WO2019007321A1 - 吲哚胺2,3-双加氧酶抑制剂化合物及其制备方法和用途 - Google Patents

吲哚胺2,3-双加氧酶抑制剂化合物及其制备方法和用途 Download PDF

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WO2019007321A1
WO2019007321A1 PCT/CN2018/094234 CN2018094234W WO2019007321A1 WO 2019007321 A1 WO2019007321 A1 WO 2019007321A1 CN 2018094234 W CN2018094234 W CN 2018094234W WO 2019007321 A1 WO2019007321 A1 WO 2019007321A1
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compound
formula
reaction
preparation
protecting group
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PCT/CN2018/094234
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English (en)
French (fr)
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张富尧
刘家清
神小明
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上海时莱生物技术有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicine, in particular to a guanamine 2,3-dioxygenase inhibitor compound, a preparation method thereof and use thereof.
  • T cells are the main components of lymphocytes, and they have a variety of biological functions, the most important of which is immune function, which becomes an important tool for attacking tumor cells and fighting disease infections in the body.
  • Tryptophan is one of the important amino acids that maintain T cell growth and proliferation. In mammals, tryptophan undergoes normal metabolism following the kynurenine pathway. The rate-limiting enzymes of this pathway include tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1, IDO1, and guanidine.
  • TDO2 tryptophan 2,3-dioxygenase
  • IDO1 indoleamine 2,3-dioxygenase 2
  • IDO2 indoleamine 2,3-dioxygenase 2
  • tumor cells overexpress the indoleamine 2,3-dioxygenase, causing the tryptophan to be rapidly and massively consumed, thus failing to provide nutrients to the T cells, causing the T cells to stop growing and proliferating, and even withering. It was cleared and died.
  • toxic products such as 3-hydroxyanthranilic acid, quinolinic acid, and picolinic acid produced by the metabolism of tryptophan by the kynurenine pathway in turn inhibit the activation of T cells.
  • hyperactive IDO also induces dendritic cells to directly inhibit and resist the recognition of antigen by T cells and T cells that cause antigenic responses.
  • an immunosuppressive tumor microenvironment is produced, which inhibits T cells from entering the tumor tissue. Therefore, by developing a suitable drug to inhibit the overexpression of indoleamine 2,3-dioxygenase, T cells can be activated to inhibit the continued growth, expansion and migration of tumor cells, thereby inhibiting tumors.
  • IDO1 indoleamine 2,3-dioxygenase 1
  • the two compounds that have progressed rapidly in clinical studies of IDO inhibitors are from Incyte and NewLink.
  • Incyte's Epacadostat directly acts on IDO1 and has progressed to clinical phase III.
  • Merck's PD-1 antibody Keytruda early data show that the overall disease control rate (73%) can be significantly improved in advanced patients.
  • the response rate to advanced melanoma also increased to 57%, while the response rate was only about 28% when using Keytruda alone.
  • the data also showed that the combination was well tolerated, and the incidence of adverse events of grade 3 or higher was low.
  • the present inventors have unexpectedly discovered that the deuterated indoleamine 2,3-dioxygenase inhibiting compounds provided by the present invention have significantly superior pharmacodynamic properties and drugs as compared to the corresponding non-deuterated compounds.
  • the kinetic performance, Cmax increased by more than 50%
  • AUC increased by more than 10%
  • the exposure of deuterated compounds in animals was significantly improved, so it is more suitable as amidoxime 2,3-dioxygenase inhibition.
  • the agent is further suitable for the preparation of a medicament for treating a guanamine 2,3-dioxygenase inhibitor-related disease.
  • a first aspect of the invention provides a compound of formula I, an isomer thereof, a crystalline form, a pharmaceutically acceptable prodrug, a salt, a hydrate or a solvate,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from hydrogen or deuterium, and at least one is deuterium.
  • At least one of R 1 , R 2 , R 3 , R 4 and R 7 is deuterium.
  • At least one of R 1 , R 2 , R 3 and R 4 is deuterium.
  • At least one of R 1 and R 2 is deuterium.
  • R 1 and R 2 are deuterium.
  • At least one of R 3 and R 4 is deuterium.
  • R 3 and R 4 are deuterium.
  • R 1 and R 2 are deuterium, and one of R 3 and R 4 is deuterium and one is hydrogen.
  • one of R 1 and R 2 is ⁇ one is hydrogen, and one of R 3 and R 4 is ⁇ one is hydrogen.
  • R 1 , R 2 , R 3 and R 4 are deuterium.
  • R 7 is hydrazine
  • R 5 is deuterium
  • R 6 is deuterium
  • R 5 , R 6 and R 7 are deuterium.
  • R 1 and R 2 are deuterium, and at least one of R 5 , R 6 and R 7 is deuterium.
  • R 1 , R 2 and R 5 are deuterium.
  • R 1 , R 2 and R 6 are deuterium.
  • R 1 , R 2 and R 7 are deuterium.
  • R 1 , R 2 , R 5 , R 6 and R 7 are deuterium.
  • R 3 , R 4 and R 7 are deuterium.
  • R 3 , R 4 , R 5 , R 6 and R 7 are deuterium.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are both deuterium.
  • the compound of Formula I is selected from any of the following compounds:
  • a second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: (1) a compound of the formula I, an isomer thereof, a crystalline form, a pharmaceutically acceptable prodrug, a salt, a hydrate or a solvate; (2) a pharmaceutically acceptable carrier.
  • a third aspect of the invention provides a process for the preparation of the pharmaceutical composition, which comprises: the compound of the formula I, an isomer thereof, a crystal form, a pharmaceutically acceptable prodrug, a salt
  • the hydrate or solvate is mixed with the pharmaceutically acceptable carrier to provide the pharmaceutical composition.
  • a fourth aspect of the invention provides a method of treating cancer by inhibiting a guanamine 2,3-dioxygenase comprising administering to a patient in need of such treatment a compound of the formula I, an isomer thereof A crystalline form, a pharmaceutically acceptable prodrug, a salt, a hydrate or a solvate, or a pharmaceutical composition as described.
  • the fifth aspect of the invention provides the compound of formula I, an isomer thereof, a crystalline form, a pharmaceutically acceptable prodrug, a salt, a hydrate or a solvate thereof, or a pharmaceutical composition thereof Use in the preparation of a guanamine 2,3-dioxygenase inhibitor, or in the preparation of a medicament for the treatment and/or prevention of indoleamine 2,3-dioxygenase inhibition of a related disease.
  • the compound of formula I an isomer thereof, a crystalline form, a pharmaceutically acceptable prodrug, a salt, a hydrate or a solvate thereof, or a pharmaceutical composition thereof may be In combination with one or more anticancer agents selected from the group consisting of alkylating agents, platinum complexes, metabolic antagonists, alkaloids, antibody drugs, hormone anticancer agents, proteasome inhibitors, CDK Kinase inhibitors, VEGFR or EGFR inhibitors, m-TOR inhibitors, PI3K kinase inhibitors, B-Raf inhibitors, PARP inhibitors, c-Met kinase inhibitors, ALK kinase inhibitors, AKT inhibitors, ABL inhibitors , FLT3 inhibitor, PD-1 inhibitor or PD-L1 inhibitor.
  • anticancer agents selected from the group consisting of alkylating agents, platinum complexes, metabolic antagonists, alkaloids, antibody drugs, hormone anticancer agents, proteasome inhibitors, CDK Kinas
  • the disease may be selected from the group consisting of an immune disease, particularly a cancer, wherein the cancer includes breast cancer, ovarian cancer, prostate cancer, melanoma, brain cancer, nasopharyngeal cancer, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colon Rectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, bone cancer, osteosarcoma, seminoma, testicular tumor, uterine tumor, head and neck tumor , multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, chorionic epithelial cancer or pediatric tumor.
  • an immune disease particularly a cancer
  • the cancer includes breast cancer, ovarian cancer, prostate cancer, melanoma, brain cancer,
  • the pharmaceutical composition is an injection, a sachet, a tablet, a pill, a powder or a granule.
  • the present invention also provides a process a for the preparation of a compound of formula I, which comprises the steps of: subjecting a compound of formula II to a ring opening reaction;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above for the compound of formula I.
  • the ring-opening reaction can be carried out in an organic solvent, and the organic solvent can be a conventional solvent such as an ether solvent in the field.
  • the organic solvent can be a conventional solvent such as an ether solvent in the field.
  • the ring-opening reaction can be carried out in the presence of a base, which can be a conventional base such as an alkali metal hydroxide in the field.
  • a base such as an alkali metal hydroxide in the field.
  • a substance such as sodium hydroxide, potassium hydroxide and/or lithium hydroxide and/or an alkali metal carbonate (sodium carbonate).
  • the temperature of the ring-opening reaction may be a conventional temperature of such a reaction in the art, such as -10 to 80 ° C (for example, 0 to 60 ° C).
  • the preparation method a of the compound of formula I may comprise the following steps:
  • the compound of the formula II is dissolved in an organic solvent at 0 to 60 ° C, and an aqueous alkali solution is added thereto, and the reaction is further stirred at the temperature for 4 to 36 hours. TLC shows the reaction is complete, and after neutralizing with phosphoric acid, ethyl acetate is extracted. After concentration, it is purified to give a compound of formula I.
  • the organic solvent is preferably one or more of tetrahydrofuran, dimethyl sulfoxide, dichloromethane, methanol, ethanol and isopropanol;
  • the base is preferably one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium carbonate.
  • the preparation method a of the compound of the formula I may further comprise the following preparation method of the compound of the formula II.
  • the invention also provides a compound of formula II,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above for the compound of formula I.
  • the compound of Formula II is selected from any of the following compounds:
  • the invention also provides a preparation method of the compound of formula II, which comprises the steps of: subjecting a compound of formula III to a hydrolysis reaction under acidic or basic conditions;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above for the compound of formula I;
  • R 8 is an amino protecting group.
  • R 8 is preferably Boc, Fmoc or Troc.
  • the protecting group hydrolysis reaction can be carried out in an organic solvent, and the organic solvent can be a conventional solvent such as an ether solvent in the field.
  • the organic solvent can be a conventional solvent such as an ether solvent in the field.
  • the protecting group hydrolysis reaction may be added with a deprotecting reagent, and the deprotecting reagent may be a conventional deprotecting reagent for such a reaction in the art, which is known to those skilled in the art.
  • the corresponding deprotecting reagent is selected depending on the type of amine protecting group.
  • the deprotecting agent when the amine protecting group is Boc, may be an organic acid and/or an inorganic acid, an organic acid such as trifluoroacetic acid or acetic acid, a mineral acid such as hydrogen chloride, hydrochloric acid or sulfuric acid;
  • the deprotecting agent may be an organic amine such as tris(2-aminoethyl)amine
  • the deprotecting agent when the amine protecting group is Troc, may be acetic acid and zinc powder.
  • the temperature of the hydrolysis reaction of the protecting group may be a conventional reaction temperature of such a reaction in the field, such as -10 to 80 ° C (for example, 0 to 60 ° C).
  • the preparation method of the compound of formula II may include the following steps:
  • the compound of the formula III is dissolved in an organic solvent at 0 to 60 ° C, and a deprotecting reagent is added. The reaction is further stirred at the temperature for 2 to 24 hours. TLC shows the reaction is complete, and the pH is adjusted to be neutral. The extract is concentrated and purified to give a compound of the formula II.
  • the organic solvent is preferably one or more of tetrahydrofuran, dichloromethane, methanol, ethanol and isopropanol;
  • the deprotecting agent is preferably trifluoroacetic acid, hydrogen chloride gas, hydrochloric acid, sulfuric acid, tris(2-aminoethyl)amine or (acetic acid and zinc powder).
  • the method for preparing the compound of the formula II may further comprise the following preparation method of the compound of the formula III.
  • the invention also provides a compound of formula III,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above for the compound of formula I;
  • R 8 is an amino protecting group.
  • R 8 is Boc, Fmoc or Troc.
  • the compound of formula III is selected from any of the following compounds:
  • the invention also provides a preparation method m of the compound of formula III, which comprises the steps of: subjecting a compound of formula IV to a condensation reaction with a compound of formula V;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above for the compound of formula I;
  • R 8 is an amino protecting group.
  • R 8 may be Boc or Fmoc.
  • the condensation reaction can be carried out in an organic solvent
  • the organic solvent can be a conventional solvent for such a reaction in the art, such as a chlorinated hydrocarbon solvent ( One or more of, for example, dichloromethane), an ester solvent (such as ethyl acetate), and an ether solvent (such as tetrahydrofuran, methyl tert-butyl ether).
  • a chlorinated hydrocarbon solvent One or more of, for example, dichloromethane
  • an ester solvent such as ethyl acetate
  • an ether solvent such as tetrahydrofuran, methyl tert-butyl ether
  • the condensation reaction is preferably carried out under basic conditions.
  • the alkaline condition may be the addition of an organic base, and the organic base may be a conventional organic base such as triethylamine, pyridine, diisopropylethylamine and 2,6-dimethyl.
  • the base may be a conventional organic base such as triethylamine, pyridine, diisopropylethylamine and 2,6-dimethyl.
  • One or more of the base pyridines is a conventional organic base such as triethylamine, pyridine, diisopropylethylamine and 2,6-dimethyl.
  • the temperature of the condensation reaction may be a conventional reaction temperature of such a reaction in the art, such as -10 to 70 ° C (for example, 0 to 50 ° C).
  • the preparation method m of the compound of the formula III may comprise the following steps:
  • the compound of the formula IV is dissolved in an organic solvent at 0 to 50 ° C, a base and a compound of the formula V are added, and the reaction is further stirred at the temperature for 2 to 8 hours. TLC shows the reaction is complete, and the reaction is quenched with water. Extraction with ethyl acetate, concentration and purification afforded the compound of formula III.
  • the organic solvent is preferably one or more of dichloromethane, ethyl acetate, tetrahydrofuran and methyl tert-butyl ether;
  • the base is preferably one or more of triethylamine, pyridine, diisopropylethylamine and 2,6-lutidine.
  • the preparation method m of the compound of the formula III may further comprise the following preparation method of the compound of the formula IV.
  • the invention also provides a process for the preparation of a compound of formula III comprising the steps of: reducing a compound of formula VII with a compound of formula IX in the presence of a reducing agent or a deuterated reducing agent.
  • Amination reaction
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above for the compound of formula I;
  • R 8 is an amino protecting group.
  • R 8 may be Boc, Fmoc or Troc.
  • the reductive amination reaction can be carried out in an organic solvent, and the organic solvent can be a conventional solvent such as a chlorinated hydrocarbon in the field.
  • the organic solvent can be a conventional solvent such as a chlorinated hydrocarbon in the field.
  • a solvent and/or an aromatic hydrocarbon solvent, the chlorinated hydrocarbon solvent may be dichloromethane, and the aromatic hydrocarbon solvent may be toluene.
  • the reducing agent or the deuterated reducing agent may be a conventional reducing agent or a deuterated reducing agent such as sodium borohydride or deuterated boron in the field.
  • a deuterated reducing agent such as sodium borohydride or deuterated boron in the field.
  • sodium hydride or sodium triacetylborohydride Sodium hydride or sodium triacetylborohydride.
  • the temperature of the reductive amination reaction may be a conventional reaction temperature of such a reaction in the art, such as 0 to 130 ° C (for example, 0 to 30 ° C).
  • the preparation method n of the compound of formula III may comprise the following steps:
  • the compound of the formula VII and the compound of the formula IX are dissolved in an organic solvent at room temperature, a Lewis acid is added, and the reaction is refluxed at 60 to 110 ° C for 6 to 12 hours. TLC shows complete reaction, and after concentration, at 0 ° C. Dissolve with methanol or deuterated methanol, add sodium borohydride or sodium borohydride, the reaction is stirred at this temperature for 1 ⁇ 2h, TLC shows the reaction is complete, quenched with water, extracted with ethyl acetate, concentrated and purified A compound of formula III.
  • the organic solvent is preferably dichloromethane and/or toluene
  • the Lewis acid is preferably p-toluenesulfonic acid and/or tetraisopropyl titanate.
  • the preparation method n of the compound of the formula III may comprise the following steps:
  • the compound of the formula VII and the compound of the formula IX are dissolved in dichloromethane at 0 to 40 ° C, acetic acid or trifluoroacetic acid is added, sodium triacetoxyborohydride is added, and the reaction is continued at this temperature. ⁇ 24h, TLC showed the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, and concentrated to give a compound of formula III.
  • the present invention also provides a process h of the compound of formula III, which comprises the steps of: subjecting a compound of formula VII to a condensation condensation reaction with a compound of formula X;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above for the compound of formula I;
  • R 8 is an amino protecting group.
  • R 8 may be Boc, Fmoc or Troc.
  • the reduction condensation reaction can be carried out in an organic solvent, and the organic solvent can be a conventional solvent for such a reaction in the art, such as a chlorinated hydrocarbon.
  • a solvent and/or an ether solvent the chlorinated hydrocarbon solvent may be dichloromethane, and the ether solvent may be tetrahydrofuran.
  • the temperature of the reductive condensation reaction may be a conventional reaction temperature of such a reaction in the art, such as -10 to 60 ° C (for example, 0 to 40 ° C).
  • the preparation method h of the compound of the formula III may comprise the following steps:
  • the compound of the formula VII and the compound of the formula X are dissolved in dichloromethane or tetrahydrofuran at 0 to 40 ° C, methanesulfonic acid and triethylsilane are added, and the reaction is further stirred at this temperature for 36 to 96 hours. TLC showed the reaction was completed. The reaction was quenched with sodium bicarbonate and extracted with ethyl acetate.
  • the invention also provides a compound of formula IV, a crystalline form or a pharmaceutically acceptable salt thereof;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above for the compound of formula I.
  • the compound of Formula IV is selected from any of the following compounds:
  • the present invention also provides a process for the preparation of a compound of formula IV, which comprises the steps of: subjecting a compound of formula VI to a protecting group hydrolysis reaction;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above for the compound of formula I;
  • R 9 is an amino protecting group.
  • R 9 may be Boc or Fmoc.
  • the protecting group hydrolysis reaction can be carried out in an organic solvent
  • the organic solvent can be a conventional solvent for such a reaction in the field, such as an ether solvent (eg, One or more of tetrahydrofuran), an alcohol solvent such as methanol, isopropanol, and a chlorinated hydrocarbon solvent such as dichloromethane.
  • an ether solvent eg, One or more of tetrahydrofuran
  • an alcohol solvent such as methanol, isopropanol
  • a chlorinated hydrocarbon solvent such as dichloromethane.
  • the protecting group hydrolysis reaction may be added with a deprotecting reagent, and the deprotecting reagent may be a conventional deprotecting reagent for such a reaction in the art, which is known to those skilled in the art.
  • the corresponding deprotecting reagent is selected depending on the type of amine protecting group.
  • the deprotecting agent may be an organic acid and/or a mineral acid such as hydrogen chloride and/or trifluoroacetic acid; when the amine protecting group is Fmoc, the deprotection
  • the reagent can be an organic amine such as tris(2-aminoethyl)amine.
  • the temperature of the hydrolysis reaction of the protecting group may be a conventional reaction temperature of the reaction in the field, such as -10 to 60 ° C (for example, 0 to 30 ° C).
  • the preparation method of the compound of the formula IV may include the following steps:
  • the compound of the formula VI is dissolved in an organic solvent at 0 to 30 ° C, and a deprotecting reagent is added. The reaction is further stirred at 0 to 60 ° C for 4 to 24 hours. TLC shows that the reaction is complete, and the pH is adjusted to be neutral. The ethyl ester is extracted, concentrated and purified to give a compound of formula IV.
  • the organic solvent is preferably one or more of tetrahydrofuran, dichloromethane, methanol and ethanol;
  • the deprotecting agent is preferably trifluoroacetic acid, hydrochloric acid or tris(2-aminoethyl)amine.
  • the invention also provides a compound of formula VI;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above for the compound of formula I;
  • R 9 is an amino protecting group.
  • R 9 may be Boc or Fmoc.
  • the compound of formula VI is selected from any of the following compounds:
  • the invention also provides a process for the preparation of the compound of formula VI, which comprises the steps of: carrying out a compound of formula VII with a compound of formula VIII in the presence of a reducing agent or a deuterated reducing agent. Reductive amination reaction;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above for the compound of formula I;
  • R 9 is an amino protecting group.
  • the reductive amination reaction can be carried out in an organic solvent
  • the organic solvent can be a conventional solvent for such a reaction in the art, such as an ether solvent and/or Or a chlorinated hydrocarbon solvent
  • the ether solvent may be tetrahydrofuran
  • the chlorinated hydrocarbon solvent may be dichloromethane
  • the reducing agent or the deuterated reducing agent may be a conventional reducing agent or deuterated reducing agent such as sodium triacetylborohydride or hydrazine in the field. Sodium borohydride.
  • the reaction temperature of the reductive amination reaction may be a conventional temperature of such a reaction in the art, such as -10 to 60 ° C (for example, 0 to 30 ° C).
  • the method of preparing a compound of formula VI comprises the steps of:
  • the compound of the formula VII and the compound of the formula VIII are dissolved in dichloromethane or tetrahydrofuran at 0 to 30 ° C, acetic acid or trifluoroacetic acid is added, sodium triacetylborohydride is added, and the reaction is continued at this temperature. After stirring for 6 to 24 hours, TLC showed the reaction was complete. The mixture was quenched with water and extracted with ethyl acetate.
  • the invention also provides a preparation method b of a compound of formula I, which comprises the steps of:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above for the compound of formula I.
  • R 8 is an amino protecting group.
  • R 8 may be Boc, Fmoc or Troc.
  • the preparation method b of the compound of the formula I may comprise the following steps:
  • reaction conditions of each step can be as described above.
  • the invention also provides a preparation method c of a compound of formula I, which comprises the steps of:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above for the compound of formula I;
  • R 8 is an amino protecting group.
  • R 8 may be Boc, Fmoc or Troc.
  • the preparation method c of the compound of the formula I may comprise the following steps:
  • reaction conditions of each step can be as described above.
  • the invention also provides a preparation method d of a compound of formula I, which comprises the steps of:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above for the compound of formula I;
  • R 8 and R 9 are an amine protecting group.
  • R 8 may be Boc, Fmoc or Troc.
  • R 9 may be Boc, Fmoc or Troc.
  • the preparation method d of the compound of the formula I may comprise the following steps:
  • the step 5 comprises:
  • the compound of the formula II is dissolved in an organic solvent at 0 to 60 ° C, and an aqueous alkali solution is added thereto, and the reaction is further stirred at the temperature for 4 to 36 hours. TLC shows the reaction is complete, and after neutralizing with phosphoric acid, ethyl acetate is extracted. After concentration, it is purified to give a compound of formula I.
  • the organic solvent is preferably one or more of tetrahydrofuran, dimethyl sulfoxide, dichloromethane, methanol, ethanol and isopropanol;
  • the base is preferably one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium carbonate.
  • reaction conditions of each step can be as described above.
  • a compound of the formula VII can be used according to the literature (ACS Med. Chem. Lett. 2017, 8, 486-491; Organometallics 2018, 37, 116-126; J. Am. Chem. Soc. 1955, 77, 4540-4542). ; J. Mol. Spectr. 1958, 2, 525-529; Bull. Chem. Soc. Jpn. 2002, 75, 789-800);
  • the compound of formula VIII can be prepared according to the literature (Chem. Eur. J. 2011, 17, 4788-4795; US 2010/9950; Tetrahedron Lett. 1982, 23, 1697-1700);
  • a compound of formula IX can be prepared according to the literature (US 2015/133674; J. Am. Chem. Soc. 2009, 131, 16054-16062);
  • the compounds of formula I can also be prepared according to the above routes using commercially available compounds of formula VII, VIII, IX, X; for example, by the purchase of the above formulas VII, VIII, IX, X The intermediate is then prepared according to the procedure provided in the above procedure.
  • the amine protecting group of the present invention is a suitable group for amine group protection known in the art, see the amine protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts). .
  • the amine protecting group may be an amide protecting group, a carbamate protecting group or the like.
  • deuterated means that one or more hydrogens in a compound or group are replaced by deuterium. Deuterated can be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • the cerium isotope content of cerium at the cerium substitution site is greater than the natural strontium isotope content (0.015%), more preferably greater than 50%, more preferably greater than 75%, and even more preferably greater than 95%, more preferably The ground is greater than 97%, more preferably greater than 99%, and even more preferably greater than 99.5%.
  • the term "pharmaceutically acceptable salt” refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, toluenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • Another preferred class of salts are the salts of the compounds of the invention with bases.
  • Bases suitable for salt formation include, but are not limited to, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, S-phenylethylamine, R-phenylethylamine, L-benzene. Glycinamide and the like.
  • the compound IIc (0.5 g, 1.07 mmol) was dissolved in methanol (10 mL) at 40 ° C, and a solution of lithium hydroxide (3.0 M, 0.5 mL) was added. The reaction was stirred at this temperature for 4 h. After neutralizing with phosphoric acid, ethyl acetate was extracted, and concentrated to give the compound Ic (367 mg).
  • the compound IIg (0.5 g, 1.07 mmol) was dissolved in dimethyl sulfoxide (10 mL) at 40 ° C, and an aqueous solution of sodium hydroxide (3.0 M, 1 mL) was added. The reaction was stirred at this temperature for 8 h. After neutralizing with phosphoric acid, extraction with ethyl acetate, concentration and purification gave compound Ig (341 mg).
  • the compound Ik was synthesized according to the method and route for synthesizing the compound Ia according to Example 29, using VIIIa and VIIg as starting materials.
  • the compound Ia was synthesized according to the method and route for synthesizing the compound Ia according to Example 29, using VIIIa and VIIh as starting materials.
  • the compound Ia was synthesized according to the method and route for synthesizing the compound Ia according to Example 29, using VIIIa and VIIi as starting materials.
  • the compound Io was synthesized according to the method and route for synthesizing the compound Ia according to Example 29, using VIIIa and VIIj as starting materials.
  • the compound Ip was synthesized by following the procedure and route for the synthesis of the compound Ib according to Example 30, using IXc and VIIg as starting materials.
  • the compound Ib was synthesized according to the method and route for synthesizing the compound Ib according to Example 30, using IXc and VIIj as starting materials.
  • the compound Id was synthesized according to the method and route for synthesizing the compound Id according to Example 32, using VIIIf and VIIa as raw materials and sodium borohydride as a reducing agent.
  • the compound Is was synthesized according to the method and route of synthesizing Compound If in Example 34, using VIIIf and VIIj as raw materials, and deuterated sodium borohydride as a reducing agent to synthesize Compound Is.
  • SD rats were used as test animals, and the drug concentration in plasma at different times after intravenous administration and intragastric administration of the compound of the example was determined by LC/MS/MS method to study the pharmacokinetics of the compound of the present invention in rats. Learn behavior and evaluate its pharmacokinetic characteristics.
  • the rats were subjected to jugular vein puncture at different time points from 0.083 to 24 h before and after administration.
  • K2-EDTA was anticoagulated, centrifuged, and plasma was taken and stored at -70 °C until LC/MS/MS analysis.
  • the deuterated compounds of the present invention compared with the corresponding non-deuterated compound epacadosta, the compounds Ia and Ib significantly increased the Cmax and AUC in the animal, the compound Ig prolonged the half-life, and significantly increased in the animal. Cmax and AUC in the body.

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Abstract

本发明公开了一种吲哚胺2,3-双加氧酶抑制剂化合物及其制备方法和用途。本发明的吲哚胺2,3-双加氧酶抑制剂化合物如式I所示，与相应的非氘代的化合物相比，本发明的氘代化合物具有明显更优异的药效学性能和药物动力学性能，Cmax提高了50％以上，AUC提高了10％以上，可见氘代化合物在动物体内的暴露量有了显著的提高，因此更适合作为吲哚胺2,3-双加氧酶抑制剂，进而更适用制备治疗吲哚胺2,3-双加氧酶抑制剂类相关疾病的药物。

Description

吲哚胺2,3-双加氧酶抑制剂化合物及其制备方法和用途
本申请要求申请日为2017年7月3日的中国专利申请CN201710535177.5的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于医药领域，具体地，涉及一种吲哚胺2,3-双加氧酶抑制剂化合物及其制备方法和用途。
背景技术
T细胞是淋巴细胞的主要组分，它具有多种生物学功能，其中最主要的作用是免疫作用，从而成为身体中攻击肿瘤细胞、抵御疾病感染的重要工具。色氨酸是维持T细胞生长和增殖的重要氨基酸之一。在哺乳动物体内，色氨酸会循犬尿氨酸途径进行正常的代谢。该途径的限速酶包括色氨酸双加氧酶(tryptophan 2,3-dioxygenase,TDO)、吲哚胺2,3-双加氧酶1(indoleamine 2,3-dioxygenase 1,IDO1)以及吲哚胺2,3-双加氧酶2(indoleamine 2,3-dioxygenase 2,IDO2)三种。然而，很多肿瘤细胞却过度表达了吲哚胺2,3-双加氧酶，导致色氨酸被迅速大量地消耗，从而无法为T细胞提供养分，造成T细胞停止生长和增殖，甚至发生凋亡而被清除。另一方面，色氨酸循犬尿氨酸途径代谢产生的3-羟基邻氨基苯甲酸、喹啉酸、吡啶甲酸等有毒产物又反过来抑制T细胞的活化。此外，在肿瘤引流淋巴结中，过度活跃的IDO还会促使树突细胞直接抑制和抵抗引起抗原反应的T细胞以及T细胞对抗原的识别。因此，在过度表达IDO的肿瘤组织以及肿瘤引流淋巴结中，都会产生一个免疫抑制的肿瘤微环境，使T细胞一进入肿瘤组织就被抑制。因此，通过开发合适的药物来抑制吲哚胺2,3-双加氧酶的过度表达，可以激活T细胞，阻碍肿瘤细胞的继续生长、扩大和迁移，进而达到抑制肿瘤的作用。
在三种色氨酸代谢限速酶中，吲哚胺2,3-双加氧酶1(IDO1)的分布最为广泛。它于1967年在兔小肠中首次被发现，2006年人体中IDO1的晶体结构被确定，其生化功能清晰，对开发IDO1抑制剂具有更为明确的指导作用。此外，实验表明，被敲除了IDO1的小鼠依然可以健康地生活。因此，抑制IDO1的安全程度高，IDO1抑制剂对人体的毒副作用风险也被大大降低。IDO抑制剂的开发分为直接作用于IDO1的小分子药物和通过多种协同途径实现IDO抑制并激活T细胞的小分子药物两大类。
对IDO抑制剂临床研究进展较快的两个化合物分别来自于Incyte公司和NewLink公 司。其中，Incyte公司旗下的Epacadostat直接作用于IDO1，目前已经进展到临床三期，通过与默沙东的PD-1抗体Keytruda联合使用，早期数据显示可以显著提高晚期患者的总疾病控制率(73％)，对晚期黑色素瘤的应答率也提高到57％，而单独使用Keytruda时，应答率只有28％左右。另外，数据也表明联合用药的耐受性良好，3级或以上的不良事件发生率较低。在另一项二期的临床试验中，当Keytruda与Newlink公司的IDO抑制剂Indoximod联用时，52％的患者会出现肿瘤明显缩小或者完全消失，73％的患者病情得到控制。这种联用方式同样也表现了很好的耐受性和较低的不良反应发生率。
现有数据表明，IDO抑制剂的开发具有非常广阔的前景，但目前为止尚未有批准上市的IDO抑制剂药物。因此开发具有更好药效学性能和药物动力学性能的IDO抑制剂将具有强大的竞争力。
发明内容
本发明的目的是提供一种吲哚胺2,3-双加氧酶抑制剂化合物及其制备方法和用途。本发明意外地发现，本发明所提供的氘代的吲哚胺2,3-双加氧酶抑制类化合物与相应的非氘代的化合物相比，具有明显更优异的药效学性能和药物动力学性能，Cmax提高了50％以上，AUC提高了10％以上，可见氘代化合物在动物体内的暴露量有了显著的提高，因此更适合作为吲哚胺2,3-双加氧酶抑制剂，进而更适用制备治疗吲哚胺2,3-双加氧酶抑制剂类相关疾病的药物。
本发明第一方面提供了一种如式I所示化合物、其异构体、晶型、药学上可接受的前药、盐、水合物或溶剂合物，
Figure PCTCN2018094234-appb-000001
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7各自独立地选自氢或氘，且至少有一个为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 1、R 2、R 3、R 4和R 7中至少一个为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 1、R 2、R 3和R 4中至少一个为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 1和R 2中至少一个为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 1和R 2为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 3和R 4中至少一个为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 3和R 4为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 1和R 2为氘，R 3和R 4中一个为氘一个为氢。
在本发明的一些方案中，所述的如式I所示化合物中，R 1和R 2中一个为氘一个为氢，R 3和R 4中一个为氘一个为氢。
在本发明的一些方案中，所述的如式I所示化合物中，R 1、R 2、R 3和R 4为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 7为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 5为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 6为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 5、R 6和R 7为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 1和R 2为氘，R 5、R 6和R 7中至少一个为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 1、R 2和R 5为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 1、R 2和R 6为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 1、R 2和R 7为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 1、R 2、R 5、R 6和R 7为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 3、R 4和R 7为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 3、R 4、R 5、R 6和R 7为氘。
在本发明的一些方案中，所述的如式I所示化合物中，R 1、R 2、R 3、R 4、R 5、R 6和R 7均为氘。
在本发明的一些方案中，所述如式I所示化合物选自以下任一化合物：
Figure PCTCN2018094234-appb-000002
本发明第二方面提供了一种药物组合物，其含有:(1)所述的如式I所示化合物、其异构体、晶型、药学上可接受的前药、盐、水合物或溶剂合物；(2)药学上可接受的载体。
本发明第三方面提供了一种所述的药物组合物的制备方法，其包括：将所述的如式I所示化合物、其异构体、晶型、药学上可接受的前药、盐、水合物或溶剂合物，和所述的药学上可接受的载体进行混合，得到所述的药物组合物。
本发明第四方面提供一种通过抑制吲哚胺2,3-双加氧酶实现治疗癌症的方法，其包含向需要此治疗的患者施用所述的如式I所示化合物、其异构体、晶型、药学上可接受的前药、盐、水合物或溶剂合物，或所述的药物组合物。
本发明第五方面提供了所述的如式I所示化合物、其异构体、晶型、药学上可接受的前药、盐、水合物或溶剂合物，或所述的药物组合物在制备吲哚胺2,3-双加氧酶抑制剂中的应用，或在制备治疗和/或预防吲哚胺2,3-双加氧酶抑制有关疾病的药物中的应用。
所述的应用中，所述的如式I所示化合物、其异构体、晶型、药学上可接受的前药、盐、水合物或溶剂合物，或所述的药物组合物可与另外一种或多种抗癌剂联合使用，所述的抗癌剂选自烷化剂、铂络合物、代谢拮抗剂、生物碱、抗体药物、激素抗癌剂、蛋白酶体抑制剂、CDK激酶抑制剂、VEGFR或EGFR抑制剂、m-TOR抑制剂、PI3K激酶抑制剂、B-Raf抑制剂、PARP抑制剂、c-Met激酶抑制剂、ALK激酶抑制剂、AKT抑制剂、ABL抑制剂、FLT3抑制剂、PD-1抑制剂或PD-L1抑制剂等。
所述疾病可选自免疫性疾病，特别是癌症，其中所述的癌症包括乳腺癌、卵巢癌、前列腺癌、黑色素癌、脑癌、鼻咽癌、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨癌、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫瘤、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤。
在另一优选例中，所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
本发明还提供一种如式I所示化合物的制备方法a，其包括如下步骤：将如式II所示的化合物进行开环反应；
Figure PCTCN2018094234-appb-000003
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如上述的如式I所示化合物。
所述的如式I所示化合物的制备方法a中，所述的开环反应可在有机溶剂中进行，所述的有机溶剂可为本领域该类反应的常规溶剂，如醚类溶剂(如四氢呋喃)、醇类溶剂(如甲醇、乙醇和/或异丙醇)、氯代烃类溶剂(如二氯甲烷)和砜类溶剂(如二甲亚砜)中的一种或多种。
所述的如式I所示化合物的制备方法a中，所述的开环反应可在碱存在的条件下进行，所述的碱可为本领域该类反应常规的碱，如碱金属氢氧化物(如氢氧化钠、氢氧化钾和/或氢氧化锂)和/或碱金属的碳酸盐(碳酸钠)。
所述的如式I所示化合物的制备方法a中，所述的开环反应的温度可为本领域该类反应的常规温度，如-10～80℃(如0～60℃)。
本发明一个优选的实施方案中，所述如式I所示化合物的制备方法a可包括下列步骤：
0～60℃下，将如式II所示化合物溶解于有机溶剂中，加入碱的水溶液，反应在该温度下继续搅拌4～36h，TLC显示反应完全，用磷酸中和后，乙酸乙酯萃取，浓缩后纯化得到如式I所示化合物。
上述如式I所示化合物的制备方法a的优选方案中，所述有机溶剂优选四氢呋喃、二甲亚砜、二氯甲烷、甲醇、乙醇和异丙醇中的一种或多种；
上述如式I所示化合物的制备方法a的优选方案中，所述碱优选氢氧化钠、氢氧化钾、氢氧化锂和碳酸钠中的一种或多种。
所述的如式I所示化合物的制备方法a还可进一步包括下述如式II所示化合物的制备方法。
本发明还提供了一种如式II所示化合物，
Figure PCTCN2018094234-appb-000004
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如上述的如式I所示化合物。
在本发明的一些方案中，所述如式II所示化合物选自以下任一化合物：
Figure PCTCN2018094234-appb-000005
本发明还提供了一种所述的如式II所示化合物的制备方法，其包括如下步骤：将如式III所示化合物在酸性或碱性条件下进行保护基水解反应；
Figure PCTCN2018094234-appb-000006
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如上述的如式I所示化合物；
R 8为胺基保护基。
所述的如式II所示化合物的制备方法中，R 8优选为Boc、Fmoc或Troc。
所述的如式II所示化合物的制备方法中，所述的保护基水解反应可在有机溶剂中进行，所述的有机溶剂可为本领域该类反应的常规溶剂，如醚类溶剂(如四氢呋喃)、醇类溶剂(如甲醇、乙醇和/或异丙醇)和氯代烃类溶剂(如二氯甲烷)中的一种或多种。
所述的如式II所示化合物的制备方法中，所述的保护基水解反应可加入去保护试剂，所述的去保护试剂可为本领域该类反应常规的去保护试剂，本领域人员知晓根据胺基保护基的类型选择相应的去保护试剂。例如，当胺基保护基为Boc时，所述的去保护试剂可为有机酸和/或无机酸，有机酸如三氟乙酸或醋酸，无机酸如氯化氢、盐酸或硫酸；当胺基保护基为Fmoc时，所述的去保护试剂可为有机胺，如三(2-胺基乙基)胺；胺基保护基为Troc时，所述的去保护试剂可为醋酸和锌粉。
所述的如式II所示化合物的制备方法中，所述的保护基水解反应的温度可为本领域该类反应常规的反应温度，如-10～80℃(如0～60℃)。
本发明一个优选的实施方案中，所述的如式II所示化合物的制备方法可包括如下步骤：
0～60℃下，将如式III所示化合物溶解于有机溶剂中，加入去保护试剂，反应在该温度下继续搅拌2～24h，TLC显示反应完全，调节pH为中性后，乙酸乙酯萃取，浓缩后纯化得到如式II所示化合物。
上述的如式II所示化合物的制备方法的优选方案中，所述有机溶剂优选四氢呋喃、二氯甲烷、甲醇、乙醇和异丙醇中的一种或多种；
上述的如式II所示化合物的制备方法的优选方案中，所述去保护试剂优选三氟乙酸、氯化氢气体、盐酸、硫酸、三(2-胺基乙基)胺或(醋酸和锌粉)。
所述的如式II所示化合物的制备方法还可进一步包括下述如式III所示化合物的制备方法。
本发明还提供一种如式III所示化合物，
Figure PCTCN2018094234-appb-000007
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如上述的如式I所示化合物；
R 8为胺基保护基。
本发明一个优选的实施方案中，R 8为Boc、Fmoc或Troc。
在本发明的一些方案中，所述的如式III所示化合物选自以下任一化合物：
Figure PCTCN2018094234-appb-000008
本发明还提供一种所述的如式III所示化合物的制备方法m，其包括如下步骤：将如式IV所示化合物与如式V所示化合物进行缩合反应；
Figure PCTCN2018094234-appb-000009
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如上述的如式I所示化合物；
R 8为胺基保护基。
所述的如式III所示化合物的制备方法m中，R 8可为Boc或Fmoc。
所述的如式III所示化合物的制备方法m中，所述的缩合反应可在有机溶剂中进行，所述的有机溶剂可为本领域该类反应的常规溶剂，如氯代烃类溶剂(如二氯甲烷)、酯类溶剂(如乙酸乙酯)和醚类溶剂(如四氢呋喃、甲基叔丁基醚)中的一种或多种。
所述的如式III所示化合物的制备方法m中，所述的缩合反应优选在碱性条件下进行。所述的碱性条件可为加入有机碱，所述的有机碱可为本领域该类反应常规的有机碱，如三乙胺、吡啶、二异丙基乙基胺和2,6-二甲基吡啶中的一种或多种。
所述的如式III所示化合物的制备方法m中，所述的缩合反应的温度可为本领域该类反应常规的反应温度，如-10～70℃(如0～50℃)。
本发明一个优选的实施方案中，所述的如式III所示化合物的制备方法m可包括如下步骤：
0～50℃下，将如式IV所示化合物溶于有机溶剂中，加入碱和如式V所示化合物，反应在该温度下继续搅拌2～8h，TLC显示反应完全，加水淬灭反应，乙酸乙酯萃取，浓缩后纯化得到如式III所示化合物。
上述如式III所示化合物的制备方法m的优选方案中，所述有机溶剂优选二氯甲烷、乙酸乙酯、四氢呋喃和甲基叔丁基醚中的一种或多种；
上述如式III所示化合物的制备方法m的优选方案中，所述碱优选三乙胺、吡啶、二异丙基乙基胺和2,6-二甲基吡啶中的一种或多种。
所述如式III所示化合物的制备方法m还可进一步包括下述如式IV所示化合物的制备方法。
本发明还提供了一种如式III所示化合物的制备方法n，其包括如下步骤：将如式VII所示化合物与如式IX所示化合物在还原剂或氘代还原剂的存在下进行还原胺化反应；
Figure PCTCN2018094234-appb-000010
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如上述的如式I所示化合物；
R 8为胺基保护基。
所述的如式III所示化合物的制备方法n中，R 8可为Boc、Fmoc或Troc。
所述的如式III所示化合物的制备方法n中，所述的还原胺化反应可在有机溶剂中进 行，所述的有机溶剂可为本领域该类反应常规的溶剂，如氯代烃类溶剂和/或芳香烃类溶剂，所述的氯代烃类溶剂可为二氯甲烷，所述的芳香烃类溶剂可为甲苯。
所述的如式III所示化合物的制备方法n中，所述的还原剂或氘代还原剂可为本领域该类反应常规的还原剂或氘代还原剂，如硼氢化钠、氘代硼氢化钠或三乙酰基硼氢化钠。
所述的如式III所示化合物的制备方法n中，所述的还原胺化反应的温度可为本领域该类反应常规的反应温度，如0～130℃(如0～30℃)。
本发明一个优选的实施方案中，所述的如式III所示化合物的制备方法n可包括如下步骤：
室温下，将如式VII所示化合物与如式IX所示化合物溶解于有机溶剂中，加入路易斯酸，反应在60～110℃下回流6～12h，TLC显示反应完全，浓缩后，在0℃下用甲醇或氘代甲醇溶解，加入硼氢化钠或氘代硼氢化钠，反应在该温度下继续搅拌1～2h，TLC显示反应完全，加水淬灭反应，乙酸乙酯萃取，浓缩后纯化得到如式III所示化合物。
上述的如式III所示化合物的制备方法n的优选方案中，所述有机溶剂优选二氯甲烷和/或甲苯；
上述的如式III所示化合物的制备方法n的优选方案中，所述路易斯酸优选对甲苯磺酸和/或钛酸四异丙酯。
本发明另一个优选的实施方案中，所述的如式III所示化合物的制备方法n可包括如下步骤：
0～40℃下，将如式VII所示化合物与如式IX所示化合物溶于二氯甲烷中，加入醋酸或三氟乙酸，加入三乙酰基硼氢化钠，反应在该温度下继续搅拌4～24h，TLC显示反应完全，加水淬灭反应，乙酸乙酯萃取，浓缩后纯化得到如式III所示化合物。
本发明还提供一种如式III所示化合物的制备方法h，其包括如下步骤：将如式VII所示化合物与如式X所示化合物进行还原缩合反应；
Figure PCTCN2018094234-appb-000011
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如上述的如式I所示化合物；
R 8为胺基保护基。
所述的如式III所示化合物的制备方法h中，R 8可为Boc、Fmoc或Troc。
所述的如式III所示的化合物的制备方法h中，所述的还原缩合反应可在有机溶剂中进行，所述的有机溶剂可为本领域该类反应的常规溶剂，如氯代烃类溶剂和/或醚类溶剂，所述的氯代烃类溶剂可为二氯甲烷，所述的醚类溶剂可为四氢呋喃。
所述的如式III所示的化合物的制备方法h中，所述的还原缩合反应的温度可为本领域该类反应常规的反应温度，如-10～60℃(如0～40℃)。
本发明一个优选的实施方案中，所述的如式III所示化合物的制备方法h可包括如下步骤：
0～40℃下，将如式VII所示化合物与如式X所示化合物溶解于二氯甲烷或四氢呋喃中，加入甲烷磺酸和三乙基硅烷，反应在该温度下继续搅拌36～96h，TLC显示反应完全，加碳酸氢钠淬灭反应，乙酸乙酯萃取，浓缩后纯化得到如式III所示化合物。
本发明还提供一种如式IV所示化合物，其晶型或药学上可接受的盐；
Figure PCTCN2018094234-appb-000012
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如上述的如式I所示化合物。
在本发明的一些方案中，所述的如式IV所示化合物选自以下任一化合物：
Figure PCTCN2018094234-appb-000013
本发明还提供一种如式IV所示化合物的制备方法，其包括如下步骤：将如式VI所示化合物进行保护基水解反应；
Figure PCTCN2018094234-appb-000014
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如上述的如式I所示化合物；
R 9为胺基保护基。
所述的如式IV所示化合物的制备方法中，R 9可为Boc或Fmoc。
所述的如式IV所示化合物的制备方法中，所述的保护基水解反应可在有机溶剂中进行，所述的有机溶剂可为本领域该类反应的常规溶剂，如醚类溶剂(如四氢呋喃)、醇类溶剂(如甲醇、异丙醇)和氯代烃类溶剂(如二氯甲烷)中的一种或多种。
所述的如式IV所示化合物的制备方法中，所述的保护基水解反应可加入去保护试剂，所述的去保护试剂可为本领域该类反应常规的去保护试剂，本领域人员知晓根据胺基保护基的类型选择相应的去保护试剂。例如，当胺基保护基为Boc时，所述的去保护试剂可为有机酸和/或无机酸，如氯化氢和/或三氟乙酸；当胺基保护基为Fmoc时，所述的去保护试剂可为有机胺，如三(2-胺基乙基)胺。
所述的如式IV所示化合物的制备方法中，所述的保护基水解反应的温度可为本领域该类反应常规的反应温度，如-10～60℃(如0～30℃)。
本发明一个优选的实施方案中，所述的如式IV所示化合物的制备方法可包括如下步骤：
0～30℃下，将如式VI所示化合物溶解于有机溶剂中，加入去保护试剂，反应在0～60℃下继续搅拌4～24h，TLC显示反应完全，调节pH为中性后，乙酸乙酯萃取，浓缩后纯化得到如式IV所示化合物。
上述的如式IV所示化合物的制备方法的优选方案中，所述有机溶剂优选四氢呋喃、二氯甲烷、甲醇和乙醇中的一种或多种；
上述的如式IV所示化合物的制备方法的优选方案中，所述去保护试剂优选三氟乙酸、盐酸或三(2-胺基乙基)胺。
本发明还提供一种如式VI所示化合物；
Figure PCTCN2018094234-appb-000015
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如上述的如式I所示化合物；
R 9为胺基保护基。
所述的如式VI所示化合物中，R 9可为Boc或Fmoc。
在本发明的一些方案中，所述的如式VI所示化合物选自以下任一化合物：
Figure PCTCN2018094234-appb-000016
本发明还提供一种所述的如式VI所示化合物的制备方法，其包括如下步骤：将如式VII所示化合物与如式VIII所示化合物在还原剂或氘代还原剂的存在下进行还原胺化反应；
Figure PCTCN2018094234-appb-000017
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如上述的如式I所示化合物；
R 9为胺基保护基。
所述的如式VI所示化合物的制备方法中，所述的还原胺化反应可在有机溶剂中进行，所述的有机溶剂可为本领域该类反应的常规溶剂，如醚类溶剂和/或氯代烃类溶剂，所述的醚类溶剂可为四氢呋喃，所述的氯代烃类溶剂可为二氯甲烷。
所述的如式VI所示化合物的制备方法中，所述的还原剂或氘代还原剂可为本领域该类反应常规的还原剂或氘代还原剂，如三乙酰基硼氢化钠或氘代硼氢化钠。
所述的如式VI所示化合物的制备方法中，所述的还原胺化反应的反应温度可为本领域该类反应的常规温度，如-10～60℃(如0～30℃)。
本发明一个优选的实施方案中，所述的如式VI所示化合物的制备方法包括如下步 骤：
0～30℃下，将如式VII所示化合物与如式VIII所示化合物溶解于二氯甲烷或四氢呋喃中，加入醋酸或三氟乙酸，加入三乙酰基硼氢化钠，反应在该温度下继续搅拌6～24h，TLC显示反应完全，加水淬灭反应，乙酸乙酯萃取，浓缩后纯化得到如式VI所示化合物。
本发明还提供了一种如式I所示化合物的制备方法b，其包括如下步骤：
Figure PCTCN2018094234-appb-000018
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如上述的如式I所示化合物。
R 8为胺基保护基。
所述如式I所示化合物的制备方法b中，R 8可为Boc、Fmoc或Troc。
所述的如式I所示化合物的制备方法b可包括如下步骤：
1)将如式VII所示化合物与如式X所示化合物进行还原缩合反应得到如式III所示化合物；
2)将如式III所示化合物进行保护基水解反应得到如式II所示化合物；
3)如如式II所示的化合物在碱性条件下进行开环反应得到如式I所示化合物。
所述的如式I所示化合物的制备方法b中，各步反应条件可如上所述。
本发明还提供了一种如式I所示化合物的制备方法c，其包括如下步骤：
Figure PCTCN2018094234-appb-000019
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如上述的如式I所示化合物；
R 8为胺基保护基。
所述如式I所示化合物的制备方法c中，R 8可为Boc、Fmoc或Troc。
所述的如式I所示化合物的制备方法c可包括如下步骤：
1)将如式VII所示化合物与如式IX所示化合物进行还原胺化反应得到如式III所示化合物；
2)将如式III所示化合物进行保护基水解反应得到如式II所示化合物；
3)将如式II所示化合物在碱性条件下进行开环反应得到如式I所示化合物。
所述的如式I所示化合物的制备方法c中，各步反应条件可如上所述。
本发明还提供一种如式I所示化合物的制备方法d，其包括如下步骤：
Figure PCTCN2018094234-appb-000020
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如上述的如式I所示化合物；
R 8和R 9为胺基保护基。
所述如式I所示化合物的制备方法d中，R 8可为Boc、Fmoc或Troc。
所述如式I所示化合物的制备方法d中，R 9可为Boc、Fmoc或Troc。
所述如式I所示化合物的制备方法d可包括如下步骤：
1)将如式VII所示化合物与如式VIII所示化合物进行还原胺化反应得到如式VI所示化合物；
2)将如式VI所示化合物进行保护基水解反应得到如式IV所示化合物；
3)将如式IV所示化合物与如式V所示化合物在碱性条件下进行缩合反应得到如式III所示化合物；
4)将如式III所示化合物进行保护基水解反应得到如式II所示化合物；
5)将如式II所示化合物在碱性条件下进行开环反应得到如式I所示化合物。
本发明一个优选的实施方案中，所述如式I所示化合物的制备方法d中，步骤5包括：
0～60℃下，将如式II所示化合物溶解于有机溶剂中，加入碱的水溶液，反应在该温度下继续搅拌4～36h，TLC显示反应完全，用磷酸中和后，乙酸乙酯萃取，浓缩后纯化 得到如式I所示化合物。
上述如式I所示化合物的制备方法d的优选方案中，所述有机溶剂优选四氢呋喃、二甲亚砜、二氯甲烷、甲醇、乙醇和异丙醇中的一种或多种；
上述如式I所示化合物的制备方法d的优选方案中，所述碱优选氢氧化钠、氢氧化钾、氢氧化锂和碳酸钠中的一种或多种。
所述的如式I所示化合物的制备方法d中，各步反应条件可如上所述。
在本发明中，如式VII所示化合物可根据文献(ACS Med.Chem.Lett.2017,8,486-491；Organometallics 2018,37,116-126；J.Am.Chem.Soc.1955,77,4540-4542；J.Mol.Spectr.1958,2,525-529；Bull.Chem.Soc.Jpn.2002,75,789-800)制备得到；
如式VIII所示化合物可根据文献(Chem.Eur.J.2011,17,4788-4795；US2010/9950；Tetrahedron Lett.1982,23,1697-1700)制备得到；
如式IX所示化合物可根据文献(US2015/133674；J.Am.Chem.Soc.2009,131,16054-16062)制备得到；
如式X所示化合物可根据文献(US2015/133674)制备得到。
如果可以购得，也可使用商品化的如式VII、VIII、IX、X所示化合物依上述路线制得式I所示化合物；例如可通过购买前述式VII、VIII、IX、X所示的中间体，而后依照上述方法中提供的步骤制得式I所示的化合物。
本发明所使用的术语，除有相反的表述外，具有如下的含义：
本发明的胺基保护基是本领域已知的适当的用于胺基保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5 Th Ed.T.W.Greene&P.G.M.Wuts)中的胺基保护基团。作为示例，优选地，所述的胺基保护基可以是酰胺保护基团，氨基甲酸酯保护基团等。例如：甲酰基，乙酰基，叔丁氧羰基，苄氧羰基，笏甲氧羰基，三氯乙氧基羰基等；
如本文所用，“氘代”指化合物或基团中的一个或多个氢被氘所取代。氘代可以是一取代、二取代、多取代或全取代。
在另一优选例中，氘在氘取代位置的氘同位素含量是大于天然氘同位素含量(0.015％)，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于97％，更佳地大于99％，更佳地大于99.5％。
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、 磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、甲苯磺酸、苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。另一类优选的盐是本发明化合物与碱形成的盐。适合形成盐的碱包括但并不限于：氢氧化钠、氢氧化锂、氢氧化钾、三乙胺、二异丙基乙基胺、S-苯乙胺、R-苯乙胺、L-苯甘氨酰胺等。
缩写表：
缩写 全称
Boc 叔丁氧羰基
Fmoc 笏甲氧羰基
Troc 三氯乙氧基羰基
具体实施方式
下表为实施例中所涉及的化合物的结构式：
Figure PCTCN2018094234-appb-000021
Figure PCTCN2018094234-appb-000022
Figure PCTCN2018094234-appb-000023
Figure PCTCN2018094234-appb-000024
实施例1-4为如式VI所示化合物的合成
实施例1：制备化合物VIa
0℃下，溶解化合物VIIIa(1g，6.21mmol)和化合物VIIa(5.31g)于四氢呋喃(20mL)中，加入三氟乙酸(20mL)和三乙酰基硼氢化钠(13.2g)，反应在该温度下继续搅拌6h，TLC显示反应完全，加入碳酸氢钠淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物VIa(2.66g)。
1H NMR(400MHz,DMSO-d 6)δ8.09(dd,1H),7.73(ddd,1H),7.60(dd,J＝8.7Hz,1H),6.87(d,1H),6.51(t,1H),3.29(d,2H),1.38(m,9H).
MS(ESI)m/z:487,489(M+H +)。
实施例2：制备化合物VIc
20℃下，溶解化合物VIIIc(1g，3.55mmol)和化合物VIIa(3.03g)于二氯甲烷(20mL)中，加入乙酸(20mL)和三乙酰基硼氢化钠(7.55g)，反应在该温度下继续搅拌24h，TLC显示反应完全，加入碳酸氢钠淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物VIc(2.03g)。
1H NMR(400MHz,DMSO-d 6)δ8.09(dd,1H),7.87(d,2H),7.72(ddd,1H),7.67(d,2H),7.60(dd,1H),7.29-7.48(m,5H),6.51(t,1H),4.31(d,2H),3.29(d,1H),3.22(dd,1H).
MS(ESI)m/z:608,610(M+H +)。
实施例3：制备化合物VIe
30℃下，溶解化合物VIIIe(1g，6.21mmol)和化合物VIIa(3.03g)于四氢呋喃(20mL)中，加入乙酸(20mL)和三乙酰基硼氢化钠(7.55g)，反应在该温度下继续搅拌16h，TLC显示反应完全，加入碳酸氢钠淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物VIe(2.32g)。
1H NMR(400MHz,DMSO-d 6)δ8.09(dd,1H),7.73(ddd,1H),7.60(dd,1H),6.87(d,1H),6.51(d,1H),3.29(m,1H),3.15(m,1H),1.38(m,9H).
MS(ESI)m/z:487,489(M+H +)。
实施例4：制备化合物VIf
30℃下，溶解化合物VIIIf(1g，6.21mmol)和化合物VIIa(2.63g)于二氯甲烷(20mL)中，加入对甲苯磺酸(66mg)，反应在60℃下回流搅拌16h，TLC显示反应完全，浓缩溶剂后，用氘代甲醇(10mL)溶解，0℃下加入氘代硼氢化钠(466mg)，反应在0℃下搅拌3h，TLC显示反应完全，加入水淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物VIf(2.28g)。
1H NMR(400MHz,DMSO-d 6)δ8.09(dd,1H),7.72(ddd,1H),7.60(dd,1H),6.87(s,1H),6.51(s,1H),1.38(m,9H).
MS(ESI)m/z:489,491(M+H +)。
实施例5-8为如式IV所示化合物的合成
实施例5：制备化合物IVa
0℃下，溶解化合物VIa(2g，4.11mmol)于异丙醇(20mL)中，加入4.0M盐酸二氧六环溶液(5mL)，反应在该温度下继续搅拌24h，TLC显示反应完全，加入碳酸氢钠淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物IVa(1.32g)。
1H NMR(400MHz,DMSO-d 6)δ8.09(m,4H),7.78(ddd,J＝8.7,4.3,2.6Hz,1H),7.61(dd,1H),6.79(t,1H),3.55(m,2H).
MS(ESI)m/z:387,389(M+H +)。
实施例6：制备化合物IVc
0℃下，溶解化合物VIc(2g，3.29mmol)于四氢呋喃(20mL)中，加入三(2-胺基乙基)胺(4.5mL)，反应在25℃下继续搅拌8h，TLC显示反应完全，加水淬灭反应 后，乙酸乙酯萃取，浓缩后纯化得到化合物IVc(1.15g)。
1H NMR(400MHz,DMSO-d 6)δ8.09(m,4H),7.78(ddd,J＝8.7,4.3,2.6Hz,1H),7.61(dd,1H),6.79(t,1H),3.54(m,2H),3.07(m,1H).
MS(ESI)m/z:386,388(M+H +)。
实施例7：制备化合物IVe
30℃下，溶解化合物VIe(2g，4.11mmol)于甲醇(20mL)中，加入盐酸(3N,5mL)，反应在60℃下继续搅拌4h，TLC显示反应完全，加入碳酸氢钠淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物IVe(1.19g)。
1H NMR(400MHz,DMSO-d 6)δ8.09(m,4H),7.78(ddd,J＝8.7,4.3,2.6Hz,1H),7.61(dd,1H),6.77(d,1H),3.55(m,1H),3.07(m,1H).
MS(ESI)m/z:387,389(M+H +)。
实施例8：制备化合物IVf
室温下，溶解化合物VIf(2g，4.10mmol)于二氯甲烷(20mL)中，加入三氟乙酸(5mL)，反应在60℃下继续搅拌12h，TLC显示反应完全，加入碳酸氢钠淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物IVf(1.33g)。
1H NMR(400MHz,DMSO-d 6)δ8.09(m,4H),7.78(ddd,J＝8.7,4.3,2.6Hz,1H),7.60(dd,1H),6.79(s,1H).
MS(ESI)m/z:389,391(M+H +)。
实施例9-18为如式III所示化合物的合成
实施例9：制备化合物IIIa
0℃下，溶解化合物IVa(1g，2.58mmol)于二氯甲烷(20mL)中，加入三乙胺(0.6mL)和化合物Va(610mg)，反应在该温度下继续搅拌8h，TLC显示反应完全，加水淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物IIIa(1.22g)。
1H NMR(400MHz,DMSO-d 6)δ10.90(s,1H),8.08(dd,1H),7.72(m,1H),7.59(dd,1H),6.58(s,1H),6.52(t,1H),3.38(d,2H),1.41(s,9H).
MS(ESI)m/z:566,568(M+H +)。
实施例10：制备化合物IIIb
室温下，溶解化合物VIIa(1g，2.94mmol)和化合物IXc(702mg)于甲苯(20mL)中，加入对甲苯磺酸(10mg)，反应在110度下回流6h，TLC显示反应完全，浓缩后，在0℃下用氘代甲醇(5mL)溶解，加入氘代硼氢化钠(300mg)，反应在该温度下继续搅拌2h，TLC显示反应完全，加水淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物IIIb(1.38g)。
1H NMR(400MHz,DMSO-d 6)δ10.91(s,1H),8.08(dd,1H),7.72(m,1H),7.59(dd,1H),6.59(t,1H),6.52(s,1H),3.11(d,2H),1.41(s,9H).
MS(ESI)m/z:566,568(M+H +)。
实施例11：制备化合物IIIc
20℃下，溶解化合物IVc(1g，2.58mmol)于乙酸乙酯(20mL)中，加入二异丙基乙基胺(0.8mL)和化合物Vb(956mg)，反应在该温度下继续搅拌6h，TLC显示反应完全，加水淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物IIIc(1.36g)。
1H NMR(400MHz,DMSO-d 6)δ11.01(s,1H),8.08(dd,1H),7.87(d,2H),7.72(ddd,1H),7.67(d,2H),7.59(dd,1H),7.40(m,4H),6.59(d,1H),6.52(t,1H),4.30(d,2H),3.38(d,2H),3.12(dd,1H).
MS(ESI)m/z:687,689(M+H +)。
实施例12：制备化合物IIId
室温下，溶解化合物VIIa(1g，2.94mmol)和化合物IXd(920mg)于二氯甲烷(20mL)中，加入钛酸四异丙酯(60mg)，反应在60℃下回流12h，TLC显示反应完全，浓缩后，在20℃下用甲醇(5mL)溶解，加入硼氢化钠(300mg)，反应在该温度下继续搅拌1h，TLC显示反应完全，加水淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物IIId(1.69g)。
1H NMR(400MHz,DMSO-d 6)δ11.05(s,1H),8.08(dd,1H),7.73(m,1H),7.59(dd,1H),6.57(t,1H),6.52(d,1H),4.72(s,2H),3.37(dd,1H),3.12(d,2H).
MS(ESI)m/z:641(M+H +)。
实施例13：制备化合物IIIe
50℃下，溶解化合物IVe(1g，2.59mmol)于甲基叔丁基醚(20mL)中，加入吡啶(0.7mL)和化合物Va(630mg)，反应在该温度下继续搅拌2h，TLC显示反应完全， 加水淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物IIIe(1.18g)。
1H NMR(400MHz,DMSO-d 6)δ10.91(s,1H),8.08(dd,1H),7.72(m,1H),7.59(dd,1H),6.59(d,1H),6.52(d,1H),3.38(d,1H),3.11(d,1H),1.41(s,9H).
MS(ESI)m/z:566,568(M+H +)。
实施例14：制备化合物IIIf
20℃下，溶解化合物IVf(1g，2.58mmol)于四氢呋喃(20mL)中，加入2,6-二甲基吡啶(0.8mL)和化合物Va(630mg)，反应在该温度下继续搅拌5h，TLC显示反应完全，加水淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物IIIf(1.26g)。
1H NMR(400MHz,DMSO-d 6)δ10.90(s,1H),8.08(dd,1H),7.72(m,1H),7.59(dd,1H),6.58(s,1H),6.51(s,1H),1.40(s,9H).
MS(ESI)m/z:568,570(M+H +)。
实施例15：制备化合物IIIg
0℃下，溶解化合物VIIg(1g，2.94mmol)和化合物Xa(1.31g)于二氯甲烷(20mL)中，加入甲烷磺酸(850mg)和三乙基硅烷(960mg)，反应在该温度下继续搅拌96h，TLC显示反应完全，加碳酸氢钠淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物IIIg(1.55g)。
1H NMR(400MHz,DMSO-d 6)δ11.01(s,1H),7.87(d,2H),7.73(dd,1H),7.67(d,2H),7.59(dd,1H),7.40(m,4H),6.59(t,1H),6.52(t,1H),4.30(d,2H),3.38(dd,2H),3.11(dd,2H).
MS(ESI)m/z:687,689(M+H +)。
实施例16：制备化合物IIIh
0℃下，溶解化合物VIIh(1g，2.94mmol)和化合物IXb(920mg)于二氯甲烷(20mL)中，加入醋酸(0.53mL)和三乙酰基硼氢化钠(1.87g)，反应在该温度下继续搅拌24h，TLC显示反应完全，加水淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物IIIh(1.62g)。
1H NMR(400MHz,DMSO-d 6)δ11.05(s,1H),8.08(d,1H),7.59(d,1H),6.57(t,1H),6.52(t,1H),4.72(s,2H),3.37(dd,2H),3.12(dd,2H).
MS(ESI)m/z:643(M+H +)。
实施例17：制备化合物IIIi
40℃下，溶解化合物VIIi(1g，2.94mmol)和化合物IXa(702mg)于二氯甲烷(20mL)中，加入三氟乙酸(0.62mL)和三乙酰基硼氢化钠(1.87g)，反应在该温度下继续搅拌4h，TLC显示反应完全，加水淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物IIIi(1.28g)。
1H NMR(400MHz,DMSO-d 6)δ10.91(s,1H),8.08(dd,1H),7.72(dd,1H),6.59(t,1H),6.52(t,1H),3.38(dd,2H),3.11(dd,2H),1.41(s,9H).
MS(ESI)m/z:565,567(M+H +)。
实施例18：制备化合物IIIj
40℃下，溶解化合物VIIj(1g，2.93mmol)和化合物Xb(915mg)于四氢呋喃(20mL)中，加入甲烷磺酸(850mg)和三乙基硅烷(960mg)，反应在该温度下继续搅拌36h，TLC显示反应完全，加碳酸氢钠淬灭反应，乙酸乙酯萃取，浓缩后纯化得到化合物IIIj(1.26g)。
1H NMR(400MHz,DMSO-d 6)δ10.90(s,1H),6.60(t,1H),6.52(t,1H),3.38(dd,2H),3.11(dd,2H),1.41(s,9H).
MS(ESI)m/z:567,569(M+H +)。
实施例19-28为如式II所示化合物的合成
实施例19：制备化合物IIa
0℃下，溶解化合物IIIa(1g，1.77mmol)于二氯甲烷(10mL)中，加入三氟乙酸(3mL)，反应在该温度下继续搅拌12h，TLC显示反应完全，用碳酸氢钠固体中和后，乙酸乙酯萃取，浓缩后纯化得到化合物IIa(766mg)。
1H NMR(400MHz,DMSO-d 6)δ8.08(dd,1H),7.72(m,1H),7.59(dd,1H),6.67(s,1H),6.55(s,2H),6.52(t,1H),3.38(d,2H).
MS(ESI)m/z:466,468(M+H +)。
实施例20：制备化合物IIb
60℃下，溶解化合物IIIb(1g，1.77mmol)于四氢呋喃(10mL)中，加入盐酸(6.0N，5mL)，反应在该温度下继续搅拌4h，TLC显示反应完全，用碳酸氢钠固体中和后， 乙酸乙酯萃取，浓缩后纯化得到化合物IIb(723mg)。
1H NMR(400MHz,DMSO-d 6)δ8.09(dd,1H),7.72(m,1H),7.59(dd,1H),6.67(d,1H),6.55(s,2H),6.52(t,1H),3.11(d,2H).
MS(ESI)m/z:466,468(M+H +)。
实施例21：制备化合物IIc
0℃下，溶解化合物IIIc(1g，1.45mmol)于四氢呋喃(10mL)中，加入三(2-胺基乙基)胺(4.5mL)，反应在25℃下继续搅拌8h，TLC显示反应完全，用1N盐酸中和后，乙酸乙酯萃取，浓缩后纯化得到化合物IIc(622mg)。
1H NMR(400MHz,DMSO-d 6)δ8.08(dd,1H),7.72(m,1H),7.60(dd,1H),6.67(d,1H),6.55(s,2H),6.53(t,1H),3.36(d,2H),3.11(dd,1H).
MS(ESI)m/z:465,467(M+H +)。
实施例22：制备化合物IId
25℃下，溶解化合物IIId(1g，1.56mmol)于四氢呋喃(10mL)中，加入醋酸(1mL)和锌粉(603mg)，反应在25℃下继续搅拌8h，TLC显示反应完全，硅藻土过滤后，碳酸氢钠中和，乙酸乙酯萃取，浓缩后纯化得到化合物IId(630mg)。
1H NMR(400MHz,DMSO-d 6)δ8.08(dd,1H),7.73(m,1H),7.59(dd,1H),6.68(t,1H),6.55(s,2H),6.52(d,1H),3.35(dd,1H),3.12(d,2H).
MS(ESI)m/z:465,467(M+H +)。
实施例23：制备化合物IIe
30℃下，溶解化合物IIIe(1g，1.77mmol)于甲醇(10mL)中，加入盐酸(3.0N，5mL)，反应在该温度下继续搅拌12h，TLC显示反应完全，用碳酸氢钠固体中和后，乙酸乙酯萃取，浓缩后纯化得到化合物IIe(738mg)。
1H NMR(400MHz,DMSO-d 6)δ8.07(dd,1H),7.72(m,1H),7.59(dd,1H),6.69(d,1H),6.55(s,2H),6.53(d,1H),3.35(d,1H),3.11(d,1H).
MS(ESI)m/z:466,468(M+H +)。
实施例24：制备化合物IIf
50℃下，溶解化合物IIIf(1g，1.77mmol)于乙醇(10mL)中，加入盐酸(6.0N， 2mL)，反应在该温度下继续搅拌8h，TLC显示反应完全，用碳酸氢钠固体中和后，乙酸乙酯萃取，浓缩后纯化得到化合物IIf(775mg)。
1H NMR(400MHz,DMSO-d 6)δ8.08(dd,1H),7.73(m,1H),7.59(dd,1H),6.69(s,1H),6.55(s,2H),6.52(s,1H).
MS(ESI)m/z:468,470(M+H +)。
实施例25：制备化合物IIg
20℃下，溶解化合物IIIg(1g，1.45mmol)于四氢呋喃(10mL)中，加入三(2-胺基乙基)胺(4.5mL)，反应在50℃下继续搅拌4h，TLC显示反应完全，用1N盐酸中和后，乙酸乙酯萃取，浓缩后纯化得到化合物IIg(613mg)。
1H NMR(400MHz,DMSO-d 6)δ7.72(dd,1H),7.59(dd,1H),6.70(t,1H),6.55(s,2H),6.54(t,1H),3.35(dd,2H),3.11(dd,2H).
MS(ESI)m/z:465,467(M+H +)。
实施例26：制备化合物IIh
50℃下，溶解化合物IIIh(1g，1.56mmol)于四氢呋喃(10mL)中，加入醋酸(1mL)和锌粉(603mg)，反应在50℃下继续搅拌2h，TLC显示反应完全，硅藻土过滤后，碳酸氢钠中和，乙酸乙酯萃取，浓缩后纯化得到化合物IIh(520mg)。
1H NMR(400MHz,DMSO-d 6)δ8.08(d,1H),7.58(d,1H),6.69(t,1H),6.55(s,2H),6.53(t,1H),3.35(dd,2H),3.11(dd,2H)..
MS(ESI)m/z:465,467(M+H +)。
实施例27：制备化合物IIi
20℃下，溶解化合物IIIi(1g，1.77mmol)于异丙醇(10mL)中，通入氯化氢气体，反应在该温度下继续搅拌24h，TLC显示反应完全，用碳酸氢钠固体中和后，乙酸乙酯萃取，浓缩后纯化得到化合物IIi(783mg)。
1H NMR(400MHz,DMSO-d 6)δ8.08(dd,1H),7.73(dd,1H),6.69(t,1H),6.55(s,2H),6.53(t,1H),3.35(dd,2H),3.11(dd,2H).
MS(ESI)m/z:465,467(M+H +)。
实施例28：制备化合物IIj
20℃下，溶解化合物IIIj(1g，1.77mmol)于二氯甲烷(10mL)中，加入三氟乙酸(5mL)，反应在该温度下继续搅拌10h，TLC显示反应完全，用碳酸氢钠固体中和后，乙酸乙酯萃取，浓缩后纯化得到化合物IIj(790mg)。
1H NMR(400MHz,DMSO-d 6)δ6.54(s,2H),6.53(t,1H),3.35(dd,2H),3.11(dd,2H).
MS(ESI)m/z:467,469(M+H +)。
实施例29-46为如式I所示化合物的合成
实施例29：制备化合物Ia
0℃下，溶解化合物IIa(0.5g，1.07mmol)于四氢呋喃(10mL)中，加入氢氧化钠的水溶液(3.0M，1mL)，反应在该温度下继续搅拌36h，TLC显示反应完全，用磷酸中和后，乙酸乙酯萃取，浓缩后纯化得到化合物Ia(401mg)。
1H NMR(400MHz,DMSO-d 6)δ11.49(s,1H),8.88(s,1H),7.18(dd,1H),7.12(dd,1H),6.77(ddd,1H),6.68(s,1H),6.58(s,2H),6.22(t,1H),3.35(d,2H).
MS(ESI)m/z:440,442(M+H +)。
实施例30：制备化合物Ib
20℃下，溶解化合物IIb(0.5g，1.07mmol)于乙醇(10mL)中，加入氢氧化钾的水溶液(3.0M，2mL)，反应在该温度下继续搅拌24h，TLC显示反应完全，用磷酸中和后，乙酸乙酯萃取，浓缩后纯化得到化合物Ib(380mg)。
1H NMR(400MHz,DMSO-d 6)δ11.49(s,1H),8.88(s,1H),7.18(dd,1H),7.12(dd,1H),6.77(ddd,1H),6.70(t,1H),6.58(s,2H),6.23(s,1H),3.11(d,2H).
MS(ESI)m/z:440,442(M+H +)。
实施例31：制备化合物Ic
40℃下，溶解化合物IIc(0.5g，1.07mmol)于甲醇(10mL)中，加入氢氧化锂的水溶液(3.0M，0.5mL)，反应在该温度下继续搅拌4h，TLC显示反应完全，用磷酸中和后，乙酸乙酯萃取，浓缩后纯化得到化合物Ic(367mg)。
1H NMR(400MHz,DMSO-d 6)δ11.40(s,1H),8.90(s,1H),7.18(t,1H),7.11(dd,1H),6.78(ddd,1H),6.71(d,1H),6.56(s,2H),6.23(t,1H),3.37(d,2H),3.12(dd,1H).
MS(ESI)m/z:439,441(M+H +)。
实施例32：制备化合物Id
20℃下，溶解化合物IId(0.5g，1.07mmol)于异丙醇(10mL)中，加入氢氧化钠的水溶液(3.0M，4mL)，反应在该温度下继续搅拌12h，TLC显示反应完全，用磷酸中和后，乙酸乙酯萃取，浓缩后纯化得到化合物Id(388mg)。
1H NMR(400MHz,DMSO-d 6)δ11.42(s,1H),8.91(s,1H),7.18(t,1H),7.12(dd,1H),6.76(ddd,1H),6.70(t,1H),6.56(s,2H),6.22(d,1H),3.36(dd,1H),3.11(d,2H).
MS(ESI)m/z:439,441(M+H +)。
实施例33：制备化合物Ie
20℃下，溶解化合物IIe(0.5g，1.07mmol)于四氢呋喃(10mL)中，加入氢氧化钠的水溶液(3.0M，1mL)，反应在该温度下继续搅拌12h，TLC显示反应完全，用磷酸中和后，乙酸乙酯萃取，浓缩后纯化得到化合物Ie(376mg)。
1H NMR(400MHz,DMSO-d 6)δ11.46(s,1H),8.90(s,1H),7.18(t,1H),7.12(dd,1H),6.76(ddd,1H),6.72(d,1H),6.58(s,2H),6.24(d,1H),3.36(d,1H),3.12(d,2H).
MS(ESI)m/z:440,442(M+H +)。
实施例34：制备化合物If
60℃下，溶解化合物IIf(0.5g，1.07mmol)于四氢呋喃(10mL)中，加入碳酸钠的水溶液(3.0M，1mL)，反应在该温度下继续搅拌10h，TLC显示反应完全，用磷酸中和后，乙酸乙酯萃取，浓缩后纯化得到化合物If(362mg)。
1H NMR(400MHz,DMSO-d 6)δ11.49(s,1H),8.88(s,1H),7.18(t,J＝8.8Hz,1H),7.12(dd,1H),6.77(ddd,1H),6.68(s,1H),6.58(s,2H),6.22(t,1H).
MS(ESI)m/z:442,444(M+H +)。
实施例35：制备化合物Ig
40℃下，溶解化合物IIg(0.5g，1.07mmol)于二甲亚砜(10mL)中，加入氢氧化钠的水溶液(3.0M，1mL)，反应在该温度下继续搅拌8h，TLC显示反应完全，用磷酸中和后，乙酸乙酯萃取，浓缩后纯化得到化合物Ig(341mg)。
1H NMR(400MHz,DMSO-d 6)δ11.49(s,1H),8.88(s,1H),7.19(dd,1H),6.77(dd,1H),6.70(t,1H),6.58(s,2H),6.23(t,1H),3.36(dd,2H),3.10(dd,2H).
MS(ESI)m/z:439,441(M+H +)。
实施例36：制备化合物Ih
50℃下，溶解化合物IIh(0.5g，1.07mmol)于二氯甲烷(10mL)中，加入氢氧化钠的水溶液(3.0M，1mL)，反应在该温度下继续搅拌12h，TLC显示反应完全，用磷酸中和后，乙酸乙酯萃取，浓缩后纯化得到化合物Ih(332mg)。
1H NMR(400MHz,DMSO-d 6)δ11.49(s,1H),8.88(s,1H),7.18(d,1H),7.13(d,1H),6.71(t,1H),6.58(s,2H),6.23(t,1H),3.37(dd,2H),3.11(dd,2H).
MS(ESI)m/z:439,441(M+H +)。
实施例37：制备化合物Ii
30℃下，溶解化合物IIi(0.5g，1.07mmol)于四氢呋喃(10mL)中，加入氢氧化钠的水溶液(3.0M，1mL)，反应在该温度下继续搅拌18h，TLC显示反应完全，用磷酸中和后，乙酸乙酯萃取，浓缩后纯化得到化合物Ii(396mg)。
1H NMR(400MHz,DMSO-d 6)δ11.49(s,1H),8.88(s,1H),7.12(dd,1H),6.78(dd,1H),6.70(t,1H),6.58(s,2H),6.23(t,1H),3.37(dd,2H),3.10(dd,2H).
MS(ESI)m/z:439,441(M+H +)。
实施例38：制备化合物Ij
30℃下，溶解化合物IIj(0.5g，1.07mmol)于四氢呋喃(10mL)中，加入氢氧化钠的水溶液(3.0M，1mL)，反应在该温度下继续搅拌18h，TLC显示反应完全，用磷酸中和后，乙酸乙酯萃取，浓缩后纯化得到化合物Ij(373mg)。
1H NMR(400MHz,DMSO-d 6)δ11.36(s,1H),8.92(s,1H),6.71(t,1H),6.56(s,2H),6.23(t,1H),3.37(dd,2H),3.11(dd,1H).
MS(ESI)m/z:441,443(M+H +)。
实施例39：制备化合物Ik
按照实施例29合成化合物Ia的方法和路线，以VIIIa和VIIg为原料，合成化合物Ik。
1H NMR(400MHz,DMSO-d 6)δ11.47(s,1H),8.86(s,1H),7.18(dd,1H),6.76(dd,1H),6.68(s,1H),6.57(s,2H),6.22(t,1H),3.35(d,2H).
MS(ESI)m/z:441,443(M+H +)。
实施例40：制备化合物Im
按照实施例29合成化合物Ia的方法和路线，以VIIIa和VIIh为原料，合成化合物Im。
1H NMR(400MHz,DMSO-d 6)δ11.48(s,1H),8.87(s,1H),7.18(d,1H),7.12(d,1H),6.69(s,1H),6.57(s,2H),6.22(t,1H),3.36(d,2H).
MS(ESI)m/z:441,443(M+H +)。
实施例41：制备化合物In
按照实施例29合成化合物Ia的方法和路线，以VIIIa和VIIi为原料，合成化合物In。
1H NMR(400MHz,DMSO-d 6)δ11.49(s,1H),8.88(s,1H),7.13(d,1H),6.75(dd,1H),6.69(s,1H),6.59(s,2H),6.23(t,1H),3.37(d,2H).
MS(ESI)m/z:441,443(M+H +)。
实施例42：制备化合物Io
按照实施例29合成化合物Ia的方法和路线，以VIIIa和VIIj为原料，合成化合物Io。
1H NMR(400MHz,DMSO-d 6)δ11.47(s,1H),8.85(s,1H),6.67(s,1H),6.58(s,2H),6.24(t,1H),3.36(d,2H).
MS(ESI)m/z:443,445(M+H +)。
实施例43：制备化合物Ip
按照实施例30合成化合物Ib的方法和路线，以IXc和VIIg为原料，合成化合物Ip。
1H NMR(400MHz,DMSO-d 6)δ11.51(s,1H),8.90(s,1H),7.18(dd,1H),6.77(dd,1H),6.71(t,1H),6.56(s,2H),6.23(s,1H),3.12(d,2H).
MS(ESI)m/z:441,443(M+H +)。
实施例44：制备化合物Iq
按照实施例30合成化合物Ib的方法和路线，以IXc和VIIj为原料，合成化合物Iq。
1H NMR(400MHz,DMSO-d 6)δ11.48(s,1H),8.86(s,1H),6.70(t,1H),6.56(s,2H),6.24(s,1H),3.11(d,2H).
MS(ESI)m/z:443,445(M+H +)。
实施例45：制备化合物Ir
按照实施例32合成化合物Id的方法和路线，以VIIIf和VIIa为原料，醋酸硼氢化钠为还原剂，合成化合物Ir。
1H NMR(400MHz,DMSO-d 6)δ11.47(s,1H),8.88(s,1H),7.18(dd,1H),7.12(dd,1H),6.77(ddd,1H),6.68(s,1H),6.58(s,2H),6.22(d,1H),3.35(d,1H).
MS(ESI)m/z:441,443(M+H +)。
实施例46：制备化合物Is
按照实施例34合成化合物If的方法和路线，以VIIIf和VIIj为原料，氘代硼氢化钠为还原剂，合成化合物Is。
1H NMR(400MHz,DMSO-d 6)δ11.49(s,1H),8.88(s,1H),6.69(s,1H),6.58(s,2H),6.24(s,1H).
MS(ESI)m/z:445,447(M+H +)。
效果实施例1：化合物Ia、Ib、Ig的大鼠药代动力学测定
1.实验方法
以SD大鼠为受试动物，应用LC/MS/MS法测定大鼠静注和灌胃给予实施例化合物后不同时刻血浆中的药物浓度，以研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。
2.实验方案
2.1 供试药品：
本发明实施例化合物Ia、Ib、Ig和阳性对照Epacadostat化合物
2.2 供试动物
健康成年雄性SD(Sprague-Dawley)大鼠，每个供试化合物各3只，6-9周龄，体重250±50g，购自上海斯莱克实验动物有限责任公司。
2.3 供试药物配制
称取适量样品，加入0.5％甲基纤维素水溶液至终体积，配制1mg/mL用于灌胃给药。
2.4 供试药品给药
雄性SD大鼠每个供试化合物各三只，禁食一夜后给予灌胃给药，剂量为5mg/kg。
3.实验操作
在给药前和后0.083-24h不同时间点于大鼠经颈静脉穿刺取血，K2-EDTA抗凝，离心，取血浆，-70℃冷冻保存直至LC/MS/MS分析。
4.药代动力学数据结果如下表所示：
Figure PCTCN2018094234-appb-000025
根据实验结果可知，本发明的氘代化合物，与相应的非氘代化合物epacadosta相比，化合物Ia和Ib显著提高了在动物体内的Cmax和AUC，化合物Ig延长了半衰期，并且显著提高了在动物体内的Cmax和AUC。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (23)

  1. 一种如式I所示化合物、其异构体、晶型、药学上可接受的前药、盐、水合物或溶剂合物，
    Figure PCTCN2018094234-appb-100001
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7各自独立地选自氢或氘，且至少有一个为氘。
  2. 如权利要求1所述的如式I所示化合物、其异构体、晶型、药学上可接受的前药、盐、水合物或溶剂合物，其特征在于：R 1、R 2、R 3、R 4和R 7中至少一个为氘。
  3. 如权利要求2所述的如式I所示化合物、其异构体、晶型、药学上可接受的前药、盐、水合物或溶剂合物，其特征在于：R 1和R 2为氘；
    和/或，R 3和R 4为氘；
    和/或，R 7为氘。
  4. 如权利要求1所述的如式I所示化合物、其异构体、晶型、药学上可接受的前药、盐、水合物或溶剂合物，其特征在于，所述的如式I所示化合物选自以下任一化合物：
    Figure PCTCN2018094234-appb-100002
  5. 一种药物组合物，其包含:(1)如权利要求1-4任一项所述的如式I所示化合物、其异构体、晶型、药学上可接受的前药、盐、水合物或溶剂合物；(2)药学上可接受的载体。
  6. 一种如权利要求5所述的药物组合物的制备方法，其特征在于：将如权利要求1-4任一项所述的如式I所示化合物、其异构体、晶型、药学上可接受的前药、盐、水合物或溶剂合物，和药学上可接受的载体进行混合，得到所述的药物组合物。
  7. 一种通过抑制吲哚胺2,3-双加氧酶实现治疗癌症的方法，其包含向需要此治疗的患者施用如权利要求1-4任一项所述的如式I所示化合物、其异构体、晶型、药学上可接受的前药、盐、水合物或溶剂合物，或如权利要求5所述的药物组合物。
  8. 一种如权利要求1-4任一项所述的如式I所示化合物、其异构体、晶型、药学上可接受的前药、盐、水合物或溶剂合物，或如权利要求5所述的药物组合物在制备治疗免疫性疾病的药物中的用途，特别是在制备治疗癌症的药物中的用途，其中所述的癌症包括乳腺癌、卵巢癌、前列腺癌、黑色素癌、脑癌、鼻咽癌、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨癌、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫瘤、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤。
  9. 如权利要求8所述的用途，其特征在于：如权利要求1-4任一项所述的如式I所示化合物、其异构体、晶型、药学上可接受的前药、盐、水合物或溶剂合物，或如权利要求5所述的药物组合物与另外一种或多种抗癌剂联合使用，所述的抗癌剂选自烷化剂、铂络合物、代谢拮抗剂、生物碱、抗体药物、激素抗癌剂、蛋白酶体抑制剂、CDK激酶抑制剂、VEGFR或EGFR抑制剂、m-TOR抑制剂、PI3K激酶抑制剂、B-Raf抑制剂、PARP抑制剂、c-Met激酶抑制剂、ALK激酶抑制剂、AKT抑制剂、ABL抑制剂、FLT3抑制剂、PD-1抑制剂或PD-L1抑制剂。
  10. 一种如式I所示化合物的制备方法，其特征在于，其包括如下步骤：将如式II所示化合物进行开环反应；
    Figure PCTCN2018094234-appb-100003
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如权利要求1-4中任一项所述。
  11. 一种如式II所示化合物，
    Figure PCTCN2018094234-appb-100004
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如权利要求1-4中任一项所述。
  12. 一种如权利要求11所述的如式II所示化合物的制备方法，其特征在于，其包括如下步骤：将如式III所示化合物进行保护基水解反应；
    Figure PCTCN2018094234-appb-100005
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如权利要求1-4中任一项所述；
    R 8为胺基保护基。
  13. 一种如式III所示化合物；
    Figure PCTCN2018094234-appb-100006
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如权利要求1-4中任一项所述；
    R 8为胺基保护基。
  14. 一种如权利要求13所述的如式III所示化合物的制备方法，其特征在于，其包括如下步骤：将如式IV所示化合物与如式V所示化合物进行缩合反应；
    Figure PCTCN2018094234-appb-100007
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如权利要求1-4中任一项所述；
    R 8为胺基保护基。
  15. 一种如权利要求13所述的如式III所示化合物的制备方法，其特征在于，其包括如下步骤：将如式VII所示化合物与如式IX所示化合物在还原剂或氘代还原剂的存在下进行还原胺化反应；
    Figure PCTCN2018094234-appb-100008
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如权利要求1-4中任一项所述；
    R 8为胺基保护基。
  16. 一种如权利要求13所述的如式III所示化合物的制备方法，其特征在于，其包括如下步骤：将如式VII所示化合物与如式X所示化合物进行还原缩合反应；
    Figure PCTCN2018094234-appb-100009
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如权利要求1-4中任一项所述；
    R 8为胺基保护基。
  17. 一种如式IV所示化合物、其晶型或药学上可接受的盐，
    Figure PCTCN2018094234-appb-100010
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如权利要求1-4中任一项所述。
  18. 一种如权利要求17所述的如式IV所示化合物、其晶型或药学上可接受的盐的制备方法，其特征在于，其包括如下步骤：将如式VI所示化合物进行保护基水解反应；
    Figure PCTCN2018094234-appb-100011
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如权利要求1-4中任一项所述；
    R 9为胺基保护基。
  19. 一种如式VI所示化合物；
    Figure PCTCN2018094234-appb-100012
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如权利要求1-4中任一项所述；
    R 9为胺基保护基。
  20. 一种如权利要求19所述的如式VI所示化合物的制备方法，其特征在于，其包括如下步骤：将如式VII所示化合物与如式VIII所示化合物在还原剂或氘代还原剂的存在下进行还原胺化反应；
    Figure PCTCN2018094234-appb-100013
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如权利要求1-4中任一项所述；
    R 9为胺基保护基。
  21. 一种如式I所示化合物的制备方法，其特征在于，其包括如下步骤：
    1)将如式VII所示化合物与如式X所示化合物进行还原缩合反应得到如式III所示化合物；
    2)将如式III所示化合物进行保护基水解反应得到如式II所示化合物；
    3)将如式II所示化合物进行开环反应得到如式I所示化合物；
    Figure PCTCN2018094234-appb-100014
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如权利要求1-4中任一项所述；
    R 8为胺基保护基。
  22. 一种如式I所示化合物的制备方法，其特征在于，其包括如下步骤：
    1)将如式VII所示化合物与如式IX所示化合物在还原剂或氘代还原剂的存在下进行还原胺化反应得到如式III所示化合物；
    2)将如式III所示化合物进行保护基水解反应得到如式II所示的化合物；
    3)将如式II所示的化合物进行开环反应得到如式I所示的化合物；
    Figure PCTCN2018094234-appb-100015
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如权利要求1-4中任一项所述；
    R 8为胺基保护基。
  23. 一种如式I所示化合物的制备方法，其特征在于，其包括如下步骤：
    1)将如式VII所示化合物与如式VIII所示化合物在还原剂或氘代还原剂的存在下进行还原胺化反应得到如式VI所示化合物；
    2)将如式VI所示化合物进行保护基水解反应得到如式IV所示化合物；
    3)将如式IV所示化合物与如式V所示化合物进行缩合反应得到如式III所示的化合物；
    4)将如式III所示化合物进行保护基水解反应得到如式II所示的化合物；
    5)将如式II所示化合物进行开环反应得到如式I所示的化合物；
    Figure PCTCN2018094234-appb-100016
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7的定义如权利要求1-4中任一项所述；
    R 8和R 9为胺基保护基。
PCT/CN2018/094234 2017-07-03 2018-07-03 吲哚胺2,3-双加氧酶抑制剂化合物及其制备方法和用途 WO2019007321A1 (zh)

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