reaction was stirred at 50°C. 1 hour.
  • the organic phase was washed with water (30mL ⁇ 3) and saturated sodium chloride solution (30mL ⁇ 2) successively.
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 5f (3.40g, yield : 99.3%).
  • reaction solution was poured into ice water, extracted with dichloromethane (50mL ⁇ 2), the organic phases were combined, washed with water (30mL), saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate Concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the title compound 5i (1.40 g, yield: 95.9%).
  • reaction solution was diluted with ethyl acetate (50mL), washed successively with water (30mL ⁇ 3) and saturated sodium chloride solution (30mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and used a silica gel column
  • the residue obtained was purified by chromatography with eluent system A to obtain the title compound 5l (140 mg, yield: 36.4%).
  • reaction solution was cooled to 0-5°C, quenched with methanol, warmed to room temperature, stirred for 30 minutes, hydrochloric acid (10mL, 6.0N) was added, stirring continued for 0.5 hours, water ((50mL), ethyl acetate (50mL ⁇ 2) was added for extraction
  • the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 6e (550 mg, yield: 57.53%).
  • reaction solution was concentrated under reduced pressure to concentrate most of the solvent, 50mL of water was added to the reaction solution, extracted with ethyl acetate (50mL ⁇ 2), the organic phases were combined, washed with 30mL saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the title compound 8g (400 mg, yield: 81.0%).
  • Test Example 1 Binding experiment of the compound of the present disclosure and MCL-1 protein.
  • His-MCL-1 protein (Shanghai Hengrui Pharmaceutical Co., Ltd., NA)
  • Binding buffer (cisbio, 62DLBDDF)
  • MCL-1 inhibitors can bind to MCL-1 protein to prevent the binding of MCL-1 to Bim protein.
  • the binding of MCL-1 and Bim protein was detected by HTRF method to evaluate the binding ability of MCL-1 inhibitor and MCL-1 protein, and the activity of the compound was evaluated according to the Ki size.
  • the human recombinant protein MCL-1 (sequence 171-327) and Bim (sequence 51-76) peptides are labeled with His and biotin, respectively.
  • 0.1nM His-MCL-1, 2.5nM bio-Bim and different concentrations of small molecule compounds (the first concentration is 10 ⁇ M, 3 times the dilution of 11 concentrations, diluted in the binding buffer) mixed and incubated for 2 hours at room temperature, and then added 0.5nM labeled europium cryptate anti-6His antibody and 1.25nM affinity streptomycin linked XL665 (diluted in detection buffer). After incubating for 2 hours at room temperature, PHERAstar was used to detect the 620nm and 665nm fluorescence signals. The data is processed using GraphPad software.
  • the binding ability of the compound of the present disclosure and MCL-1 protein can be determined by the above test, and the measured Ki value is shown in Table 1.
  • the compound of the present disclosure has a strong binding ability with MCL-1 protein, and can well inhibit the binding of MCL-1 with Bim protein.
  • the optical activity has a certain influence on the activity of the compound.
  • AMO-1 human bone marrow plasmacytoma (Nanjing Kebai, CBP60242)
  • MV-4-11 human acute monocytic leukemia cells (ATCC, CRL-9591)
  • Microplate reader (BMG, PHERAsta)
  • AMO-1 cells were cultured in RPMI1640 medium containing 20% FBS, and MV-4-11 cells were cultured in IMDM medium containing 10% FBS for passage 2 to 3 times a week, with a passage ratio of 1:4 or 1:6 .
  • transfer the cells to a centrifuge tube, centrifuge at 1200 rpm for 3 minutes, discard the supernatant medium and add fresh medium to resuspend the cells.
  • the culture plate was cultured in an incubator for 24 hours (37°C, 5% CO 2 ).
  • the inhibition of AMO-1 and MV-4-11 cell proliferation by the compounds of the present disclosure can be determined by the above test, and the measured IC 50 values are shown in Table 2.
  • Table 2 discloses the compounds proliferation IC 50 values for inhibition of AMO-1 and MV-4-11 cells.
  • the compound of the present disclosure has a good cell proliferation inhibitory effect on both AMO-1 and MV-4-11.

Abstract

本公开涉及吲哚类大环衍生物、其制备方法及其在医药上的应用。具体而言，本公开涉及一种通式(I)所示的吲哚类大环衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂，特别是作为MCL-1抑制剂的用途，和其治疗肿瘤、自身免疫性疾病或免疫系统疾病的用途，其中通式(I)的各取代基与说明书中的定义相同。

Description

吲哚类大环衍生物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种通式(I)所示的吲哚类大环衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂，特别是作为MCL-1抑制剂的用途，和其治疗肿瘤、自身免疫性疾病或免疫系统疾病的用途。
背景技术
肿瘤细胞区别于正常细胞的一个重要特点就是细胞凋亡受到抑制，从而赋予了他们更大的生存优势。细胞凋亡也称为程序性死亡，可分为外源性凋亡和内源性凋亡。其中内源性凋亡是癌症发生发展的重要屏障。BCL-2家族蛋白是内源性凋亡的重要调节因子。
BCL-2家族蛋白主要存在于线粒体膜上，根据功能可分为抗凋亡蛋白和促凋亡蛋白两大类。抗凋亡蛋白包括BCL-2、BCL-XL、BCL-w和MCL-1。促凋亡蛋白包括Bax、Bak以及BH3-only蛋白。Bax和Bak被激活的时候，会形成多聚体空洞，使细胞线粒体膜的通透性增加，促进细胞色素C等释放到细胞质中，导致细胞死亡。BH3-only蛋白只包含BH3结构域。在细胞存活的状态下，BH3-only蛋白(如Bim)与抗凋亡蛋白结合。当细胞受到外界压力时，结合的平衡被打破，BH3-only蛋白被释放出来与线粒体上Bax结合，促进Bax/Bak形成多聚体，促进细胞色素C和SMAC释放到细胞质中，激活下游凋亡通路。
现有的临床数据表明MCL-1在多种肿瘤内出现过表达，例如在55％的乳腺癌以及84％的肺癌样品中检测到MCL-1过表达。在多发性骨髓瘤样品中中，随着癌症恶化程度的增加，MCL-1表达明显提高，但是BCL-2的表达没有变化。此外MCL-1表达量与病人的存活率负相关。在乳腺癌和多发性骨髓瘤病人中都观察到了MCL-1高表达伴随着更低存活率。由此可见MCL-1是一个重要的肿瘤治疗的靶标。
诺华(Novartis)、安进(Amgen)以及阿斯利康(AstraZeneca)都开发了针对MCL-1的小分子抑制剂，但现在还处于临床阶段，因此需要进一步开发MCL-1抑制剂药物。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
Figure PCTCN2020087671-appb-000001
其中：
R m、R n和R w相同或不同，且各自独立地选自氢原子、卤素、烷基、氘代烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、环烷基氧基和杂环基；
或者R m和R n与相连的碳原子一起形成环烷基，且R w选自氢原子、卤素、氘代烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、环烷基氧基和杂环基；
或者R n和R w与相连的碳原子一起形成环烷基，且R m选自氢原子、卤素、氘代烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、环烷基氧基和杂环基；
Z为S原子、O原子或-CH 2-；
M为S原子、O原子或-NR 6-；
R 1选自氢原子、卤素、烷基、氘代烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、环烷基氧基和杂环基；
R 2相同或不同，且各自选自氢原子、卤素、烷基、氘代烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基和硝基；
R 3选自氢原子、卤素、烷基、氘代烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基和硝基；
R 4选自氢原子、烷基、氘代烷基和环烷基；
R 5选自氢原子、烷基、氘代烷基和环烷基；
R 6选自氢原子、烷基和环烷基；
n为0、1、2或3。
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐为通式(I-1)和通式(I-2)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
Figure PCTCN2020087671-appb-000002
其中：R m、R n、R w、Z、M、R 1～R 5和n如通式(I)化合物中所定义。
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中：R m、R n和R w相同或不同，且各自独立地选自氢原子、卤素和烷基；或者R m和R n与相连的碳原子一起形成环烷基，且R w选自氢原子、卤素和烷基；或者R n和R w与相连的碳原子一起形成环烷基，且R m选自氢原子、卤素和烷基。
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中：R m、R n和R w相同或不同，且各自独立地选自氢原子、卤素和烷基；或者R m和R n与相连的碳原子一起形成C 4～6环烷基，且R w为氢原子；或者R n和R w与相连的碳原子一起形成C 4～6环烷基，且R m为氢原子。
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中
Figure PCTCN2020087671-appb-000003
选自：
Figure PCTCN2020087671-appb-000004
R m、R n和R w相同或不同，且各自独立地选自氢原子、卤素和烷基；p为0、1或2；q为0、1或2。
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中
Figure PCTCN2020087671-appb-000005
选自：
Figure PCTCN2020087671-appb-000006
Figure PCTCN2020087671-appb-000007
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其为通式(II)、通式(III)或通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
Figure PCTCN2020087671-appb-000008
其中：
p为0、1或2；
q为0、1或2；
R m、R n和R w相同或不同，且各自独立地选自氢原子、卤素和烷基；且
Z、M和R 1～R 5如通式(I)化合物中所定义。
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述的Z为S原子或O原子。
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述的M为S原子或-NR 6-，且R 6为氢原子或烷基。
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述的R 1为氢原子或烷基。
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述的R 2为卤素。
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述的R 3和R 4各自为烷基。
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述的R 5为烷基。
本公开的典型化合物包括但不限于：
Figure PCTCN2020087671-appb-000009
Figure PCTCN2020087671-appb-000010
Figure PCTCN2020087671-appb-000011
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐。
本公开的另一方面涉及一种通式(IA)所示的化合物或其互变异构体、内消旋体、 外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
Figure PCTCN2020087671-appb-000012
其中：
R a为烷基；
R m、R n、R w、Z、M、R 1～R 5和n如通式(I)化合物中所定义。
在本公开一些优选的实施方案中，所述的通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中：R m、R n和R w相同或不同，且各自独立地选自氢原子、卤素和烷基；或者R m和R n与相连的碳原子一起形成环烷基，且R w选自氢原子、卤素和烷基；或者R n和R w与相连的碳原子一起形成环烷基，且R m选自氢原子、卤素和烷基。
在本公开一些优选的实施方案中，所述的通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中：R m、R n和R w相同或不同，且各自独立地选自氢原子、卤素和烷基；R m和R n与相连的碳原子一起形成C 4～6环烷基，且R w为氢原子；或者R n和R w与相连的碳原子一起形成C 4～6环烷基，且R m为氢原子。
在本公开一些优选的实施方案中，所述的通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中
Figure PCTCN2020087671-appb-000013
选自：
Figure PCTCN2020087671-appb-000014
R m、R n和R w相同或不同，且各自独立地选自氢原子、卤素和烷基；p为0、1或2；q为0、1或2。
在本公开一些优选的实施方案中，所述的通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其 可药用的盐，其中
Figure PCTCN2020087671-appb-000015
选自：
Figure PCTCN2020087671-appb-000016
Figure PCTCN2020087671-appb-000017
本公开通式(IA)的典型化合物包括但不限于：
Figure PCTCN2020087671-appb-000018
Figure PCTCN2020087671-appb-000019
Figure PCTCN2020087671-appb-000020
Figure PCTCN2020087671-appb-000021
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐。
本公开的另一方面涉及一种制备通式(I)所示的化合物的方法，该方法包括：
Figure PCTCN2020087671-appb-000022
通式(IA)的化合物脱去保护基R a，得到通式(I)的化合物，
其中：
R a为烷基；
R m、R n、R w、Z、M、R 1～R 5和n如通式(I)化合物中所定义。
本公开的另一方面涉及一种制备通式(I-1)或通式(I-2)所示的化合物的方法，该方法包括：
Figure PCTCN2020087671-appb-000023
通式(IA)的化合物进行手性制备得到通式(IA-1)的化合物或通式(IA-2)的化合物；
通式(IA-1)的化合物或通式(IA-2)的化合物脱去保护基R a，得到通式(I-1)或通式(I-2)的化合物，
其中：
R a为烷基；
R m、R n、R w、Z、M、R 1～R 5和n如通式(I)化合物中所定义。
本公开的另一方面涉及一种制备通式(II)所示的化合物的方法，该方法包括：
Figure PCTCN2020087671-appb-000024
通式(IIA)的化合物脱去保护基R a，得到通式(II)的化合物，
其中：
R a为烷基；
R m、R n、Z、M和R 1～R 5如通式(II)化合物中所定义。
本公开的另一方面涉及一种制备通式(III)所示的化合物的方法，该方法包括：
Figure PCTCN2020087671-appb-000025
通式(IIIA)的化合物脱去保护基R a，得到通式(III)的化合物，
其中：
R a为烷基；
R w、Z、M、R 1～R 5和p如通式(III)化合物中所定义。
本公开的另一方面涉及一种制备通式(IV)所示的化合物的方法，该方法包括：
Figure PCTCN2020087671-appb-000026
通式(IVA)的化合物脱去保护基R a，得到通式(IV)的化合物，
其中：
R a为烷基；
R m、Z、M、R 1～R 5和q如通式(IV)化合物中所定义。
本公开的另一方面涉及一种药物组合物，所述药物组合物含有治疗有效量的本公开通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开另一方面涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在制备用于抑制MCL-1的药物中的用途。
本公开另一方面涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在制备用于治疗或预防MCL-1介导的疾病的药物中的用途。
本公开另一方面涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在制备用于治疗肿瘤、自身免疫性疾病或免疫系统疾病的药物中的用途；其中所述的肿瘤优选选自膀胱癌、脑瘤、乳腺癌、子宫癌、宫颈癌、子宫内膜癌、卵巢癌、白血病(如慢性粒细胞白血病、慢性淋巴性白血病、成淋巴细胞白血病或急性髓性白血病)、肾癌、结肠癌、直肠癌、结肠直肠癌、食道癌、肝癌、胃癌、头颈癌、皮肤癌、淋巴瘤、胰腺癌、黑色素瘤、骨髓瘤(如多发性骨髓瘤)、骨癌、神经母细胞瘤、神经胶质瘤、肉瘤、肺癌肺癌(如非小细胞肺癌或小细胞肺癌)、甲状腺癌和前列腺癌。
本公开另一方面涉及一种抑制MCL-1的方法，其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物。
本公开另一方面涉及一种治疗或预防MCL-1介导的疾病的方法，其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物。
本公开另一方面涉及一种治疗肿瘤、自身免疫性疾病或免疫系统疾病的方法，其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物；其中所述的肿瘤优选选自膀胱癌、脑瘤、乳腺癌、子宫癌、宫颈癌、子宫内膜癌、卵巢癌、白血病(如慢性粒细胞白血病、慢性淋巴性白血病、成淋巴细胞白血病或急性髓性白血病)、肾癌、结肠癌、直肠癌、结肠直肠癌、食道癌、肝癌、胃癌、头颈癌、皮肤癌、淋巴瘤、胰腺癌、黑色素瘤、骨髓瘤(如多发性骨髓瘤)、骨癌、神经母细胞瘤、神经胶质瘤、肉瘤、肺癌肺癌(如非小细胞肺癌或小细胞肺癌)、甲状腺癌和前列腺癌。
本公开另一方面涉及一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物，其用作药物。
本公开另一方面涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物，其用作MCL-1抑制剂。
本公开另一方面涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物，其用于治疗或预防MCL-1介导的疾病。
本公开另一方面涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物，其用于治疗肿瘤、自身免疫性疾病或免疫系统疾病；其中所述的肿瘤优选选自膀胱癌、脑瘤、乳腺癌、子宫癌、宫颈癌、子宫内膜癌、卵巢癌、白血病(如慢性粒细胞白血病、慢性淋巴性白血病、成淋巴细胞白血病或急性髓性白血病)、肾癌、结肠癌、直肠癌、结肠直肠癌、食道癌、肝癌、胃癌、头颈癌、皮肤癌、淋巴瘤、胰腺癌、黑色素瘤、骨髓瘤(如多发性骨髓瘤)、骨癌、神经母细胞瘤、神经胶质瘤、肉瘤、肺癌肺癌(如非小细胞肺癌或小细胞肺癌)、甲状腺癌和前列腺癌。
可将活性化合物制成适合于通过任何适当途径给药的形式，活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。
本公开治疗方法中所用化合物或组合物的剂量通常将随疾病的严重性、患者 的体重和化合物的相对功效而改变。不过，作为一般性指导，合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油中配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。
通过加入水可使适用于制备水混悬液的可分散粉末和颗粒提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂可说明上述的例子。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。
本公开的药物组合物也可以是水包油乳剂的形式。
药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、通式化合物(I)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
术语定义
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选为含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自H原子、D原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基所取代。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自H原子、D原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基所取代。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，优选包含3至8个碳原子，更优选包含4至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2020087671-appb-000027
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2020087671-appb-000028
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2020087671-appb-000029
所述环烷基环包括如上所述的环烷基(包括单环、螺环、稠环和桥环)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制 性实例包括茚满基、四氢萘基、苯并环庚烷基等；优选苯基并环戊基、四氢萘基。
环烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基所取代。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子，其中1-3是杂原子；更优选包含3至6个环原子，其中1-3个是杂原子；最优选包含5或6个环原子，其中1-3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2.3.6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2020087671-appb-000030
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2020087671-appb-000031
Figure PCTCN2020087671-appb-000032
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2020087671-appb-000033
所述杂环基环包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2020087671-appb-000034
所述杂环基环包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2020087671-appb-000035
杂环基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基所取代。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2020087671-appb-000036
芳基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基所取代。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，更优选为5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、三唑基、四唑基等。所述杂芳基环包括如上述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2020087671-appb-000037
杂芳基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基所取代。
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH基团。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基、环烷基如上所定义。
本公开还包括各种氘化形式的式(I)化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本公开化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
本公开的化合物还可包含其同位素衍生物。术语“同位素衍生物”指结构不同仅在于存在一种或多种同位素富集原子的化合物。例如，具有本公开的结构，除了用“氘”或“氚”代替氢，或者用 18F-氟标记( 18F同位素)代替氟，或者用 11C-， 13C-，或者 14C-富集的碳( 11C-， 13C-，或者 14C-碳标记； 11C-， 13C-，或者 14C-同位素) 代替碳原子的化合物处于本公开的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针，或者可以用作疾病的体内诊断成像示踪剂，或者作为药效学、药动学或受体研究的示踪剂。氘代物通常可以保留与未氘代的化合物相当的活性，并且当氘代在某些特定位点时可以取得更好的代谢稳定性，从而获得某些治疗优势(如体内半衰期增加或剂量需求减少)。
针对药物或药理学活性剂而言，术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
本公开通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2020087671-appb-000038
通式(IA)的化合物在碱性条件下脱去保护基R a，得到通式(I)的化合物，
其中：
R a为烷基；
R m、R n、R w、Z、M、R 1～R 5和n如通式(I)化合物中所定义。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、乙酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于碳酸氢钠、碳酸氢钾、氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂及其水合物；优选氢氧化锂一水合物；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、正丁醇、叔丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二 甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水和N,N-二甲基甲酰胺及其混合物。
方案二
本公开通式(I-1)或通式(I-2)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2020087671-appb-000039
通式(IA)的化合物进行手性制备得到通式(IA-1)的化合物或通式(IA-2)的化合物；
通式(IA-1)的化合物或通式(IA-2)的化合物在碱性条件下脱去保护基R a，得到通式(I-1)或通式(I-2)的化合物，
其中：
R a为烷基；
R m、R n、R w、Z、M、R 1～R 5和n如通式(I)化合物中所定义。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、乙酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于碳酸氢钠、碳酸氢钾、氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂及其水合物；优选氢氧化锂一水合物；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、正丁醇、叔丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二 甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水和N,N-二甲基甲酰胺及其混合物。
方案三
本公开通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2020087671-appb-000040
通式(IIA)的化合物在碱性条件下脱去保护基R a，得到通式(II)的化合物，
其中：
R a为烷基；
R m、R n、Z、M和R 1～R 5如通式(II)化合物中所定义。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、乙酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于碳酸氢钠、碳酸氢钾、氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂及其水合物；优选氢氧化锂一水合物；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、正丁醇、叔丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水和N,N-二甲基甲酰胺及其混合物。
方案四
本公开通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2020087671-appb-000041
通式(IIIA)的化合物脱去保护基R a，得到通式(III)的化合物，
其中：
R a为烷基；
R w、Z、M、R 1～R 5和p如通式(III)化合物中所定义。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、乙酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于碳酸氢钠、碳酸氢钾、氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂及其水合物；优选氢氧化锂一水合物；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、正丁醇、叔丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水和N,N-二甲基甲酰胺及其混合物。
方案五
本公开通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2020087671-appb-000042
通式(IVA)的化合物脱去保护基R a，得到通式(IV)的化合物，
其中：
R a为烷基；
R m、Z、M、R 1～R 5和q如通式(IV)化合物中所定义。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、乙酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于碳酸氢钠、碳酸氢钾、氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂及其水合物；优选氢氧化锂一水合物；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、正丁醇、叔丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水和N,N-二甲基甲酰胺及其混合物。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高压液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
17-氯-5,13,14,22-四甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂庚环[27.6.1.1 4,7.0 11,15.0 16,21.0 20,24.0 31,35]三十七-1(36),4(37),6,11,14,16,18,20,23,29,31(35)-十一烯-23-甲酸1
Figure PCTCN2020087671-appb-000043
Figure PCTCN2020087671-appb-000044
第一步
(E)-3-(3-溴-5-甲氧基苯基)丙烯酸甲酯1b
钠氢(1.34g，34.97mmol，60％纯度)溶于四氢呋喃(100mL)中，置换氩气三次，冰浴下滴加三甲基膦酰基乙酸酯(6.35g，34.87mmol)，在冰浴下搅拌30分钟，滴加3-溴-5-甲氧基苯甲醛1a(5.00g，23.25mmol)的四氢呋喃(30mL)溶液，反应液在室温下搅拌反应1小时。冰浴下，加入乙酸乙酯(100mL)和水(100mL)，分液，有机相用饱和氯化钠溶液(30mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物1b(6.20g，产率：98.4％)。
MS m/z(ESI):271.1 273.1[M+1]
第二步
3-(3-溴-5-甲氧基苯基)丙酸甲酯1c
室温下将化合物1b(6.00g，22.1mmol)溶于甲醇(75mL)和四氢呋喃(75mL)中，加入5％干铑碳(600mg)，置换氢气三次，反应液室温搅拌反应90分钟。反应液过滤减压浓缩，得到标题化合物1c(6.04g，产率：99.3％)。
MS m/z(ESI):273.0 275.0[M+1]
第三步
3-(3-溴-5-甲氧基苯基)丙酸1d
室温下将化合物1c(6.20g，22.7mmol)溶于甲醇(30mL)、四氢呋喃(30mL)和水(30mL)中，加入氢氧化锂一水合物(2.86g，68.2mmol)，加热50℃搅拌反应1小时。反应液减压浓缩以下，加入水和二氯甲烷各(100mL)，用1M盐酸调pH＝2-3，用二氯甲烷和甲醇(V:V＝10:1)混合溶剂(50mL)萃取分液，有机相依次用水(30mL×3)和饱和氯化钠溶液(30mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物1d(5.80g，产率：98.6％)。
MS m/z(ESI):257.2 259.2[M-1]
第四步
7-溴-5-甲氧基-2,3-二氢-1H-茚-1-酮1e-1
5-溴-7-甲氧基-2,3-二氢-1H-茚-1-酮1e-2
室温下将化合物1d(5.50g，21.2mmol)称量于100mL反应瓶中，加入多聚磷酸(120g，35.5mmol)，加热95℃搅拌反应1.5小时。倒入冰水中，加入二氯甲烷(200mL)，分液，有机相先后用碳酸氢钠、水和饱和氯化钠各30mL×3洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物1e-1(3.50g，产率：68.4％)和标题化合物1e-2(1.00g，产率：19.5％)。
MS m/z(ESI):241.1 243.1[M+1]
第五步
4-溴-6-甲氧基-2,3-二氢-1H-茚1f
室温下将化合物1e-1(3.50g，14.5mmol)溶于三氟乙酸(30ml)，加入三乙基硅烷3.37g，29.0mmol)，加热80℃搅拌反应1.5小时。反应液减压浓缩，加入乙酸乙酯(50mL)和水(50mL)，分液，有机相先后用水和饱和氯化钠各30mL×3洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物1f(2.70g，产率：81.9％)。
第六步
7-溴-2,3-二氢-1H-茚-5-酚1g
室温下将化合物1f(2.70g，11.9mmol)溶于30mL二氯甲烷中，冰浴下滴加1M三溴化硼(40mL，40.0mmol)的二氯甲烷溶液，室温搅拌反应2小时。将反应液倒入冰水中，用二氯甲烷(50mL×2)萃取，合并有机相，用水(30mL)，饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物1g(2.20g，产率：86.8％)。
MS m/z(ESI):211.0 213.0[M-1]
第七步
2-乙基己基3-((6-羟基-2,3-二氢-1H-茚-4-基)硫代)丙酸酯1h
室温下将化合物1g(800mg，3.75mmol)、2-乙基己基3-巯基丙酸酯(984mg，4.51mmol)、N,N-二异丙基乙胺(971mg，7.51mmol)、三(二亚苄基丙酮)二钯(172mg，0.19mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(217mg，0.38mmol)溶于20mL二氧六环中，置换氩气三次，加热95℃搅拌反应16小时。垫硅藻土过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物1h(450mg，产率：34.2％)。
MS m/z(ESI):351.1[M+1]
第八步
7-巯基-2,3-二氢-1H-茚-5-酚1i
冰浴下将化合物1h(450mg，1.28mmol)溶于4mL四氢呋喃中，置换氩气三次，滴加入1M叔丁醇钾(4.1mL，4.10mmol)的四氢呋喃溶液，室温反应搅拌2小时。得到标题化合物1i，反应液直接下一步。
第九步
6-氯-7-(3-((((5-(((6-羟基-2,3-二氢-1H-茚-4-基)硫代)甲基)-1-甲基-1H-吡唑-3-基)甲基)硫代)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3-甲氧基-3-氧代丙基)-1-甲基-1H-吲哚-2-羧酸甲酯1k
室温下将6-氯-7-(3-((((5-(氯甲基)-1-甲基-1H-吡唑-3-基)甲基)硫代)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3-甲氧基-3-氧代丙基)-1-甲基-1H-吲哚-2-羧酸甲酯1j(150mg，0.25mmol，采用专利申请”WO2017182625中说明书第46页中间体20”公开的方法制备而得)溶于甲醇(10mL)和四氢呋喃(3mL)中，冰浴下滴加上一步的反应液0.16M化合物1i(2.4mL，0.38mmol)的四氢呋喃溶液，室温下搅拌反应1小时。反应液用乙酸乙酯(50mL)稀释，依次用水(30mL×3)和饱和氯化钠溶液(30mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物1k(200mg，产率：100％)。
MS m/z(ESI):722.0[M+1]
第十步
6-氯-7-(3-((((5-(((6-羟基-2,3-二氢-1H-茚-4-基)硫代)甲基)-1-甲基-1H-吡唑-3-基)甲基)硫代)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3-羟基丙基)-1-甲基-1H-吲哚-2-羧酸甲酯1l
室温下将化合物1k(200mg，277μmol)溶于四氢呋喃(3mL)中，反应液冷却至0-5℃，缓慢滴加1.0M硼烷四氢呋喃溶液(2.8mL)，反应液升温至室温，继续搅反应16小时。反应液冷却至0-5℃，甲醇淬灭，升温至室温，搅拌30分钟，加入盐酸(3.2mL，6.0N)，继续搅拌30分钟，二氯甲烷和甲醇(V:V＝10:1)混合溶剂(30mL×3)萃取，合并有机相，用饱和氯化钠溶液(30mL)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物1l(90mg，产率：46.8％)。
MS m/z(ESI):693.9[M+1]
第十一步
17-氯-5,13,14,22-四甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂庚环[27.6.1.1 4,7.0 11,15.0 16,21.0 20,24.0 31,35]三十七-1(36),4(37),6,11,14,16,18,20,23,29,31(35)-十一烯-23-甲酸甲酯1m
室温下将化合物1l(90mg，130μmol)溶于甲苯(10mL)和四氢呋喃(5ml)，加入三正丁基膦(131mg，0.65mmol)，置换氩气三次，滴加偶氮二甲酸二哌啶(163mg，0.65mmol)的甲苯溶液(3mL)溶液，加热60℃搅拌反应2小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物1m(90mg，产 率：100％)。
MS m/z(ESI):676.0[M+1]
第十二步
17-氯-5,13,14,22-四甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂庚环[27.6.1.1 4,7.0 11,15.0 16,21.0 20,24.0 31,35]三十七-1(36),4(37),6,11,14,16,18,20,23,29,31(35)-十一烯-23-甲酸1
室温下将化合物1m(90mg，133μmol)溶于10mL四氢呋喃和甲醇(V:V＝1:1)的混合溶液中，加入氢氧化锂一水合物(56mg，1.33mmol)的水(2mL)溶液，反应液加热至50℃，搅拌反应1小时。冷却至室温并用水(15mL)稀释，减压浓缩除去大部分有机溶剂，滴加稀盐酸(1.0N)至pH＝2-3，用二氯甲烷和甲醇(V:V＝10:1)的混合溶剂(50mL×2)萃取，合并有机相，用水(30mL)，饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱法纯化(Gilson GX-281，洗脱体系：H 2O(10mmol NH 4OAc)、ACN)，得到标题化合物1(20mg，产率：22.7％)。
MS m/z(ESI):662.0[M+1]
1H NMR(400MHz,CDCl 3)δ7.64-7.66(m,1H),7.14-7.16(m,1H),6.76(s,1H),6.18(s,1H),4.96(s,1H),3.77-3.89(m,5H),3.56-3.74(m,8H),3.43-3.55(m,2H),3.29-3.39(m,1H),3.09-3.20(m,2H),2.71-2.97(m,5H),2.11-2.37(m,2H),1.96-2.11(m,5H)。
实施例2
17-氯-5,9,13,14,22-五甲基-28-氧杂-2-硫杂-5,6,9,12,13,22-六氮杂庚环[27.6.1.1 4,7.0 11,15.0 16,21.0 20,24.0 31,35]三十七-1(36),4(37),6,11,14,16,18,20,23,29,31(35)-十一烯-23-甲酸2
Figure PCTCN2020087671-appb-000045
Figure PCTCN2020087671-appb-000046
第一步
1-(5-(((叔丁基二苯基硅基)氧基)甲基)-1-甲基-1H-吡唑-3-基)-N-甲基甲胺2b
将5-(((叔丁基二苯基硅基)氧基)甲基)-3-(氯甲基)-1-甲基-1H-吡唑2a(7g，17.54mmol，采用专利申请”WO2017182625中说明书第39页中间体10”公开的方法制备而得)溶于甲胺的乙醇溶液(～30wt％，80mL)，升温至50℃，搅拌1小时。反应液冷却至室温，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物2b(5.0g，产率：72.41％)。
第二步
7-(3-((((5-(((叔丁基二苯基硅基)氧基)甲基)-1-甲基-1H-吡唑-3-基)甲基)(甲基)氨基)甲基)-1,5-二甲基-1H-吡唑-4-基)-6-氯-3-(3-甲氧基-3-氧代丙基)-1-甲基-1H-吲哚-2-羧酸甲酯2d
将6-氯-7-(3-(碘甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3-甲氧基-3-氧代丙基)-1-甲基-1H-吲哚-2-羧酸甲酯2c(4.8g，8.83mmol，采用专利申请“WO2017182625A1说明书第44页中间体17”公开的方法制备而得)溶于N,N-二甲基甲酰胺(50mL)中，然后分别加入碳酸钾(3.7g，26.77mmol，Titan)和2b(4.2g，10.67mmol)，反应液升温至60℃，搅拌反应1小时。反应液冷却至室温，用乙酸乙酯(300mL)稀释，用水(100mL×2)和饱和氯化钠溶液(100mL×2)分别洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物2d(5.0g，产率：70％)。
MS m/z(ESI):809.2[M+1]
第三步
6-氯-7-(3-((((5-(羟基甲基)-1-甲基-1H-吡唑-3-基)甲基)(甲基)氨基)甲基)-1,5-二甲基
-1H-吡唑-4-基)-3-(3-甲氧基-3-氧代丙基)-1-甲基-1H-吲哚-2-羧酸甲酯2e
室温下将化合物2d(4.8g，5.93mmol)溶于四氢呋喃(50mL)中，然后滴加四正丁基氟化铵(6mL，6.0mmol，1M in四氢呋喃)，反应液在室温下搅拌反应1小时。反应液减压浓缩，所得残留物溶于乙酸乙酯(200mL)中，依次用水(50mL×3)和饱和氯化钠溶液(50mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物2e(3.0g，产率：89％)。
MS m/z(ESI):571.2[M+1]
1H NMR(400MHz,CDCl 3)δ7.63(d,1H),7.23(d,1H),5.39(s,1H),4.45(s,2H),3.93(s,3H),3.87(s,3H),3.75(s,3H),3.63(s,3H),3.51(s,3H),3.50(bs,1H),3.47-3.42(m,2H),3.39-3.33(m,2H),3.27(d,1H),3.17(d,1H),2.72–2.66(m,2H),2.09(s,3H),2.04(s,3H)。
第四步
6-氯-7-(3-((((5-(氯甲基)-1-甲基-1H-吡唑-3-基)甲基)(甲基)氨基)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3-甲氧基-3-氧代丙基)-1-甲基-1H-吲哚-2-羧酸甲酯2f
室温下将化合物2e(3.0g，5.25mmol)溶于二氯甲烷(30mL)中，溶液冷却至0-5℃，缓慢滴加氯化亚砜(1.00mL，13.78mmol)，反应液室温搅拌反应30分钟。反应液减压浓缩，得到标题化合物2f(3.0g，产率：97％)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):589.2[M+1]
第五步
6-氯-7-(3-((((5-(((6-羟基-2,3-二氢-1H-茚-4-基)硫代)甲基)-1-甲基-1H-吡唑-3-基)甲基)(甲基)氨基)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3-甲氧基-3-氧代丙基)-1-甲基-1H-吲哚-2-羧酸甲酯2g
室温下将化合物2f(150mg，0.25mmol)溶于甲醇(10mL)和四氢呋喃(3mL)中，冰浴下滴加上一步的反应液0.16M 1i(2.4mL，0.38mmol)的四氢呋喃溶液，室温下搅拌反应1小时。反应液用乙酸乙酯(50mL)稀释，依次用水(30mL×3)和饱和氯化钠溶液(30mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物2g(130mg，产率：71.0％)。
MS m/z(ESI):719.0[M+1]
第六步
6-氯-7-(3-((((5-(((6-羟基-2,3-二氢-1H-茚-4-基)硫代)甲基)-1-甲基-1H-吡唑-3-基)甲基)(甲基)氨基)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3-羟基丙基)-1-甲基-1H-吲哚-2-羧酸甲酯2h
室温下将化合物2g(130mg，181μmol)溶于四氢呋喃(3mL)中，反应液冷却至 0-5℃，缓慢滴加1.0M硼烷四氢呋喃溶液(1.8mL)，反应液升温至室温，继续搅反应16小时。反应液冷却至0-5℃，甲醇淬灭，升温至室温，搅拌30分钟，加入盐酸(2.2mL，6.0N)，继续搅拌30分钟，用碳酸氢钠调pH＝7，二氯甲烷和甲醇(V:V＝10:1)混合溶剂(30mL×3)萃取，合并有机相，用饱和氯化钠溶液(30mL)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物2h(40mg，产率：32.0％)。
MS m/z(ESI):691.0[M+1]
第七步
17-氯-5,9,13,14,22-五甲基-28-氧杂-2-硫杂-5,6,9,12,13,22-六氮杂庚环[27.6.1.1 4,7.0 11,15.0 16,21.0 20,24.0 31,35]三十七
-1(36),4(37),6,11,14,16(21),17,19,23,29,31(35)-十一烯-23-甲酸甲酯2i
室温下将化合物2h(40mg，58μmol)溶于甲苯(10mL)和四氢呋喃(5ml)，加入三正丁基膦(58mg，0.36mmol)，置换氩气三次，滴加偶氮二甲酸二哌啶(73mg，0.36mmol)的甲苯溶液(3mL)溶液，加热60℃搅拌反应2小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物2i(100mg，产率：100％)。
MS m/z(ESI):673.0[M+1]
第八步
17-氯-5,9,13,14,22-五甲基-28-氧杂-2-硫杂-5,6,9,12,13,22-六氮杂庚环[27.6.1.1 4,7.0 11,15.0 16,21.0 20,24.0 31,35]三十七-1(36),4(37),6,11,14,16,18,20,23,29,31(35)-十一烯-23-甲酸2
室温下将化合物2i(100mg，149μmol)溶于10mL四氢呋喃和甲醇(V:V＝1:1)的混合溶液中，加入氢氧化锂一水合物(62mg，1.48mmol)的水(2mL)溶液，反应液加热至50℃，搅拌反应1小时。冷却至室温并用水(15mL)稀释，减压浓缩除去大部分有机溶剂，滴加稀盐酸(1.0N)至pH＝6，用二氯甲烷和甲醇(V:V＝10:1)的混合溶剂(50mL×2)萃取，合并有机相，用水(30mL)，饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱法纯化(Gilson GX-281，洗脱体系：H 2O(10mmol NH 4OAc)、ACN)，得到标题化合物2(20mg，产率：20.4％)。
MS m/z(ESI):659.0[M+1]
1H NMR(400MHz,CDCl 3)δ7.56-7.59(m,1H),7.09-7.11(m,1H),6.65(s,1H),6.34(s,1H),5.23(s,1H),3.85-4.00(m,5H),3.77-3.85(m,1H),3.59-3.76(m,5H),3.29-3.58(m,7H),3.15-3.26(m,1H),2.94-3.12(m,2H),2.65-2.92(m,4H),1.93-2.34(m,8H)。
实施例3
17-氯-5,13,14,22-四甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂庚环[27.6.1.1 4,7.0 11,15.0 16,21.0 20,24.0 30,34]三十七-1(36),4(37),6,11,14,16,18,20,23,29,34-十一 烯-23-甲酸3
Figure PCTCN2020087671-appb-000047
第一步
6-溴-4-甲氧基-2,3-二氢-1H-茚3a
室温下将化合物1e-2(1.00g，4.15mmol)溶于三氟乙酸(10ml)，加入三乙基硅烷(965mg，8.30mmol)，加热80℃搅拌反应1.5小时。反应液减压浓缩，加入乙酸乙酯(50mL)和水(50mL)，分液，有机相先后用水和饱和氯化钠各30mL×3洗涤，无水硫酸钠干燥，过滤，浓缩干，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物3a(880mg，产率：93.4％)。
第二步
6-溴-2,3-二氢-1H-茚-4-酚3b
室温下将化合物3a(900mg，3.96mmol)溶于10mL二氯甲烷中，冰浴下滴加1M三溴化硼(13.9mL，13.9mmol)的二氯甲烷溶液，室温搅拌反应2小时。将反应液倒入冰水中，用二氯甲烷(50mL×2)萃取，合并有机相，用水(30mL)，饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物3b(620mg，产率：73.4％)。
MS m/z(ESI):211.0 213.0[M-1]
第三步
2-乙基己基3-((7-羟基-2,3-二氢-1H-茚-5-基)硫代)丙酸酯3c
室温下将化合物3b(620mg，2.91mmol)、2-乙基己基3-巯基丙酸酯(762mg，3.49mmol)、N,N-二异丙基乙胺(752mg，5.82mmol)、三(二亚苄基丙酮)二钯(133mg，0.15mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(168mg，0.29mmol)溶于20mL二氧六环中，置换氩气三次，加热95℃搅拌反应16小时。垫硅藻土过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物3c(550mg，产率：53.9％)。
MS m/z(ESI):351.3[M+1]
第四步
6-巯基-2,3-二氢-1H-茚-4-酚3d
冰浴下将化合物3c(550mg，1.57mmol)溶于10mL四氢呋喃中，置换氩气三次，滴加入1M叔丁醇钾(5.0mL，5.0mmol)的四氢呋喃溶液，室温反应搅拌2小时。得到标题化合物3d，反应液直接下一步。
第五步
6-氯-7-(3-((((5-(((7-羟基-2,3-二氢-1H-茚-5-基)硫代)甲基)-1-甲基-1H-吡唑-3-基)甲基)硫代)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3-甲氧基-3-氧代丙基)-1-甲基-1H-吲哚-2-羧酸甲酯3e
室温下将化合物1j(150mg，0.25mmol)溶于甲醇(10mL)和四氢呋喃(3mL)中，冰浴下滴加上一步的反应液0.16M化合物3d(1.6mL，0.25mmol)的四氢呋喃溶液，室温下搅拌反应1小时。反应液用乙酸乙酯(50mL)稀释，依次用水(30mL×3)和饱和氯化钠溶液(30mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物3e(150mg，产率：82.0％)。
MS m/z(ESI):721.9[M+1]
第六步
6-氯-7-(3-((((5-(((7-羟基-2,3-二氢-1H-茚-5-基)硫代)甲基)-1-甲基-1H-吡唑-3-基)甲基)硫代)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3-羟基丙基)-1-甲基-1H-吲哚-2-羧酸甲酯3f
室温下将化合物3e(150mg，208μmol)溶于四氢呋喃(3mL)中，反应液冷却至0-5℃，缓慢滴加1.0M硼烷四氢呋喃溶液(2.1mL)，反应液升温至室温，继续搅反应16小时。反应液冷却至0-5℃，甲醇淬灭，升温至室温，搅拌30分钟，加入盐酸(3.2mL，6.0N)，继续搅拌30分钟，二氯甲烷和甲醇(V:V＝10:1)混合溶剂(30mL×3)萃取，合并有机相，用饱和氯化钠溶液(30mL)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物3f(80mg，产率：55.5％)。
MS m/z(ESI):693.8[M+1]
第七步
17-氯-5,13,14,22-四甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂庚环[27.6.1.1 4,7.0 11,15.0 16,21.0 20,24.0 30,34]三十七-1(36),4(37),6,11,14,16,18,20,23,29,34-十一烯-23-甲酸甲酯3g
室温下将化合物3f(80mg，115μmol)溶于甲苯(10mL)和四氢呋喃(5mL)，加入三正丁基膦(116mg，0.57mmol)，置换氩气三次，滴加偶氮二甲酸二哌啶(145mg，0.58mmol)的甲苯溶液(3mL)溶液，加热60℃搅拌反应2小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物3g(50mg，产率：64.2％)。
MS m/z(ESI):676.0[M+1]
第八步
17-氯-5,13,14,22-四甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂庚环[27.6.1.1 4,7.0 11,15.0 16,21.0 20,24.0 30,34]三十七-1(36),4(37),6,11,14,16,18,20,23,29,34-十一烯-23-甲酸3
室温下将化合物3g(50mg，74μmol)溶于10mL四氢呋喃和甲醇(V:V＝1:1)的混合溶液中，加入氢氧化锂一水合物(31mg，0.74mmol)的水(2mL)溶液，反应液加热至50℃，搅拌反应1小时。冷却至室温并用水(15mL)稀释，减压浓缩除去大部分有机溶剂，滴加稀盐酸(1.0N)至pH＝2-3，用二氯甲烷和甲醇(V:V＝10:1)的混合溶剂(50mL×2)萃取，合并有机相，用水(30mL)，饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱法纯化(Gilson GX-281，洗脱体系：H 2O(10mmol NH 4OAc)、ACN)，得到标题化合物3(10mg，白色固体，产率：20.4％)。
MS m/z(ESI):662.0[M+1]
1H NMR(400MHz,CDCl 3)δ7.52-7.54(m,1H),7.04-7.06(m,1H),6.96(s,1H),6.07(s,1H),4.89(s,1H),3.85(s,3H),3.73-3.82(m,2H),3.62-3.72(m,7H),3.54-3.62(m,1H),3.38-3.52(m,2H),3.30-3.37(m,1H),3.03-3.18(m,2H),2.80-3.03(m,4H),2.51-2.63(m,1H),2.19-2.30(m,1H)，2.01-2.17(m,6H)。
实施例4
17-氯-5,9,13,14,22-五甲基-28-氧杂-2-硫杂-5,6,9,12,13,22-六氮杂庚环[27.6.1.1 4,7.0 11,15.0 16,21.0 20,24.0 30,34]三十七-1(36),4(37),6,11,14,16,18,20,23,29,34-十一烯-23-甲酸4
Figure PCTCN2020087671-appb-000048
第一步
6-氯-7-(3-((((5-(((7-羟基-2,3-二氢-1H-茚-5-基)硫代)甲基)-1-甲基-1H-吡唑-3-基)甲基)(甲基)氨基)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3-甲氧基-3-氧代丙基)-1-甲基-1H-吲哚-2-羧酸甲酯4a
室温下将化合物2f(150mg，0.25mmol)溶于甲醇(10mL)和四氢呋喃(3mL)中，冰浴下滴加上一步的反应液0.16M化合物3d(2.6mL，0.41mmol)的四氢呋喃溶液，室温下搅拌反应1小时。反应液用乙酸乙酯(50mL)稀释，依次用水(30mL×3)和饱和氯化钠溶液(30mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物4a(150mg，产率：82.0％)。
MS m/z(ESI):719.0[M+1]
第二步
6-氯-7-(3-((((5-(((7-羟基-2,3-二氢-1H-茚-5-基)硫代)甲基)-1-甲基-1H-吡唑-3-基)甲基)(甲基)氨基)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3-羟基丙基)-1-甲基-1H-吲哚-2-羧酸甲酯4b
室温下将化合物4a(150mg，209μmol)溶于四氢呋喃(3mL)中，反应液冷却至0-5℃，缓慢滴加1.0M硼烷四氢呋喃溶液(2.1mL)，反应液升温至室温，继续搅反应16小时。反应液冷却至0-5℃，甲醇淬灭，升温至室温，搅拌30分钟，加入盐 酸(3.2mL，6.0N)，继续搅拌30分钟，用碳酸氢钠调pH＝7，二氯甲烷和甲醇(V:V＝10:1)混合溶剂(30mL×3)萃取，合并有机相，用饱和氯化钠溶液(30mL)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物4b(100mg，产率：69.4％)。
MS m/z(ESI):691.0[M+1]
第三步
17-氯-5,9,13,14,22-五甲基-28-氧杂-2-硫杂-5,6,9,12,13,22-六氮杂庚环[27.6.1.1 4,7.0 11,15.0 16,21.0 20,24.0 30,34]三十七-1(36),4(37),6,11,14,1618,20,23,29,34-十一烯-23-甲酸甲酯4c
室温下将化合物4b(100mg，145μmol)溶于甲苯(10mL)和四氢呋喃(5ml)，加入三正丁基膦(146mg，0.72mmol)，置换氩气三次，滴加偶氮二甲酰二哌啶(182mg，0.72mmol)的甲苯溶液(3mL)溶液，加热60℃搅拌反应2小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物4c(60mg，产率：61.6％)。
MS m/z(ESI):673.0[M+1]
第四步
17-氯-5,9,13,14,22-五甲基-28-氧杂-2-硫杂-5,6,9,12,13,22-六氮杂庚环[27.6.1.1 4,7.0 11,15.0 16,21.0 20,24.0 30,34]三十七-1(36),4(37),6,11,14,16,18,20,23,29,34-十一烯-23-甲酸4
室温下将化合物2i(60mg，89μmol)溶于10mL四氢呋喃和甲醇(V:V＝1:1)的混合溶液中，加入氢氧化锂一水合物(37mg，0.88mmol)的水(2mL)溶液，反应液加热至50℃，搅拌反应1小时。冷却至室温并用水(15mL)稀释，减压浓缩除去大部分有机溶剂，滴加稀盐酸(1.0N)至pH＝6，用二氯甲烷和甲醇(V:V＝10:1)的混合溶剂(50mL×2)萃取，合并有机相，用水(30mL)，饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱法纯化(Gilson GX-281，洗脱体系：H 2O(10mmol NH 4OAc)、ACN)，得到标题化合物4(10mg，产率：17.0％)。
MS m/z(ESI):659.0[M+1]
1H NMR(400MHz,CDCl 3)δ7.52-7.54(m,1H),7.06-7.09(m,1H),6.84(s,1H),6.27(s,1H),5.26(s,1H),3.77-3.96(m,6H),3.64-3.75(m,4H),3.45-3.64(m,6H),3.37-3.45(m,3H),2.96-3.17(m,2H),2.76-2.96(m,3H),2.20.-3.34(m,3H),1.99-2.20(m,6H)。
实施例5
17-氯-5,9,13,14,22-五甲基-28-氧杂-2-硫杂-5,6,9,12,13,22-六氮杂庚环[27.7.1.1 4,7.0 11,15.0 16,21.0 20,24.0 30,35]三十八-1(37),4(38),6,11,14,16,18,20,23,29,35-十一烯-23-甲酸5
Figure PCTCN2020087671-appb-000049
第一步
2-(4-溴-2-甲氧基苯基)乙醇5b
将4-溴-2-甲氧基苯乙酸5a(5.00g，20.40mmol)溶于四氢呋喃(50mL)中，反应液冷却至0-5℃，缓慢滴加1M硼烷四氢呋喃溶液(27mL)，反应液升温至室温，继续搅反应16小时。反应液冷却至0-5℃，甲醇(6mL)淬灭，再加入水(12mL)，搅拌30分钟，乙酸乙酯(50mL×3)萃取，合并有机相，用饱和氯化钠溶液(30mL)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物5b(4.71g,产率：100％)。
第二步
2-(4-溴-2-甲氧基苯基)乙醛5c
将化合物5b(3.70g，16.01mmol)溶于二氯甲烷(50mL)中，冰浴下分批加入戴斯-马丁氧化剂(10.19g，24.03mmol)，反应液升至室温，搅拌反应1小时。冰浴下，加入水和二氯甲烷各50mL，加入饱和硫代硫酸钠和饱和碳酸氢钠，分液，有机相用饱和氯化钠溶液洗涤三次，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物5c(3.00g，产率：81.8％)。
第三步
(E)-4-(4-溴-2-甲氧基苯基)丁-2-烯酸甲酯5d
钠氢(753mg，19.65mmol，60％纯度)溶于四氢呋喃(30mL)中，置换氩气三次，冰浴下滴加三甲基膦酰基乙酸酯(3.58g，19.66mmol)，在冰浴下搅拌30分钟，滴加化合物5c的四氢呋喃(10mL)溶液，反应液在室温下搅拌反应1小时。冰浴下，加入乙酸乙酯(100mL)和水(100mL)，分液，有机相用饱和氯化钠溶液(30mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物5d(2.37g，产率：63.5％)。
MS m/z(ESI):285.0 287.0[M+1]
第四步
4-(4-溴-2-甲氧基苯基)丁酸甲酯5e
室温下将化合物5d(2.80g，9.82mmol)溶于甲醇(50mL)中，加入5％干铑碳(280mg)，置换氢气三次，反应液室温搅拌反应60分钟。反应液过滤减压浓缩，得到标题化合物5e(2.50g，产率：88.7％)。
MS m/z(ESI):287.1 289.1[M+1]
第五步
4-(4-溴-2-甲氧基苯基)丁酸5f
室温下将粗品5e(3.60g，12.54mmol)溶于甲醇(30mL)、四氢呋喃(30mL)和水(30mL)中，加入氢氧化锂一水合物(2.63g，62.67mmol)，加热50度搅拌反应1小时。反应液减压浓缩以下，加入水和二氯甲烷各(100mL)，用1M盐酸调PH＝2-3，用二氯甲烷和甲醇(V:V＝10:1)混合溶剂(50mL)萃取分液，有机相依次用水(30mL×3)和饱和氯化钠溶液(30mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物5f(3.40g，产率：99.3％)。
MS m/z(ESI):271.1 273.1[M-1]
第六步
7-溴-5-甲氧基-3,4-二氢萘-1(2H)-酮5g
室温下将化合物5f(3.40g，12.45mmol)称量于100mL反应瓶中，加入多聚磷酸(60g，17.75mmol)，加热95℃反应搅拌1.5小时。倒入冰水中，加入二氯甲烷(100mL)，分液，有机相先后用碳酸氢钠、水和饱和氯化钠各30mL×3洗涤，无水硫酸钠干燥，过滤，滤液减压浓度，用硅胶柱色谱法以洗脱剂体系B纯化所 得残余物，得到标题化合物5g(1.76g，产率：55.4％)。
MS m/z(ESI):255.1 257.1[M+1]
第七步
7-溴-5-甲氧基-1,2,3,4-四氢萘5h
室温下将化合物5g(1.76g，6.90mmol)溶于三氟乙酸(20ml)，加入三乙基硅烷(1.60g，13.76mmol)，加热80℃搅拌反应1.5小时。反应液减压浓缩，加入乙酸乙酯(50mL)和水(50mL)，分液，有机相先后用水和饱和氯化钠各30mL×3洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物5h(1.60g，产率：96.2％)。
第八步
3-溴-5,6,7,8-四氢萘-1-酚5i
室温下将化合物5h(1.55g，6.43mmol)溶于20mL二氯甲烷中，冰浴下滴加1M三溴化硼(22.5mL，22.5mmol)的二氯甲烷溶液，室温搅拌反应2小时。将反应液倒入冰水中，用二氯甲烷(50mL×2)萃取，合并有机相，用水(30mL)，饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物5i(1.40g，产率：95.9％)。
MS m/z(ESI):225.0 227.0[M-1]
第九步
2-乙基己基3-((4-羟基-5,6,7,8-四氢萘-2-基)硫代)丙酸酯5j
室温下将化合物5i(500mg，2.20mmol)、2-乙基己基3-巯基丙酸酯(577mg，2.64mmol)、N,N-二异丙基乙胺(569mg，4.40mmol)、三(二亚苄基丙酮)二钯(101mg，0.11mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(127mg，0.22mmol)溶于20mL二氧六环中，置换氩气三次，加热95℃搅拌反应16小时。垫硅藻土过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物5j(800mg，产率：99.7％)。
MS m/z(ESI):365.3[M+1]
第十步
3-巯基-5,6,7,8-四氢萘-1-酚5k
冰浴下将化合物5j(650mg，1.78mmol)溶于20mL四氢呋喃中，置换氩气三次，滴加入1M叔丁醇钾(5.7mL，5.70mmol)的四氢呋喃溶液，室温反应搅拌2小时。得到标题化合物5k，反应液直接下一步。
第十一步
6-氯-7-(3-((((5-(((4-羟基-5,6,7,8-四氢萘-2-基)硫代)甲基)-1-甲基-1H-吡唑-3-基)甲基)(甲基)氨基)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3-甲氧基-3-氧代丙基)-1-甲基-1H-吲哚-2-羧酸甲酯5l
室温下将化合物2f(309mg，0.52mmol)溶于甲醇(20mL)和四氢呋喃(8mL)中，冰浴下滴加上一步的反应液0.07M化合物5k(7.4mL，0.52mmol)的四氢呋喃溶液，室温下搅拌反应1小时。反应液用乙酸乙酯(50mL)稀释，依次用水(30mL×3)和饱和氯化钠溶液(30mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物5l(140mg，产率：36.4％)。
MS m/z(ESI):733.3[M+1]
第十二步
6-氯-7-(3-((((5-(((4-羟基-5,6,7,8-四氢萘-2-基)硫代)甲基)-1-甲基-1H-吡唑-3-基)甲基)(甲基)氨基)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3-羟基丙基)-1-甲基-1H-吲哚-2-羧酸甲酯5m
室温下将化合物5l(100mg，136μmol)溶于四氢呋喃(5mL)中，反应液冷却至0-5℃，缓慢滴加1.0M硼烷四氢呋喃溶液(1.4mL)，反应液升温至室温，继续搅反应16小时。反应液冷却至0-5℃，甲醇淬灭，升温至室温，搅拌30分钟，加入盐酸(0.76mL，6.0N)，继续搅拌30分钟，用碳酸氢钠调pH＝7，二氯甲烷和甲醇(V:V＝10:1)混合溶剂(30mL×3)萃取，合并有机相，用饱和氯化钠溶液(30mL)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物5m(46mg，产率：47.8％)。
MS m/z(ESI):705.4[M+1]
第十三步
17-氯-5,9,13,14,22-五甲基-28-氧杂-2-硫杂-5,6,9,12,13,22-六氮杂庚环[27.7.1.1 4,7.0 11,15.0 16,21.0 20,24.0 30,35]三十八-1(37),4(38),6,11,14,16,18,20,23,29,35-十一烯-23-甲酸甲酯5n
室温下将化合物5m(46mg，65μmol)溶于甲苯(10mL)和四氢呋喃(1ml)，加入三正丁基膦(66mg，0.33mmol)，置换氩气三次，滴加偶氮二甲酸二哌啶(83mg，0.33mmol)的甲苯溶液(5mL)溶液，加热60℃搅拌反应2小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物5n(20mg，产率：44.6％)。
MS m/z(ESI):687.3[M+1]
第十四步
17-氯-5,9,13,14,22-五甲基-28-氧杂-2-硫杂-5,6,9,12,13,22-六氮杂庚环[27.7.1.1 4,7.0 11,15.0 16,21.0 20,24.0 30,35]三十八-1(37),4(38),6,11,14,16,18,20,23,29,35-十一烯-23-甲酸5
室温下将化合物5n(20mg，29μmol)溶于4mL四氢呋喃和甲醇(V:V＝1:1)的混合溶液中，加入氢氧化锂一水合物(13mg，0.31mmol)的水(2mL)溶液，反应液加热至50℃，搅拌反应2小时。冷却至室温并用水(15mL)稀释，减压浓缩除去大部 分有机溶剂，滴加稀盐酸(1.0N)至pH＝6，用二氯甲烷和甲醇(V:V＝10:1)的混合溶剂(50mL×2)萃取，合并有机相，用水(30mL)，饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，用高效液相色谱法纯化(GilsonGX-281，洗脱体系：H 2O(10mmol NH 4OAc)、ACN)，得到标题化合物5(3mg，产率：15.3％)。
MS m/z(ESI):673.3[M+1]
1H NMR(400MHz,DMSO-d 6)8.34(d,1H),7.72(d,1H),6.95(s,1H),6.06(s,1H),5.86-5.74(m,1H),4.66-4.58(m,1H),4.55-4.43(m,1H),4.32(s,3H),4.25-4.16(m,5H),4.12-3.97(m,5H),3.72-3.62(m,1H),3.59-3.48(m,2H),3.06-2.91(m,4H),2.79-2.62(m,2H),2.62-2.51(m,6H),2.20-1.94(m,6H)。
实施例6
17-氯-5,13,14,22,31-五甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂己环[27.3.1.1 4,7.0 11,15.0 16,21.0 20,24]三十四-1(33),4(34),6,11,14,16,18,20,23,29,31-十一烯-23-甲酸6
Figure PCTCN2020087671-appb-000050
第一步
2-乙基己基3-((3-羟基-5-甲基苯基)硫代)丙酸酯6c
将3-溴-5-甲基苯酚6a(550mg，2.94mmol，adamas)和2-乙基己基3-巯基丙酸酯6b((800mg,3.66mmol,TCI)溶于二氧六环(10mL)，加入N,N-二异丙基乙胺((760mg,5.88mmol)，三(二亚苄基茚丙酮)二钯((140mg,0.15mmol，adamas)和4,5-双二苯基膦-9,9-二甲基氧杂蒽((190mg,0.33mmol，韶远)。氮气保护下，升温至100℃，搅拌3小时。反应液冷却至室温，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物6c(620mg,65.98％)。
MS m/z(ESI):325.2[M+1
第二步
3-巯基-5-甲基苯酚6d
将金属钠(140mg，6.09mmol，国药)溶于无水乙醇(2mL)中，溶解完全后，将此溶液加到化合物6c的乙醇(400mg 6c溶于4.0mL乙醇)溶液中，室温搅拌16小时。浓缩，固体用二氯甲烷洗涤，过滤，收集滤饼真空干燥，得到标题化合物6d(120mg，粗品)，产品不经纯化直接进行下一步反应。
MS m/z(ESI):140.2[M+1]
第三步
6-氯-7-(3-((((5-(氯甲基)-1-甲基-1H-吡唑-3-基)甲基)硫代)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3羟基丙基)-1-甲基-1H-吲哚-2-羧酸甲酯6e
将化合物1j(1.0g，5.93mmol)溶于四氢呋喃(10mL)中，0℃下，缓慢滴加1M硼烷四氢呋喃溶液(10mL，adamas)，加完室温继续搅反应6小时。反应液冷却至0-5℃，甲醇淬灭，升温至室温，搅拌30分钟，加入盐酸(10mL，6.0N)，继续搅拌0.5小时，加水((50mL)，乙酸乙酯(50mL×2)萃取，合并有机相，用饱和氯化钠溶液(30mL)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物6e(550mg，产率：57.53％)。
MS m/z(ESI):564.2[M+1]
第四步
6-氯-7-(3-((((5-(((3-羟基-5-甲基苯基)硫代)甲基)-1-甲基-1H-吡唑-3-基)甲基)硫代)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3羟基丙基)-1-甲基-1H-吲哚-2-羧酸甲酯6f
将化合物6e(400mg，0.71mmol)和化合物6d(120mg,0.86mmol)溶于N,N-二甲基甲酰胺(6.0mL)，加入碳酸钾(490mg，3.55mmol，国药)，室温下搅拌反应10小时。加水(10mL)，乙酸乙酯(10mL)萃取，浓缩，用采用薄层色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物6f(300mg，产率：63.35％)。
MS m/z(ESI):668.2[M+1]
第五步
17-氯-5,13,14,22,31-五甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂己环[27.3.1.1 4,7.0 11,15.0 16,21.0 20,24]三十四-1(33),4(34),6,11,14,16,18,20,23,29,31-十一烯-23- 甲酸甲酯6g
将化合物6f(300mg，0.49mmol)和三丁基膦(400mg,1.98mmol，adamas)溶于甲苯(20mL)中，氩气置换三次，加入偶氮二甲酸二哌啶(500mg，1.98mmol，韶远)，60℃反应3小时，加水(10mL)，乙酸乙酯(10mL)萃取，浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物6g(150mg，产率：51.37％)。MS m/z(ESI):650.2[M+1]
第六步
17-氯-5,13,14,22,31-五甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂己环[27.3.1.1 4,7.0 11,15.0 16,21.0 20,24]三十四-1(33),4(34),6,11,14,16,18,20,23,29,31-十一烯-23-甲酸6
室温下将化合物6g(15mg，23.11μmol)溶于1mL四氢呋喃和甲醇(V:V＝1:1)的混合溶液中，加入氢氧化锂一水合物(10mg，238.10μmol，国药)的水(0.3mL)溶液，50℃搅拌反应1小时。冷却至室温，滴加稀盐酸(1.0N)至pH＝4-5，乙酸乙酯(5mL×2)萃取，过滤，浓缩，用高效液相色谱法纯化(Gilson GX-281，洗脱体系：水(10mmol醋酸铵)、乙腈)，得到标题化合物6(3mg，产率：20.44％)。
MS m/z(ESI):636.2[M+1]
1H NMR(400MHz,CD 3OD)δ7.73(d,1H),7.16(d,1H),6.76(s,1H),6.67(s,1H),6.34(s,1H),4.86(s,1H),4.07-3.95(m,2H),3.84(s,3H),3.73(s,3H),3.71-3.63(m,5H),3.49-3.46(m,2H),3.33-3.32(m,1H),3.15-3.11(m,2H),2.78-2.75(m,1H),2.25(s,3H),2.22-2.10(m,2H),2.15(s,3H)。
实施例6-1，6-2
(Ra)-17-氯-5,13,14,22,31-五甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂己环[27.3.1.1 4,7.0 11,15.0 16,21.0 20,24]三十四-1(33),4(34),6,11,14,16,18,20,23,29,31-十一烯-23-甲酸6-1
(Sa)-17-氯-5,13,14,22,31-五甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂己环[27.3.1.1 4,7.0 11,15.0 16,21.0 20,24]三十四-1(33),4(34),6,11,14,16,18,20,23,29,31-十一烯-23-甲酸6-2
Figure PCTCN2020087671-appb-000051
Figure PCTCN2020087671-appb-000052
第一步
(Ra)-17-氯-5,13,14,22,31-五甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂己环[27.3.1.1 4,7.0 11,15.0 16,21.0 20,24]三十四-1(33),4(34),6,11,14,16,18,20,23,29,31-十一烯-23-甲酸甲酯6g-1
(Sa)-17-氯-5,13,14,22,31-五甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂己环[27.3.1.1 4,7.0 11,15.0 16,21.0 20,24]三十四-1(33),4(34),6,11,14,16,18,20,23,29,31-十一烯-23-甲酸甲酯6g-2
将化合物6g(150mg，0.23mmol)进行手性制备(分离条件：CHIRALPAK IF手性制备柱，Prep 20*250mm；5um；流动相：正己烷/乙醇/二乙胺＝70/30/0.1(V/V/V))，流速：20mL/min)，收集其相应组分，减压浓缩，得到标题化合物(70mg,70mg)。
单一构型化合物(较短保留时间)
MS m/z(ESI):650.2[M+1]
手性HPLC分析：保留时间6.214min，手性纯度：100％(色谱柱：CHIRALPAK IG 150*4.6mm,5um；流速：1.0ml/min；流动相：正己烷/乙醇/三氟乙酸＝75/25/0.1(v/v/v)。
单一构型化合物(较长保留时间)
MS m/z(ESI):650.2[M+1]
手性HPLC分析：保留时间10.652min，手性纯度：100％(色谱柱：CHIRALPAK IG 150*4.6mm,5um；流速：1.0ml/min；流动相：正己烷/乙醇/三氟乙酸＝75/25/0.1(v/v/v)。
第二步
(Ra)-17-氯-5,13,14,22,31-五甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂己环 [27.3.1.1 4,7.0 11,15.0 16,21.0 20,24]三十四-1(33),4(34),6,11,14,16,18,20,23,29,31-十一烯-23-甲酸6-1
(Sa)-17-氯-5,13,14,22,31-五甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂己环[27.3.1.1 4,7.0 11,15.0 16,21.0 20,24]三十四-1(33),4(34),6,11,14,16,18,20,23,29,31-十一烯-23-甲酸6-2
室温下将第一步所得的化合物(70mg/70mg，107.65μmol/107.65μmol)分别溶于2.5mL四氢呋喃/甲醇/水(V:V:V＝2:2:1)的混合溶液中，加入氢氧化锂一水合物(45mg/45mg，1.07mmol/1.07mmol)，50℃反应1小时。冷却至室温，加稀盐酸(1.0N)至pH＝4～5，EA(5mL×2)萃取，干燥，浓缩，用高效液相色谱法纯化(Gilson GX-281，洗脱体系：水(10mmol醋酸铵)、乙腈)，分别得到标题化合物(40mg，40mg)。
单一构型化合物(较短保留时间)
MS m/z(ESI):636.2[M+1]
手性HPLC分析：保留时间6.208min，手性纯度：100％(色谱柱：CHIRALPAK IG 150*4.6mm,5um；流速：1.0ml/min；流动相：正己烷/乙醇/三氟乙酸＝75/25/0.1(v/v/v))。
1H NMR(400MHz,CD 3OD)δ7.72(d,1H),7.15(d,1H),6.76(s,1H),6.67(s,1H),6.34(s,1H),4.87(s,1H),4.07-3.95(m,2H),3.84(s,3H),3.73(s,3H),3.71-3.63(m,5H),3.49-3.46(m,2H),3.33-3.32(m,1H),3.15-3.11(m,2H),2.78-2.75(m,1H),2.25(s,3H),2.22-2.10(m,2H),2.09(s,3H)。
单一构型化合物(较长保留时间)
MS m/z(ESI):636.2[M+1]
手性HPLC分析：保留时间10.649min，手性纯度：95.2％(色谱柱：CHIRALPAK IG 150*4.6mm,5um；流速：1.0ml/min；流动相：正己烷/乙醇/三氟乙酸＝75/25/0.1(v/v/v))。
1H NMR(400MHz,CD 3OD)δ7.74(d,1H),7.16(d,1H),6.76(s,1H),6.67(s,1H),6.33(s,1H),4.89(s,1H),4.06-3.95(m,2H),3.84(s,3H),3.73(s,3H),3.71-3.63(m,5H),3.49-3.46(m,2H),3.33-3.32(m,1H),3.15-3.11(m,2H),2.78-2.75(m,1H),2.25(s,3H),2.22-2.10(m,2H),2.09(s,3H)。
实施例7
17-氯-5,13,14,22,31-五甲基-2,28-二氧杂-9-硫杂-5,6,12,13,22-五氮杂己环[27.3.1.1 4,7.0 11,15.0 16,21.0 20,24]三十四-1(33),4(34),6,11,14,16,18,20,23,29,31-十一烯-23-甲酸7
Figure PCTCN2020087671-appb-000053
第一步
6-氯-7-(3-((((5-(3-羟基-5-甲基苯氧基)甲基)-1-甲基-1H-吡唑-3-基)甲基)硫代)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3-羟基丙基)-1-甲基-1H-吲哚-2-羧酸甲酯7b
将化合物6e(100mg，177.64μmol)和化合物7a(30mg,241.67μmol，毕得)溶于N,N-二甲基甲酰胺(1.5mL)，加入碳酸钾(100mg，724.64μmol，国药)，室温下搅拌反应10小时。加水(10mL)，乙酸乙酯(10mL)萃取，浓缩，采用薄层色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物7b(40mg，产率：34.62％)。
MS m/z(ESI):652.2[M+1]
第二步
17-氯-5,13,14,22,31-五甲基-2,28-二氧杂-9-硫杂-5,6,12,13,22-五氮杂己环[27.3.1.1 4,7.0 11,15.0 16,21.0 20,24]三十四-1(33),4(34),6,11,14,16,18,20,23,29,31-十一烯-23-甲酸甲酯7c
将化合物7b(40mg，61.33μmol)和三丁基膦(62mg,306.93μmol，adamas)溶于甲苯(2mL)中，氩气置换三次，加入偶氮二甲酸二哌啶(80mg，317.46μmol，韶远)，60℃反应3小时，加水(10mL)，乙酸乙酯(10mL)萃取，有机相减压浓缩， 用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物7c(30mg，产率：77.13％)。
MS m/z(ESI):634.2[M+1]
第三步
17-氯-5,13,14,22,31-五甲基-2,28-二氧杂-9-硫杂-5,6,12,13,22-五氮杂己环[27.3.1.1 4,7.0 11,15.0 16,21.0 20,24]三十四-1(33),4(34),6,11,14,16,18,20,23,29,31-十一烯-23-甲酸7
室温下将化合物7c(30mg，47.30μmol)溶于2.5mL四氢呋喃/甲醇/水(V:V:V＝2:2:1)的混合溶液中，加入氢氧化锂一水合物(20mg，476.19μmol)50℃搅拌反应1小时。冷却至室温，滴加稀盐酸(1.0N)至pH＝4-5，乙酸乙酯(5mL×2)萃取，过滤，浓缩，采用薄层色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物7(10mg，产率：34.09％)。
MS m/z(ESI):619.9[M+1]
1H NMR(400MHz,CD 3OD)δ7.71(d,1H),7.20(d,1H),6.26(s,2H),6.13(s,1H),5.31(s,1H),5.21-5.03(m,2H),3.85(s,3H),3.77(s,3H),3.77-3.70(m,2H),3.62(s,3H),3.56-3.42(m,4H),3.22-3.04(m,2H),2.17(s,3H),2.15-2.10(m,2H),2.06(s,3H)。
实施例8
17-氯-5,13,14,22,30,31-六甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂己环[27.3.1.1 4,7.0 11,15.0 16,21.0 20,24]三十四-1(33),4(34),6,11,14,16,18,20,23,29,31-十一烯-23-甲酸8
Figure PCTCN2020087671-appb-000054
Figure PCTCN2020087671-appb-000055
第一步
5–溴-2,3-二甲基苯胺8b
将5–溴-1,2-二甲基-3-硝基苯胺8a(4.8g，20.8mmol)加入到80mL乙醇和30mL水中，室温下加入铁粉(9.3g，167.0mmol)，氯化铵(5.5g，104.0mmol)。80℃搅拌反应1小时。反应液过滤，滤液浓缩，加入水和乙酸乙酯各50mL，分液，水相用50mL乙酸乙酯萃取，有机相合并后无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物8b(4.0g，产率：96.4％)。
MS m/z(ESI):200.0[M+1]
第二步
5-溴-2,3-二甲基苯酚8c
将化合物8b(4.3g，14.7mmol)溶于50mL 50％硫酸中，0℃下加亚硝酸钠(1.8g,25.8mmol)，0℃下搅拌1小时。将上述反应液加入到100℃的50mL硫酸铜饱和溶液中，100℃搅拌10分钟。反应液冷却后，用50mL乙酸乙酯萃取两次。有机相合并后用饱和氯化钠溶液洗一次，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物8c(820mg，产率：19.0％)。
MS m/z(ESI):199.1[M-1]
第三步
2-乙基己基3-((3-羟基-4,5-二甲基苯基)硫代)丙酸酯8e
将化合物8c(770mg，3.8mmol)溶于15mL二氧六环中，加入化合物8d(1.7g,7.7mmol)，三(二亚苄基丙酮)二钯(350.5mg,0.38mmol)，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(442.8mg,0.77mmol)，N,N-异丙基乙胺(990.0mg,7.7mmol)。氩气 保护下100℃搅拌过夜。加入水和乙酸乙酯各50mL，分液，水相用乙酸乙酯萃取(50mL)，有机相合并后无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物8e(800mg，产率：61.7％)。
MS m/z(ESI):339.3[M+1]
第四步
5-巯基-2,3-二甲基苯酚8f
将化合物8e(800mg，2.4mmol)溶于20mL四氢呋喃中，加入叔丁醇钾(795mg,7.1mmol)，室温搅拌2小时。反应液用2N盐酸中和至中性，用乙酸乙酯萃取(50mL×2)，有机相合并后无水硫酸钠干燥，过滤，滤液减压浓缩得到标题化合物8f(360mg，产率：98.8％)，产品不经纯化直接进行下一步反应。
MS m/z(ESI):153.2[M-1]
第五步
6-氯-7-(3-((((5-(((3-羟基-4,5-二甲基苯基)硫代)甲基)-1-甲基-1H-吡唑-3-基)甲基)硫代)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3-甲氧基-3-氧代丙基)-1-甲基-1H-吲哚-2-羧酸甲酯8g
将化合物1j(412mg，0.7mmol)溶于8mL甲醇中，加入碳酸钾(288.0mg，2.1mmol)，化合物8f(322mg，2.1mmol)，氩气保护下，室温反应2小时。反应液减压浓缩大部分溶剂，向反应液中加入50mL水，用乙酸乙酯萃取(50mL×2)，合并有机相，用30mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物8g(400mg，产率：81.0％)。
MS m/z(ESI):710.3[M+1]
第六步
6-氯-7-(3-((((5-(((3-羟基-4,5-二甲基苯基)硫代)甲基)-1-甲基-1H-吡唑-3-基)甲基)硫代)甲基)-1,5-二甲基-1H-吡唑-4-基)-3-(3-羟基丙基)-1-甲基-1H-吲哚-2-羧酸甲酯8h
将化合物8g(100mg，0.14mmol)溶于1mL四氢呋喃中，冰浴下滴加入1.0M的硼烷四氢呋喃溶液(0.14mL，0.14mmol)，室温搅拌反应过夜。冰浴下，滴加1mL甲醇和1mL 6N盐酸，冰浴下搅拌5分钟，50℃搅拌30分钟。反应液用碳酸氢钠水溶液中和至中性，分出有机相，水相用50mL二氯甲烷和甲醇(V:V＝10:1)混合溶剂萃取两次，合并有机相，用30mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物8h(60mg，产率：62.5％)。
MS m/z(ESI):682.1[M+1]
第七步
17-氯-5,13,14,22,30,31-六甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂己环[27.3.1.1 4,7.0 11,15.0 16,21.0 20,24]三十四-1(33),4(34),6,11,14,16,18,20,23,29,31-十一烯-23-
甲酸甲酯8i
将化合物8h(60mg，0.09mmol)溶于0.5mL无水四氢呋喃和3mL无水甲苯中，室温下加入三正丁基膦(89.0mg，0.44mmol)，偶氮二甲酸二哌啶(111mg，0.44mmol)，氩气保护，60℃反应3小时。反应液减压浓缩除去溶剂，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物8i(40.0mg，产率：68.5％)。
MS m/z(ESI):664.2[M+1]
第八步
17-氯-5,13,14,22,30,31-六甲基-28-氧杂-2,9-二硫杂-5,6,12,13,22-五氮杂己环[27.3.1.1 4,7.0 11,15.0 16,21.0 20,24]三十四-1(33),4(34),6,11,14,16,18,20,23,29,31-十一烯-23-甲酸8
将化合物8i(40.0mg，0.06mmol)溶于1mL甲醇，0.5mL四氢呋喃和0.5mL水的混合溶剂中，加入氢氧化锂一水合物(51.0mg，1.2mmol)，50℃搅拌反应1小时。反应液用2N盐酸中和至中性，减压浓缩除去大部分溶剂，反相纯化制备(Sharpsil-T C18Column 21.2*150mm 5um，洗脱体系：10mmoL/L醋酸铵，水，乙腈)，得到标题化合物8(2.1mg，产率：5.1％)。
MS m/z(ESI):650.2[M+1]
1H NMR(400MHz,CD3OD)δ7.68-7.66(d,1H),7.14-7.12(d,1H,),6.80(s,1H),6.28(s,1H),4.86(s,1H),3.99-3.84(m,5H),3.70-3.44(m,11H),3.27-3.06(m,3H),2.70-2.67(d,1H),2.23-2.05(m,10H)。
测试例：
生物学评价
测试例1、本公开化合物与MCL-1蛋白结合实验。
以下方法用来测定本公开化合物与MCL-1蛋白的结合能力。实验方法简述如下：
一、实验材料及仪器
1.His-MCL-1蛋白(上海恒瑞医药有限公司，NA)
2.生物素标记Bim蛋白(R&D，3526/1)
3.标记铕穴状化合物抗6His抗体(cisbio，61HI2KLA)
4.亲和链霉素链接XL665(cisbio，611SAXLA)
5.结合缓冲液(cisbio，62DLBDDF)
6.检测缓冲液(cisbio，62DB1FDG)
7.酶标仪(BMG，PHERAsta)
二、实验步骤
MCL-1抑制剂可与MCL-1蛋白结合来阻止MCL-1与Bim蛋白的结合。本实验通过HTRF的方法检测MCL-1和Bim蛋白的结合来评价MCL-1抑制剂与MCL-1蛋白的结合能力，并根据Ki大小评价化合物的活性。
人重组蛋白MCL-1(序列171-327)和Bim(序列51-76)肽段分别标记了His和生物素。0.1nM的His-MCL-1，2.5nM的bio-Bim以及不同浓度的小分子化合物(首浓度10μM，3倍梯度稀释11个浓度,稀释在结合缓冲液中)混合室温孵育2小时，然后加入0.5nM标记铕穴状化合物抗6His抗体和1.25nM亲和链霉素链接XL665(稀释在检测缓冲液中)。室温孵育2小时后用PHERAstar检测620nm和665nm荧光信号。数据使用GraphPad软件处理。
三、实验数据
本公开化合物与MCL-1蛋白的结合能力可通过以上的试验进行测定，测得的Ki值见表1。
表1本公开化合物与MCL-1蛋白的结合的Ki。
Figure PCTCN2020087671-appb-000056
结论：本公开化合物与MCL-1蛋白具有较强的结合能力，能很好的抑制MCL-1与Bim蛋白的结合，光学活性对化合物活性有一定影响。
测试例2、细胞增殖实验
以下方法通过检测细胞内ATP含量，根据IC 50大小评价本申请化合物对AMO-1和MV-4-11细胞增殖的抑制效果。实验方法简述如下：
一、实验材料及仪器
1. AMO-1，人骨髓浆细胞瘤(南京科佰，CBP60242)
2. MV-4-11，人急性单核细胞白血病细胞(ATCC，CRL-9591)
3.胎牛血清(GIBCO,10099)
4. RPMI1640(GE，SH30809.01)
5. IMDM(Gibco，12440053)
6. 2-巯基乙醇(sigma，60-24-2)
7. CellTite(Promega，G7573)
8. 96孔细胞培养板(corning，3903)
9.台盼蓝溶液(Sigma,T8154-100ML)
10.酶标仪(BMG，PHERAsta)
11.细胞计数仪(上海睿钰生物科技有限公司，IC1000)
二、实验步骤
AMO-1细胞培养在含20％FBS的RPMI1640培养基中，MV-4-11细胞培养在含10％FBS的IMDM培养基中一周传代2～3次，传代比列1:4或1:6。传代时，将细胞转至离心管中，1200rpm离心3分钟，弃去上清培养基残液，加入新鲜培养基重悬细胞。在96孔细胞培养板中加入90μL的细胞悬液，密度为1.33×10 5细胞/ml，96孔板外围只加入100μL的完全培养基。将培养板在培养箱培养24小时(37℃，5％CO 2)。
将待测样品用DMSO稀释成20mM，并以4倍依次稀释成9个浓度，并设置空白和对照孔。取配制成梯度浓度的待测化合物溶液5μL加入到95μL新鲜培养基中。再向培养板中加入10μL上述含药物的培养基溶液。将培养板在培养箱孵育3天(37℃，5％CO 2)。在96孔细胞培养板中，每孔加入50μL CellTiter-Glo试剂，室温避光放置5-10min，在PHERAstar中读取化学发光信号值，数据使用GraphPad软件处理。
三、实验数据
本公开化合物对AMO-1和MV-4-11细胞增殖抑制可通过以上的试验进行测定，测得的IC 50值见表2。
表2本公开化合物对AMO-1和MV-4-11细胞增殖抑制的IC 50值。
Figure PCTCN2020087671-appb-000057
结论：本公开化合物对AMO-1和MV-4-11均具有很好的细胞增殖抑制效果。

Claims (18)

  1. 一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
    Figure PCTCN2020087671-appb-100001
    其中：
    R m、R n和R w相同或不同，且各自独立地选自氢原子、卤素、烷基、氘代烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、环烷基氧基和杂环基；
    或者R m和R n与相连的碳原子一起形成环烷基，且R w选自氢原子、卤素、氘代烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、环烷基氧基和杂环基；
    或者R n和R w与相连的碳原子一起形成环烷基，且R m选自氢原子、卤素、氘代烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、环烷基氧基和杂环基；
    Z为S原子、O原子或-CH 2-；
    M为S原子、O原子或-NR 6-；
    R 1选自氢原子、卤素、烷基、氘代烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、环烷基氧基和杂环基；
    R 2相同或不同，且各自选自氢原子、卤素、烷基、氘代烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基和硝基；
    R 3选自氢原子、卤素、烷基、氘代烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基和硝基；
    R 4选自氢原子、烷基、氘代烷基和环烷基；
    R 5选自氢原子、烷基、氘代烷基和环烷基；
    R 6选自氢原子、烷基和环烷基；
    n为0、1、2或3。
  2. 根据权利要求1中所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中：R m、R n和R w相同或不同，且各自独立地选自氢原子、卤素和烷基；或者R m和R n与相连的碳原子一起形成环烷基，且R w选自氢原子、卤素和烷基；或者R n和R w与相连的碳原子一起形成环烷基，且R m选自氢原子、卤素和烷基。
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中
    Figure PCTCN2020087671-appb-100002
    选自：
    Figure PCTCN2020087671-appb-100003
    R m、R n和R w相同或不同，且各自独立地选自氢原子、卤素和烷基；p为0、1或2；q为0、1或2。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其为通式(II)、通式(III)或通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
    Figure PCTCN2020087671-appb-100004
    其中：
    p为0、1或2；
    q为0、1或2；
    R m、R n和R w相同或不同，且各自独立地选自氢原子、卤素和烷基；且
    Z、M和R 1～R 5如权利要求1中所定义。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其互变异构体、 内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述的Z为S原子或O原子。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述的M为S原子或-NR 6-，且R 6为氢原子或烷基。
  7. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述的R 1为氢原子或烷基。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述的R 2为卤素。
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述的R 3和R 4各自为烷基。
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述的R 5为烷基。
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其选自：
    Figure PCTCN2020087671-appb-100005
    Figure PCTCN2020087671-appb-100006
  12. 一种通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
    Figure PCTCN2020087671-appb-100007
    其中：
    R a为烷基；
    R m、R n、R w、Z、M、R 1～R 5和n如权利要求1中所定义。
  13. 根据权利要求12所述的通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其选自：
    Figure PCTCN2020087671-appb-100008
  14. 一种制备根据权利要求1所述的通式(I)所示的化合物的方法，所述方法包括：
    Figure PCTCN2020087671-appb-100009
    通式(IA)的化合物脱去保护基R a，得到通式(I)的化合物，
    其中：
    R a为烷基；
    R m、R n、R w、Z、M、R 1～R 5和n如权利要求1中所定义。
  15. 一种药物组合物，所述药物组合物含有治疗有效量的根据权利要求1～11中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  16. 根据权利要求1～11中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐或根据权利要求15所述的药物组合物在制备用于抑制MCL-1的药物中的用途。
  17. 根据权利要求1～11中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐或根据权利要求15所述的药物组合物在制备用于治疗或预防MCL-1介导的疾病的药物中的用途。
  18. 根据权利要求1～11中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐或根据权利要求15所述的药物组合物在制备用于治疗肿瘤、自身免疫性疾病或免疫系统疾病的药物中的用途，
    优选地，所述肿瘤选自膀胱癌、脑瘤、乳腺癌、子宫癌、宫颈癌、子宫内膜癌、卵巢癌、白血病、肾癌、结肠癌、直肠癌、结肠直肠癌、食道癌、肝癌、胃癌、头颈癌、皮肤癌、淋巴瘤、胰腺癌、黑色素瘤、骨髓瘤、骨癌、神经母细胞瘤、神经胶质瘤、肉瘤、肺癌、甲状腺癌和前列腺癌。
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