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WO2020238776A1 - 取代的稠合双环类衍生物、其制备方法及其在医药上的应用 - Google Patents

取代的稠合双环类衍生物、其制备方法及其在医药上的应用 Download PDF

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Publication number
WO2020238776A1
WO2020238776A1 PCT/CN2020/091695 CN2020091695W WO2020238776A1 WO 2020238776 A1 WO2020238776 A1 WO 2020238776A1 CN 2020091695 W CN2020091695 W CN 2020091695W WO 2020238776 A1 WO2020238776 A1 WO 2020238776A1
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Prior art keywords
alkyl
amino
halogen
general formula
alkoxy
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PCT/CN2020/091695
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English (en)
French (fr)
Inventor
李心
王斌
白东栋
贺峰
陶维康
Original Assignee
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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Publication date
Application filed by 江苏恒瑞医药股份有限公司, 上海恒瑞医药有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to US17/595,533 priority Critical patent/US20220204512A1/en
Priority to JP2021569422A priority patent/JP2022534224A/ja
Priority to CN202080033699.5A priority patent/CN113825757B/zh
Priority to EP20813761.2A priority patent/EP3978498A1/en
Publication of WO2020238776A1 publication Critical patent/WO2020238776A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a substituted fused bicyclic derivative, a preparation method thereof, and application in medicine.
  • the present disclosure relates to substituted fused bicyclic derivatives represented by the general formula (I), their preparation methods and pharmaceutical compositions containing the derivatives, and their use as ERK inhibitors to treat ERK-mediated diseases and disorders Or inhibit the use of MAPK-ERK signaling pathway.
  • Mitogen-activated protein kinase plays an extremely important role in the signal transduction pathway, and extracellular signal regulated kinase (ERK) is a member of the MAPK family.
  • ERK extracellular signal regulated kinase
  • RAS-RAF-MEK-ERK the exogenous stimulating signal is transmitted to the ERK, and the activated ERK transfers into the nucleus to regulate the activity of transcription factors, thereby regulating the biological functions of cell proliferation, differentiation and apoptosis, or through phosphorylation
  • the cytoskeleton components in the cytoplasm are involved in the regulation of cell morphology and the redistribution of the cytoskeleton.
  • B-RAF/MEK inhibitors not only inhibit tumor growth, but also regulate the immune microenvironment of tumors.
  • B-RAF/MEK inhibitors can enhance the expression of tumor-specific antigens, improve the recognition and killing of tumors by antigen-specific T cells, and promote the migration and infiltration of immune cells.
  • the expression of PD-L1 in tumor tissues is enhanced.
  • checkpoint molecule antibodies such as PD-1 antibody, CTLA4 antibody
  • the purpose of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or Mixture form or its pharmaceutically acceptable salt:
  • G 1 , G 2 and G 3 are the same or different, and are each independently selected from CH, C or N;
  • L is a bond or an alkylene group, and the alkylene group is optionally further selected from alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, aminoalkyl , Cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • R 1 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic, aryl and heteroaryl;
  • R 2 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl
  • the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each optionally further selected from alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, Substituted by one or more substituents among hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 3 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclic group;
  • R 4 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic, aryl and heteroaryl;
  • R 5 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl base;
  • R 6 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy and hydroxyalkyl;
  • R 7 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl
  • the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each optionally further selected from alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, Substituted by one or more substituents among hydroxy, hydroxyalkyl, haloalkyl, haloalkoxy and aminoalkyl;
  • n 1, 2 or 3;
  • n 0, 1, or 2.
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer is the compound represented by the general formula (I-1) or (I-2) or its stereoisomer, tautomer, meso, exo Racemates, enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
  • G 1 , G 2 , G 3 , L, m, n, and R 1 to R 7 are as defined in the compound of general formula (I); preferably, R 5 is selected from halogen, alkyl, alkoxy, haloalkane Group, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, G 1 , G 2 , G 3 , L, m, n, R 1 to R 4 , R 6 and R 7 are as defined in the compound of general formula (I).
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a compound, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or its mixture form or its pharmaceutically acceptable salt is a compound represented by general formula (II-1), (II-2), (II-3) or (II-4) or its stereoisomers, Tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
  • z is 0, 1, 2, 3 or 4; and L, m and R 1 to R 7 are as defined in the compound of the general formula (I).
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (II-11), (II-21), (II-31) or (II-41) or its stereoisomers Forms, tautomers, mesoisomers, racemates, enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
  • L, m, R 1 to R 7 are as defined in the compound of general formula (I); preferably, R 5 is selected from halogen, alkyl, alkoxy, haloalkyl , Haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; z is 0, 1, 2, 3 or 4; and L, m , R 1 to R 4 , R 6 and R 7 are as defined in the compound of general formula (I).
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or its mixture form or its pharmaceutically acceptable salt is a compound represented by general formula (II-12), (II-22), (II-32) or (II-42) or its stereoisomers, Tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
  • z is 0, 1, 2, 3 or 4;
  • L, m and R 1 to R 7 are as defined in the compound of formula (I); preferably, R 5 is selected from halogen, alkyl, alkoxy, and haloalkyl , Haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; z is 0, 1, 2, 3 or 4; and L, m , R 1 to R 4 , R 6 and R 7 are as defined in the compound of general formula (I).
  • L is -CH(R 8 )-;
  • R 8 is selected from alkane Group, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or its mixture form or its pharmaceutically acceptable salt is the compound represented by general formula (III-1), (III-2), (III-3) or (III-4) or its stereoisomer, Tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
  • R 8 is selected from alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • z 0, 1, 2, 3 or 4;
  • R 1 , R 2 , R 4 , R 5 , R 7 and m are as defined in the compound of general formula (I).
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or its mixture form or its pharmaceutically acceptable salt is a compound represented by general formula (III-11), (III-21), (III-31) or (III-41) or its stereoisomer, Tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
  • R 8 is selected from alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • z 0, 1, 2, 3 or 4;
  • R 1 , R 2 , R 4 , R 5 , R 7 and m are as defined in the compound of formula (I); preferably, R 5 is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, Hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl; z is 0, 1 , 2 , 3, or 4; and R 1 , R 2 , R 4 , R 7 and m are as defined in the compound of general formula (I).
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or its mixture form or its pharmaceutically acceptable salt is a compound represented by general formula (III-12), (III-22), (III-32) or (III-42) or its stereoisomer, Tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
  • R 8 is selected from alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • z 0, 1, 2, 3 or 4;
  • R 1 , R 2 , R 4 , R 5 , R 7 and m are as defined in the compound of formula (I); preferably, R 5 is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, Hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl; z is 0, 1 , 2 , 3, or 4; and R 1 , R 2 , R 4 , R 7 and m are as defined in the compound of general formula (I).
  • the compound represented by the general formula (I) or its stereoisomers, tautomers, mesoisomers, racemates, enantiomers, Diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof wherein said R 7 is an aryl group or a heteroaryl group, and each of the aryl group and heteroaryl group is optionally further selected from alkane Group, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy and hydroxyalkyl substituted by one or more substituents; preferably, R 7 is an aryl group, the aryl group Optionally further substituted by one or more substituents selected from alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy and hydroxyalkyl; more preferably, R 7 is Phenyl, said phenyl is optionally further selected from C 1-6 alkyl, C 1-6 alkoxy, oxo
  • R 5 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy and hydroxyalkyl
  • the group is preferably selected from a hydrogen atom, a halogen and an alkyl group, more preferably a C 1-6 alkyl group; most preferably a methyl group.
  • the C 1-6 alkyl, 3 to 8 membered heterocyclic group and 5 to 10 membered heteroaryl are each optionally further selected from C 1-6 alkyl, C 1-6 alkoxy, oxo , Halogen, amino, cyano, nitro, hydroxy and C 1-6 hydroxyalkyl substituted by one or more substituents.
  • R 1 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl and hydroxyalkane
  • the group is preferably selected from hydrogen atom, halogen and alkyl group, more preferably selected from hydrogen atom, halogen and C 1-6 alkyl group, most preferably halogen.
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy and hydroxyalkyl
  • the group is preferably a hydrogen atom or an alkyl group; more preferably a hydrogen atom or a C 1-6 alkyl group.
  • Typical compounds of general formula (I) in the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form or its pharmaceutically acceptable salt:
  • G 1 , G 2 and G 3 are the same or different, and are each independently selected from CH, C and N;
  • R 1 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic, aryl and heteroaryl;
  • R 2 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl
  • the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each optionally further selected from alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, Substituted by one or more substituents among hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 3 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclic group;
  • R 4 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic, aryl and heteroaryl;
  • R 5 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl base;
  • n 1, 2 or 3;
  • n 0, 1, or 2.
  • Medicinal salts include but are not limited to:
  • Another aspect of the present disclosure relates to a preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IA) and (IB) undergo a condensation reaction under basic conditions to obtain the compound of general formula (I) or its tautomer, meso, racemate, enantiomer A structure, a diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: the basic condition is preferably N,N-diisopropylethylamine; R 6 is a hydrogen atom; and G 1. G 2 , G 3 , R 1 to R 5 , R 7 , L, m and n are as defined in the compound of general formula (I).
  • the compounds represented by the typical general formula (IB) of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to a pharmaceutical composition containing a therapeutically effective amount of a compound represented by general formula (I) or general formula (II) or general formula (III) of the present disclosure or its interconversion Isomers, mesosomes, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers , Diluent or excipient.
  • a pharmaceutical composition containing a therapeutically effective amount of a compound represented by general formula (I) or general formula (II) or general formula (III) of the present disclosure or its interconversion Isomers, mesosomes, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers , Diluent or excipient.
  • the present disclosure further relates to compounds represented by general formula (I) or general formula (II) or general formula (III) or tautomers, mesoisomers, racemates, enantiomers, non- Use of enantiomers or their mixtures, or their pharmaceutically acceptable salts, or pharmaceutical compositions containing them, in the preparation of drugs for inhibiting ERK.
  • the present disclosure further relates to compounds represented by general formula (I) or general formula (II) or general formula (III) or tautomers, mesoisomers, racemates, enantiomers, non- Use of enantiomers or their mixtures, or their pharmaceutically acceptable salts, or pharmaceutical compositions containing them in the preparation of drugs for the treatment or prevention of cancer, inflammation, or other proliferative diseases, preferably in preparation Use in drugs for the treatment or prevention of cancer; said cancer is selected from melanoma, liver cancer, kidney cancer, lung cancer (such as non-small cell lung cancer or small cell lung cancer), nasopharyngeal cancer, colorectal cancer, colon cancer, Rectal cancer, pancreatic cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, leukemia, head and neck squamous cell carcinoma, cervical cancer, thyroid cancer, lymphoma, sarcoma, neuroblastoma, brain tumor, bone marrow Tumors (such as multiple myelom
  • the present disclosure also relates to a method for inhibiting ERK, which comprises administering to a desired patient a therapeutically effective amount of a compound represented by general formula (I) or general formula (II) or general formula (III) or its tautomer, Meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.
  • the present disclosure also relates to a method for treating or preventing ERK-mediated diseases, which comprises administering to a patient a therapeutically effective amount of a compound represented by general formula (I) or general formula (II) or general formula (III) or Tautomers, mesosomes, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • a compound represented by general formula (I) or general formula (II) or general formula (III) or Tautomers mesosomes, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • the present disclosure also relates to a method for treating or preventing cancer, inflammation, or other proliferative diseases, preferably a method for treating or preventing cancer, which comprises administering a therapeutically effective amount of general formula (I) or general formula (II) to a patient in need Or the compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable Salt, or a pharmaceutical composition containing it; wherein the cancer is selected from melanoma, liver cancer, kidney cancer, lung cancer (such as non-small cell lung cancer or small cell lung cancer), nasopharyngeal cancer, colorectal cancer, colon cancer, Rectal cancer, pancreatic cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, leukemia, head and neck squamous cell carcinoma, cervical cancer, thyroid cancer, lymphoma, sarcoma, neuroblastoma, brain tumor, bone marrow Tumors
  • the present disclosure further relates to a compound represented by general formula (I) or general formula (II) or general formula (III) or its tautomers, mesosomes, racemates, enantiomers , Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, which are used as medicines.
  • the present disclosure also relates to compounds represented by general formula (I) or general formula (II) or general formula (III) or tautomers, mesosomes, racemates, enantiomers, non- Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, which are used as ERK inhibitors.
  • the present disclosure also relates to compounds represented by general formula (I) or general formula (II) or general formula (III) or tautomers, mesosomes, racemates, enantiomers, non- Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, which are used to treat or prevent ERK-mediated diseases.
  • the present disclosure also relates to compounds represented by general formula (I) or general formula (II) or general formula (III) or tautomers, mesosomes, racemates, enantiomers, non- Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, for the treatment or prevention of cancer, inflammation, or other proliferative diseases, preferably for the treatment or prevention of cancer;
  • the cancer is selected from melanoma, liver cancer, kidney cancer, lung cancer (such as non-small cell lung cancer or small cell lung cancer), nasopharyngeal cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, ovarian cancer , Breast cancer, bladder cancer, prostate cancer, leukemia, head and neck squamous cell carcinoma, cervical cancer, thyroid cancer, lymphoma, sarcoma, neuroblastoma, brain tumor, myeloma (such as multiple myeloma), stellate Cell tumors and
  • 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.
  • excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.
  • Oral preparations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient is mixed with a water-soluble carrier or oil vehicle.
  • Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • Oil suspensions can be formulated by suspending the active ingredients in vegetable oil or mineral oil.
  • the oil suspension may contain thickening agents.
  • the above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • dispersible powders and granules suitable for preparing water 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.
  • the pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion.
  • the oil phase can be vegetable oil, or mineral oil or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • the pharmaceutical composition of the present disclosure 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 injection oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase.
  • the injection or microemulsion can be injected into the patient's bloodstream by local mass injection. Alternatively, it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present disclosure.
  • 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 of the present disclosure 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. For this purpose, any blended fixed oil can be used.
  • fatty acids can also be used to prepare injections.
  • 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.
  • 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.
  • alkylene refers to a saturated linear or branched aliphatic hydrocarbon group, which has 2 residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms, more preferably an alkylene group containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 -) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc.
  • the alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy Substituted by one or more substituents in the group, cycloalkylthio, heterocycloalkylthio and oxo.
  • alkenyl refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above.
  • the alkenyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, hydroxyl groups, It is substituted by one or more substituents among hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.
  • alkynyl refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above.
  • the alkynyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, hydroxyl groups, It is substituted by one or more substituents among hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.
  • 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 (e.g. 3, 4, 5, 6 , 7, 8, 9, 10, 11 and 12) carbon atoms, preferably containing 3 to 8 carbon atoms, more preferably containing 3 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 (for example, 7, 8, 9 or 10 yuan).
  • 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 (for example, 7, 8, 9 or 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, and 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 are selected from nitrogen, oxygen, sulfur, S( O) or S(O) 2 heteroatoms, but not including the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • It preferably contains 3 to 12 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (for example, 1, 2, 3 and 4) are heteroatoms; More preferably contains 3 to 8 ring atoms, of which 1-3 are heteroatoms; more preferably contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably contains 5 or 6 ring atoms, of which 1- Three are heteroatoms.
  • 3 to 12 for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12
  • 1 to 4 for example, 1, 2, 3 and 4
  • 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 5- to 20-membered monocyclic rings, in which one or more ring atoms are selected from nitrogen, oxygen, sulfur, and S (O) or S(O) 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 (for example, 7, 8, 9 or 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, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, S(O) or S(O) 2 , and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 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, sulfur, S(O) or S(O) 2 and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 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), -C(O)O(cycloalkyl), -OC(O)alkyl or -OC(O)cycloalkyl, where the alkane
  • the radical 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.
  • in addition to using “deuterium” or “tritium” instead of hydrogen, or using 18 F-fluorine label ( 18 F isotope) instead of fluorine, or using 11 C-, 13 C-, or 14 C-rich Compounds in which a set of 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 the same activity as 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 present disclosure provides a novel ERK inhibitor, and finds that compounds with such structures have strong inhibitory activity and high selectivity, and compounds with such structures have good pharmacokinetic absorption.
  • the compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its forms or pharmacologically
  • the salt preparation method used includes the following steps:
  • reaction conditions are the same as in Scheme 1: That is, condensation reaction occurs under alkaline conditions to prepare the product.
  • the reagents that provide basic conditions in the above reaction include organic bases and inorganic bases.
  • the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and diisopropylamine.
  • Lithium base amide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, hydroxide Sodium, lithium hydroxide and potassium hydroxide; preferably N,N-diisopropylethylamine.
  • the above reaction is carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1, 4-Dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof, preferably N,N-dimethylformamide.
  • the condensing agent in the above-mentioned condensation reaction includes but is not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N, N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1 -Hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzotriazole Azole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea six Fluorophosphat
  • 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 means that the reaction flask is 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, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and Adjust with alkaline or acidic reagents such as acetic acid.
  • reaction solution was added with 100 mL of water, extracted with ethyl acetate (150 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography with eluent system B to obtain the title compound 1f (2.2g). Yield: 33%.
  • N-(1-methyl-1H-pyrazol-5-yl)carboxamide 1o (270mg, 2.15mmol, prepared by the method disclosed in the patent application "Example 2 on page 88 of the specification in WO201780979"), Dissolve in N,N-dimethylformamide, add sodium hydride (60%, 250 mg, 6.5 mmol) at 0°C, stir and react for 0.5 hour, add crude compound 1n (445 mg, 2.15 mmol), and continue the reaction for 2 hours.
  • compound 1i 400mg, 1.02mmol
  • compound 1j 252mg, 1.12mmol
  • cesium carbonate 668mg, 2.05mmol
  • [1,1' -Bis(diphenylphosphino)ferrocene]palladium dichloride 150mg, 0.20mmol
  • the filtrate was concentrated, and purified by column chromatography with eluent system A to obtain the title compound 1k (340 mg), yield: 73.1%.
  • HPLC analysis retention time 16.1 minutes, purity: 98.5% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 23%- 42%)
  • compound 1i (580mg, 1.48mmol) was dissolved in 6mL of dioxane and 1mL of water, and compound 2a (327mg, 1.78mmol, Shanghai Bach Pharmaceutical Co., Ltd.), sodium carbonate (315mg, 2.97mmol) ) And [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (126mg, 0.15mmol), react in microwave at 80°C for 1 hour. Cooled, filtered through Celite, concentrated the filtrate, and purified by column chromatography with eluent system A to obtain the title compound 2b (200 mg), yield: 32.7%.
  • HPLC analysis retention time 16.1 minutes, purity: 98.2% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 30%- 48%)
  • HPLC analysis retention time 18.2 minutes, purity: 96.8% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 30%- 48%)
  • Dissolve compound 3f (0.1g, 0.29mmol) in 5mL N,N-dimethylformamide, cool to 0°C, add sodium hydride (60%, 20mg, 0.86mmol), stir and react for 0.5 hours, add 2- Tert-butyl bromopropionate (89 mg, 0.43 mmol, Shanghai Beat Pharmaceutical Co., Ltd.) was stirred for 14 hours.
  • the filtrate was concentrated and purified with the developing solvent system A of thin layer chromatography to obtain 3 g (100 mg) of the title compound, yield: 73.1%.
  • HPLC analysis retention time 15.5 minutes, purity: 99.1% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 30%- 45%)
  • HPLC analysis retention time 17.8 minutes, purity: 98.2% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 30%- 45%)
  • the filtrate was concentrated and purified by liquid preparation (Instrument model: Gilson 281 column: X-Bridge, Prep 30*150mm; 5 ⁇ m; C18 mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, flow rate: 30mL/ min column temperature: room temperature) to obtain title compounds 4-P1 and 4-P2 (5 mg, 5 mg), yields: 26.7%, 26.7%.
  • HPLC analysis retention time 17.6 minutes, purity: 96.8% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 23%- 42%)
  • compound 6b (200mg, 0.61mmol) was dissolved in 3mL 1,4-dioxane, and 4,4,4',4',5,5,5',5'-A Methyl-2,2'-bis(1,3,2-dioxaborolane) (184mg, 0.72mmol), potassium acetate (119mg, 1.21mmol) and [1,1'-bis(diphenyl) Phosphinyl)ferrocene]palladium dichloride (44mg, 0.06mmol), stirred at 90°C for 2 hours. After cooling, filtering through diatomaceous earth, the filtrate was concentrated, and purified by thin layer chromatography with developing solvent system C to obtain the title compound 6c (100 mg), yield: 44.0%.
  • compound 6c (100mg, 0.265mmol) was dissolved in 50mL of dioxane, and compound 6d (60mg, 0.242mmol), potassium carbonate (67mg, 0.485mmol) and [1,1'-bis (Diphenylphosphino)ferrocene]palladium dichloride (18mg, 0.025mmol), stirred in a microwave at 85°C for 1.5 hours. Cooled, filtered through Celite, concentrated the filtrate, and purified by column chromatography with eluent system A to obtain the title compound 6e (50 mg), yield: 45.0%.
  • HPLC analysis retention time 18.5 minutes, purity: 98.2% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium acetate) B-acetonitrile, gradient ratio: A 25%-45 %)
  • compound 6c (1.2g, 3.2mmol) was dissolved in 30mL of dioxane and 6mL of water, and compound 2a (702mg, 3.83mmol, Shanghai Beat Pharmaceutical Co., Ltd.), sodium carbonate (676mg, 6.37 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (233 mg, 0.32 mmol) at 80°C for 14 hours. Cooled, filtered through Celite, concentrated the filtrate, and purified by column chromatography with eluent system A to obtain the title compound 7a (400 mg), yield: 31.5%.
  • HPLC analysis retention time 12.4 minutes, purity: 98.2% (column: X-Bridge, Prep 30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium acetate) B-acetonitrile, gradient ratio: A 30%- 46%)
  • HPLC analysis retention time 14.5 minutes, purity: 97.2% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium acetate) B-acetonitrile, gradient ratio: A 30%-46 %)
  • HPLC analysis retention time 13.1 minutes, purity: 98.5% (column X-Bridge, Prep 30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 22%- 40%)
  • HPLC analysis retention time 15.5 minutes, purity: 97.9% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A22%-40 %)
  • compound 4b (5g, 19.92mmol) was dissolved in 100mL of dioxane and 10mL of water, and compound 2a (4.38g, 23.88mmol), sodium carbonate (3.16g, 29.81mmol) and [1, 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (2.49g, 2.99mmol), stirred at 80°C for 3 hours. Cooled, filtered through Celite, concentrated the filtrate, and purified by column chromatography with eluent system A to obtain the title compound 9a (3g), yield: 55.3%.
  • HPLC analysis retention time 11.1 minutes, purity: 98.2% (column: X-Bridge, Prep 30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium acetate) B-acetonitrile, gradient ratio: A 40%- 60%)
  • HPLC analysis retention time 12.5 minutes, purity: 97.2% (column: X-Bridge, Prep 30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium acetate) B-acetonitrile, gradient ratio: A 40%- 60%)
  • the crude compound 10d (600 mg, 2.04 mmol) was dissolved in 10 mL of ammonia methanol solution (7 mol/L) and stirred for 14 hours. Concentrated under reduced pressure to obtain the crude compound 10e (534 mg). The product was directly used in the next reaction without purification.
  • compound 10h (150mg, 0.38mmol) was dissolved in 6mL dioxane, and compound 7b (56mg, 0.58mmol), cesium carbonate (375mg, 1.15mmol) and 4,5-bis(two Phenylphosphine)-9,9-dimethylxanthene (35mg, 38.2 ⁇ mol), tris(dibenzylideneacetone)dipalladium (35mg, 38 ⁇ mol), stirred at 90°C for 14 hours. After cooling, filtering through celite, the filtrate was concentrated, and purified by column chromatography with eluent system A to obtain 10 g (100 mg) of the title compound, yield: 57.7%.
  • HPLC analysis retention time 11.3 minutes, purity: 98.2% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25%- 39%)
  • HPLC analysis retention time 12.5 minutes, purity: 98.5% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25%- 39%)
  • HPLC analysis retention time 17.5 minutes, purity: 96.2% (column: Sharpsil-T, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (0.1% trifluoroacetic acid) B-acetonitrile, gradient ratio: A 31% -49%)
  • HPLC analysis retention time 15.4 minutes, purity: 96.8% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25%- 45%)
  • HPLC analysis retention time 17.2 minutes, purity: 97.2% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25%- 45%)
  • HPLC analysis retention time 15.4 minutes, purity: 96.8% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 33%- 51%)
  • HPLC analysis retention time 17.5 minutes, purity: 97.2% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 33%- 51%)
  • HPLC analysis retention time 12.4 minutes, purity: 98.6% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium acetate) B-acetonitrile, gradient ratio: A 25%-39 %).
  • HPLC analysis retention time 13.5 minutes, purity: 99.2% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium acetate) B-acetonitrile, gradient ratio: A 25%-39 %).
  • the first step raw material compound 10a was replaced with 2,4-dichloropyrimidine to obtain compounds 18-P1 and 18-P2 (30 mg, 30 mg).
  • HPLC analysis retention time 13.2 minutes, purity: 96.8% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium acetate) B-acetonitrile, gradient ratio: A 20%-36 %)
  • HPLC analysis retention time 15.4 minutes, purity: 97.2% (column: X-Bridge, Prep 30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium acetate) B-acetonitrile, gradient ratio: A 20%- 36%)
  • HPLC analysis retention time 11.6 minutes, purity: 98.1% (column: X-Bridge, Prep30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium acetate) B-acetonitrile, gradient ratio: A 25%-39 %).
  • HPLC analysis retention time 12.7 minutes, purity: 98.5% (column: X-Bridge, Prep 30*150mm; 5 ⁇ m; mobile phase: A-water (10mM ammonium acetate) B-acetonitrile, gradient ratio: A 25%- 39%).
  • Test example 1 ERK1 enzyme activity test
  • the purpose of this experiment is to test the inhibitory ability of the compounds of the present disclosure on the enzyme activity of ERK1, and to evaluate the in vitro activity of the compounds based on the IC50.
  • This experiment uses the ADP-Glo TM Kinase Assay Kit. Under the action of the enzyme, the substrate is phosphorylated and ADP is produced at the same time. ADP-Glo reagent is added to remove unreacted ATP in the reaction system. Kinase detection reagent detects ADP produced by the reaction. In the presence of the compound, the inhibition rate of the compound is calculated by measuring the signal value.
  • Enzyme and substrate configuration ERK1 (1879-KS-010, R&D) and substrate (AS-61777, anaspec) were configured in buffer to 0.75ng/ ⁇ l and 1005n respectively, and then the enzyme solution and substrate solution were The volume ratio of 2:1 is prepared into a mixed solution, ready for use. Dilute ATP to 300 ⁇ M with buffer, dissolve the compound with DMSO (dimethyl sulfoxide, Shanghai Titan Technology Co., Ltd.) to prepare a stock solution with an initial concentration of 20 mM, and then prepare the compound with Bravo.
  • DMSO dimethyl sulfoxide
  • each well of the 384-well plate add 3 plates of each enzyme and substrate mixture solution, 1 substrate with different concentrations of compound (the initial concentration is 50 ⁇ M, 4-fold dilution), incubate at 30°C for 10 minutes, and finally each well Add another minute, and finally each well of ⁇ M ATP solution, incubate at 30°C for 2 hours. Then add 5 ⁇ L of ADP-Glo and incubate at 30°C for 40 minutes, then add 10 ⁇ L of kinase detection buffer and incubate at 30°C for 40 minutes. Take out the 384-well plate and place it in a microplate reader (BMG labtech, PHERAstar FS), and measure the chemiluminescence with the microplate reader.
  • a microplate reader BMG labtech, PHERAstar FS
  • the compound of the present disclosure has a significant inhibitory effect on ERK1 enzyme activity.
  • Test example 2 ERK2 enzyme activity test
  • the purpose of this experiment is to test the inhibitory ability of the compounds of the present disclosure on ERK2 enzyme activity, and to evaluate the in vitro activity of the compounds based on IC50.
  • This experiment uses the ADP-Glo TM Kinase Assay Kit. Under the action of the enzyme, the substrate is phosphorylated and ADP is produced at the same time. ADP-Glo reagent is added to remove unreacted ATP in the reaction system. Kinase detection reagent detects ADP produced by the reaction. In the presence of the compound, the inhibition rate of the compound is calculated by measuring the signal value.
  • Enzyme and substrate configuration ERK2 (1230-KS-010, R&D) and substrate (custom peptide, Gill Biochemical) are configured in buffer (40mM Tris, 20mM MgCl 2 , 0.1mg/ml BSA, 50 ⁇ M DTT) 0.75ng/ ⁇ l and 1500/, then the enzyme solution and the substrate solution are made into a mixed solution at a volume ratio of 2:1, and set aside. Dilute ATP to 500 ⁇ M with buffer, dissolve the compound with DMSO (dimethyl sulfoxide, Shanghai Titan Technology Co., Ltd.) to prepare a stock solution with an initial concentration of 20 mM, and then prepare the compound with Bravo.
  • buffer 40mM Tris, 20mM MgCl 2 , 0.1mg/ml BSA, 50 ⁇ M DTT
  • each well of the 384-well plate add 3 plates of each enzyme and substrate mixture solution, 1 substrate with different concentrations of compound (the initial concentration is 50 ⁇ M, 4-fold dilution), incubate at 30°C for 10 minutes, and finally each well Add another minute, and finally each well of ⁇ M ATP solution, incubate at 30°C for 2 hours. Then add 5 ⁇ L of ADP-Glo and incubate at 30°C for 40 minutes, then add 10 ⁇ L of kinase detection buffer and incubate at 30°C for 40 minutes. Take out the 384-well plate, place it in a microplate reader (BMG labtech, PHERAstar FS), and measure chemiluminescence with a microplate reader.
  • a microplate reader BMG labtech, PHERAstar FS
  • Test Example 3 In vitro proliferation inhibition test for Colo205 tumor cells
  • the purpose of this experiment is to detect the compound of the present disclosure on Colo205 cells (CCL-222, ATCC)
  • Luminescent Cell Viability Assay Luminescent Cell Viability Assay, Promega, article number: G7573 reagent detects the proliferation of cells, and evaluates the in vitro activity of the compound based on the IC50 value.
  • the following takes the in vitro proliferation inhibition test method of Colo205 cells as an example to illustrate the method for the in vitro proliferation inhibition activity test of the compound of the present disclosure on tumor cells. This method is also applicable to, but not limited to, in vitro proliferation inhibitory activity testing on other tumor cells.
  • Digest Colo205 resuspend after centrifugation, mix the single cell suspension, adjust the viable cell density to 5.0 ⁇ 10 4 cells/ml with cell culture medium (RPMI1640+2% FBS), add 95 ⁇ L/well to 96-well cell culture plate . Only add 100 ⁇ L of medium to the peripheral wells of the 96-well plate. The culture plate was cultured in an incubator for 24 hours (37°C, 5% CO 2 ).
  • the compound was dissolved in DMSO (dimethyl sulfoxide, Shanghai Titan Technology Co., Ltd.) to prepare a storage solution with an initial concentration of 20 mM.
  • the initial concentration of the small molecule compound is 2 mM, diluted 4 times, 9 points of dilution, and the tenth point is DMSO.
  • Take another 96-well plate add 90 ⁇ L of cell culture medium (RPMI1640+2%FBS) to each well, then add 10 ⁇ L of different concentrations of the test sample to each well, mix well, and then add 5 ⁇ L of different concentrations to the cell culture plate Samples to be tested, each sample has two duplicate holes.
  • the culture plate was incubated in an incubator for 3 days (37°C, 5% CO 2 ).
  • the compound of the present disclosure has a significant inhibitory effect on the proliferation of Colo205 tumor cells.
  • Test Example 4 Mouse pharmacokinetic test of the compound of the present disclosure
  • mice Using mice as the test animal, the LC/MS/MS method was used to determine the plasma levels of compounds 1-P2, 2-P2, 4-P2, 6-P2, 9-P2, 10-P2 and 11-P2 at different times The concentration of the drug. To study the pharmacokinetic behavior of the compound of the present disclosure in mice and evaluate its pharmacokinetic characteristics.
  • mice There are 63 C57 mice, female, equally divided into 7 groups, purchased from Shanghai Jiesjie Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2013-0006.
  • mice were fasted overnight and then administered by gavage.
  • the dosage was 2mg/kg, and the dosage was 0.2ml/10g.
  • mice were given intragastrically, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours before and after administration, 0.1ml of blood was collected, placed in a heparinized test tube, and centrifuged at 3500 rpm for 10 After a minute, the plasma was separated and stored at -20°C.
  • the compound of the present disclosure has better pharmacokinetic absorption and has pharmacokinetic advantages.

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Abstract

本公开涉及取代的稠合双环类衍生物、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)所示的新的取代的稠合双环类衍生物、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ERK抑制剂的用途，和其在制备治疗和/或预防癌症、炎症、或其它增殖性疾病的药物中的用途，其中通式(I)的各取代基与说明书中的定义相同。

Description

取代的稠合双环类衍生物、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，涉及一种取代的稠合双环类衍生物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(I)所示的取代的稠合双环类衍生物、其制备方法及含有该衍生物的药物组合物，以及其作为ERK抑制剂治疗ERK介导的疾病及病症或抑制MAPK-ERK信号通路的用途。
背景技术
正常细胞的增殖、分化、代谢、凋亡受到体内细胞信号转导通路的严格调节。丝裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)在信号转导通路中起着极为重要的作用，胞外信号调节激酶(extracellular signal regulated kinase，ERK)是MAPK家族的一员。通过RAS-RAF-MEK-ERK步骤，外源的刺激信号被传递给ERK，活化后的ERK转移进入细胞核，调节转录因子活性，从而调节细胞的增殖分化凋亡等生物学功能，或者通过磷酸化胞浆中细胞骨架成分参与细胞形态的调节及细胞骨架的重新分布。
RAS跟RAF基因突变造成MAPK-ERK信号通路的持续激活，促使细胞恶性转化、异常增殖，最终产生肿瘤(Roberts PJ等，Oncogene，2007，26(22)，3291-3310)。MEK抑制剂跟B-RAF抑制剂联用可以进一步提高B-RAF抑制剂抑制肿瘤生长的效果，可以显著提高携带BRAFV600E跟V600K突变的黑色素瘤病人的无病进展期和总体生存率(Frederick DT等，Clinical Cancer Research，2013.19(5)，1225-1231)。虽然B-RAF/MEK抑制剂联用可以起到抑制肿瘤的效果，但是他们的疗效是短暂的，在2-18个月内绝大多数患者会产生耐药，肿瘤会进一步恶化。B-RAF/MEK抑制剂耐药性的产生机制非常复杂，大多与ERK信号通路的重新激活有着直接关系(Smalley I等，Cancer Discovery，2018，8(2)，140-142)。所以，开发新的ERK抑制剂，不仅对MAPK信号通路产生突变的病人有效，对于B-RAF/MEK抑制剂产生耐药的病人也同样有效。
B-RAF/MEK抑制剂在抑制肿瘤生长的同时，对肿瘤的免疫微环境起到了调控作用。B-RAF/MEK抑制剂可以增强肿瘤特异性抗原的表达，提高抗原特异性T细胞对肿瘤的识别和杀伤，促进免疫细胞的迁移和浸润。动物模型中，经过B-RAF/MEK抑制剂处理后，肿瘤组织中PD-L1表达增强，与检查点(checkpoint)分子的抗体(例如PD-1抗体、CTLA4抗体)联用时，更显示出优于B-RAF/MEK抑制剂单用时的抑制肿瘤生长的效果(Boni A等，Cancer Research，2010，70(13)，5213-5219)。研究表明，ERK抑制剂与B-RAF/MEK抑制剂类似，与检查点抗体联用可以起到调节肿瘤微环境的作用，提高细胞毒性T细胞的功能，达到抑制肿瘤生长的效果。
目前已有多个ERK抑制剂化合物被开发。其中BioMed Valley Discoveries公司的BVD-523在临床二期，默克公司的MK-8353以及Astex的Astex-029在临床一期。相关的专利申请有WO1999061440A1、WO2001056557A2、WO2001056993A2、WO2001057022A2、WO2002022601A1、WO2012118850A1、WO2013018733A1、WO2014179154A2、WO2015103133A1、WO2016192063A1、WO2017180817A1、WO2018049127A1。
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 PCTCN2020091695-appb-000001
其中：
G 1、G 2和G 3相同或不同，且各自独立地选自CH、C或N；
L为键或亚烷基，所述的亚烷基任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、氨基烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
R 2选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 3选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基；
R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、 卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
R 5选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
R 6选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基和羟烷基；
R 7选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、卤代烷基、卤代烷氧基和氨基烷基中的一个或多个取代基所取代；
n为1、2或3；且
m为0、1或2。
在本公开的一些实施方案中，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)或(I-2)所示的化合物或其立体异构体、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 PCTCN2020091695-appb-000002
其中：G 1、G 2、G 3、L、m、n和R 1～R 7如通式(I)化合物中所定义；优选地，R 5选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基，G 1、G 2、G 3、L、m、n、R 1～R 4、R 6和R 7如通式(I)化合物中所定义。
在本公开的一些实施方案中，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n为1或2。
在本公开的一些实施方案中，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(II-1)、(II-2)、(II-3)或(II-4)所示的化合物或其立体异构体、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 PCTCN2020091695-appb-000003
其中：
z为0、1、2、3或4；且L、m和R 1～R 7如通式(I)化合物中所定义。
在本公开的一些实施方案中，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-11)、(II-21)、(II-31)或(II-41)所示的化合物或其立体异构体、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 PCTCN2020091695-appb-000004
其中：
z为0、1、2、3或4，L，m，R 1～R 7如通式(I)化合物中所定义；优选地，R 5选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；z为0、1、2、3或4；且L、m、R 1～R 4、R 6和R 7如通式(I)化合物中所定义。
在本公开的一些实施方案中，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(II-12)、(II-22)、(II-32)或(II-42)所示的化合物或其立体异构体、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 PCTCN2020091695-appb-000005
其中：
z为0、1、2、3或4；L、m和R 1～R 7如通式(I)化合物中所定义；优选地，R 5选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；z为0、1、2、3或4；且L、m、R 1～R 4、R 6和R 7如通式(I)化合物中所定义。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其立体异构体、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L为亚烷基，所述的亚烷基任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基和氨基烷基中的一个或多个取代基所取代，优选地，L为-CH(R 8)-；R 8选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、氨基烷基、环烷基、杂环基、芳基和杂芳基。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其立体异构体、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L为亚烷基，所述的亚烷基任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基和氨基烷基中的一个或多个取代基所取代，优选进一步被羟烷基所取代。
在本公开的一些实施方案中，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(III-1)、(III-2)、(III-3)或(III-4)所示的化合物或其立体异构体、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 PCTCN2020091695-appb-000006
其中：
R 8选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、氨基烷基、环烷基、杂环基、芳基和杂芳基；
z为0、1、2、3或4；且
R 1、R 2、R 4、R 5、R 7和m如通式(I)化合物中所定义。
在本公开的一些实施方案中，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(III-11)、(III-21)、(III-31)或(III-41)所示的化合物或其立体异构体、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 PCTCN2020091695-appb-000007
其中：
R 8选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、氨基烷基、环烷基、杂环基、芳基和杂芳基；
z为0、1、2、3或4；且
R 1、R 2、R 4、R 5、R 7和m如通式(I)化合物中所定义；优选地，R 5选自卤 素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；z为0、1、2、3或4；且R 1、R 2、R 4、R 7和m如通式(I)化合物中所定义。
在本公开的一些实施方案中，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(III-12)、(III-22)、(III-32)或(III-42)所示的化合物或其立体异构体、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 PCTCN2020091695-appb-000008
其中：
R 8选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、氨基烷基、环烷基、杂环基、芳基和杂芳基；
z为0、1、2、3或4；且
R 1、R 2、R 4、R 5、R 7和m如通式(I)化合物中所定义；优选地，R 5选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；z为0、1、2、3或4；且R 1、R 2、R 4、R 7和m如通式(I)化合物中所定义。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其立体异构体、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 7为芳基或杂芳基，所述的芳基和杂芳基各自任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基和羟烷基中的一个或多个取代基所取代；优选地，R 7为芳基，所述的芳基任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基和羟烷基中的一个或多个取代基所取代；更优选地，R 7为苯基，所述的苯基任选进一步被选自C 1-6烷基、C 1-6烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基和C 1-6羟烷基中的一个或多个取代基所取代。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其立体异构体、 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 7为芳基，所述的芳基任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基和羟烷基中的一个或多个取代基所取代。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其立体异构体、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 8选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基和氨基烷基，优选为羟烷基或氨基烷基；更优选为C 1-6羟烷基或氨基C 1-6烷基。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其立体异构体、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选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基和羟烷基，优选选自氢原子、卤素和烷基，更优选为C 1-6烷基；最优选为甲基。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其立体异构体、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选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基和羟烷基，优选选自卤素和烷基，更优选为C 1-6烷基；最优选为甲基。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其立体异构体、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选自C 1-6烷基、3至8元杂环基和5至10元杂芳基，所述的C 1-6烷基、3至8元杂环基和5至10元杂芳基各自任选进一步被选自C 1-6烷基、C 1-6烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基和C 1-6羟烷基中的一个或多个取代基所取代。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其立体异构体、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为杂环基，所述的杂环基任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基和羟烷基中的一个或多个取代基所取代。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其立体异构体、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为杂芳基，所述的杂芳基任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基和羟烷基中的一个或多个取代基所取代。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其立体异构体、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选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基和羟烷基，优选选自氢原子、卤素和烷基，更优选选自氢原子、卤素和C 1-6烷基，最优选为卤素。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其立体异构体、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 4选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基和羟烷基，优选为氢原子或烷基；更优选为氢原子或C 1-6烷基。
本公开的典型的通式(I)化合物包括但不限于：
Figure PCTCN2020091695-appb-000009
Figure PCTCN2020091695-appb-000010
Figure PCTCN2020091695-appb-000011
Figure PCTCN2020091695-appb-000012
Figure PCTCN2020091695-appb-000013
Figure PCTCN2020091695-appb-000014
Figure PCTCN2020091695-appb-000015
Figure PCTCN2020091695-appb-000016
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 PCTCN2020091695-appb-000017
其中：
G 1、G 2和G 3相同或不同，且各自独立地选自CH、C和N；
R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
R 2选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 3选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基；
R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
R 5选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷 基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
n为1、2或3；且
m为0、1或2。
本公开的典型通式(IA)所示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包括但不限于：
Figure PCTCN2020091695-appb-000018
Figure PCTCN2020091695-appb-000019
Figure PCTCN2020091695-appb-000020
本公开的另一方面涉及一种制备通式(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方法，所述方法包括：
Figure PCTCN2020091695-appb-000021
通式(IA)的化合物和(IB)，在碱性条件下发生缩合反应，得到通式(I)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：所述碱性条件优选为N,N-二异丙基乙胺；R 6为氢原子；且G 1、G 2、G 3、R 1～R 5、R 7、L、m和n如通式(I)化合物中所定义。
本公开的典型通式(IB)所示化合物包括但不限于：
Figure PCTCN2020091695-appb-000022
(S)-2-氨基-2-(间甲苯基)乙醇、(S)-2-氨基-2-(间氯苯基)乙醇。
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)或通式(II)或通式(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。
本公开进一步涉及通式(I)或通式(II)或通式(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，或其可药用盐，或包含其的药物组合物，在制备用于抑制ERK的药物中的用途。
本公开进一步涉及通式(I)或通式(II)或通式(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，或其可药用盐，或包含其的药物组合物在制备用于治疗或预防癌症，炎症，或其它增殖性疾病的药物中的用途，优选在制备用于治疗或预防癌症的药物中的用途；所述的癌症选自黑色素瘤、肝癌、肾癌、肺癌(如非小细胞肺癌或小细胞肺癌)、鼻咽癌、结肠直肠癌、、结肠癌、直肠癌、胰腺癌、宫颈癌、卵巢癌、乳腺癌、膀胱癌、前列腺癌、白血病、头颈鳞状细胞癌、子宫颈癌、甲状腺癌、淋巴瘤、肉瘤、成神经细胞瘤、脑瘤、骨髓瘤(如多发性骨髓瘤)和星形细胞瘤，胶质瘤。
本公开还涉及一种抑制ERK的方法，其包括给予所需患者治疗有效量的通式(I)或通式(II)或通式(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，或其可药用盐，或包含其的药物组合物。
本公开还涉及一种治疗或预防ERK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)或通式(II)或通式(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，或其可药用盐，或包含其的药物组合物。
本公开还涉及一种治疗或预防癌症，炎症，或其它增殖性疾病的方法，优选治疗或预防癌症的方法，其包括给予所需患者治疗有效量的通式(I)或通式(II)或通式(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，或其可药用盐，或包含其的药物组合物；其中所述的癌症选自黑色素瘤、肝癌、肾癌、肺癌(如非小细胞肺癌或小细胞肺癌)、鼻咽癌、结肠直肠癌、、结肠癌、直肠癌、胰腺癌、宫颈癌、卵巢癌、乳腺癌、膀胱癌、前列腺癌、白血病、头颈鳞状细胞癌、子宫颈癌、甲状腺癌、淋巴瘤、肉瘤、成神经细胞瘤、脑瘤、骨髓瘤(如多发性骨髓瘤)、星形细胞瘤和胶质瘤。
本公开进一步涉及一种通式(I)或通式(II)或通式(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、或其可药用盐或包含其的药物组合物，其用作药物。
本公开还涉及通式(I)或通式(II)或通式(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，或其可药用盐，或包含其的药物组合物，其用作ERK抑制剂。
本公开还涉及通式(I)或通式(II)或通式(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，或其可药用盐，或包含其的药物组合物，其用于治疗或预防ERK介导的疾病。
本公开还涉及通式(I)或通式(II)或通式(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，或其可药用盐，或包含其的药物组合物，其用于治疗或预防癌症，炎症，或其它增殖性疾病，优选用于治疗或预防癌症；其中所述的癌症选自黑色素瘤、肝癌、肾癌、肺癌(如非小细胞肺癌或小细胞肺癌)、鼻咽癌、结肠直肠癌、、结肠癌、直肠癌、胰腺癌、宫颈癌、卵巢癌、乳腺癌、膀胱癌、前列腺癌、白血病、头颈鳞状细胞癌、子宫颈癌、甲状腺癌、淋巴瘤、肉瘤、成神经细胞瘤、脑瘤、骨髓瘤(如多发性骨髓瘤)、星形细胞瘤和胶质瘤。
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。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
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。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、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，或矿物油配制而成。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。可通过加入抗氧化剂保存这些组合物。
通过加入水可使适用于制备水混悬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。油相可以是植物油，或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开的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。
本公开的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。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
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。
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。
术语部分
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“亚烷基”指饱和的直链或支链脂肪族烃基，其具有2个从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，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，更优选含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)等。亚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烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基所取代。
术语“烯基”指分子中含有碳碳双键的烷基化合物，其中烷基的定义如上所述。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。
术语“炔基”指分子中含有碳碳三键的烷基化合物，其中烷基的定义如上所述。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和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(例如3、4、5、6、7、8、9、10、11和12)碳原子，优选包含3至8个碳原子，更优选包含3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 PCTCN2020091695-appb-000023
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(例如7、8、9或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 PCTCN2020091695-appb-000024
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(例如7、8、9或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 PCTCN2020091695-appb-000025
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、硫、S(O)或S(O) 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(例如 3、4、5、6、7、8、9、10、11和12)环原子，其中1～4个(例如1、2、3和4)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、硫、S(O)或S(O) 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(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 PCTCN2020091695-appb-000026
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、硫、S(O)或S(O) 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(例如7、8、9或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 PCTCN2020091695-appb-000027
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、硫、S(O)或S(O) 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(例如7、8、9或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 PCTCN2020091695-appb-000028
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 PCTCN2020091695-appb-000029
Figure PCTCN2020091695-appb-000030
等。
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 PCTCN2020091695-appb-000031
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 PCTCN2020091695-appb-000032
Figure PCTCN2020091695-appb-000033
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 PCTCN2020091695-appb-000034
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)、-C(O)O(环烷基)、-OC(O)烷基或-OC(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。
本公开提供一种新型ERK抑制剂，并发现具有此类结构的化合物具有强抑制活性和高选择性，并且此类结构的化合物药代吸收良好。
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制备方法，包括以下步骤：
Figure PCTCN2020091695-appb-000035
中间体1通式(IA)化合物和中间体2通式(IB)化合物，在碱性条件下发生缩合反应，得到通式(I)化合物，其中：R 1～R 7、L、m和n如通式(I)化合物中所定义。
其他方案
在制备通式(II-1)、(II-2)、(II-3)、(II-4)、(III-1)、(III-2)、(III-3)或(III-4)所示的化合物的其它方案中、将方案一中的中间体1通式(IA)化合物替换为通式(II-1A)、(II-2A)、(II-3A)、(II-4A)、(III-1A)、(III-2A)、(III-3A)或(III-4A)所示化合物；中间体2通式(IB)化合物也作相应替换，具体如下表：
Figure PCTCN2020091695-appb-000036
Figure PCTCN2020091695-appb-000037
Figure PCTCN2020091695-appb-000038
Figure PCTCN2020091695-appb-000039
反应条件与方案一相同：即在碱性条件下发生缩合反应，制备得到产物。
上述反应中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、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、醋酸钠、醋酸钾、碳酸钾或碳酸铯、氢氧化钠、氢氧化锂和氢氧化钾；优选N,N-二异丙基乙胺。
上述反应在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、正丁醇、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、水或N,N-二甲基甲酰胺及其混合物，优选N,N-二甲基甲酰胺。
上述缩合反应中的缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N，N'，N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。
在以上说明书中提出了本公开一种或多种实施方式的细节。虽然可使用与本文所述类似或相同的任何方法和材料来实施或测试本公开，但是以下描述优选的方法和材料。通过说明书和权利要求书，本公开的其他特点、目的和优点将是显而易见的。在说明书和权利要求书中，除非上下文中有清楚的另外指明，单数形式包括复数指代物的情况。除非另有定义，本文使用的所有技术和科学术语都具有本公开所属领域普通技术人员所理解的一般含义。说明书中引用的所有专利、专利申请和出版物都通过引用纳入。提出以下实施例是为了更全面地说明本公开的优选实施方式。这些实施例不应以任何方式理解为限制本公开的范围，本公开的范围由权利要求书限定。
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-6110/6120Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole 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，C：石油醚/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
(S)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(6-(5-甲基-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)丙酰胺1-P1
(R)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(6-(5-甲基-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)丙酰胺1-P2
Figure PCTCN2020091695-appb-000040
Figure PCTCN2020091695-appb-000041
第一步
4-溴-2-(2-甲氧基乙烯基)-1-甲苯磺酰基-1H-吡咯1c
将(甲氧基甲基)三苯基氯化膦1b(12.5g，36.6mmol)溶于150mL四氢呋喃，降温至0℃，加入叔丁醇钾(4.1g，36.6mmol)，搅拌反应0.5小时，加入4-溴-1-甲苯磺酰基-1H-吡咯-2-甲醛1a(4.0g，612.19mmol，Journal of Organic Chemistry,2006,vol.71,#11,p.4092–4102)，搅拌14小时。加100mL水，反应液减压浓缩，用柱层析以洗脱剂体系C纯化得到标题化合物1c(5.2g)，产率：79.8％。
MS m/z(ESI):356.0[M+1]
第二步
2-(4-溴-1-甲苯磺酰基-1H-吡咯-2-基)乙醛1d
将化合物1c(5.2g，14.6mmol)溶于20mL四氢呋喃中，加入15mL浓盐酸，搅拌反应3小时。加饱和碳酸氢钠调节pH至7。反应液用乙酸乙酯萃取(150mL×2)，有机相浓缩，得到标题粗品化合物1d(4.9g)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):342.1[M+1]
第三步
(R)-2-((2-(4-溴-1-甲苯磺酰基-1H-吡咯-2-基)乙基)氨基)丙酸叔丁酯1f
将D-丙氨酸叔丁酯盐酸盐1e(3.11g，21.5mmol，上海毕得医药科技有限公司)溶于25mL甲醇，加入无水碳酸钾(4.76g，34.4mmol)，搅拌0.5小时，过滤除去不溶物，加入化合物1d(4.9g，14.3mmol)，降温至0℃，加入硼氰化钠(1.35g,21.5mmol)，搅拌14小时。反应液中加100mL水，乙酸乙酯萃取(150mL×2)，无水硫酸钠干燥，减压浓缩，用柱层析以洗脱剂体系B纯化得到标题化合物1f(2.2g)，产率：33％。
MS m/z(ESI):471.1[M+1]
第四步
(R)-2((2-(4-溴-1H-吡咯-2-基)乙基)氨基)丙酸叔丁酯1g
将化合物1f(2.2g，4.67mmol)溶于10mL四氢呋喃中，加入15mL四丁基氟化铵1M四氢呋喃溶液，65℃搅拌反应1小时。加50mL饱和碳酸氢钠溶液。反应液乙酸乙酯萃取(100mL×2)，有机相浓缩，用柱层析以洗脱剂体系B纯化得到标题化合物1g(700mg),产率：47.2％。
MS m/z(ESI):317.2[M+1]
第五步
(R)-2-(6-溴-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)丙酸叔丁酯1h
将化合物1g(700mg，2.21mmol)溶于10mL四氢呋喃中，加入N,N'-羰基二咪唑(1.07g，6.62mmol)，搅拌0.5小时，加入氢化钠(60％，254mg，6.62mmol)，搅拌反应14小时。加水，反应液减压浓缩，用薄层色谱法的展开剂体系C纯化得到标题化合物1h(680mg)，产率：89.7％。
MS m/z(ESI):343.2M+1]
第六步
(R)-2-(1-氧代-6-(4,4,5,5-四甲基1,3,2-二氧代硼杂环戊烷-2-基)-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)丙酸叔丁酯1i
在氩气氛下，将化合物1h(680mg，1.98mmol)溶于30mL 1,4-二氧六环中，依次加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(290mg，0.40mmol)，乙酸钾(389mg，3.96mmol)，在70℃搅拌2小时。冷却，通过硅藻土过滤，将滤液浓缩，用薄层色谱法的展开剂体系C纯化得到标题化合物1i(550mg)，产率：71.1％。
MS m/z(ESI):391.2[M+1]
第七步
4-氯-5-甲基-2-(甲基磺酰基)嘧啶1n
将4-氯-5-甲基-2-(甲硫基)嘧啶1m(500mg，2.86mmol，上海毕得医药有限公司)溶于10mL的二氯甲烷中，加入间氯过氧苯甲酸(1.270g，6.3mmol)，搅拌反应2小时。饱和硫代硫酸钠溶液洗涤，饱和氯化钠溶液洗涤，无水硫酸钠干燥， 过滤，滤液减压浓缩得到粗品标题化合物1n(445mg)，产物不经纯化，直接用于下步反应。
MS m/z(ESI):207.2[M+1]
第八步
4-氯-5-甲基-N-(1-甲基-1H-吡唑-5-基)嘧啶-2-胺1j
将N-(1-甲基-1H-吡唑-5-基)甲酰胺1o(270mg，2.15mmol，采用专利申请“WO201780979中说明书第88页的实施例2”公开的方法制备而得)，溶于N,N-二甲基甲酰胺中，0℃下加入氢化钠(60％，250mg，6.5mmol)，搅拌反应0.5小时，加入粗品化合物1n(445mg，2.15mmol)，继续反应2小时。加水20mL，乙酸乙酯萃取(20mL×3)，合并有机相减压浓缩，用薄层色谱法以展开剂体系C纯化所得残余物，得到标题化合物1j(240mg)，产率：49.7％。
MS m/z(ESI):224.3[M+1]
第九步
(R)-2-(6-(5-甲基-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)丙酸叔丁酯1k
在氩气氛下，将化合物1i(400mg，1.02mmol)溶于6mL二氧六环和1mL水中，依次加入化合物1j(252mg，1.12mmol)，碳酸铯(668mg，2.05mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(150mg，0.20mmol)，80℃搅拌14小时。冷却，通过硅藻土过滤，将滤液浓缩，用柱层析以洗脱剂体系A纯化得到标题化合物1k(340mg)，产率：73.1％。
MS m/z(ESI):452.2[M+1]
第十步
(R)-2-(6-(5-甲基-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)丙酸1l
将化合物1k(340mg，0.75mmol)溶于3mL二氯甲烷中，滴加1mL三氟乙酸，加毕，搅拌反应1小时。有机相浓缩，得到标题化合物1l(297mg)，产率：99％。MS m/z(ESI):396.2[M+1]
第十一步
(S)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(6-(5-甲基-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)丙酰胺1-P1
(R)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(6-(5-甲基-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)丙酰胺1-P2
将化合物1l(297mg，0.75mmol)和化合物1p(139mg，0.75mmol，上海皓鸿生物医药科技有限公司)溶于5mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(286mg,0.75mmol)，N,N-二异丙基乙胺(194mg,1.5mmol)，搅拌反应14小时。减压浓缩，残余物用液相制备纯化(仪器型号:Gilson281色谱柱:X-Bridge，Prep 30*150mm；5μm；C18流动相:A-水(10mM碳酸氢铵) B-乙腈，流速:30mL/min柱温:室温)得到标题化合物1-P1和1-P2(30mg，30mg)。
单一构型化合物(较短保留时间)1-P1
MS m/z(ESI):563.2[M+1]
HPLC分析:保留时间16.1分钟，纯度：98.5％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM碳酸氢铵)B-乙腈，梯度配比：A 23％-42％)
1H NMR(400MHz,CD 3OD)δ8.18(d,1H),7.84(s,1H),7.96(s,1H),7.42-7.42(m,1H)6.57-6.73(m,3H),6.63-6.32(m,1H),5.17-5.18(m,1H),4.89-4.94(m,1H),3.74-3.81(m,10H),2.95-3.00(m,2H),2.37(s,3H),1.52(d,3H)。
单一构型化合物(较长保留时间)1-P2
MS m/z(ESI):563.2[M+1]
HPLC分析:保留时间18.4分钟，纯度：97.2％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM碳酸氢铵)B-乙腈，梯度配比：A 23％-42％)MS m/z(ESI):563.2[M+1]
1H NMR(400MHz,CD 3OD)δ8.22(s,1H),7.96(s,1H),7.58(s,1H),6.59-6.75(m,4H),6.48(s,1H),5.17-5.19(m,1H),4.95-4.96(m,1H),3.72-3.81(m,10H),3.02-3.05(m,2H),2.43(s,3H),1.50(d,3H)。
实施例2
(S)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺2-P1
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺2-P2
Figure PCTCN2020091695-appb-000042
Figure PCTCN2020091695-appb-000043
第一步
(R)-2-(6-(2,5-二氯嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)丙酸叔丁酯2b
在氩气氛下，将化合物1i(580mg，1.48mmol)溶于6mL二氧六环和1mL水中，依次加入化合物2a(327mg，1.78mmol,上海毕得医药有限公司)，碳酸钠(315mg，2.97mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(126mg，0.15mmol)，微波80℃反应1小时。冷却，通过硅藻土过滤，将滤液浓缩，用柱层析以洗脱剂体系A纯化得到标题化合物2b(200mg)，产率：32.7％。
MS m/z(ESI):411.2[M+1]
第二步
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)丙酸叔丁酯2d
将化合物2b(200mg，0.49mmol)，化合物2c(148mg，1.45mmol，上海毕得医药有限公司)，N,N-二异丙基乙胺(126mg，0.98mmol)溶于10mL四氢呋喃，微波100℃搅拌反应4小时。冷却，反应液减压浓缩，用薄层色谱法的展开剂体系C纯化得到标题化合物2d(100mg)，产率：43.2％。
MS m/z(ESI):476.2[M+1]
第三步
(R)-2-(6-(5-甲基-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)丙酸2e
将化合物2d(100mg，0.21mmol)溶于3mL二氯甲烷中，滴加1mL三氟乙酸，加毕，搅拌反应1小时。有机相浓缩，得到标题化合物2e(88mg)，产率：99％。MS m/z(ESI):420.1[M+1]
第四步
(S)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺2-P1
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺2-P2
将化合物2e(88mg，0.21mmol)和化合物1p(38.8mg，0.21mmol)溶于5mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(79.7mg,0.21mmol)，N,N-二异丙基乙胺(54.2mg,0.42mmol)，搅拌反应14小时。减压浓缩，残余物用液相制备纯化(仪器型号:Gilson 281色谱柱:Sharpsil-T，X-Bridge，Prep 30*150mm；5μm；C18流动相:A-水(10mM碳酸氢胺)B-乙腈，流速:30mL/min柱温:室温)得到标题化合物2-P1和2-P2(30mg，30mg)。
单一构型化合物(较短保留时间)2-P1
MS m/z(ESI):587.2[M+1]
HPLC分析:保留时间16.1分钟，纯度：98.2％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM碳酸氢铵)B-乙腈，梯度配比：A 30％-48％)
1H NMR(400MHz,CD 3OD)δ8.24(s,1H),8.19(s,1H),6.71-6.75(m,3H)6.56(d,1H),5.16-5.18(m,1H),4.94-4.98(m,1H),3.98-4.01(m,3H),3.74-3.78(m,5H),3.51-3.62(m,4H),2.95-2.99(m,2H),1.99-2.01(m,2H),1.52-1.62(m,5H)。
单一构型化合物(较长保留时间)2-P2
MS m/z(ESI):587.2[M+1]
HPLC分析:保留时间18.2分钟，纯度：96.8％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM碳酸氢铵)B-乙腈，梯度配比：A 30％-48％)
1H NMR(400MHz,CD 3OD)δ8.22(s,1H),8.15(s,1H),6.67-6.74(m,3H)6.56(d,1H),5.14-5.16(m,1H),4.90-4.93(m,1H),3.94-3.97(m,3H),3.56-3.97(m,9H),2.95-3.02(m,2H),1.95-1.99(m,2H),1.45-1.60(m,5H)。
实施例3
(S)-2-(2-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-8-氧代-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺3-P1
(R)-2-(2-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-8-氧代-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺3-P2
Figure PCTCN2020091695-appb-000044
第一步
(叔丁氧基羰基)(2-(4-(2,5-二氯嘧啶-4-基)-2-(乙氧羰基)-1H-咪唑-1-基)乙基)氨基磺酸3b
将4-(2,5-二氯嘧啶-4-基)-1H-咪唑-2-羧酸乙酯3a(830mg，2.89mmol，采用专利申请“WO201780979A1中说明书第114页的实施例31”公开的方法制备而得)，碳酸钾(1.2g，8.68mmol)和18-冠醚-6(0.153g，0.58mmol)溶于20mL的二氧六环中，加入2,2-二氧杂噻唑烷-3-羧酸叔丁酯，加毕升温至110℃反应14小时。反应液冷却，过滤，滤饼用二氯甲烷洗，收集滤液，滤液旋干得到标题化合物3b粗品(1.3g)，直接用于下一步反应。
MS m/z(ESI):510.1[M+1]
第二步
1-(2-氨基乙基)-4-(2,5-二氯嘧啶-4-基)-1H-咪唑-2-羧酸乙酯3c
将粗品化合物3b(1.3g，2.55mmol)溶解于盐酸异丙醇溶液(5mol/L)，搅拌1小时。旋干得到标题化合物3c粗品(0.84g)，直接用于下一步反应。
MS m/z(ESI):330.1[M+1]
第三步
2-(2,5-二氯嘧啶-4-基)-6,7-二氢咪唑并[1,2-a]吡嗪-8(5H)-酮3d
将粗品化合物3c(0.84g，2.55mmol)溶解于氨甲醇溶液(7mol/L)，搅拌14小时。反应液浓缩，用柱层析以洗脱剂体系A得到标题化合物3d(0.7g，2.46mmol)，产率：59.2％。
MS m/z(ESI):284.0[M+1]
第四步
2-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-6,7-二氢咪唑并[1,2-a]吡嗪-8(5H)-酮3f
将化合物3d(0.15g，0.53mmol)，化合物2c(53.40mg，0.53mmol)，N,N二异丙基乙胺(0.34g，2.64mmol)，N,N-二甲基乙酰胺(3mL)混合，微波110℃反应1.5小时。将滤液浓缩，用薄层层析以展开剂体系A纯化所得残余物得到标题化合物3f(0.1g，0.29mmol)，产率：54.0％.
MS m/z(ESI):349.2[M+1]
第五步
2-(2-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-8-氧代-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)丙酸叔丁酯3g
将化合物3f(0.1g，0.29mmol)溶于5mL N,N-二甲基甲酰胺中，降温至0℃，加入氢化钠(60％，20mg，0.86mmol)，搅拌反应0.5小时，加入2-溴丙酸叔丁酯(89mg，0.43mmol，上海毕得医药有限公司)，搅拌14小时。将滤液浓缩，用薄层色谱法的展开剂体系A纯化得到标题化合物3g(100mg)，产率：73.1％。
MS m/z(ESI):477.2[M+1]
第六步
2-(2-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-8-氧代-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)丙酸3h
将化合物3g(100mg，0.21mmol)溶于10mL二氯甲烷中，滴加1mL三氟乙酸，加毕，搅拌反应1小时。有机相浓缩，得到标题化合物3h(88mg)，产率：99.0％。MS m/z(ESI):421.1[M+1]
第七步
(S)-2-(2-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-8-氧代-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺3-P1
(R)-2-(2-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-8-氧代-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺3-P2
将化合物3h(88mg，0.21mmol)和化合物1p(32mg，0.21mmol)溶于5mL N,N- 二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(148mg,0.63mmol)，N,N-二异丙基乙胺(81mg,0.63mmol)，搅拌反应14小时。减压浓缩，残余物用液相制备纯化(仪器型号:Gilson 281色谱柱:X-Bridge，Prep 30*150mm；5μm；C18流动相:A-水(10mM碳酸氢铵)B-乙腈，流速:30mL/min柱温:室温)得到标题化合物3-P1和3-P2(2mg，5mg)。
单一构型化合物(较短保留时间)3-P1
MS m/z(ESI):588.2[M+1]
HPLC分析:保留时间15.5分钟，纯度：99.1％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM碳酸氢铵)B-乙腈，梯度配比：A 30％-45％)
1H NMR(400MHz,CDCl 3):8.76(s,1H)，8.32(s,1H),8.15(s,1H),6.78-6.70(m,1H),6.60(d,1H),6.57(d,1H),5.43-5.40(m,1H),4.98-4.95(m,1H),4.6-4.3(m,2H),4.2-4.1(m,1H),4.0-3.9(m,4H),3.76(s,3H),3.62-3.45(m,3H),2.37-2.33(m,1H),2.0-1.92(m,2H),1.71-1.52(m,2H),1.45(d,3H)。
单一构型化合物(较长保留时间)3-P2
MS m/z(ESI):588.2[M+1]
HPLC分析:保留时间17.8分钟，纯度：98.2％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM碳酸氢铵)B-乙腈，梯度配比：A 30％-45％)
1H NMR(400MHz,CDCl 3):δ8.76(s,1H),8.32(s,1H),8.15(s,1H),6.78-6.70(m,1H),6.60(d,1H),6.57(d,1H),5.43-5.40(m,1H),4.98-4.95(m,1H),4.6-4.3(m,2H),4.2-4.1(m,1H),4.0-3.9(m,4H),3.76(s,3H),3.62-3.45(m,3H),2.37-2.33(m,1H),2.0-1.92(m,2H),1.71-1.52(m,2H),1.45(d,3H)。
实施例4
(S)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺4-P1
(R)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺4-P2
Figure PCTCN2020091695-appb-000045
Figure PCTCN2020091695-appb-000046
第一步
4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡咯-2-羧酸甲酯4b
在氩气氛下，将4-溴-1H-吡咯-2-甲酸甲酯4a(15g，73.52mmol，南京药石科技有限公司)溶于300mL 1,4-二氧六环中，依次加入4,4,4’,4’,5,5,5’,5’-八甲基-2,2’-二(1,3,2-二氧硼杂环戊烷)(22.41g，88.25mmol，韶远科技(上海)有限公司)，乙酸钾(14.13g，147.03mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(8g，10.93mmol)，在90℃搅拌16小时。冷却，通过硅藻土过滤，将滤液浓缩，用薄层层析以展开剂体系C纯化得到标题化合物4b(10g)，产率：54.0％。
MS m/z(ESI):252.2[M+1]
第二步
4-(2,5-二氯嘧啶-4-基)-1H-吡咯-2-羧酸甲酯4c
在氩气氛下，将化合物4b(5g，19.91mmol)溶于100mL二氧六环，10mL水 中，依次加入化合物2a(4g，21.81mmol,韶远科技(上海)有限公司)，碳酸钠(4.22g，39.82mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(2.48g，2.98mmol)，80℃搅拌3小时。冷却，通过硅藻土过滤，将滤液浓缩，用柱层析以洗脱剂体系A纯化得到标题化合物4c(2.6g)，产率：48.0％。
MS m/z(ESI):272.1[M+1]
第三步
1-(2-((叔丁氧基羰基)氨基)乙基)-4-(2,5-二氯嘧啶-4-基)-1H-吡咯-2-羧酸甲酯4e
将化合物4c(2.2g，8.9mmol)溶于20mL二氧六环中，依次加入化合物4d(1.8g，8.06mmol,韶远科技(上海)有限公司)，碳酸钾(3.35g，24.23mmol)和18-冠-6(427.4mg，1.6mmol)，110℃搅拌14小时。冷却，通过硅藻土过滤，将滤液浓缩，用柱层析以洗脱剂体系A纯化得到标题化合物4e(3.2g)，产率：95.3％。
MS m/z(ESI):415.1[M+1]
第四步
1-(2-((叔丁氧基羰基)氨基)乙基)-4-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1H-吡咯-2-羧酸甲酯4f
将化合物4e(1.56g，7.7mmol)，化合物2c(1.56g，15.4mmol，上海毕得医药有限公司)，N,N二异丙基乙胺(0.78g，7.7mmol)，N,N-二甲基乙酰胺(3mL)混合，微波110℃反应1.5小时。将滤液浓缩，用薄层层析以展开剂体系A纯化所得残余物得到标题化合物4f(1.7g)，产率：46％。
MS m/z(ESI):480.3[M+1]
第五步
1-(2-氨乙基)-4-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1H-吡咯-2-羧酸甲酯4g
将化合物4f(1.7g，3.54mmol)溶于10mL二氯甲烷中，滴加20mL 4.0M氯化氢二氧六环溶液，加毕，搅拌反应2小时。减压浓缩，得到粗品化合物4g(1.4g)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):380.2[M+1]
第六步
7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-3,4-二氢吡咯并[1,2-a]吡嗪-2-(1H)-酮4h
将粗品化合物4g(1.4g，3.4mmol)溶解于10ml氨甲醇溶液(7mol/L)，搅拌14小时。减压浓缩，得到粗品化合物4h(1.1g)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):348.1[M+1]
第七步
2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2-(1H)-基)丙酸叔丁酯4i
将化合物4h(1.4g，3.16mmol)溶于20mL N,N-二甲基甲酰胺中，降温至0℃，加入氢化钠(60％，411.4mg，9.5mmol)，搅拌反应0.5小时，加入2-溴丙酸叔丁酯(992mg，4.74mmol)，搅拌14小时。将滤液浓缩，用薄层色谱法的展开剂体系A纯化得到标题化合物4i(1.2g)，产率：62.6％。
MS m/z(ESI):476.2[M+1]
第八步
2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2-(1H)-基)丙酸4j
将化合物4i(1.2g，2.52mmol)溶于10mL二氯甲烷中，滴加1mL三氟乙酸，加毕，搅拌反应1小时。减压浓缩，得到粗品化合物4j(1.3g)，产物不经纯化，直接用于下一步反应
MS m/z(ESI):420.1[M+1]
第九步
(S)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺4-P1
(R)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺4-P2
将化合物4j(17mg，31.8μmol)和化合物1p(7.1mg，38.2μmol)溶于5mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(11.2mg,47.8μmol)，N,N-二异丙基乙胺(12.4mg,0.1mmol)，搅拌反应14小时。将滤液浓缩，用液相制备纯化(仪器型号:Gilson 281色谱柱:X-Bridge，Prep 30*150mm；5μm；C18流动相:A-水(10mM碳酸氢铵)B-乙腈，流速:30mL/min柱温:室温)得到标题化合物4-P1和4-P2(5mg，5mg)，产率：26.7％，26.7％。
单一构型化合物(较短保留时间)4-P1
MS m/z(ESI):587.2[M+1]
HPLC分析:保留时间17.6分钟，纯度：96.8％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM碳酸氢铵)B-乙腈，梯度配比：A 23％-42％)
1H NMR(400MHz,CDCl 3):δ8.21(s,1H),7.74(d,1H),7.67(d,1H),749-7.45(m,2H),6.63-6.61(m,2H),6.04-5.91(m,1H),5.43-5.37(m,3H),5.25-5.22(m,1H),5.03-5.01(m,1H),4.17-4.15(m,2H),4.05-4.02(m,2H),3.92-3.87(m,2H),3.72(s,3H),3.60-3.58(m,3H),2.12-2.03(m,4H),1.45(d,3H)。
单一构型化合物(较长保留时间)4-P2
MS m/z(ESI):587.2[M+1]
HPLC分析:保留时间19.1分钟，纯度：98.2％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM碳酸氢铵)B-乙腈，梯度配比：A 23％-42％) 1H NMR(400MHz,CDCl 3):δ8.21(s,1H),7.67(d,1H),7.56(d,1H),748-7.45(m,2H),6.71-6.67(m,2H),6.59-6.51(m,1H),5.40-5.37(m,3H),5.20-5.18(m,1H), 5.08-5.06(m,1H),4.17-4.10(m,2H),4.05-4.02(m,2H),3.89-3.83(m,3H),3.82(s,3H),3.62-3.57(m,2H),2.32-2.23(m,4H),1.47(d,3H)。
实施例5
2-(2-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-8-氧代-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺5
Figure PCTCN2020091695-appb-000047
采用实施例3中的合成路线，将第七步原料化合物1p替换为化合物(S)-2-氨基-2-(间甲苯基)乙醇(上海毕得医药科技有限公司)，制得标题化合物5(12mg)。
MS m/z(ESI):554.2[M+1]
1H NMR(400MHz,CDCl 3):δ8.76(s,1H),8.32(s,1H),8.15(s,1H),6.79(s,1H),6.60-6.59(d,1H),6.56(d,1H),5.43-5.39(m,1H),4.97-4.94(m,1H),4.6-4.5(m,1H),4.5-4.4(m,1H),4.15-4.05(m,1H),4.05-3.9(m,4H),3.9-3.7(m,2H),3.6-3.4(m,2H),2.05-1.95(m,2H),1.63-1.53(m,2H),1.44(d,3H),1.28(s,3H)。
实施例6
(S)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-3-氧代-1H-吡咯并[1,2-c]咪唑-2(3H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟基乙基)丙酰胺6-P1
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-3-氧代-1H-吡咯并[1,2-c]咪唑-2(3H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟基乙基)丙酰胺6-P2
Figure PCTCN2020091695-appb-000048
Figure PCTCN2020091695-appb-000049
第一步
((4-溴-1H-吡咯-2-基)甲基)-D-丙氨酸叔丁酯6a
将化合物1e(417mg，2.30mmol，上海毕得医药科技有限公司)溶于甲醇(5mL)，加入无水碳酸钾(476mg，3.44mmol)，搅拌30分钟，过滤除去不溶物，加入化合物1b(500mg，2.87mmol)，降温至0℃，加入硼氢化钠(108mg，2.87mmol)，搅拌反应2小时。反应液中加水，乙酸乙酯萃取(10mL×2)，无水硫酸钠干燥，减压浓缩，用柱层析以洗脱剂体系B纯化得到标题化合物6a(600mg)，产率：68.0％。MS m/z(ESI):303.1[M+1]
第二步
(R)-2-(6-溴-3-氧代-1H-吡咯并[1,2-c]咪唑-2(3H)-基)丙酸叔丁酯6b
将化合物6a(800mg，2.64mmol)，N,N'-羰基二咪唑(513mg，3.16mmol)溶于60mL四氢呋喃，搅拌反应0.5小时。加入氢化钠(60％，121mg，3.16mmol)，搅拌14小时。加水，反应液减压浓缩，用柱层析以洗脱剂体系B纯化得到标题化合物6b(400mg)，产率：46.0％。
MS m/z(ESI):329.1[M+1]
第三步
(R)-2-(3-氧代-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡咯并[1,2-c]咪唑-2(3H)-基)丙酸叔丁酯6c
在氩气氛下，将化合物6b(200mg，0.61mmol)溶于3mL 1,4-二氧六环中，依次加入4,4,4’,4’,5,5,5’,5’-八甲基-2,2’-二(1,3,2-二氧硼杂环戊烷)(184mg，0.72mmol)，乙酸钾(119mg，1.21mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(44mg，0.06mmol)，在90℃搅拌2小时。冷却，通过硅藻土过滤，将滤液浓缩，用薄层层析以展开剂体系C纯化得到标题化合物6c(100mg)，产率：44.0％。
MS m/z(ESI):377.2[M+1]
第四步
4,5-二氯-N-(四氢-2H-吡喃-4-基)嘧啶-2-胺6d
将化合物2a(1g，5.45mmol)，化合物2c(551mg，5.45mmol)，N,N-二异丙基乙胺(2g，15.47mmol)，2mL N,N-二甲基乙酰胺，在140℃反应0.5小时，冷却，减压浓缩，用柱层析以洗脱剂体系C纯化得到标题化合物6d(120mg)，产率：8.8％。MS m/z(ESI):248.1[M+1]
第五步
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-3-氧代-1H-吡咯并[1,2-c]咪唑-2(3H)-基)丙酸叔丁酯6e
在氩气氛下，将化合物6c(100mg，0.265mmol)溶于50mL二氧六环中，依次加入化合物6d(60mg，0.242mmol)，碳酸钾(67mg，0.485mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(18mg，0.025mmol)，在微波85℃搅拌1.5小时。冷却，通过硅藻土过滤，将滤液浓缩，用柱层析以洗脱剂体系A纯化得到标题化合物6e(50mg)，产率：45.0％。
MS m/z(ESI):462.2[M+1]
第六步
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-3-氧代-1H-吡咯并[1,2-c]咪唑-2(3H)-基)丙酸6f
将化合物6e(60mg，0.14mmol)溶于3mL二氯甲烷中，滴加0.5mL三氟乙酸，加毕，搅拌反应2小时。减压浓缩，得到粗品化合物6f(52mg)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):406.2[M+1]
第七步
(S)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-3-氧代-1H-吡咯并[1,2-c]咪唑-2(3H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟基乙基)丙酰胺6-P1
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-3-氧代-1H-吡咯并[1,2-c]咪唑-2(3H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟基乙基)丙酰胺6-P2
将粗品化合物6f(52mg，0.013mmol)和化合物1p(35mg，0.019mmol)溶于5mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(45mg，0.19mmol)和N,N-二异丙基乙胺(82mg，0.63mmol)，搅拌反应1.5小 时。减压浓缩，高效液相制备纯化得到化合物6-P1和6-P2(12mg,12mg)，产率：16.3％,16.3％。
单一构型化合物(较短保留时间)6-P1
MS m/z(ESI):573.3[M+1]
HPLC分析:保留时间17.1分钟，纯度：97.9％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM乙酸铵)B-乙腈，梯度配比：A 5％-95％)
1H NMR(400MHz,CD 3OD):δ8.20(s,1H),8.04(s,1H),6.90(s,1H),6.73(s,1H),6.68(d,1H),6.55(d,1H),4.78-4.65(m,3H),4.01-3.98(m,3H),3.80-3.72(m,6H),3.59-3.57(m,2H),2.02-1.96(m,2H),1.65-1.55(m,5H)。
单一构型化合物(较长保留时间)6-P2
MS m/z(ESI):573.3[M+1]
HPLC分析:保留时间18.5分钟，纯度：98.2％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM乙酸铵)B-乙腈，梯度配比：A 25％-45％)
1H NMR(400MHz,CD 3OD):δ8.19(s,1H),8.05(s,1H),6.90(s,1H),6.74(s,1H),6.64(d,1H),6.59(d,1H),4.73-4.69(m,3H),4.00-3.97(m,3H),3.80-3.72(m,6H),3.58-3.53(m,2H),2.02-1.96(m,2H),1.65-1.55(m,5H)。
实施例7
(S)-2-(6-(5-氯-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-3-氧代-1H-吡咯并[1,2-c]咪唑-2(3H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟基乙基)丙酰胺7-P1
(R)-2-(6-(5-氯-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-3-氧代-1H-吡咯并[1,2-c]咪唑-2(3H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟基乙基)丙酰胺7-P2
Figure PCTCN2020091695-appb-000050
Figure PCTCN2020091695-appb-000051
第一步
(R)-2-(6-(2,5-二氯嘧啶-4-基)-3-氧代-1H-吡咯并[1,2-c]咪唑-2(3H)-基)-丙酸叔丁酯7a
在氩气氛下，将化合物6c(1.2g，3.2mmol)溶于30mL二氧六环和6mL水中，依次加入化合物2a(702mg，3.83mmol，上海毕得医药有限公司)，碳酸钠(676mg，6.37mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(233mg，0.32mmol)，80℃搅拌14小时。冷却，通过硅藻土过滤，将滤液浓缩，用柱层析以洗脱剂体系A纯化得到标题化合物7a(400mg)，产率：31.5％。
MS m/z(ESI):397.2[M+1]
第二步
(R)-2-(6-(5-氯-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-3-氧代-1H-吡咯并[1,2-c]咪唑-2(3H)-基)丙酸叔丁酯7c
在氩气氛下，将化合物7a(400mg，1.01mmol)溶于15mL 1,4-二氧六环，加入三(二亚苄基丙酮)二钯(92mg，0.1μmol)，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(117mg，0.2μmol)，碳酸铯(656mg，2.01mmol)，1-甲基-5-氨基吡唑7b(147mg，1.51mmol，上海毕得医药有限公司)，100℃搅拌反应14小时。冷却，通过硅藻土过滤，滤液浓缩，用薄层色谱法的展开剂体系A纯化得到标题化合物7c(180mg)，产率：39.0％。
MS m/z(ESI):458.2[M+1]
第三步
(R)-2-(6-(5-氯-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-3-氧代-1H-吡咯并[1,2-c]咪唑-2(3H)-基)丙酸7d
将化合物7c(180mg，0.39mmol)溶于3mL二氯甲烷中，滴加0.5mL三氟乙酸，加毕，搅拌反应2小时。减压浓缩，得到粗品化合物7d(157mg)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):402.2[M+1]
第四步
(S)-2-(6-(5-氯-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-3-氧代-1H-吡咯并[1,2-c]咪唑-2(3H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟基乙基)丙酰胺7-P1
(R)-2-(6-(5-氯-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-3-氧代-1H-吡咯并[1,2-c]咪唑-2(3H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟基乙基)丙酰胺7-P2
将粗品化合物7d(158mg，0.39mmol)和化合物1p(73mg，0.39mmol)溶于5mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(179mg,0.47mmol)，N,N-二异丙基乙胺(152mg,1.18mmol)，搅拌反应14小时。减压浓缩，高效液相制备纯化得到化合物7-P1，7-P2(20mg，20mg)，产率：9％,9％。
单一构型化合物(较短保留时间)7-P1
MS m/z(ESI):569.1[M+1]
HPLC分析:保留时间12.4分钟，纯度：98.2％(色谱柱:X-Bridge，Prep 30*150mm；5μm；流动相:A-水(10mM乙酸铵)B-乙腈，梯度配比：A 30％-46％)
1H NMR(400MHz,CD 3OD):δ8.37(s,1H),8.08(s,1H),7.45(d,1H),6.85(s,1H),6.67-6.66(m,2H),6.56-6.53(m,1H),6.33(d,1H),4.86-4.84(m,1H),4.60(d,2H),3.77-3.72(m,9H),1.61(d,3H)。
单一构型化合物(较长保留时间)7-P2
MS m/z(ESI):569.1[M+1]
HPLC分析:保留时间14.5分钟，纯度：97.2％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM乙酸铵)B-乙腈，梯度配比：A 30％-46％)
1H NMR(400MHz,CD 3OD):δ8.37(s,1H),8.10(s,1H),7.44(d,1H),6.75(s,1H),6.68-6.66(m,2H),6.56-6.53(m,1H),6.33(d,1H),4.86-4.84(m,1H),4.60(d,2H),3.80-3.74(m,9H),1.56(d,3H)。
实施例8
(S)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基-2-(6-(5-甲基-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-3-氧代-1H-吡咯并[1,2-c]咪唑-2(3H)-基)丙酰胺8-P1
(R)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基-2-(6-(5-甲基-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-3-氧代-1H-吡咯并[1,2-c]咪唑-2(3H)-基)丙酰胺8-P2
Figure PCTCN2020091695-appb-000052
采用实施例3中的合成路线，将第四步原料化合物2a替换为化合物1j，制得化合物8-P1和8-P2(5mg，5mg)。
单一构型化合物(较长保留时间)8-P1
MS m/z(ESI):549.2[M+1]
HPLC分析:保留时间13.1分钟，纯度：98.5％(色谱柱X-Bridge，Prep 30*150mm；5μm；流动相:A-水(10mM碳酸氢铵)B-乙腈，梯度配比：A 22％-40％)
1H NMR(400MHz,CDCl 3):8.10(s,1H),7.69(s,1H),7.58(s,1H),6.85-6.81(m,3H),6.66-6.63(m,1H),6.44(s,1H),5.05-5.02(m,1H),4.75(d,1H),4.56-4.50(m,2H),3.99-3.98(m,2H),3.97(s,3H),3.80(s,3H),2.43(s,3H),1.35(d,3H)。
单一构型化合物(较长保留时间)8-P2
MS m/z(ESI):549.2[M+1]
HPLC分析:保留时间15.5分钟，纯度：97.9％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM碳酸氢铵)B-乙腈，梯度配比：A22％-40％)
1H NMR(400MHz,CD 3OD):8.24(s,1H),7.77(s,1H),7.59(s,1H),6.78-6.75(m,2H),6.70-6.59(m,2H),6.49(s,1H),4.95-4.93(m,1H),4.86(d,1H),4.73(d,1H),4.58(d,1H),3.81-3.73(m,8H),2.43(s,3H),1.56(d,3H)。
实施例9
(S)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺9-P1
(R)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺9-P2
Figure PCTCN2020091695-appb-000053
Figure PCTCN2020091695-appb-000054
第一步
4-(2,5-二氯嘧啶-4-基)-1H-吡咯-2-羧酸甲酯9a
在氩气氛下，将化合物4b(5g，19.92mmol)溶于100mL二氧六环，10mL水中，依次加入化合物2a(4.38g，23.88mmol)，碳酸钠(3.16g，29.81mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(2.49g，2.99mmol)，80℃搅拌3小时。冷却，通过硅藻土过滤，将滤液浓缩，用柱层析以洗脱剂体系A纯化得到标题化合物9a(3g)，产率：55.3％。
MS m/z(ESI):272.0[M+1]
第二步
1-(2-((叔丁氧基羰基)氨基)乙基)-4-(2,5-二氯嘧啶-4-基)-1H-吡咯-2-羧酸甲酯9b
将化合物9a(2.2g，8.9mmol)溶于20mL二氧六环中，依次加入化合物4d(1.8g，8.06mmol)，碳酸钾(3.35g，24.23mmol)和18-冠-6(427.4mg，1.6mmol)，110℃搅拌14小时。冷却，通过硅藻土过滤，将滤液浓缩，用柱层析以洗脱剂体系A纯化得到标题化合物9b(3.2g)，产率：95.3％。
MS m/z(ESI):415.1[M+1]
第三步
1-(2-((叔丁氧基羰基)氨基)乙基)-4-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1H-吡咯-2-羧酸甲酯9c
将化合物9b(1.56g，7.7mmol)，化合物2c(1.56g，15.4mmol)，N,N二异丙 基乙胺(0.78g，7.7mmol)，N,N-二甲基乙酰胺(3mL)混合，微波110℃反应1.5小时。将滤液浓缩，用薄层层析以展开剂体系A纯化所得残余物得到标题化合物9c(1.7g)，产率：46％.
MS m/z(ESI):480.3[M+1]
第四步
1-(2-氨乙基)-4-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1H-吡咯-2-羧酸甲酯9d
将化合物9c(1.7g，3.54mmol)溶于10mL二氯甲烷中，滴加20mL 4.0M氯化氢二氧六环溶液，加毕，搅拌反应2小时。减压浓缩，得到粗品化合物9d(1.4g)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):380.2[M+1]
第五步
7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-3,4-二氢吡咯并[1,2-a]吡嗪-1(2H)-酮9e
将粗品化合物9d(1.4g，3.4mmol)溶解于10mL氨甲醇溶液(7mol/L)，搅拌14小时。减压浓缩，得到粗品化合物9e(1.1g)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):348.1[M+1]
第六步
2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酸叔丁酯9f
将化合物9e(1.4g，3.16mmol)溶于20mL N,N-二甲基甲酰胺中，降温至0℃，加入氢化钠(60％，411.4mg，9.5mmol)，搅拌反应0.5小时，加入2-溴丙酸叔丁酯(992mg，4.74mmol)，搅拌14小时。将滤液浓缩，用薄层色谱法的展开剂体系A纯化得到标题化合物9f(1.2g)，产率：62.6％。
MS m/z(ESI):476.2[M+1]
第七步
2-(7-(5-氯-2-(四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酸9g
将化合物9f(1.2g，2.52mmol)溶于10mL二氯甲烷中，滴加1mL三氟乙酸，加毕，搅拌反应1小时。减压浓缩，得到粗品化合物9g(1.3g)，产物不经纯化，直接用于下一步反应
MS m/z(ESI):420.1[M+1]
第八步
(S)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺9-P1
(R)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并 [1,2-a]吡嗪-2(1H)-基)-N-((S)-2-羟基-1-(间-甲苯基)乙基)丙酰胺9-P2
将化合物9g(120mg，0.25mmol)和化合物(S)-2-氨基-2-(间甲苯基)乙醇(44.2mg，0.29mmol)溶于5mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(79.33mg,0.37mmol)，N,N-二异丙基乙胺(72.6mg,0.56mmol)，搅拌反应14小时。减压浓缩，高效液相制备纯化得到化合物9-P1，9-P2(20mg，20mg)，产率：16％,16％。
单一构型化合物(较短保留时间)9-P1
MS m/z(ESI):553.2[M+1]
HPLC分析:保留时间11.1分钟，纯度：98.2％(色谱柱:X-Bridge，Prep 30*150mm；5μm；流动相:A-水(10mM乙酸铵)B-乙腈，梯度配比：A 40％-60％)
1H NMR(400MHz,CD 3OD):8.17(s,1H),7.90(s,1H),7.71(s,1H),7.19-7.04(m,4H),5.35-5.41(m,1H),4.97-4.94(m,1H),4.39-4.29(m,2H),4.02-3.99(m,3H),3.87-3.84(m,2H),3.77-3.74(m,2H),3.65-3.58(m,2H),2.25(s,3H),2.03-2.01(m,2H),1.66-1.59(m,2H),1.48(d,3H)。
单一构型化合物(较长保留时间)9-P2
MS m/z(ESI):553.2[M+1]
HPLC分析:保留时间12.5分钟，纯度：97.2％(色谱柱:X-Bridge，Prep 30*150mm；5μm；流动相:A-水(10mM乙酸铵)B-乙腈，梯度配比：A 40％-60％)
1H NMR(400MHz,CD 3OD):8.18(s,1H),7.93(s,1H),7.71(s,1H),7.24-7.08(m,4H),5.38-5.33(m,1H),4.98-4.95(m,1H),4.39-4.29(m,2H),4.02-3.99(m,3H),3.87-3.84(m,2H),3.76-3.73(m,2H),3.62-3.56(m,2H),2.35(s,3H),2.03-2.01(m,2H),1.67-1.58(m,2H),1.48(d,3H)。
实施例10
(S)-N-((S)-2-羟基-1-(间甲苯基)乙基)-2-(7-(5-甲基-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酰胺10-P1
(R)-N-((S)-2-羟基-1-(间甲苯基)乙基)-2-(7-(5-甲基-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酰胺10-P2
Figure PCTCN2020091695-appb-000055
Figure PCTCN2020091695-appb-000056
第一步
4-(2氯-5-甲基嘧啶-4-基)-1H-吡咯-2-羧酸甲酯10b
在氩气氛下，将化合物4b(12g，47.79mmol)溶于100mL二氧六环，10mL水中，依次加入化合物10a(8.6g，52.51mmol,韶远科技(上海)有限公司)，碳酸钠(10.1g，95.58mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(5.85g，7.18mmol)，80℃搅拌3小时。冷却，通过硅藻土过滤，将滤液浓缩，用柱层析以洗脱剂体系A纯化得到标题化合物10b(2g)，产率：16.6％。
MS m/z(ESI):252.1[M+1]
第二步
1-(2-((叔丁氧基羰基)氨基)乙基)-4-(2-氯-5-甲基嘧啶-4-基)-1H-吡咯-2-羧酸甲酯10c
将化合物10b(1g，3.97mmol)溶于20mL二氧六环中，依次加入化合物4d(887mg，3.97mmol)，碳酸钾(1.65g，11.9mmol)和18-冠-6(210mg，0.79mmol)，110℃搅拌14小时。冷却，通过硅藻土过滤，将滤液浓缩，用柱层析以洗脱剂体系A纯化得到标题化合物10c(800mg)，产率：51％。
MS m/z(ESI):395.1[M+1]
第三步
1-(2-氨乙基)-4-(2-氯-5-甲基嘧啶-4-基)-1H-吡咯-2-羧酸甲酯10d
将化合物10c(800mg，2mmol)溶于3mL二氯甲烷中，滴加5mL 4.0M氯化氢二氧六环溶液，加毕，搅拌反应2小时。减压浓缩，得到粗品化合物10d(638mg)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):295.1[M+1]
第四步
7-(2-氯-5-甲基嘧啶-4-基)-3,4-二氢吡咯并[1,2-a]吡嗪-1(2H)-酮10e
将粗品化合物10d(600mg，2.04mmol)溶解于10mL氨甲醇溶液(7mol/L)，搅拌14小时。减压浓缩，得到粗品化合物10e(534mg)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):263.2[M+1]
第五步
2-(7-(2-氯-5-甲基嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酸叔丁酯10f
将化合物10e(0.6g，2.28mmol)溶于5mL N,N-二甲基甲酰胺中，降温至0℃，加入氢化钠(60％，262mg，6.84mmol)，搅拌反应0.5小时，加入2-溴丙酸叔丁酯(955mg，4.57mmol)，搅拌14小时。将滤液浓缩，用薄层色谱法的展开剂体系A纯化得到标题化合物10f(600mg)，产率：67.2％。
MS m/z(ESI):391.1[M+1]
第六步
2-(7-(5-甲基-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酸叔丁酯10g
在氩气氛下，将化合物10h(150mg，0.38mmol)溶于6mL二氧六环中，依次加入化合物7b(56mg，0.58mmol)，碳酸铯(375mg，1.15mmol)和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(35mg，38.2μmol)，三(二亚苄基丙酮)二钯(35mg，38μmol)，90℃搅拌14小时。冷却，通过硅藻土过滤，将滤液浓缩，用柱层析以洗脱剂体系A纯化得到标题化合物10g(100mg)，产率：57.7％。
MS m/z(ESI):452.3[M+1]
第七步
2-(7-(5-甲基-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酸10h
将化合物10g(100mg，0.21mmol)溶于5mL二氯甲烷中，滴加1mL三氟乙酸，加毕，搅拌反应1小时。减压浓缩，得到粗品化合物10h(107mg)，产物不经纯化，直接用于下一步反应
MS m/z(ESI):396.2[M+1]
第八步
(S)-N-((S)-2-羟基-1-(间甲苯基)乙基)-2-(7-(5-甲基-2-((1-甲基-1H-吡唑-5-基)氨基) 嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酰胺10-P1
(R)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)-2-(7-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-1-oxo-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propanamide
(R)-N-((S)-2-羟基-1-(间-甲苯基)乙基)-2-(7-(5-甲基-2-(1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酰胺10-P2
将化合物10h(107mg，0.21mmol)和(S)-2-氨基-2-(间甲苯基)乙醇(38mg，0.25mmol)溶于5mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(100mg,0.26mmol)，N,N-二异丙基乙胺(81mg,0.63mmol)，搅拌反应14小时。减压浓缩，残余物用液相制备纯化(仪器型号:Gilson 281色谱柱:X-Bridge，Prep 30*150mm；5μm；C18流动相:A-水(10mM碳酸氢铵)B-乙腈，流速:30mL/min柱温:室温)得到标题化合物10-P1,10-P2(17mg，17mg)。产率：(15％，15％)。
单一构型化合物(较短保留时间)10-P1
MS m/z(ESI):529.3[M+1]
HPLC分析:保留时间11.3分钟，纯度：98.2％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM碳酸氢铵)B-乙腈，梯度配比：A 25％-39％)
1H NMR(400MHz,CD 3OD):8.14(s,1H),7.55(s,1H),7.46(s,1H),7.42(s,1H),7.19-7.06(m,3H),7.02(d,1H),6.32(s,1H),5.36(q,1H),5.00-4.93(m,1H),4.24-4.02(m,2H),3.74(s,6H),3.65-3.54(m,1H),2.35(s,3H),2.22(s,3H),1.46(d,3H)。
单一构型化合物(较长保留时间)10-P2
MS m/z(ESI):529.3[M+1]
HPLC分析:保留时间12.5分钟，纯度：98.5％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM碳酸氢铵)B-乙腈，梯度配比：A 25％-39％)
1H NMR(400MHz,CD 3OD):8.14(s,1H),7.55(s,1H),7.44(d,2H),7.25-7.04(m,4H),6.33(s,1H),5.33(q,1H),5.00-4.95(m,1H),4.41-4.18(m,2H),3.88-3.68(m,7H),2.34(d,6H),1.43(d,3H)。
实施例11
(S)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺11-P1
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺11-P2
Figure PCTCN2020091695-appb-000057
将化合物2e(70mg，0.17mmol)和化合物(S)-2-氨基-2-(间甲苯基)乙醇(25mg，0.17mmol)溶于5mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(70mg,0.18mmol)，N,N-二异丙基乙胺(64mg,0.49mmol)，搅拌反应14小时。减压浓缩，残余物用液相制备纯化(仪器型号:Gilson 281色谱柱:Sharpsil-T，Prep30*150mm；5μm；C18流动相:A-水(0.1％三氟乙酸)B-乙腈，流速:30mL/min柱温:室温)得到标题化合物11-P1和11-P2(15mg，15mg)。产率：(16.2％，16.2％)
单一构型化合物(较短保留时间)11-P1
MS m/z(ESI):553.2[M+1]
HPLC分析:保留时间16.6分钟，纯度：97.2％(色谱柱:Sharpsil-T，Prep30*150mm；5μm；流动相:A-水(0.1％三氟乙酸)B-乙腈，梯度配比：A31％-49％)
1H NMR(400MHz,CD 3OD)δ8.29(s,1H),8.22(s,1H),7.15-7.19(m,4H),6.77(s,1H),5.19(d,1H),4.91-4.94(m,1H),3.98-4.01(m,3H),3.74-3.77(m,2H),3.57-3.59(m,4H),3.51-3.54(m,1H),2.92-2.93(m,1H),2.28(s,3H),1.99-2.02(m,2H)，1.61-1.63(m,2H),1.50(d,3H)。
单一构型化合物(较长保留时间)11-P2
MS m/z(ESI):553.2[M+1]
HPLC分析:保留时间17.5分钟，纯度：96.2％(色谱柱:Sharpsil-T，Prep30*150mm；5μm；流动相:A-水(0.1％三氟乙酸)B-乙腈，梯度配比：A 31％-49％)
MS m/z(ESI):553.2[M+1]
1H NMR(400MHz,CD 3OD)δ8.19(s,1H),8.13(s,1H),7.06-7.21(m,4H),6.69(s,1H),5.17(d,1H),4.95-4.97(m,1H),3.75-3.98(m,3H),3.72-3.75(m,2H), 3.50-3.59(m,4H),3.08-3.10(m,1H),2.96-2.97(m,1H),2.31(s,3H),1.96-1.99(m,2H),1.59-1.60(m,2H),1.44(d,3H)。
实施例12
(S)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(7-(5-甲基-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酰胺12-P1
(R)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(7-(5-甲基-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酰胺12-P2
Figure PCTCN2020091695-appb-000058
采用实施例10中的合成路线，将第八步原料化合物(S)-2-氨基-2-(间甲苯基)乙醇替换为化合物1p，制得标题化合物12-P1，12-P2(20mg，20mg)。
单一构型化合物(较短保留时间)12-P1
MS m/z(ESI):563.2[M+1]
HPLC分析:保留时间11.01分钟，纯度：96.2％(色谱柱:Sharpsil-T，Prep30*150mm；5μm；流动相:A-水(0.1％三氟乙酸)B-乙腈，梯度配比：A 21％-39％)
1H NMR(400MHz,CD 3OD)δ8.19(s,1H),7.69(s,1H),7.52-7.54(m,2H),6.66-6.72(m,2H),6.54-6.55(m,1H),6.45(s,1H),5.32-5.37(m,1H),4.95-4.96(m,1H),4.25-4.28(m,2H),3.73-3.81(m,10H),2.42(s,3H),1.51(d,3H)。
单一构型化合物(较长保留时间)12-P2
MS m/z(ESI):563.2[M+1]
HPLC分析:保留时间16.3分钟，纯度：98.2％(色谱柱:Sharpsil-T，Prep30*150mm；5μm；流动相:A-水(0.1％三氟乙酸)B-乙腈，梯度配比：A 21％-39％)
1H NMR(400MHz,CD 3OD)δ8.20(s,1H),7.76(s,1H),7.63(s,1H),7.55(s,1H),6.65-6.75(m,4H),5.34-5.35(m,1H),4.94-4.95(m,1H),4.33-4.40(m,2H),3.72-3.88(m,10H),2.45(s,3H),1.48(d,3H)。
实施例13
(S)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氯苯基)-2-羟乙基)丙酰胺13-P1
(R)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氯苯基)-2-羟乙基)丙酰胺13-P2
Figure PCTCN2020091695-appb-000059
采用实施例9中的合成路线，将第八步原料化合物(S)-2-氨基-2-(间甲苯基)乙醇替换为化合物(S)-2-氨基-2-(间氯苯基)乙醇(上海毕得医药有限公司)，制得化合物13-P1，13-P2(18mg，18mg)。
单一构型化合物(较短保留时间)13-P1
MS m/z(ESI):573.1[M+1]
HPLC分析:保留时间12.1分钟，纯度：96.8％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM醋酸铵)B-乙腈，梯度配比：A 29％-44％)
1H NMR(400mHz,CDCl 3):8.09(s,1H),7.92(s,1H),7.85(s,1H),7.25-7.18(m,4H),5.44-5.38(m,1H),5.06-5.02(m,1H),4.20-4.15(m,3H),4.06-4.03(m,2H),3.96-3.94(m,1H),3.89-3.87(m,1H),3.79-3.75(m,1H),3.62-3.57(m,3H),2.06-2.03(m,2H),1.80-1.77(m,2H),1.49(d,3H).
单一构型化合物(较长保留时间)13-P2
MS m/z(ESI):573.1[M+1]
HPLC分析:保留时间13.2分钟，纯度：97.2％(色谱柱:X-Bridge，Prep 30*150mm；5μm；流动相:A-水(10mM醋酸铵)B-乙腈，梯度配比：A 29％-44％) 1H NMR(400mHz,CD 3OD):8.53-8.51(d,1H),8.22(s,1H),8.00(s,1H),7.72(s,1H),7.39(s,1H),7.30-7.28(m,2H),5.37-5.32(m,1H),5.00-4.95(m,1H),4.43-4.37(m,1H),4.36-4.31(m,1H),4.02-3.99(m,3H),3.85-3.82(m,2H),3.79-3.71(m,2H),3.62-3.56(m,2H),2.04-2.01(m,2H),1.69-1.59(m,2H),1.47(d,3H)。
实施例14
(S)-2-(2-(5-氯-2-(((S)-1-羟丙基-2-基)氨基)嘧啶-4-基)-8-氧代-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺14-P1
(R)-2-(2-(5-氯-2-(((S)-1-羟丙基-2-基)氨基)嘧啶-4-基)-8-氧代-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺14-P2
Figure PCTCN2020091695-appb-000060
第一步
(S)-1-((叔丁基二甲基硅基)氧基)丙基-2-胺14b
将化合物14a(2g，26.6mmol，上海皓鸿生物医药科技有限公司)，咪唑(3.6g，52.9mmol)溶于80mL二氯甲烷中，冰浴下加入叔丁基二甲基氯硅烷(6g，39.8mmol)，搅拌反应14小时。加水，二氯甲烷萃取(80mL×2)。合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用柱层析以洗脱剂体系C纯化得到标题化合物14b(4.0g)，产率：79.3％。
MS m/z(ESI):190.2[M+1]
第二步
(S)-2-(2-(5-氯-2-(((S)-1-羟丙基-2-基)氨基)嘧啶-4-基)-8-氧代-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺14-P1
(R)-2-(2-(5-氯-2-(((S)-1-羟丙基-2-基)氨基)嘧啶-4-基)-8-氧代-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺14-P2
采用实施例3中的合成路线，将第三步原料化合物2c替换为化合物14b，制得化合物14-P1和14-P2(20mg,20mg)。
单一构型化合物(较短保留时间)14-P1
MS m/z(ESI):562.2[M+1]
HPLC分析:保留时间15.4分钟，纯度：96.8％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM碳酸氢铵)B-乙腈，梯度配比：A 25％-45％)
1H NMR(400MHz,CD 3OD):δ8.27(s,1H),8.06(s,1H),6.82(s,1H),6.81-6.73(m,1H),6.61-6.57(m,1H),5.45-5.43(m,1H),4.99-4.97(m,1H),4.61-4.51(m,1H), 4.37-4.34(m,1H),4.31-4.15(m,1H),3.92-3.89(m,2H),3.79(s,3H),3.78-3.72(m,1H),3.59-3.58(m,2H),1.44(d,3H),1.29-1.23(m,1H),1.22(d,3H)。
单一构型化合物(较长保留时间)14-P2
MS m/z(ESI):562.2[M+1]
HPLC分析:保留时间17.2分钟，纯度：97.2％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM碳酸氢铵)B-乙腈，梯度配比：A 25％-45％)
1H NMR(400MHz,CD 3OD):δ8.27(s,1H),8.06(s,1H),6.82(s,1H),6.81-6.73(m,1H),6.61-6.57(m,1H),5.45-5.43(m,1H),4.99-4.97(m,1H),4.61-4.51(m,1H),4.37-4.34(m,1H),4.31-4.15(m,1H),3.92-3.89(m,2H),3.79(s,3H),3.78-3.72(m,1H),3.59-3.58(m,2H),1.44(d,3H),1.29-1.23(m,1H),1.22(d,3H)。
实施例15
(R)-2-(7-(5-氯-2-(((S)-1-羟丙基-2-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺15
Figure PCTCN2020091695-appb-000061
采用实施例4中的合成路线，将第四步原料化合物2c替换为化合物14b，制得化合物15(20mg)。
MS m/z(ESI):561.2[M+1]
1H NMR(400MHz,CDCl 3)δ8.20(s,1H),7.60(s,1H),6.71-6.74(m,2H),6.53-6.63(m,2H),5.37-5.40(m,1H),5.07-5.20(m,3H),4.32-4.36(m,2H),4.14-4.16(m,2H),3.69-3.81(m,7H),1.15-1.25(m,5H)。
实施例16
(S)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)-N-((S)-1-(3-氯苯基)-2-羟乙基)丙酰胺16-P1
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-c]嘧啶-2(1H)-基)-N-((S)-1-(3-氯苯基)-2-羟乙基)丙酰胺16-P2
Figure PCTCN2020091695-appb-000062
采用实施例11中的合成路线，将第十步原料化合物(S)-2-氨基-2-(间甲苯基)乙醇替换为化合物(S)-2-氨基-2-(间氯苯基)乙醇，制得化合物16-P1和16-P2(30mg，30mg)。
单一构型化合物(较短保留时间)16-P1
MS m/z(ESI):573.1[M+1]
HPLC分析:保留时间15.4分钟，纯度：96.8％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM碳酸氢铵)B-乙腈，梯度配比：A 33％-51％)
1H NMR(400mHz,CDCl 3):8.49(s,1H),8.10(s,1H),7.25(s,1H),7.18(s,1H),7.03(d,1H),6.75(s,1H),5.22-5.17(m,1H),5.07-5.03(m,1H),4.20-4.14(m,1H),4.06-4.03(m,2H),3.99-3.88(m,2H),3.60-3.55(m,3H),3.47-3.44(m,1H),3.03-2.97(m,3H),2.07-2.04(m,2H),1.78-1.76(m,2H),1.53(d,3H)。
单一构型化合物(较长保留时间)16-P2
MS m/z(ESI):573.1[M+1]
HPLC分析:保留时间17.5分钟，纯度：97.2％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM碳酸氢铵)B-乙腈，梯度配比：A 33％-51％)
1H NMR(400mHz,CDCl 3):9.18(s,1H),8.47(s,1H),8.10(s,1H),7.34-7.30(m,3H),7.22-7.21(m,1H),7.08(s,1H),6.75(s,1H),5.23-5.18(m,1H),5.07(s,1H),4.36(s,1H),4.14(s,1H),4.07-4.04(m,2H),3.93-3.91(m,1H),3.85-3.80(m,1H),3.74-3.69(m,1H),3.67-3.64(m,1H),3.65-3.60(m,2H),3.17-3.12(m,1H),3.06-3.01(m,1H),2.06-2.03(m,2H),1.80-1.78(m,2H),1.54(d,3H)。
实施例17
(S)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(7-(5-甲基-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酰胺17-P1
(R)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(7-(5-甲基-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酰胺17-P2
Figure PCTCN2020091695-appb-000063
采用实施例10中的合成路线，将第六步原料化合物7b替换为化合物2c，将第八步原料化合物化合物(S)-2-氨基-2-(间甲苯基)乙醇替换为化合物1p，制得标题化合物17-P1，17-P2(6mg，6mg)。
单一构型化合物(较短保留时间)17-P1
MS m/z(ESI):567.2[M+1]
HPLC分析:保留时间12.4分钟，纯度：98.6％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM乙酸铵)B-乙腈，梯度配比：A 25％-39％)。
1H NMR(400MHz,CD 3OD):8.01(s,1H),7.57(s,1H),7.47(s,1H),6.78-6.62(m,2H),6.54(d,1H),5.34(q,1H),4.29-4.14(m,2H),4.10-3.89(m,3H),3.88-3.64(m,8H),3.57(t,2H),2.30(s,3H),2.04-1.97(m,2H),1.64-1.53(m,2H),1.49(d,3H)。
单一构型化合物(较长保留时间)17-P2
MS m/z(ESI):567.2[M+1]
HPLC分析:保留时间13.5分钟，纯度：99.2％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM乙酸铵)B-乙腈，梯度配比：A 25％-39％)。
1H NMR(400MHz,CD 3OD):8.02(s,1H),7.59(s,1H),7.48(s,1H),6.75(s,1H),6.69(d,1H),6.59(d,1H),5.34(q,1H),4.45-4.23(m,2H),4.13-3.93(m,3H),3.91-3.66(m,8H),3.58(t,2H),2.31(s,3H),1.99(s,2H),1.65-1.56(m,2H),1.46(d,3H)。
实施例18
(S)-N-((S)-2-羟基-1-(间-甲苯基)乙基)-2-(7-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酰胺18-P1
(R)-N-((S)-2-羟基-1-(间-甲苯基)乙基)-2-(7-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酰胺18-P2
Figure PCTCN2020091695-appb-000064
采用实施例10中的合成路线，将第一步原料化合物10a替换为2,4-二氯嘧啶，制得化合物18-P1和18-P2(30mg,30mg)。
单一构型化合物(较短保留时间)18-P1
MS m/z(ESI):515.3[M+1]
HPLC分析:保留时间13.2分钟，纯度：96.8％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM醋酸铵)B-乙腈，梯度配比：A 20％-36％)
1H NMR(400mHz,CDCl 3):8.34(s,1H),7.49(s,1H),7.39(s,2H),7.12-7.09(m,2H),7.03-7.00(m,3H),6.93(m,1H),6.70(s,1H),6.33(s,1H),5.43-5.38(m,1H),5.01-5.00(m,1H),4.10-4.05(m,1H),3.97-3.95(m,1H),3.86-3.82(m,2H),3.81(s,3H),3.68-3.63(m,1H),3.53-3.48(m,1H),2.24-2.21(m,1H),1.44(d,3H)
单一构型化合物(较长保留时间)18-P2
MS m/z(ESI):515.3[M+1]
HPLC分析:保留时间15.4分钟，纯度：97.2％(色谱柱:X-Bridge，Prep 30*150mm；5μm；流动相:A-水(10mM醋酸铵)B-乙腈，梯度配比：A 20％-36％)
1H NMR(400mHz,CDCl 3):8.29(s,1H),7.76(s,1H),7.51(s,1H),7.24-7.22(m,2H),7.18-7.16(m,2H),7.11-7.10(m,2H),6.79(s,1H),6.33(s,1H),5.40-5.36(m,1H),5.13(s,1H),4.24-4.21(m,1H),4.05-4.01(m,1H),3.91-3.79(m,6H),3.73-3.68(m,1H),2.35(s,3H),2.24-2.22(m,1H),2.06-2.04(m,1H)。
实施例19
(S)-N-((S)-2-羟基-1-(间甲苯基)乙基)-2-(1-氧代-7-(2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酰胺19-P1
(R)-N-((S)-2-羟基-1-(间甲苯基)乙基)-2-(1-氧代-7-(2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-3,4-二氢吡咯并[1,2-a]吡嗪-2(1H)-基)丙酰胺19-P2
Figure PCTCN2020091695-appb-000065
采用实施例9中的合成路线，将第一步原料化合物2a替换为2,4-二氯嘧啶，制得化合物19-P1，19-P2(60mg，30mg)。
单一构型化合物(较短保留时间)19-P1
MS m/z(ESI):519.2[M+1]
HPLC分析:保留时间11.6分钟，纯度：98.1％(色谱柱:X-Bridge，Prep30*150mm；5μm；流动相:A-水(10mM醋酸铵)B-乙腈，梯度配比：A 25％-39％)。
H NMR(400MHz,CD 3OD):δ8.15(d,1H),7.96(s,1H),7.21-7.14(m,4H),7.00(d,1H),6.54(s,1H),5.20(q,1H),4.98-4.97(m,1H),4.01-3.98(m,3H),3.77-3.74(m,2H),3.63-3.45(m,4H),2.91-2.89(m,2H)，2.29(s,3H),2.03-2.01(m,2H),1.64-1.60(m,2H),1.49(d,3H)。
单一构型化合物(较长保留时间)19-P2
MS m/z(ESI):519.2[M+1]
HPLC分析:保留时间12.7分钟，纯度：98.5％(色谱柱:X-Bridge，Prep 30*150mm；5μm；流动相:A-水(10mM醋酸铵)B-乙腈，梯度配比：A 25％-39％)。
H NMR(400MHz,CD 3OD):δ8.16(d,1H),7.96(s,1H),7.20-7.10(m,4H),7.00(d,1H),6.54(s,1H),5.19(q,1H),4.98-4.95(m,1H),4.01-3.98(m,3H),3.76-3.55(m,6H),3.20-2.98(m,2H)，2.34(s,3H),2.04-2.01(m,2H),1.64-1.60(m,2H),1.47(d,3H)。
生物学评价
测试例1：ERK1酶学活性测试
一、测试目的
本实验的目的是为了检测本公开化合物对ERK1酶活性的抑制能力，根据IC50大小评价化合物的体外活性。本实验使用ADP-Glo TM激酶检测试剂盒(Kinase Assay Kit)，在酶的作用下，底物被磷酸化同时产生ADP，加入ADP-Glo试剂除去反应体系中未反应的ATP，激酶检测试剂检测反应产生的ADP。在化合物存在的条件下，通过测量信号值算出化合物的抑制率。
二、实验方法
酶和底物配置：将ERK1(1879-KS-010，R&D)和底物(AS-61777，anaspec) 在缓冲液中分别配置成0.75ng/μl和1005n，然后将酶溶液和底物溶液以2：1的体积比配制成混合溶液，待用。用缓冲液将ATP稀释至300μM，用DMSO(二甲基亚砜，上海泰坦科技股份有限公司)溶解化合物，配制成初始浓度为20mM的存储液，然后用Bravo配制化合物。最后在384孔板每孔中依次加入3板每酶和底物的混合液溶液，1底物不同浓度的化合物(起始浓度为50μM，4倍稀释)，30℃孵育10分钟，最后每孔再加入1钟，最后每孔μM的ATP溶液，在30℃孵育2小时。然后加入5μL的ADP-Glo，30℃孵育40分钟，接着加入10μL的激酶检测缓冲液，30℃孵育40分钟。取出384孔板，置于酶标仪(BMG labtech，PHERAstar FS)中，用酶标仪测定化学发光。
三、数据分析
用Microsoft Excel，Graphpad Prism 5对数据进行处理分析。得出化合物的IC 50值，结果参见下表。
实施例编号 IC 50(nM)
1-P2 7
2-P2 4.6
3-P2 4.6
4-P2 3.8
9-P2 9
10-P2 8.5
11-P2 17
12-P2 9.4
17-P2 22
结论：本公开化合物对ERK1酶活性有明显的抑制作用。
测试例2：ERK2酶学活性测试
一、测试目的
本实验的目的是为了检测本公开化合物对ERK2酶活性的抑制能力，根据IC50大小评价化合物的体外活性。本实验使用ADP-Glo TM激酶检测试剂盒(Kinase Assay Kit)，在酶的作用下，底物被磷酸化同时产生ADP，加入ADP-Glo试剂除去反应体系中未反应的ATP，激酶检测试剂检测反应产生的ADP。在化合物存在的条件下，通过测量信号值算出化合物的抑制率。
二、实验方法
酶和底物配置：将ERK2(1230-KS-010，R&D)和底物(定制多肽，吉尔生化)在缓冲液(40mM Tris，20mM MgCl 2，0.1mg/ml BSA，50μM DTT)中配置成0.75ng/μl和1500/，然后将酶溶液和底物溶液以2：1的体积比配制成混合溶液，待用。用缓冲液将ATP稀释至500μM，用DMSO(二甲基亚砜，上海泰坦科技股份有限公司)溶解化合物，配制成初始浓度为20mM的存储液，然后用Bravo 配制化合物。最后在384孔板每孔中依次加入3板每酶和底物的混合液溶液，1底物不同浓度的化合物(起始浓度为50μM，4倍稀释)，30℃孵育10分钟，最后每孔再加入1钟，最后每孔μM的ATP溶液，在30℃孵育2小时。然后加入5μL的ADP-Glo，30℃孵育40分钟，接着加入10μL的激酶检测缓冲液，30℃孵育40分钟。取出384孔板，置于酶标仪(BMG labtech，PHERAstar FS)中，用酶标仪测定化学发光。
三、数据分析
用Microsoft Excel，Graphpad Prism 5对数据进行处理分析。得出化合物的IC 50值，结果参见下表。
实施例编号 IC 50(nM)
1-P1 811
1-P2 1.5
2-P1 336
2-P2 1.7
3-P2 1.75
4-P1 819
4-P2 1
5 3.6
6-P1 2541
6-P2 7.5
8-P1 2121
8-P2 26
9-P2 1.9
10-P2 1.1
11-P1 75
11-P2 2.1
12-P1 948
12-P2 0.9
13-P2 2.8
14-P1 1527
14-P2 4.9
15 28.7
16-P2 4.2
17-P2 3.1
18-P2 5.5
19-P2 6.7
结论：本公开化合物对ERK2酶活性有明显的抑制作用。
测试例3：对Colo205肿瘤细胞体外增殖抑制测试
一、测试目的
本实验的目的是为了检测本公开化合物对Colo205细胞(CCL-222，ATCC)
体外增殖的抑制活性。以不同浓度的化合物体外处理细胞，经3天培养后，采用CTG
Figure PCTCN2020091695-appb-000066
发光法细胞活力检测试剂盒(Luminescent Cell Viability Assay)，Promega，货号：G7573)试剂对细胞的增值进行检测，根据IC50值评价该化合物的体外活性。
二、实验方法
下面以对Colo205细胞体外增殖抑制测试方法为例，用于举例说明本公开化合物对肿瘤细胞进行体外增殖抑制活性测试的方法。本方法同样适用于，但不限于对其它肿瘤细胞进行体外增殖抑制活性测试。
将Colo205消化，离心后重悬，单细胞悬液混匀，用细胞培养液(RPMI1640+2％FBS)调整活细胞密度至5.0×10 4细胞/ml，以95μL/孔加入96孔细胞培养板。96孔板外周孔只加入100μL培养基。将培养板在培养箱培养24小时(37℃，5％CO 2)。
用DMSO(二甲基亚砜，上海泰坦科技股份有限公司)溶解化合物，配制成初始浓度为20mM的存储液。小分子化合物的起始浓度为2mM，4倍稀释，稀释9个点，第十个点为DMSO。另取一块96孔板，每孔加入90μL的细胞培养液(RPMI1640+2％FBS)，然后每孔加入10μL不同浓度的待测样品，混匀，接着向细胞培养板中加入5μL的不同浓度的待测样品，每个样品两复孔。将培养板在培养箱孵育3天(37℃，5％CO 2)。取出96孔细胞培养板，向每孔加入50μL CTG溶液，室温孵育10分钟。于酶标仪(BMG labtech，PHERAstar FS)中，用酶标仪测定化学发光。
三、数据分析
用Microsoft Excel，Graphpad Prism 5对数据进行处理分析。实施例结果参见下表：
实施例编号 IC 50(nM)
1-P2 17.4
2-P2 15
4-P2 10
9-P2 17.7
10-P2 100
11-P2 26
12-P2 82
13-P2 31
16-P2 54
17-P2 38
19-P2 67
结论：本公开化合物对Colo205肿瘤细胞增殖有明显的抑制作用。
药代动力学评价
测试例4、本公开化合物的小鼠药代动力学测试
1、摘要
以小鼠为受试动物，应用LC/MS/MS法测定了化合物1-P2、2-P2、4-P2、6-P2、9-P2、10-P2和11-P2后不同时刻血浆中的药物浓度。研究本公开化合物在小鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1 试验药品
化合物1-P2、2-P2、4-P2、6-P2、9-P2、10-P2和11-P2。
2.2 试验动物
C57小鼠63只，雌性，平均分为7组，购自上海杰思捷实验动物有限公司，动物生产许可证号：SCXK(沪)2013-0006。
2.3 药物配制
称取一定量化合物，加5％体积的DMSO和5％吐温80使其溶解，后加90％生理盐水配置成0.1mg/ml无色澄明溶液。
Figure PCTCN2020091695-appb-000067
2.4 给药
C57小鼠禁食过夜后灌胃给药，给药剂量均为2mg/kg，给药体积均为0.2ml/10g。
3、操作
小鼠灌胃给药，于给药前及给药后0.25，0.5，1.0，2.0，4.0，6.0，8.0，11.0，24.0小时采血0.1ml，置于肝素化试管中，3500转/分钟离心10分钟后分离血浆，于-20℃保存。
测定不同浓度的药物注射给药后小鼠血浆中的待测化合物含量：取给药后各时刻的小鼠血浆25μl，加入内标溶液喜树碱50μl(100ng/mL)，乙腈200μl，涡旋混合5分钟，离心10分钟(4000转/分钟)，血浆样品取上清液4μl进行LC/MS/MS分析。
4、药代动力学参数结果
本公开化合物的药代动力学参数如下：
结论：本公开化合物的药代吸收较好，具有药代动力学优势。

Claims (23)

  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 PCTCN2020091695-appb-100001
    其中：
    G 1、G 2和G 3相同或不同，且各自独立地选自CH、C和N；
    L为键或亚烷基，所述的亚烷基任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、氨基烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
    R 2选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 3选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基；
    R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
    R 5选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
    R 6选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基和羟烷基；
    R 7选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、卤代烷基、卤代烷氧基和氨基烷基中的一个或多个取代基所取代；
    n为1、2或3；且
    m为0、1或2。
  2. 根据权利要求1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(I-1)或(I-2)所示的化合物或其立体异构体、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 PCTCN2020091695-appb-100002
    其中：
    R 5选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；且
    G 1、G 2、G 3、L、m、n、R 1～R 4、R 6和R 7如权利要求1中所定义。
  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n为1或2。
  4. 根据权利要求1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-1)、(II-2)、(II-3)或(II-4)所示的化合物或其立体异构体、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 PCTCN2020091695-appb-100003
    其中：
    z为0、1、2、3或4；且
    L、m和R 1～R 7如权利要求1中所定义。
  5. 根据权利要求1或4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-12)、(II-22)、(II-32)或(II-42)所示的化合物或其立体异构体、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 PCTCN2020091695-appb-100004
    其中：
    R 5选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
    z为0、1、2、3或4；且
    L、m、R 1～R 4、R 6和R 7如权利要求1中所定义。
  6. 根据权利要求1至5任一项所述的通式(I)所示的化合物或其立体异构体、 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L为亚烷基，所述的亚烷基任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、氨基烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代，优选地，L为-CH(R 8)-；R 8选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、氨基烷基、环烷基、杂环基、芳基和杂芳基。
  7. 根据权利要求1、4和6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(III-1)、(III-2)、(III-3)或(III-4)所示的化合物或其立体异构体、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 PCTCN2020091695-appb-100005
    其中：
    R 8选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、氨基烷基、环烷基、杂环基、芳基和杂芳基；
    z为0、1、2、3或4；且
    R 1、R 2、R 4、R 5、R 7和m如权利要求1中所定义。
  8. 根据权利要求1、4、6和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，其为通式(III-12)、(III-22)、(III-32)或(III-42)所示的化合物或其立体异构体、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 PCTCN2020091695-appb-100006
    其中：
    R 5选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
    R 8选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、氨基烷基、环烷基、杂环基、芳基和杂芳基；
    z为0、1、2、3或4；且
    R 1、R 2、R 4、R 7和m如权利要求1中所定义。
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其立体异构体、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 7为芳基，所述的芳基任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基和羟烷基中的一个或多个取代基所取代；优选地，R 7为苯基，所述的苯基任选进一步被选自C 1-6烷基、C 1-6烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基和C 1-6羟烷基中的一个或多个取代基所取代。
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其立体异构体、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 8选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基和氨基烷基，优选地，R 8为C 1-6羟烷基或氨基C 1-6烷基。
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其立体异构体、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选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基和羟烷基，优选为氢原子、卤素或烷基，更优选为C 1-6烷基。
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其立体异构体、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选自C 1-6烷基、3至8元杂环基和5至10元杂芳基，所述的C 1-6烷基、3至8元杂环基和5至10元杂芳基各自任选进一步被选自C 1-6烷基、C 1-6烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基和C 1-6羟烷基中的一个或多个取代基所取代。
  13. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其立体异构体、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为杂环基，所述的杂环基任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基和羟烷基中的一个或多个取代基所取代。
  14. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其立体异构体、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为杂芳基，所述的杂芳基任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基和羟烷基中的一个或多个取代基所取代。
  15. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其立体异构体、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选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基和羟烷基，优选选自氢原子、卤素和C 1-6烷基，更优选为卤素。
  16. 根据权利要求1至15中任一项所述的通式(I)所示的化合物或其立体异构体、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 4选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基和羟烷基，优选为氢原子或烷基；更优选为氢原子或C 1-6烷基。
  17. 根据权利要求1至16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 PCTCN2020091695-appb-100007
    Figure PCTCN2020091695-appb-100008
  18. 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 PCTCN2020091695-appb-100009
    其中：
    G 1、G 2和G 3相同或不同，且各自独立地选自CH、C和N；
    R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
    R 2选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自任选进一步被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 3选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基；
    R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
    R 5选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
    n为1、2或3；且
    m为0、1或2。
  19. 根据权利要求18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 PCTCN2020091695-appb-100010
  20. 一种制备根据权利要求1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的方法，所述方法包括：
    Figure PCTCN2020091695-appb-100011
    通式(IA)的化合物和(IB)，在碱性条件下发生缩合反应，得到通式(I)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：所述碱性条件优选为N,N-二异丙基乙胺；R 6为氢原子；且G 1、G 2、G 3、R 1～R 5、R 7、L、m和n如权利要求1中所定义。
  21. 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至17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。
  22. 根据权利要求1至17中任一项所述的通式(I)所示的化合物或其立体异构体、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21所述的药物组合物，在制备用于抑制ERK的药物中的用途。
  23. 根据权利要求1至17中任一项所述的通式(I)所示的化合物或其立体异构体、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21所述的药物组合物在制备用于治疗或预防癌症、炎症、或其它增殖性疾病，优选癌症的药物中的用途；所述的癌症选自黑色素瘤、肝癌、肾癌、肺癌、鼻咽癌、结肠直肠癌、结肠癌、直肠癌、胰腺癌、宫颈癌、卵巢癌、乳腺癌、膀胱癌、前列腺癌、白血病、头颈鳞状细胞癌、子宫颈癌、甲状腺癌、淋巴瘤、肉瘤、成神经细胞瘤、脑瘤、骨髓瘤、星形细胞瘤和胶质瘤。
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