WO2021213460A1 - 三并环类激酶抑制剂 - Google Patents

三并环类激酶抑制剂 Download PDF

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Publication number
WO2021213460A1
WO2021213460A1 PCT/CN2021/088926 CN2021088926W WO2021213460A1 WO 2021213460 A1 WO2021213460 A1 WO 2021213460A1 CN 2021088926 W CN2021088926 W CN 2021088926W WO 2021213460 A1 WO2021213460 A1 WO 2021213460A1
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alkyl
amino
pharmaceutically acceptable
compound
halogenated
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PCT/CN2021/088926
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English (en)
French (fr)
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刘斌
陈博
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山东轩竹医药科技有限公司
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Publication of WO2021213460A1 publication Critical patent/WO2021213460A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention belongs to the technical field of medicine, and specifically relates to a triad of DNA-PK kinase inhibitor compound, its pharmaceutically acceptable salt or its isomer, containing said compound, its pharmaceutically acceptable salt or its isomer Pharmaceutical compositions and preparations, methods for preparing the compound, its pharmaceutically acceptable salt or its isomer, and the use of the compound, its pharmaceutically acceptable salt or its isomer.
  • Cancer is a malignant disease that is difficult to treat in the world. It is difficult to treat and has a high mortality rate. It brings a heavy burden to patients and families. It is a major disease that affects the health of Chinese residents. In recent years, the incidence of cancer in China has increased significantly, and its mortality rate is also gradually increasing. Cancer prevention and treatment are facing a severe situation.
  • radiotherapy and chemotherapy are the most effective means to treat cancer in addition to surgical resection, and radiotherapy is the most effective non-surgical treatment for malignant tumors.
  • Radiation and many anti-cancer drugs can directly or indirectly act on DNA or DNA metabolism, causing DNA damage.
  • DNA double-strand break (DSB) is the most deadly for cancer cells. After DNA damage, it will trigger a series of cellular responses such as damaged DNA repair, and the result of repair is to improve the survival of cancer cells, which is also one of the mechanisms by which tumor cells resist radiotherapy and chemotherapy. If DNA double-strand breaks are not repaired in a timely and complete manner, cancer cells will die due to apoptosis or/and mitotic disorders. Therefore, as long as the repair of these DNA damages is inhibited, the sensitivity of cancer cells to radiotherapy and chemotherapy can be improved, and cell proliferation can be inhibited.
  • DNA-dependent protein kinase DNA-Dependent Protein Kinase, DNA-PK
  • DNA-PKcs DNA-dependent protein kinase
  • DNA-PKcs belongs to the phosphatidylinositol 3-kinase (PI3K) superfamily and is a serine/threonine protein kinase; the PI3K superfamily also includes ATM, ATR, mTOR and 4 PI3K subtypes. Only when DNA-PK binds to broken DNA can its kinase activity be activated.
  • PI3K phosphatidylinositol 3-kinase
  • the important function of Ku is to bind to the end of DNA and recruit DNA-PKcs, which form the DNA-PK holoenzyme and activate DNA-PKcs; activated DNA-PKcs guide Artemis protein (an endonuclease) to bind to the damaged site Point, rely on its ribozyme activity to perform DNA end-breaking treatment to facilitate ligation repair, then the XRCC4/DNA-ligase IV complex is recruited by activated DNA-PKcs, and finally the DNA-ligase IV locates and connects the broken DNA double strands At the end, the repair is completed.
  • XRCC4 is a protein that forms a complex with DNA-ligase IV and can increase the activity of DNA-ligase IV.
  • DNA-PKcs has 40 amino acid residues that can be autophosphorylated. The most typical autophosphorylation sites occur in Ser2056 (POR cluster) and Thr2609 (ABCDE cluster). NHEJ is considered to be carried out through three key steps: identifying the DSB-Ku70/80 binds to the incomplete DNA end, recruiting two molecules of DNA-PKcs to the adjacent side of the DSB; performing DNA processing to remove the incomplete end of the DNA. Connect the ends or other forms of damage; finally connect the DNA ends.
  • tumor cells have a higher basic level of endogenous replication pressure (oncogene-induced replication pressure) and DNA damage, and the efficiency of the DNA repair mechanism in tumor cells is low, tumor cells are more sensitive to DNA-PK .
  • One of the technical problems to be solved by the present invention is to provide a triacyl compound with novel structure and good inhibitory effect on DNA-PK. Further, such compounds can be used to increase the sensitivity of a subject to radiotherapy and/or one or more anticancer agents. Furthermore, such compounds can be used in combination with radiotherapy and/or one or more anticancer agents to prevent and/or treat benign tumors or cancers.
  • the present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, or an isomer thereof,
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from CR 2 or N;
  • X 5 is selected from C, CH or N;
  • Each X 6 , X 7 , X 8 is independently selected from CR 3 R 4 , NR 5 , CR 6 , N, O or S;
  • Y 1 , Y 2 , Y 3 , and Y 4 are each independently selected from CH or N;
  • Ring A is selected from 3-8 membered cycloalkyl or 3-8 membered heterocyclic group optionally substituted by 1-3 substituents, and the substituents are selected from halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylcarbonyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, hydroxy C 1-6 alkane Oxy, hydroxy C 1-6 alkylthio, amino C 1-6 alkoxy, amino C 1-6 alkylthio;
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkylamino , Two (C 1-6 alkyl) amino, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkane Thio, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, hydroxy C 1-6 alkoxy, hydroxy C 1-6 alkylthio, amino C 1-6 alkoxy, Amino C 1-6 alkylthio;
  • Virtual bond --- is a chemical bond or does not exist, and adjacent virtual bonds are not chemical bonds at the same time;
  • n is selected from 1, 2 or 3.
  • the heteroatom in the 3-8 membered heterocyclic group is at least one (eg, 1, 2, 3, 4, or 5) nitrogen atom, oxygen atom and/or sulfur Atoms, optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the 3-8 membered heterocyclic group may be oxo with one or two oxygen atoms.
  • Ring A is selected from 3-6 membered cycloalkyl or 3-6 membered heterocyclyl optionally substituted with 1-2 substituents.
  • ring A is selected from 3-6 membered cycloalkyl or 3-6 membered heterocyclyl optionally substituted with 1-2 substituents; said substituents are selected from halogen, hydroxyl, amino, Nitro, cyano, C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylcarbonyl, halogenated C 1-6 alkyl, hydroxyl C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogenated C 1-6 alkoxy or halogenated C 1-6 alkylthio .
  • Ring A is selected from 3-6 membered cycloalkyl or 3-6 membered heterocyclyl.
  • Ring A is selected from 3-6 membered saturated cycloalkyl or 3-6 membered saturated heterocyclyl optionally substituted with 1-2 substituents.
  • Ring A is selected from 3-6 membered saturated cycloalkyl or 3-6 membered saturated heterocyclyl.
  • Ring A is selected from 5-6 membered cycloalkyl or 5-6 membered heterocyclyl optionally substituted with 1-2 substituents.
  • Ring A is selected from 5-6 membered cycloalkyl or 5-6 membered heterocyclyl. In certain embodiments, Ring A is selected from 5-6 membered saturated cycloalkyl or 5-6 membered saturated heterocyclyl optionally substituted with 1-2 substituents.
  • ring A is selected from 5-6 membered saturated cycloalkyl or 5-6 membered saturated heterocyclyl optionally substituted with 1-2 substituents; said substituents are selected from halogen, hydroxyl, Amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylcarbonyl, halogenated C 1-6 alkyl , Hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogenated C 1-6 alkoxy or halogenated C 1-6 alkane Sulfur-based.
  • Ring A is selected from 5-6 membered saturated cycloalkyl or 5-6 membered saturated heterocyclyl.
  • Ring A is selected from cyclohexyl or 6-membered saturated heterocyclyl.
  • ring A is selected from cyclohexyl, tetrahydropyranyl, tetrahydropyranyl, or
  • the substituents on ring A are selected from fluorine, chlorine, bromine, iodine, hydroxy, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, hydroxymethyl, amino Methyl, methoxy, ethoxy, propoxy, isopropoxy or trifluoromethoxy.
  • Ring A is substituted with 2 identical substituents.
  • ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxanyl, aziridinyl, oxo, optionally substituted with 1-2 substituents.
  • ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, aziridinyl, oxetanyl, azetidinyl, Tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolidinyl, tetrahydropyrazolidinyl, tetrahydroimidazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, piperazinyl, hexahydropyrimidine Or morpholinyl.
  • ring A is selected from cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolidinyl, tetrahydropyranyl, tetrahydropyranyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, Hydrothiopyranyl, piperidinyl, piperazinyl or morpholinyl; the substituent is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, methyl Carbonyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, trifluoromethoxy or trifluoromethylthio.
  • ring A is selected from cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, piperazine Or morpholinyl.
  • ring A is a 3-8 membered heterocyclic group optionally substituted with 1-3 substituents, the 3-8 membered heterocyclic group is at least one heteroatom and the number of ring atoms is 3-8 saturated or partially saturated monocyclic cyclic groups without aromaticity, the heteroatom is a sulfur atom, and optionally, the sulfur atom in the cyclic structure can be oxo with an oxygen atom;
  • the substituents are selected from halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkyl Carbonyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogenated C 1-6 alkane Oxy or halogenated C 1-6 alkylthio.
  • ring A is selected from those optionally substituted with 1-2 substituents
  • the substituents are selected from halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkyl Carbonyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogenated C 1-6 alkane Oxy or halogenated C 1-6 alkylthio.
  • ring A is selected from those optionally substituted with 1-2 substituents
  • the substituent is selected from fluorine, chlorine, bromine, iodine, hydroxy, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy Group, propoxy, isopropoxy or trifluoromethoxy.
  • R 1 and R 2 are each independently selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halo C 1-6 alkyl, C 1- 6 alkoxy, C 1-6 alkylthio, halo C 1-6 alkoxy or halo C 1-6 alkylthio;
  • R 3 , R 4 , and R 6 are each independently selected from H, halogen, hydroxy, amino, C 1-6 alkyl or halo C 1-6 alkyl;
  • R 5 is selected from hydrogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
  • R 1 and R 2 are each independently selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, halo C 1-4 alkyl, C 1- 4 alkoxy, C 1-4 alkylthio, halo C 1-4 alkoxy or halo C 1-4 alkylthio;
  • R 3 , R 4 , and R 6 are each independently selected from H, halogen, hydroxy, amino, C 1-4 alkyl or halo C 1-4 alkyl;
  • R 5 is selected from hydrogen, C 1-4 alkyl or halogenated C 1-4 alkyl.
  • R 1 and R 2 are each independently selected from H, halogen, hydroxyl, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methyl Oxy, ethoxy, trifluoromethoxy, methylthio, ethylthio, or trifluoromethylthio.
  • R 3 , R 4 , and R 6 are each independently selected from H, halogen, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, or trifluoroethyl .
  • R 5 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, or trifluoroethyl.
  • R 1 and R 2 are each independently selected from H, halogen, hydroxyl, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methyl Oxy, ethoxy, trifluoromethoxy, methylthio, ethylthio or trifluoromethylthio;
  • R 5 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl or trifluoroethyl.
  • R 1 is methyl
  • Y 1 , Y 2 , and Y 4 are each N, and Y 3 is selected from CH or N.
  • Y 1 , Y 2 , and Y 4 are each N, and Y 3 is CH.
  • X 1 , X 2 , and X 4 are all N; X 3 is selected from CH or N; X 5 is selected from C, CH or N.
  • X 1 , X 2 , and X 4 are all N; X 3 is selected from CH or N; X 5 is selected from C or N.
  • X 1 , X 2 , and X 4 are all N; X 3 is CH; X 5 is selected from C, CH, or N.
  • X 1 , X 2 , and X 4 are all N; X 3 is CH; X 5 is selected from C or N.
  • each X 6 , X 7 , X 8 is independently selected from CR 3 R 4 , NR 5 , CR 6 , N, O, or S.
  • each X 6 , X 7 , X 8 is independently selected from CH 2 , CH, NH, C(CH 3 ), N, O, or S.
  • each of X 6 , X 7 , and X 8 is independently selected from CH 2 , CH, C(CH 3 ), N, O, or S, respectively.
  • each of X 6 and X 8 is independently selected from CH 2 , CH or N, and X 7 is a carbonyl group. In certain embodiments, n is selected from 1 or 2.
  • n 1
  • n is 2.
  • each of X 6 , X 7 , and X 8 is independently selected from CR 3 R 4 , NR 5 , CR 6 , N, O, or S;
  • R 5 is selected from H, methyl, ethyl or trifluoromethyl.
  • X 1 , X 2 and X 4 are all N; X 3 is CH or N;
  • X 5 is selected from C or N;
  • Each X 6 , X 7 , X 8 is independently selected from CR 3 R 4 , NR 5 , CR 6 , N, O or S;
  • Y 1 , Y 2 , and Y 4 are respectively N, and Y 3 is CH or N;
  • Ring A is selected from cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolidinyl, tetrahydro which are optionally substituted by 1-2 substituents Pyranyl, tetrahydrothiopyranyl, piperidinyl, piperazinyl or morpholinyl; the substituent is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, iso Propyl, methylcarbonyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, trifluoromethoxy or trifluoromethylthio;
  • R 1 is selected from H, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy;
  • R 3 , R 4 , and R 6 are each independently selected from H, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl or trifluoromethyl;
  • R 5 is selected from H, methyl, ethyl, propyl, isopropyl or trifluoromethyl
  • Virtual bond --- is a chemical bond or does not exist, and adjacent virtual bonds are not chemical bonds at the same time;
  • n is selected from 1 or 2.
  • X 1 , X 2 , and X 4 are all N; X 3 is CH;
  • X 5 is selected from C or N;
  • Each X 6 , X 7 , X 8 is independently selected from CR 3 R 4 , NR 5 , CR 6 , N, O or S;
  • Y 1 , Y 2 , Y 4 are respectively N, and Y 3 is CH;
  • Ring A is selected from cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolidinyl, tetrahydro which are optionally substituted by 1-2 substituents Pyranyl, tetrahydrothiopyranyl, piperidinyl, piperazinyl or morpholinyl; the substituent is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, iso Propyl, methylcarbonyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, trifluoromethoxy or trifluoromethylthio;
  • R 1 is selected from H, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy;
  • R 3 , R 4 , and R 6 are each independently selected from H, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl or trifluoromethyl;
  • R 5 is selected from H, methyl, ethyl, propyl, isopropyl or trifluoromethyl
  • Virtual bond --- is a chemical bond or does not exist, and adjacent virtual bonds are not chemical bonds at the same time;
  • n is selected from 1 or 2.
  • X 1 , X 2 , and X 4 are all N; X 3 is CH;
  • X 5 is selected from C or N;
  • X 6 , X 7 , and X 8 are each independently selected from CR 3 R 4 , NR 5 , CR 6 , N, O or S;
  • Y 1 , Y 2 , Y 4 are respectively N, and Y 3 is CH;
  • Ring A is selected from cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidine optionally substituted by 1-2 substituents Group, piperazinyl or morpholinyl; the substituent is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, methylcarbonyl, trifluoromethyl, Methoxy, ethoxy, propoxy, isopropoxy, methylthio, trifluoromethoxy or trifluoromethylthio;
  • R 1 is selected from H, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy;
  • R 3 , R 4 , and R 6 are each independently selected from H, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl or trifluoromethyl;
  • R 5 is selected from H, methyl, ethyl, propyl, isopropyl or trifluoromethyl
  • Virtual bond --- is a chemical bond or does not exist, and adjacent virtual bonds are not chemical bonds at the same time;
  • n is 1.
  • R 1 is positioned ortho to -NH-.
  • the compound represented by general formula (I), its pharmaceutically acceptable salt or isomers thereof further has a structure represented by the following general formula (II),
  • R 1 is positioned ortho to -NH-.
  • the compound represented by general formula (I), its pharmaceutically acceptable salt or isomers thereof further has a structure represented by the following general formula (IIa),
  • R 1 is positioned ortho to -NH-.
  • X 1 and X 2 are each N, and X 3 is CH; each X 6 , X 7 and X 8 are each independently selected from CH 2 , CH, C(CH 3 ), N, O, or S; ring A is selected from cyclopentyl, cyclohexyl, and tetrahydrofuran optionally substituted by 1-2 substituents Group, tetrahydrothienyl, tetrahydropyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, piperidinyl, piperazinyl or morpholinyl; The substituent is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl,
  • X 1 and X 2 are each N, and X 3 is CH; each X 6 , X 7 and X 8 are each independently selected from CH 2 , CH, CCH 3 , N, O or S; ring A is selected from cyclohexyl, tetrahydropyranyl and tetrahydro which are optionally substituted by 1-2 substituents Thianyl, 1,1-dioxotetrahydrothiopyranyl; the substituent is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, methyl Carbonyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, trifluoromethoxy or trifluoromethylthio; R 1 is selected from H, fluorine, chlorine,
  • X 1 and X 2 are each N, and X 3 is CH; each X 6 , X 7 and X 8 are each independently selected from CH 2 , CH, CCH 3 , N, O or S; ring A is selected from cyclohexyl, tetrahydropyranyl and tetrahydro which are optionally substituted by 1-2 substituents Thianyl, 1,1-dioxotetrahydrothiopyranyl; the substituent is selected from fluorine, chlorine, bromine, iodine, and hydroxyl; R 1 is selected from H, fluorine, chlorine, bromine, iodine, hydroxyl, and amino , Methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy; virtual bond --- is a chemical bond
  • X 1 and X 2 are each N, and X 3 is CH; each X 6 , X 7 and X 8 are each independently selected from CH 2 , CH, CH 3 , N, O or S; ring A is selected from cyclohexyl, tetrahydropyranyl, tetrahydro optionally substituted by 1-2 substituents Thianyl, 1,1-dioxotetrahydrothiopyranyl; the substituent is selected from fluorine, hydroxyl; R 1 is selected from H, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl , Propyl, isopropyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy; virtual bond --- is a chemical bond or does not exist, and adjacent virtual bonds are not chemical bonds at the same time;
  • X 1 and X 2 are each N, and X 3 is CH; each X 6 , X 7 and X 8 are each independently selected from CH 2 , CH, CH 3 , N, O or S; ring A is selected from cyclohexyl, tetrahydropyranyl, tetrahydro optionally substituted by 1-2 substituents Thianyl, 1,1-dioxotetrahydrothiopyranyl; the substituent is selected from fluorine, hydroxyl; R 1 is methyl; virtual bond --- is a chemical bond or does not exist, and adjacent virtual bonds It is not a chemical bond at the same time; n is 1.
  • each X 6 and X 7 are independently selected from CH 2 , CH, C( CH 3 ), N, O or S, and X 8 is selected from N, O or S.
  • X 1 and X 2 are each N, and X 3 is CH; each X 6 , X 7 is each independently selected from CH 2 , CH, C(CH 3 ), N, O, or S, X 8 is selected from N, O, or S; ring A is selected from a ring optionally substituted with 1-2 substituents Hexyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl; the substituent is selected from fluorine, hydroxyl; R 1 is methyl; virtual bond --- is a chemical bond Or it does not exist, and adjacent virtual bonds are not chemical bonds at the same time; n is 1.
  • the compound represented by general formula (I), its pharmaceutically acceptable salt or isomers thereof further has a structure represented by the following general formula (IIb),
  • R 1 is located in the ortho position of -NH-.
  • the compound represented by the general formula (IIb), its pharmaceutically acceptable salt or its isomer isomer
  • X 7 is a carbonyl group
  • Ring A is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic group optionally substituted by 1-3 substituents,
  • the substituents are selected from halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halogenated C 1-6 Alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylcarbonyl, halogenated C 1-6 alkane Oxy, halogenated C 1-6 alkylthio, hydroxy C 1-6 alkoxy, hydroxy C 1-6 alkylthio, amino C 1-6 alkoxy, amino C 1-6 alkylthio;
  • Virtual bond --- is a chemical bond or does not exist, and adjacent virtual bonds are not chemical bonds at the same time;
  • n is selected from 1, 2 or 3.
  • the compound represented by the general formula (IIb), its pharmaceutically acceptable salt or its isomer isomer
  • X 5 is selected from C, CH or N;
  • X 7 is a carbonyl group
  • R 1 is selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halogenated C 1-6 Alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogenated C 1-6 alkoxy, halogenated C 1- 6 Alkylthio, hydroxy C 1-6 alkoxy, hydroxy C 1-6 alkylthio, amino C 1-6 alkoxy, amino C 1-6 alkylthio;
  • Ring A is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic group optionally substituted by 1-3 substituents,
  • the substituents are selected from halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halogenated C 1-6 Alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylcarbonyl, halogenated C 1-6 alkane Oxy, halogenated C 1-6 alkylthio, hydroxy C 1-6 alkoxy, hydroxy C 1-6 alkylthio, amino C 1-6 alkoxy, amino C 1-6 alkylthio;
  • n is selected from 1, 2 or 3.
  • R 1 is selected from H, halogen, hydroxy, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, aminomethyl, amino Ethyl, methoxy, ethoxy or trifluoromethoxy.
  • ring A is selected from cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, optionally substituted with 1-2 substituents.
  • ring A is selected from those optionally substituted with 1-2 substituents
  • the substituents are selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, carbonyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, Ethoxy, propoxy, isopropoxy or trifluoromethoxy.
  • X 5 is N; each X 6 and X 8 are each independently selected from CH 2 , CH, N; X 7 is carbonyl;
  • R 1 is H, halogen, hydroxy, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
  • ring A is selected from cyclohexyl, tetrahydropyranyl, tetrahydrothiopyranyl optionally substituted by 1-2 substituents , 1,1-dioxotetrahydrothiopyranyl; the substituent is selected from halogen, hydroxy, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, Amino C 1-6 alkyl, C 1-6 alkoxy
  • R 1 is a C 1-6 alkyl group.
  • X 5 is N; each X 6 and X 8 are each independently selected from CH 2 , CH, N; X 7 is a carbonyl group; R 1 is a C 1-4 alkyl group; ring A is selected from cyclohexyl, tetrahydropyranyl, tetrahydrothiopyranyl, optionally substituted by 1-2 substituents, 1,1-dioxotetrahydrothiopyranyl; the substituent is selected from halogen, hydroxy, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy; n is 1 or 2.
  • X 5 is N; each X 6 and X 8 are each independently selected from CH 2 , CH, N; X 7 is a carbonyl group; R 1 is a methyl group; ring A is selected from cyclohexyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,1- Dioxotetrahydrothiopyranyl; the substituent is selected from halogen, hydroxy, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy; n is 1 or 2.
  • X 5 is N; each X 6 and X 8 are each independently selected from CH 2 , CH, N; X 7 is a carbonyl group; R 1 is a methyl group; ring A is selected from cyclohexyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,1- Dioxotetrahydrothiopyranyl; the substituent is selected from halogen and hydroxyl; n is 1 or 2.
  • X 5 is N; each X 6 and X 8 are each independently selected from CH 2 , CH, N; X 7 is a carbonyl group; R 1 is a methyl group; ring A is selected from cyclohexyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,1- Dioxotetrahydrothiopyranyl; the substituent is selected from fluorine and hydroxyl; virtual bond--- is a chemical bond or does not exist, and adjacent virtual bonds are not chemical bonds at the same time; n is 1 or 2.
  • the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt or its isomers are selected from the following compounds:
  • the present invention also provides a preparation method of the compound of the present invention:
  • X, X', X" are each independently selected from halogen, amino or hydroxyl; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , ring A, n, and virtual bond---as described in any of the preceding schemes.
  • intermediate 1 is reacted with chloroacetaldehyde to obtain intermediate 2
  • intermediate 2 is reacted with intermediate 3 to obtain the compound of formula (I).
  • intermediate 1 is reacted with chloroacetaldehyde to obtain intermediate 2, and intermediate 2 and intermediate 3 are reacted under catalyst and basic conditions to obtain formula (I) Compound.
  • the catalyst is selected from Pd-containing catalysts, preferably BrettPhos Pd G3.
  • the alkaline condition means that the pH of the reaction solution is greater than 7, which is generally achieved by adding a certain amount of alkaline reagent.
  • the alkaline reagent is selected from K 2 CO 3 , Na 2 CO 3 , and Cs 2 CO 3. NaOH, KOH or KOAc.
  • X is selected from halogen, amino or hydroxyl; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 2 , R 3 , R 4 , R 5 , R 6 , Ring A, n and virtual bond --- as described in any of the previous schemes.
  • the present invention also provides the compound represented by the general formula (III), its pharmaceutically acceptable salt or its isomers for preparing the compound of the present invention, its pharmaceutically acceptable salt or its isomers. the use of.
  • the present invention also provides a pharmaceutical preparation, which contains the compound of the present invention, a pharmaceutically acceptable salt or isomer thereof, and one or more pharmaceutically acceptable excipients.
  • the formulation can be any pharmaceutically acceptable dosage form.
  • a pharmaceutically acceptable excipient is a substance that is non-toxic, compatible with the active ingredient, and is suitable for the organism in other aspects such as biological properties. The choice of a particular excipient will depend on the mode of administration or the type and state of disease used to treat a particular patient.
  • the above-mentioned pharmaceutical preparations can be administered to patients or subjects in need of such treatment by oral, parenteral, rectal, or pulmonary administration.
  • the pharmaceutical composition can be made into oral preparations, for example, can be made into conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as Oral solutions, oral suspensions, syrups, etc.
  • suitable fillers, binders, disintegrants, lubricants, etc. can be added.
  • parenteral administration the above-mentioned pharmaceutical preparations can also be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections.
  • the pharmaceutical composition When preparing an injection, it can be produced by a conventional method in the existing pharmaceutical field. When preparing an injection, it is not necessary to add an additive, or an appropriate additive can be added according to the nature of the drug.
  • the pharmaceutical composition When used for rectal administration, the pharmaceutical composition can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical composition can be made into inhalation preparations, aerosols, powder mists or sprays and the like.
  • the present invention also relates to the use of the compound of the present invention, its pharmaceutically acceptable salt or its isomer in the preparation of a medicine for the prevention and/or treatment of benign tumors or cancers. Including carcinoma in situ and metastatic cancer.
  • the present invention also relates to the use of pharmaceutical preparations containing the compound of the present invention, its pharmaceutically acceptable salts or isomers thereof in the preparation of drugs for the prevention and/or treatment of benign tumors or cancers, etc.
  • the cancer includes carcinoma in situ and metastatic cancer.
  • the present invention also relates to the use of the compound of the present invention, its pharmaceutically acceptable salt or its isomers in the preparation of a medicine for preventing and/or treating diseases such as benign tumors or cancer.
  • the cancer includes carcinoma in situ and metastatic cancer.
  • the present invention also relates to the use of pharmaceutical preparations containing the compound of the present invention, its pharmaceutically acceptable salts or isomers thereof in the preparation of drugs for the prevention and/or treatment of benign tumors or cancers, etc.
  • the drug can be used in combination with radiotherapy and/or one or more anticancer agents, and the cancer includes carcinoma in situ and metastatic cancer.
  • the present invention also relates to the use of the compound of the present invention, its pharmaceutically acceptable salt or its isomers in the preparation of a medicament for sensitizing cancer cells to anticancer agents and/or ionizing radiation.
  • the present invention also relates to the use of a pharmaceutical preparation containing the compound of the present invention, its pharmaceutically acceptable salt or its isomer in the preparation of a drug for making cancer cells sensitive to anticancer agents and/or ionizing radiation .
  • the ionizing radiation refers to the radiation of rays of various energies received by the patient in the course of receiving radiotherapy.
  • the present invention also provides a pharmaceutical composition, which contains the compound of the present invention, a pharmaceutically acceptable salt or isomer thereof, and optionally, the pharmaceutical composition further comprises one or more A second therapeutically active agent, the second therapeutically active agent is selected from anticancer agents, including mitotic inhibitors, alkylating agents, antimetabolites, DNA chimeras, antitumor antibiotics, growth factor inhibitors, signal conduction inhibitors Agents, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormone drugs, angiogenesis inhibitors, cell growth inhibitors, Targeting antibodies, HMG-CoA reductase inhibitors and prenyl protein transferase inhibitors.
  • anticancer agents including mitotic inhibitors, alkylating agents, antimetabolites, DNA chimeras, antitumor antibiotics, growth factor inhibitors, signal conduction inhibitors Agents, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitor
  • the second therapeutically active agent can be a drug that reduces or reduces one or more side effects of the compound of the present invention when used to treat a disease in a subject, or it can be a drug that enhances the present invention.
  • Compound medicinal drugs can be a drug that reduces or reduces one or more side effects of the compound of the present invention when used to treat a disease in a subject, or it can be a drug that enhances the present invention.
  • Compound medicinal drugs can be a drug that reduces or reduces one or more side effects of the compound of the present invention when used to treat a disease in a subject, or it can be a drug that enhances the present invention.
  • Compound medicinal drugs can be a drug that reduces or reduces one or more side effects of the compound of the present invention when used to treat a disease in a subject, or it can be a drug that enhances the present invention.
  • Compound medicinal drugs can be a drug that reduces or reduces one or more side effects of the compound of the present invention when used to treat
  • the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients as described above.
  • the present invention also relates to the use of a pharmaceutical composition containing the compound of the present invention, a pharmaceutically acceptable salt or isomer thereof in the preparation of a medicament for the prevention and/or treatment of benign tumors or cancers.
  • the cancer includes carcinoma in situ and metastatic cancer.
  • the present invention also relates to the use of a pharmaceutical composition containing the compound of the present invention, a pharmaceutically acceptable salt or isomer thereof in the preparation of a medicament for the prevention and/or treatment of benign tumors or cancers.
  • the drug can be combined with radiotherapy and/or one or more anticancer agents, and the cancer includes carcinoma in situ and metastatic cancer.
  • the present invention also relates to the use of a pharmaceutical composition containing the compound of the present invention, its pharmaceutically acceptable salt or its isomer in the preparation of a drug for making cancer cells sensitive to anticancer agents and/or ionizing radiation .
  • the present invention also provides a method for treating diseases related to excessive activation of DNA-PK, the method comprising administering to a patient in need an effective amount of the compound of the present invention, its pharmaceutically acceptable salt or The isomers thereof, the aforementioned pharmaceutical preparations or pharmaceutical compositions; the diseases related to the excessive activation of DNA-PK are selected from benign tumors or cancers, and the cancers include carcinomas in situ and metastatic cancers.
  • the present invention also provides a method for treating diseases related to excessive activation of DNA-PK, the method comprising administering an effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, to a patient before/after radiotherapy. Or its isomers, the aforementioned pharmaceutical preparations or pharmaceutical compositions; the disease associated with excessive activation of DNA-PK is selected from benign tumors or cancers, and the cancers include carcinomas in situ and metastatic cancers.
  • the present invention also provides a method for treating diseases associated with excessive DNA-PK activation, the method comprising administering an effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, to a patient before/after chemotherapy.
  • the aforementioned pharmaceutical preparations or pharmaceutical compositions the disease associated with excessive activation of DNA-PK is selected from benign tumors or cancers, and the cancers include carcinomas in situ and metastatic cancers.
  • the present invention also provides a method for enhancing the sensitivity of a patient to anticancer agents or radiotherapy, the method comprising administering to a patient in need an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or Its isomers, the aforementioned pharmaceutical preparations or pharmaceutical compositions; the anticancer agent is as follows.
  • the present invention also provides a method for enhancing the sensitivity of a patient to anticancer agents or radiotherapy, the method comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or Its isomers, the aforementioned pharmaceutical preparations or pharmaceutical compositions; the anticancer agent is as follows.
  • the present invention also provides a method for enhancing the sensitivity of patients to anticancer agents or radiotherapy, the method comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or Its isomers, the aforementioned pharmaceutical preparations or pharmaceutical compositions; the anticancer agent is as follows.
  • the present invention also provides a kit, comprising:
  • the "anticancer agent” in the present invention refers to an agent that has a certain therapeutic effect on tumors, including but not limited to mitosis inhibitors, alkylating agents, antimetabolites, DNA chimeras, antitumor antibiotics, growth factor inhibitors, Signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormone drugs, angiogenesis inhibitors, cell growth Inhibitors, targeting antibodies, HMG-CoA reductase inhibitors and prenyl protein transferase inhibitors, etc.
  • the tumors described in the present invention include benign tumors and cancers.
  • the "effective amount” in the present invention refers to the dose of a drug capable of preventing, alleviating, delaying, inhibiting or curing the subject's symptoms.
  • the size of the administered dose is related to the method of drug administration, the pharmacokinetics of the drug, the severity of the disease, and the subject's personality signs (gender, weight, height, age) and so on.
  • halogen in the present invention refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-4 alkyl group in the present invention refers to a specific example of a C 1-6 alkyl group containing 1 to 4 carbon atoms.
  • C 1-6 alkoxy group in the present invention refers to “C 1-6 alkyl-O-", and the “C 1-6 alkyl group” is as defined above.
  • C 1-4 alkoxy in the present invention refers to “C 1-4 alkyl-O-”, and the “C 1-4 alkyl” is as defined above.
  • C 1-6 alkylthio in the present invention refers to “C 1-6 alkyl-S-", and the “C 1-6 alkyl” is as defined above.
  • C 1-4 alkylthio group in the present invention refers to “C 1-4 alkyl-S-”, and the “C 1-4 alkyl group” is as defined above.
  • hydroxy C 1-6 alkoxy group, amino C 1-6 alkoxy group, and halogenated C 1-6 alkoxy group in the present invention means one or more of the "C 1-6 alkoxy group” (E.g., 1, 2, 3, 4, or 5) hydrogen is replaced with one or more (e.g., 1, 2, 3, 4, or 5) hydroxyl, amino, or halogen.
  • Haldroxy C 1-6 alkylthio, amino C 1-6 alkylthio, halogenated C 1-6 alkylthio in the present invention means one or more of "C 1-6 alkylthio" (E.g., 1, 2, 3, 4, or 5) hydrogen is replaced with one or more (e.g., 1, 2, 3, 4, or 5) hydroxyl, amino, or halogen.
  • C 1-6 alkylamino and di(C 1-6 alkyl)amino respectively refer to C 1-6 alkyl-NH-
  • C 1-6 alkylcarbonyl group in the present invention refers to C 1-6 alkyl-C(O)-.
  • the "3-8 membered cycloalkyl group” in the present invention refers to a saturated or partially saturated monocyclic cyclic group containing 3-8 ring atoms without aromaticity.
  • the "3- "8-membered cycloalkyl” includes “3-8 membered saturated cycloalkyl” and “3-8 membered partially saturated cycloalkyl", for example, “3-6 membered cycloalkyl", “3-6 membered saturated cycloalkane” "Group”, “5-6 membered cycloalkyl”, “5-6 membered saturated cycloalkyl” and the like. Examples thereof include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexenyl and the like.
  • the "3-8 membered heterocyclic group” as used in the present invention refers to those containing at least one (for example, containing 1, 2, 3, 4, or 5) heteroatoms and the number of ring atoms is 3-8
  • the saturated or partially saturated and non-aromatic monocyclic cyclic group, the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom (such as a carbon atom) in the cyclic structure , Nitrogen atom or sulfur atom) can be oxo with one or two oxygen atoms.
  • the "3-8 membered heterocyclic group” in the present invention includes "3-8 membered saturated heterocyclic group” and "3-8 membered partially saturated heterocyclic group”.
  • the “3-8 membered heterocyclic group” is, for example, "3-6 membered heterocyclic group”, “3-6 membered saturated heterocyclic group”, “3-5 membered heterocyclic group”, and "3-5 membered saturated heterocyclic group”. "Heterocyclic group”, “5-6 membered heterocyclic group”, “5-6 membered saturated heterocyclic group” and the like.
  • each of X 6 means that when n is 2 or 3, each of a plurality of X 6 X 6 group is independently selected from the above technical solutions described.
  • substituent means that one or more (for example, 1, 2, 3, 4, or 5) hydrogen atoms on the substituted group are replaced by one or more (For example, 1, 2, 3, 4, or 5) Two cases of "substituted” or “unsubstituted” substituents.
  • the "chemotherapy” mentioned in the present invention is the abbreviation of chemotherapy, which mainly achieves the purpose of treatment by using chemotherapy drugs to kill cancer cells.
  • the "radiotherapy” in the present invention refers to a tumor treatment method, namely tumor radiotherapy, which mainly uses radiation for local tumor treatment.
  • the "radiation” includes ⁇ , ⁇ , ⁇ rays and various x-rays produced by radioisotopes. X-rays, electron beams, proton beams and other particle beams produced by radiotherapy machines or accelerators.
  • the "pharmaceutically acceptable salt” in the present invention refers to a salt formed by an acidic functional group (such as -COOH, -OH, -SO 3 H, etc.) present in a compound and an appropriate inorganic or organic cation (base), including Salts formed with alkali metals or alkaline earth metals, ammonium salts, and salts formed with nitrogen-containing organic bases; and salts formed with basic functional groups (such as -NH 2 etc.) existing in compounds and appropriate inorganic or organic anions (acids) , Including salts formed with inorganic acids or organic acids (such as carboxylic acids, etc.).
  • an acidic functional group such as -COOH, -OH, -SO 3 H, etc.
  • the "isomer" in the present invention means that the compound of the present invention may contain one or more asymmetric centers, and thus can be used as racemates and racemic mixtures, single enantiomers, and diastereomers. Mixtures of isomers and single diastereomers.
  • the compounds of the present invention may have asymmetric centers, and such asymmetric centers each independently produce two optical isomers.
  • the scope of the present invention includes all possible optical isomers and their mixtures. If the compound of the present invention contains an olefin double bond, unless otherwise specified, it includes the cis-isomer and the trans-isomer.
  • the compounds of the present invention may exist in the form of tautomers (a kind of functional group isomers), which have different hydrogen connection points through one or more double bond displacements, for example, ketones and its alkene.
  • the alcohol form is a keto-enol tautomer.
  • the compound of the present invention contains a cyclic structure. Affected by the three-dimensional structure of the ring, substituents on the ring may exist on both sides of the ring to form relative cis and trans isomers. All tautomers and mixtures thereof are included in the scope of the present invention. Enantiomers, diastereomers, racemates, mesoisomers, cis-trans isomers, tautomers, geometric isomers, epimers and their Mixtures and the like are all included in the scope of the present invention.
  • the compounds of the present invention can be prepared in the form of individual enantiomers by enantiomer-specific synthesis or resolution from a mixture of enantiomers.
  • Conventional resolution techniques include the use of various well-known chromatographic methods to resolve a mixture of enantiomers of the starting material or the final product.
  • the named or depicted stereoisomer is at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight relative to other stereoisomers. Or 99.9% by weight pure.
  • the depicted or named enantiomer is at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight, or 99.9% by weight pure.
  • the optical purity weight% is the weight ratio of the weight of the enantiomer to the weight of the enantiomer plus the weight of its optical isomer.
  • the compound of the present invention has excellent DNA-PK inhibitory effects, and they have good pharmacokinetic properties in the organism, lasting action, high bioavailability, and can enhance The sensitivity of cancer cells to radiotherapy and/or one or more anticancer agents.
  • the compound of the present invention has a good therapeutic effect on benign tumors and cancers, and the liver microsomes have high stability.
  • the compound of the present invention has simple preparation process, high drug purity and stable quality, and is easy to carry out large-scale industrial production.
  • Ammonia gas contains 9-((1r,4r)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-2,8-dichloro-9H-purinone (1.25g, In 2.4mmol) of DMSO (10mL), the reaction was carried out at 70°C for 3 hours. After cooling to room temperature, the reaction solution was slowly added dropwise to ice water to precipitate a white solid, filtered, and the filter cake was washed 3 times with water, and dried under reduced pressure to obtain the target compound (1.05 g, yield: 86.44%).
  • EDTA ethylenediaminetetraacetic acid
  • Tris Tris
  • Test product the compound of the present invention, its structural formula and preparation method are shown in the examples.
  • the initial detection concentration of the compound is 1 ⁇ M, and it is formulated as a 100-fold concentration, that is, 100 ⁇ M. Take 2 ⁇ l of 10mM compound and add 198 ⁇ l of 100% DMSO to prepare a 100 ⁇ M compound solution. Add 100 ⁇ l of 100-fold compound to the second well of the 96-well plate, and add 60 ⁇ l of 100% DMSO to the other wells. Take 30 ⁇ l of the compound from the second well and add it to the third well, and then make a 3-fold dilution in sequence to a total of 10 concentrations.
  • Inhibition percentage (max-conversion)/(max-min)*100. Where max refers to the conversion rate of the DMSO control, min refers to the conversion rate of the control without enzyme activity, and conversion refers to the conversion rate at each concentration of the test compound.
  • Test product The compound of the present invention, self-made, its chemical name and preparation method are shown in the preparation examples of each compound.
  • Cynomolgus monkey mixed liver microsomes were purchased from Reid Liver Disease Research Center (Shanghai Co., Ltd.), batch number: ZXBZ, and liver microsomal protein concentration was 20 mg ⁇ mL -1 .
  • liver microsomes of humans, Beagle dogs, and SD rats were purchased from Corning, and the batch numbers were 38292, 9259006, and 9259001, respectively.
  • the concentration of liver microsomal protein was 20 mg ⁇ mL -1 .
  • the experimental initiation factor ⁇ -NADPH was purchased from Solarbio; the pH 7.4 phosphate buffered saline (PBS) was made by our laboratory.
  • DMSO dimethyl sulfoxide
  • liver microsomes (20 mg protein/mL) from the -80°C refrigerator, and place them on a 37°C water bath constant temperature shaker for pre-incubation for 3 minutes.
  • Sample group (containing microsomes and ⁇ -NADPH): Take 616 ⁇ L of incubation system mixed solution 2, add 14 ⁇ L of 50 ⁇ M working solution of the test product, and add 70 ⁇ L of 10mM ⁇ -NADPH working solution. Mix and repeat. The sampling time points are 0min, 5min, 10min, 20min, 30min, 60min. This sample set is used to evaluate the metabolic stability of the compound mediated by ⁇ -NADPH.
  • Control group (contains microsomes, does not contain ⁇ -NADPH, and replaces ⁇ -NADPH with water): Take 264 ⁇ L of incubation system mixed solution 2, add 6 ⁇ L of 50 ⁇ M working solution of the test product, and add 30 ⁇ L of water. Mix and repeat. The sampling time points are 0min and 60min. The negative control group is used to evaluate whether there is a non- ⁇ -NADPH-mediated metabolism of the compound in the liver microsome incubation system.
  • the ratio of the peak area of the test product to the internal standard in the following formula is converted into a percentage of the remaining amount.
  • the compound of the present invention has good stability in human, monkey, dog and rat liver microsomes.
  • Test product The compound of the example of the present invention, self-made, see the preparation example for its chemical name and preparation method.
  • Test animals SD rats, male, weighing 190-210g, 3 animals/group.
  • the preparation method of the blank solvent (1) Weigh 28g HP- ⁇ -CD, add an appropriate amount of water for injection to dissolve, and then dilute to 100 mL with water for injection, vortex and mix well to obtain 28% HP- ⁇ -CD.
  • the preparation method of the blank solvent (2) weigh 20g HPC, slowly add 500mL of stirring purified water, then add 1mL Tween 80, stir until clear and transparent, dilute to 1000mL, stir evenly, that is, 2% HPC+0.1 %Tween 80.
  • IV (intravenous bolus) administration
  • the IV dose is 2 mg/kg, the dose concentration is 1 mg/mL, and the dose volume is 2 mL/kg.
  • the dose of PO administration is 4 mg/kg, the administration concentration is 0.4 mg/mL, and the administration volume is 10 mL/kg.
  • IV blood sampling time points 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24h after administration.
  • PO administration blood sampling time points 0.167, 0.5, 1, 2, 4, 6, 8, 24 h after administration.
  • Plasma samples Collect about 100 ⁇ L of whole blood from the tail vein at each time point, place it in an anticoagulant tube containing EDTA-K 2 anticoagulant, and centrifuge at 8000 rpm for 6 minutes at 4°C to obtain a plasma sample. Plasma is at -80°C Store in the refrigerator for analysis.
  • the compound of the present invention has good pharmacokinetic properties, and has higher exposure and bioavailability.

Abstract

本发明属于医药技术领域，具体涉及通式(I)所示的三并环类DNA-PK激酶抑制剂化合物、其药学上可接受的盐或其异构体，含有所述化合物、其药学上可接受的盐或其异构体的药物组合物及制剂，制备所述化合物、其药学上可接受的盐或其异构体的方法，以及所述化合物、其药学上可接受的盐或其异构体的用途。

Description

三并环类激酶抑制剂 技术领域
本发明属于医药技术领域，具体涉及三并环类DNA-PK激酶抑制剂化合物、其药学上可接受的盐或其异构体，含有所述化合物、其药学上可接受的盐或其异构体的药物组合物及制剂，制备所述化合物、其药学上可接受的盐或其异构体的方法，以及所述化合物、其药学上可接受的盐或其异构体的用途。
背景技术
癌症是全世界难治疗的恶性疾病，治疗难度大，死亡率高，给患者和家庭带来沉重的负担，是影响我国居民健康的主要疾病。近年来，我国癌症发病率明显增加，其死亡率也呈逐渐上升趋势，癌症防治面临着严峻的形势。
目前，放疗以及化疗是除手术切除外治疗癌症的最有效手段，同时放疗是对恶性肿瘤最有效的非手术治疗。放射线和相当多的抗癌药物均可直接或间接作用于DNA或DNA代谢过程，从而导致DNA损伤，其中，DNA双链断裂(DNA double strand break，DSB)对于癌细胞来讲是最致命的。DNA损伤后，会引发受损DNA修复等一系列细胞反应，而修复的结果就是提高癌细胞的存活，这也是肿瘤细胞对放化疗抵抗的机制之一。DNA双链断裂如果不及时和完整修复，癌细胞则会因细胞凋亡或/和有丝分裂障碍导致细胞死亡。因此，只要抑制这些DNA损伤的修复，就可以提高癌细胞对放化疗的敏感性，抑制细胞增殖。
在人等高等真核生物细胞中，DSB的修复主要是通过DNA依赖性蛋白激酶(DNA-Dependent Protein Kinase，DNA-PK)主导的DNA非同源末端连接(nonhomologous end joining，NHEJ)进行，由此修复损伤的DNA，保持细胞活性和基因组稳定性。NHEJ修复主要参与G1/S期DNA损伤修复，并且不需要DNA末端连接模板。NHEJ修复需要许多蛋白质和信号通路的共济协调。Ku70/80亚单位的异质二聚体和催化亚单元DNA依赖性蛋白激酶(DNA-PKcs)，共同组成了有活性的DNA-PK酶复合物。
DNA-PKcs属于磷脂酰肌醇3激酶(PI3K)超家族成员，是一种丝氨酸/苏氨酸蛋白激酶；PI3K超家族还包括ATM、ATR、mTOR和4个PI3K亚型。当DNA-PK与断裂的DNA结合时，才能激活其激酶活性。Ku的重要功能是与DNA末端结合，招募DNA-PKcs，二者组成DNA-PK全酶并激活DNA-PKcs；活化的DNA-PKcs引导Artemis蛋白(一种内切核酸酶)结合于受损位点，依靠其核酶活性进行DNA断端处理以利于连接修复，然后XRCC4/DNA-连接酶IV复合物被活化的DNA-PKcs招募，最后由DNA-连接酶IV定位并连接断裂的DNA 双链末端，完成修复。XRCC4是与DNA-连接酶IV形成复合体的一种蛋白质，可以增加DNA-连接酶IV的活性。DNA-PKcs存在40个可自身磷酸化的氨基酸残基，最典型的自磷酸化位点发生在Ser2056(POR簇)和Thr2609(ABCDE簇)。NHEJ被认为通过三个关键的步骤开展：识别DSB——Ku70/80结合至不完全的DNA末端，募集两分子的DNA-PKcs至DSB的相邻侧；进行DNA加工以移除端点处的不可连接末端或其他损伤形式；最后连接DNA末端。
由于肿瘤细胞具有较高基础水平的内源性复制压力(癌基因诱导的复制压力)和DNA损伤，并且在肿瘤细胞中DNA修复机制效率较低，因此肿瘤细胞对DNA-PK的敏感性更高。
目前，开发高效且选择性好的DNA-PK的抑制剂具有重要的临床意义，其可协同增强放疗和化疗效果，有效抑制肿瘤生长，同时可有效降低对正常细胞的损伤，减少副作用。
发明内容
本发明要解决的技术问题之一是提供一种结构新颖的、对DNA-PK具有良好抑制作用的三并环类化合物。进一步地，该类化合物可用于增加受试者对于放疗和/或一种或多种抗癌剂的敏感性。更进一步地，该类化合物可与放疗和/或一种或多种抗癌剂联用用于预防和/或治疗良性肿瘤或癌症。
本发明的技术方案如下：
在一方面，本发明提供了如下通式(I)所示的化合物、其药学上可接受的盐或其异构体，
Figure PCTCN2021088926-appb-000001
其中，
X 1、X 2、X 3、X 4分别独立地选自CR 2或N；
X 5选自C、CH或N；
每一X 6、X 7、X 8分别独立地选自CR 3R 4、NR 5、CR 6、N、O或S；
Y 1、Y 2、Y 3、Y 4分别独立地选自CH或N；
环A选自任选被1-3个取代基取代的3-8元环烷基或3-8元杂环基，所述取代基选自卤素、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基羰基、卤代C 1-6烷氧基、 卤代C 1-6烷硫基、羟基C 1-6烷氧基、羟基C 1-6烷硫基、氨基C 1-6烷氧基、氨基C 1-6烷硫基；
R 1、R 2、R 3、R 4、R 5、R 6分别独立地选自H、卤素、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、羟基C 1-6烷氧基、羟基C 1-6烷硫基、氨基C 1-6烷氧基、氨基C 1-6烷硫基；
虚键---为化学键或不存在，且相邻的虚键不同时为化学键；
n选自1、2或3。
在某些实施方案中，所述3-8元杂环基中的杂原子为至少一个(例如，1个、2个、3个、4个或5个)氮原子、氧原子和/或硫原子，任选地，所述3-8元杂环基中的环原子(例如碳原子、氮原子或硫原子)可以被一个或两个氧原子氧代。
在某些实施方案中，环A选自任选被1-2个取代基取代的3-6元环烷基或3-6元杂环基。
在某些实施方案中，环A选自任选被1-2个取代基取代的3-6元环烷基或3-6元杂环基；所述取代基选自卤素、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、C 1-6烷基羰基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、卤代C 1-6烷氧基或卤代C 1-6烷硫基。在某些实施方案中，环A选自3-6元环烷基或3-6元杂环基。
在某些实施方案中，环A选自任选被1-2个取代基取代的3-6元饱和环烷基或3-6元饱和杂环基。
在某些实施方案中，环A选自任选被1-2个取代基取代的3-6元饱和环烷基或3-6元饱和杂环基；所述取代基选自卤素、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、C 1-6烷基羰基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、卤代C 1-6烷氧基或卤代C 1-6烷硫基。
在某些实施方案中，环A选自3-6元饱和环烷基或3-6元饱和杂环基。
在某些实施方案中，环A选自任选被1-2个取代基取代的5-6元环烷基或5-6元杂环基。
在某些实施方案中，环A选自任选被1-2个取代基取代的5-6元环烷基或5-6元杂环基；所述取代基选自卤素、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、C 1-6烷基羰基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、卤代C 1-6烷氧基或卤代C 1-6烷硫基。
在某些实施方案中，环A选自5-6元环烷基或5-6元杂环基。在某些实施方案中，环 A选自任选被1-2个取代基取代的5-6元饱和环烷基或5-6元饱和杂环基。
在某些实施方案中，环A选自任选被1-2个取代基取代的5-6元饱和环烷基或5-6元饱和杂环基；所述取代基选自卤素、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、C 1-6烷基羰基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、卤代C 1-6烷氧基或卤代C 1-6烷硫基。
在某些实施方案中，环A选自5-6元饱和环烷基或5-6元饱和杂环基。
在某些实施方案中，环A选自环己基或6元饱和杂环基。
在某些实施方案中，环A选自任选被1-2个取代基取代的环己基或6元饱和杂环基。
在某些实施方案中，环A选自任选被1-2个取代基取代的环己基或6元含氧或含硫饱和杂环基。任选地，所述6元含硫饱和杂环基被一个或两个氧原子氧代。
在某些实施方案中，环A选自任选被1-2个取代基取代的环己基、四氢吡喃基、四氢噻喃基或
Figure PCTCN2021088926-appb-000002
在某些实施方案中，环A上的取代基选自氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、三氟甲基、羟基甲基、氨基甲基、甲氧基、乙氧基、丙氧基、异丙氧基或三氟甲氧基。
在某些实施方案中，环A被2个相同的取代基取代。
在某些实施方案中，环A选自任选被1-2个取代基取代的环丙基、环丁基、环戊基、环己基、氧杂环丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢噻吩基、四氢吡咯烷基、四氢吡唑烷基、四氢咪唑烷基、四氢吡喃基、四氢噻喃基、哌啶基、哌嗪基、六氢嘧啶基或吗啉基；所述取代基选自卤素、羟基、氨基、硝基、氰基、甲基、乙基、丙基、异丙基、甲基氨基、二甲基氨基、甲基羰基、一氟甲基、二氟甲基、三氟甲基、羟基甲基、氨基甲基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、一氟甲氧基、二氟甲氧基、三氟甲氧基或三氟甲硫基。
在某些实施方案中，环A选自环丙基、环丁基、环戊基、环己基、氧杂环丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢噻吩基、四氢吡咯烷基、四氢吡唑烷基、四氢咪唑烷基、四氢吡喃基、四氢噻喃基、哌啶基、哌嗪基、六氢嘧啶基或吗啉基。
在某些实施方案中，环A选自任选被1-2个取代基取代的环戊基、环己基、四氢呋喃基、四氢噻吩基、四氢吡咯烷基、四氢吡喃基、四氢噻喃基、哌啶基、哌嗪基或吗啉基；所述取代基选自氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、甲基羰基、三氟甲基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、三氟甲氧基或三氟甲硫基。
在某些实施方案中，环A选自环戊基、环己基、四氢呋喃基、四氢噻吩基、四氢吡咯烷基、四氢吡喃基、四氢噻喃基、哌啶基、哌嗪基或吗啉基。在某些实施方案中，环A为任选被1-3个取代基取代的3-8元杂环基，所述3-8元杂环基为至少含有一个杂原子的且环原子数为3-8个的饱和或部分饱和的且不具有芳香性的单环环状基团，所述杂原子为硫原子，任选地，环状结构中硫原子可以被氧原子氧代；
所述取代基选自卤素、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、C 1-6烷基羰基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、卤代C 1-6烷氧基或卤代C 1-6烷硫基。
在某些实施方案中，环A选自任选被1-2个取代基取代的
Figure PCTCN2021088926-appb-000003
Figure PCTCN2021088926-appb-000004
所述取代基选自卤素、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、C 1-6烷基羰基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、卤代C 1-6烷氧基或卤代C 1-6烷硫基。
在某些实施方案中，环A选自任选被1-2个取代基取代的
Figure PCTCN2021088926-appb-000005
Figure PCTCN2021088926-appb-000006
所述取代基选自氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、三氟甲基、羟基甲基、氨基甲基、甲氧基、乙氧基、丙氧基、异丙氧基或三氟甲氧基。
在某些实施方案中，R 1、R 2分别独立地选自H、卤素、羟基、氨基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、卤代C 1-6烷氧基或卤代C 1-6烷硫基；
R 3、R 4、R 6分别独立地选自H、卤素、羟基、氨基、C 1-6烷基或卤代C 1-6烷基；
R 5选自氢、C 1-6烷基或卤代C 1-6烷基。
在某些实施方案中，R 1、R 2分别独立地选自H、卤素、羟基、氨基、硝基、氰基、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、卤代C 1-4烷氧基或卤代C 1-4烷硫基；
R 3、R 4、R 6分别独立地选自H、卤素、羟基、氨基、C 1-4烷基或卤代C 1-4烷基；
R 5选自氢、C 1-4烷基或卤代C 1-4烷基。
在某些实施方案中，R 1、R 2分别独立地选自H、卤素、羟基、氨基、硝基、氰基、甲基、乙基、丙基、异丙基、三氟甲基、甲氧基、乙氧基、三氟甲氧基、甲硫基、乙硫基或 三氟甲硫基。
在某些实施方案中，R 3、R 4、R 6分别独立地选自H、卤素、羟基、氨基、甲基、乙基、丙基、异丙基、三氟甲基或三氟乙基。
在某些实施方案中，R 5选自氢、甲基、乙基、丙基、异丙基、三氟甲基或三氟乙基。
在某些实施方案中，R 1、R 2分别独立地选自H、卤素、羟基、氨基、硝基、氰基、甲基、乙基、丙基、异丙基、三氟甲基、甲氧基、乙氧基、三氟甲氧基、甲硫基、乙硫基或三氟甲硫基；
R 3、R 4、R 6分别独立地选自H、卤素、羟基、氨基、甲基、乙基、丙基、异丙基、三氟甲基或三氟乙基；
R 5选自氢、甲基、乙基、丙基、异丙基、三氟甲基或三氟乙基。
在某些实施方案中，R 1为甲基。
在某些实施方案中，Y 1、Y 2、Y 4分别为N，Y 3选自CH或N。
在某些实施方案中，Y 1、Y 2、Y 4分别为N，Y 3为CH。
在某些实施方案中，X 1、X 2、X 4均为N；X 3选自CH或N；X 5选自C、CH或N。
在某些实施方案中，X 1、X 2、X 4均为N；X 3选自CH或N；X 5选自C或N。
在某些实施方案中，X 1、X 2、X 4均为N；X 3为CH；X 5选自C、CH或N。
在某些实施方案中，X 1、X 2、X 4均为N；X 3为CH；X 5选自C或N。
在某些实施方案中，每一X 6、X 7、X 8分别独立地选自CR 3R 4、NR 5、CR 6、N、O或S。
在某些实施方案中，每一X 6、X 7、X 8分别独立地选自CH 2、CH、NH、C(CH 3)、N、O或S。
在某些实施方案中，每一X 6、X 7、X 8分别独立地选自CH 2、CH、C(CH 3)、N、O或S。
在某些实施方案中，每一X 6、X 8分别独立地选自CH 2、CH或N，X 7为羰基。在某些实施方案中，n选自1或2。
在某些实施方案中，n为1。
在某些实施方案中，n为2。
在某些实施方案中，每一X 6、X 7、X 8分别独立地选自CR 3R 4、NR 5、CR 6、N、O或S；
R 3、R 4、R 6分别独立地选自H、氟、氯、溴、碘、羟基、氨基、甲基、乙基或三氟甲基；
R 5选自H、甲基、乙基或三氟甲基。
在某些实施方案中，X 1、X 2、X 4均为N；X 3为CH或N；
X 5选自C或N；
每一X 6、X 7、X 8分别独立地选自CR 3R 4、NR 5、CR 6、N、O或S；
Y 1、Y 2、Y 4分别为N，Y 3为CH或N；
环A选自任选被1-2个取代基取代的环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢噻吩基、四氢吡咯烷基、四氢吡喃基、四氢噻喃基、哌啶基、哌嗪基或吗啉基；所述取代基选自氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、甲基羰基、三氟甲基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、三氟甲氧基或三氟甲硫基；
R 1选自H、氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、三氟甲基、甲氧基、乙氧基或三氟甲氧基；
R 3、R 4、R 6分别独立地选自H、氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基或三氟甲基；
R 5选自H、甲基、乙基、丙基、异丙基或三氟甲基；
虚键---为化学键或不存在，且相邻的虚键不同时为化学键；
n选自1或2。
在某些实施方案中，X 1、X 2、X 4均为N；X 3为CH；
X 5选自C或N；
每一X 6、X 7、X 8分别独立地选自CR 3R 4、NR 5、CR 6、N、O或S；
Y 1、Y 2、Y 4分别为N，Y 3为CH；
环A选自任选被1-2个取代基取代的环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢噻吩基、四氢吡咯烷基、四氢吡喃基、四氢噻喃基、哌啶基、哌嗪基或吗啉基；所述取代基选自氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、甲基羰基、三氟甲基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、三氟甲氧基或三氟甲硫基；
R 1选自H、氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、三氟甲基、甲氧基、乙氧基或三氟甲氧基；
R 3、R 4、R 6分别独立地选自H、氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基或三氟甲基；
R 5选自H、甲基、乙基、丙基、异丙基或三氟甲基；
虚键---为化学键或不存在，且相邻的虚键不同时为化学键；
n选自1或2。
在某些实施方案中，X 1、X 2、X 4均为N；X 3为CH；
X 5选自C或N；
X 6、X 7、X 8分别独立地选自CR 3R 4、NR 5、CR 6、N、O或S；
Y 1、Y 2、Y 4分别为N，Y 3为CH；
环A选自任选被1-2个取代基取代的环戊基、环己基、四氢呋喃基、四氢噻吩基、四氢吡咯烷基、四氢吡喃基、四氢噻喃基、哌啶基、哌嗪基或吗啉基；所述取代基选自氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、甲基羰基、三氟甲基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、三氟甲氧基或三氟甲硫基；
R 1选自H、氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、三氟甲基、甲氧基、乙氧基或三氟甲氧基；
R 3、R 4、R 6分别独立地选自H、氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基或三氟甲基；
R 5选自H、甲基、乙基、丙基、异丙基或三氟甲基；
虚键---为化学键或不存在，且相邻的虚键不同时为化学键；
n为1。在某些实施方案中，通式(I)中，R 1位于-NH-的邻位。
在某些实施方案中，通式(I)所示的化合物、其药学上可接受的盐或其异构体，其进一步具有如下通式(II)所示的结构，
Figure PCTCN2021088926-appb-000007
其中，X 1、X 2、X 3、X 4、X 5、X 6、X 7、X 8、Y 1、Y 2、Y 3、Y 4、R 1、R 2、R 3、R 4、R 5、R 6、环A、n和虚键---如前文任一方案所述。在某些实施方案中，通式(II)中，R 1位于-NH-的邻位。
在某些实施方案中，通式(I)所示的化合物、其药学上可接受的盐或其异构体，其进一步具有如下通式(IIa)所示的结构，
Figure PCTCN2021088926-appb-000008
其中，X 1、X 2、X 3、X 4、X 5、X 6、X 7、X 8、R 1、R 2、R 3、R 4、R 5、R 6、环A、n和虚键---如前文任一方案所述。在某些实施方案中，通式(IIa)中，R 1位于-NH-的邻位。
在某些实施方案中，通式(IIa)所示的化合物、其药学上可接受的盐或其异构体中，X 1、X 2各自为N，X 3为CH；每一X 6、X 7、X 8分别独立地选自CH 2、CH、C(CH 3)、N、O或S； 环A选自任选被1-2个取代基取代的环戊基、环己基、四氢呋喃基、四氢噻吩基、四氢吡咯烷基、四氢吡喃基、四氢噻喃基、1,1-二氧代四氢噻喃基、哌啶基、哌嗪基或吗啉基；所述取代基选自氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、甲基羰基、三氟甲基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、三氟甲氧基或三氟甲硫基；R 1选自H、氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、三氟甲基、甲氧基、乙氧基或三氟甲氧基；虚键---为化学键或不存在，且相邻的虚键不同时为化学键；n为1。
在某些实施方案中，通式(IIa)所示的化合物、其药学上可接受的盐或其异构体中，X 1、X 2各自为N，X 3为CH；每一X 6、X 7、X 8分别独立地选自CH 2、CH、CCH 3、N、O或S；环A选自任选被1-2个取代基取代的环己基、四氢吡喃基、四氢噻喃基、1,1-二氧代四氢噻喃基；所述取代基选自氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、甲基羰基、三氟甲基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、三氟甲氧基或三氟甲硫基；R 1选自H、氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、三氟甲基、甲氧基、乙氧基或三氟甲氧基；虚键---为化学键或不存在，且相邻的虚键不同时为化学键；n为1。
在某些实施方案中，通式(IIa)所示的化合物、其药学上可接受的盐或其异构体中，X 1、X 2各自为N，X 3为CH；每一X 6、X 7、X 8分别独立地选自CH 2、CH、CCH 3、N、O或S；环A选自任选被1-2个取代基取代的环己基、四氢吡喃基、四氢噻喃基、1,1-二氧代四氢噻喃基；所述取代基选自氟、氯、溴、碘、羟基；R 1选自H、氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、三氟甲基、甲氧基、乙氧基或三氟甲氧基；虚键---为化学键或不存在，且相邻的虚键不同时为化学键；n为1。
在某些实施方案中，通式(IIa)所示的化合物、其药学上可接受的盐或其异构体中，X 1、X 2各自为N，X 3为CH；每一X 6、X 7、X 8分别独立地选自CH 2、CH、CH 3、N、O或S；环A选自任选被1-2个取代基取代的环己基、四氢吡喃基、四氢噻喃基、1,1-二氧代四氢噻喃基；所述取代基选自氟、羟基；R 1选自H、氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、三氟甲基、甲氧基、乙氧基或三氟甲氧基；虚键---为化学键或不存在，且相邻的虚键不同时为化学键；n为1。
在某些实施方案中，通式(IIa)所示的化合物、其药学上可接受的盐或其异构体中，X 1、X 2各自为N，X 3为CH；每一X 6、X 7、X 8分别独立地选自CH 2、CH、CH 3、N、O或S；环A选自任选被1-2个取代基取代的环己基、四氢吡喃基、四氢噻喃基、1,1-二氧代四氢噻喃基；所述取代基选自氟、羟基；R 1为甲基；虚键---为化学键或不存在，且相邻的虚键不同时为化学键；n为1。
在某些实施方案中，通式(IIa)所示的化合物、其药学上可接受的盐或其异构体中，每一X 6、X 7分别独立地选自CH 2、CH、C(CH 3)、N、O或S，X 8选自N、O或S。
在某些实施方案中，通式(IIa)所示的化合物、其药学上可接受的盐或其异构体中，X 1、X 2各自为N，X 3为CH；每一X 6、X 7分别独立地选自CH 2、CH、C(CH 3)、N、O或S，X 8选自N、O或S；环A选自任选被1-2个取代基取代的环己基、四氢吡喃基、四氢噻喃基、1,1-二氧代四氢噻喃基；所述取代基选自氟、羟基；R 1为甲基；虚键---为化学键或不存在，且相邻的虚键不同时为化学键；n为1。
在某些实施方案中，通式(I)所示的化合物、其药学上可接受的盐或其异构体，其进一步具有如下通式(IIb)所示的结构，
Figure PCTCN2021088926-appb-000009
其中，X 5、X 6、X 7、X 8、R 1、R 3、R 4、R 5、R 6、环A、n和虚键---如前文任一方案所述。
在某些实施方案中，通式(IIb)中，R 1位于-NH-的邻位。
在某些实施方案中，通式(IIb)所示的化合物、其药学上可接受的盐或其异构体，
Figure PCTCN2021088926-appb-000010
其中，X 5、每一X 6、X 8、R 1、R 3、R 4、R 5、R 6如前文任一方案所述，
X 7为羰基；
环A选自任选被1-3个取代基取代的3-8元环烷基、3-8元杂环基、
Figure PCTCN2021088926-appb-000011
Figure PCTCN2021088926-appb-000012
所述取代基选自卤素、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基羰基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、羟基C 1-6烷氧基、羟基C 1-6烷硫基、氨基C 1-6烷氧基、氨基C 1-6烷硫基；
虚键---为化学键或不存在，且相邻的虚键不同时为化学键；
n选自1、2或3。
在某些实施方案中，通式(IIb)所示的化合物、其药学上可接受的盐或其异构体，
Figure PCTCN2021088926-appb-000013
其中，X 5选自C、CH或N；
每一X 6、X 8分别独立地选自CH 2、CH、CHR 3、CR 3、NH、N、O或S；
X 7为羰基；
R 1选自H、卤素、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、羟基C 1-6烷氧基、羟基C 1-6烷硫基、氨基C 1-6烷氧基、氨基C 1-6烷硫基；
环A选自任选被1-3个取代基取代的3-8元环烷基、3-8元杂环基、
Figure PCTCN2021088926-appb-000014
Figure PCTCN2021088926-appb-000015
所述取代基选自卤素、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基羰基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、羟基C 1-6烷氧基、羟基C 1-6烷硫基、氨基C 1-6烷氧基、氨基C 1-6烷硫基；
n选自1、2或3。
在某些实施方案中，R 1选自H、卤素、羟基、氨基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基。
在某些实施方案中，R 1选自H、卤素、羟基、氨基、甲基、乙基、丙基、异丙基、三氟甲基、羟基甲基、羟基乙基、氨基甲基、氨基乙基、甲氧基、乙氧基或三氟甲氧基。
在某些实施方案中，环A选自任选被1-2个取代基取代的环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢噻吩基、四氢吡咯烷基、四氢吡喃基、四氢噻喃基、1,1-二氧代四氢噻喃基、哌啶基、哌嗪基或吗啉基；所述取代基选自卤素、羟基、氨基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基。
在某些实施方案中，环A选自任选被1-2个取代基取代的
Figure PCTCN2021088926-appb-000016
Figure PCTCN2021088926-appb-000017
所述取代基选自氟、氯、溴、碘、羟基、氨基、羰基、甲基、乙基、丙基、异丙基、三氟甲基、羟基甲基、氨基甲基、甲氧基、乙氧基、丙氧基、异丙氧基或三氟甲氧基。
在某些实施方案中，通式(IIb)所示的化合物、其药学上可接受的盐或其异构体中，X 5为N；每一X 6、X 8分别独立地选自CH 2、CH、N；X 7为羰基；R 1为H、卤素、羟基、氨基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基；环A选自任选被1-2个取代基取代的环己基、四氢吡喃基、四氢噻喃基、1,1-二氧代四氢噻喃基；所述取代基选自卤素、羟基、氨基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基；n为1或2。
在某些实施方案中，通式(IIb)所示的化合物、其药学上可接受的盐或其异构体中，R 1为C 1-6烷基。
在某些实施方案中，通式(IIb)所示的化合物、其药学上可接受的盐或其异构体中，X 5为N；每一X 6、X 8分别独立地选自CH 2、CH、N；X 7为羰基；R 1为C 1-4烷基；环A选自任选被1-2个取代基取代的环己基、四氢吡喃基、四氢噻喃基、1,1-二氧代四氢噻喃基；所述取代基选自卤素、羟基、氨基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基；n为1或2。
在某些实施方案中，通式(IIb)所示的化合物、其药学上可接受的盐或其异构体中，X 5为N；每一X 6、X 8分别独立地选自CH 2、CH、N；X 7为羰基；R 1为甲基；环A选自任选被1-2个取代基取代的环己基、四氢吡喃基、四氢噻喃基、1,1-二氧代四氢噻喃基；所述取代基选自卤素、羟基、氨基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基；n为1或2。
在某些实施方案中，通式(IIb)所示的化合物、其药学上可接受的盐或其异构体中，X 5为N；每一X 6、X 8分别独立地选自CH 2、CH、N；X 7为羰基；R 1为甲基；环A选自任选被1-2个取代基取代的环己基、四氢吡喃基、四氢噻喃基、1,1-二氧代四氢噻喃基；所述取代基选自卤素、羟基；n为1或2。
在某些实施方案中，通式(IIb)所示的化合物、其药学上可接受的盐或其异构体中，X 5为N；每一X 6、X 8分别独立地选自CH 2、CH、N；X 7为羰基；R 1为甲基；环A选自任选被 1-2个取代基取代的环己基、四氢吡喃基、四氢噻喃基、1,1-二氧代四氢噻喃基；所述取代基选自氟、羟基；虚键---为化学键或不存在，且相邻的虚键不同时为化学键；n为1或2。
本发明中各技术方案之间可以相互组合形成新的技术方案，所形成的新的技术方案同样包括在本发明的范围之内。
在某些实施方案中，前述通式(I)所示的化合物、其药学上可接受的盐或其异构体，选自如下化合物：
Figure PCTCN2021088926-appb-000018
Figure PCTCN2021088926-appb-000019
另一方面，本发明还提供了本发明化合物的制备方法：
制备通式(I)所示的化合物的方法：
Figure PCTCN2021088926-appb-000020
1)中间体1经过一步或多步反应环合成中间体2；
2)中间体2和中间体3经过偶联反应得到式(I)化合物，
其中，X、X'、X”分别独立地选自卤素、氨基或羟基；X 1、X 2、X 3、X 4、X 5、X 6、X 7、X 8、Y 1、Y 2、Y 3、Y 4、R 1、R 2、R 3、R 4、R 5、R 6、环A、n和虚键---如前文任一方案所述。
在某些实施方案中，式(I)化合物的制备方法中，中间体1和氯乙醛反应得到中间体2；中间体2与中间体3反应得到式(I)化合物。
在某些实施方案中，式(I)化合物的制备方法中，中间体1和氯乙醛反应得到中间体2；中间体2与中间体3在催化剂以及碱性条件下反应得到式(I)化合物。
在某些实施方案中，所述的催化剂选自含Pd催化剂，优选BrettPhos Pd G3。
所述的碱性条件是指反应液pH大于7，一般通过加入一定量的碱性试剂来实现，优选的，所述的碱性试剂选自K 2CO 3、Na 2CO 3、Cs 2CO 3、NaOH、KOH或KOAc。
在另一方面，本发明还提供了如下通式(III)所示的化合物、其药学上可接受的盐或其异构体，其可作为制备式(I)化合物的中间体，
Figure PCTCN2021088926-appb-000021
其中，X选自卤素、氨基或羟基；X 1、X 2、X 3、X 4、X 5、X 6、X 7、X 8、R 2、R 3、R 4、R 5、R 6、环A、n和虚键---如前文任一方案所述。
在另一方面，本发明还提供了通式(III)所示的化合物、其药学上可接受的盐或其异构体在制备本发明化合物、其药学上可接受的盐或其异构体的用途。
在另一个方面，本发明还提供一种药物制剂，含有本发明的化合物、其药学上可接受的盐或其异构体，以及一种或多种药学上可接受的赋形剂，该药物制剂可为药学上可接受的任一剂型。药学上可接受的赋形剂是无毒性、与活性成分相容且其他方面如生物学性质上适用于生物体的物质。特定赋形剂的选择将取决于用于治疗特定患者的给药方式或疾病类型和状态。
在某些实施方案中，上述药物制剂可以以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时，所述药物组合物可制成口服制剂，例如可以制成常规的口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，上述药物制剂也可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配制注射剂时，可以不加入附加剂，也可以根据药物的性质加入适宜的附加剂。用于直肠给药时，所述药物组合物可制成栓剂等。用于经肺给药时，所述药物组合物可制成吸入制剂、气雾剂、粉雾剂或喷雾剂等。
在另一方面，本发明还涉及本发明的化合物、其药学上可接受的盐或其异构体在制备 用于预防和/或治疗良性肿瘤或癌症等疾病的药物中的用途，所述癌症包括原位癌和转移的癌症。
进一步地，本发明还涉及含有本发明的化合物、其药学上可接受的盐或其异构体的药物制剂在制备用于预防和/或治疗良性肿瘤或癌症等疾病的药物中的用途，所述癌症包括原位癌和转移的癌症。
在另一方面，本发明还涉及本发明的化合物、其药学上可接受的盐或其异构体在制备用于预防和/或治疗良性肿瘤或癌症等疾病的药物中的用途，所述药物与放疗和/或一种或多种抗癌剂联用，所述癌症包括原位癌和转移的癌症。
进一步地，本发明还涉及含有本发明的化合物、其药学上可接受的盐或其异构体的药物制剂在制备用于预防和/或治疗良性肿瘤或癌症等疾病的药物中的用途，所述药物可与放疗和/或一种或多种抗癌剂联用，所述癌症包括原位癌和转移的癌症。
在另一方面，本发明还涉及本发明的化合物、其药学上可接受的盐或其异构体在制备用于使癌细胞对于抗癌剂和/或电离辐射敏感的药物中的用途。
进一步地，本发明还涉及含有本发明的化合物、其药学上可接受的盐或其异构体的药物制剂在制备用于使癌细胞对于抗癌剂和/或电离辐射敏感的药物中的用途。
所述的电离辐射是指患者在接受放疗过程中所接受的各种不同能量的射线的辐射。
在另一个方面，本发明还提供一种药物组合物，其含有本发明的化合物、其药学上可接受的盐或其异构体，任选地，所述药物组合物还包含一种或多种第二治疗活性剂，所述的第二治疗活性剂选自抗癌剂，包括有丝分裂抑制剂、烷化剂、抗代谢物、DNA嵌合剂、抗肿瘤抗生素、生长因子抑制剂、信号传导抑制剂、细胞周期抑制剂、酶抑制剂、类维生素A受体调控剂、蛋白酶体抑制剂、拓扑异构酶抑制剂、生物应答调节剂、激素类药物、血管再生抑制剂、细胞生长抑制剂、靶向抗体、HMG-CoA还原酶抑制剂和异戊二烯基蛋白质转移酶抑制剂。
在某些实施方案中，所述的第二治疗活性剂可以是减轻或降低本发明化合物在用于治疗受试者疾病时所产生的一种或多种副作用的药物，也可以是增强本发明化合物药效的药物。
在某些实施方案中，所述药物组合物还包括一种或多种药学上可接受的赋形剂，所述赋形剂如前文所述。
在另一方面，本发明还涉及含有本发明的化合物、其药学上可接受的盐或其异构体的药物组合物在制备用于预防和/或治疗良性肿瘤或癌症等疾病的药物中的用途，所述癌症包括原位癌和转移的癌症。
在另一方面，本发明还涉及含有本发明的化合物、其药学上可接受的盐或其异构体的药物组合物在制备用于预防和/或治疗良性肿瘤或癌症等疾病的药物中的用途，所述药物可与放疗和/或一种或多种抗癌剂联用，所述癌症包括原位癌和转移的癌症。
进一步，本发明还涉及含有本发明的化合物、其药学上可接受的盐或其异构体的药物组合物在制备用于使癌细胞对于抗癌剂和/或电离辐射敏感的药物中的用途。
在另一方面，本发明还提供了一种治疗与DNA-PK过度活化相关的疾病的方法，该方法包括向有需要的患者施用有效量的本发明的化合物、其药学上可接受的盐或其异构体，前述药物制剂或药物组合物；所述与DNA-PK过度活化相关的疾病选自良性肿瘤或癌症，所述的癌症包括原位癌和转移的癌症。
进一步地，本发明还提供了一种治疗与DNA-PK过度活化相关的疾病的方法，该方法包括向接受放疗前/后的患者施用有效量的本发明的化合物、其药学上可接受的盐或其异构体，前述药物制剂或药物组合物；所述与DNA-PK过度活化相关的疾病选自良性肿瘤或癌症，所述的癌症包括原位癌和转移的癌症。
进一步地，本发明还提供了一种治疗与DNA-PK过度活化相关的疾病的方法，该方法包括向接受化疗前/后的患者施用有效量的本发明的化合物、其药学上可接受的盐或其异构体，前述药物制剂或药物组合物；所述与DNA-PK过度活化相关的疾病选自良性肿瘤或癌症，所述的癌症包括原位癌和转移的癌症。
在另一方面，本发明还提供了一种增强患者对于抗癌剂或放疗敏感性的方法，该方法包括向有需要的患者施用有效量的本发明的化合物、其药学上可接受的盐或其异构体，前述药物制剂或药物组合物；所述的抗癌剂如下文所述。
进一步，本发明还提供了一种增强患者对于抗癌剂或放疗敏感性的方法，该方法包括向接受放疗前/后的患者施用有效量的本发明的化合物、其药学上可接受的盐或其异构体，前述药物制剂或药物组合物；所述的抗癌剂如下文所述。
进一步，本发明还提供了一种增强患者对于抗癌剂或放疗敏感性的方法，该方法包括向接受化疗前/后的患者施用有效量的本发明的化合物、其药学上可接受的盐或其异构体，前述药物制剂或药物组合物；所述的抗癌剂如下文所述。
在另一方面，本发明还提供了一种试剂盒，包含：
(a)有效量的一种或多种本发明的化合物、其药学上可接受的盐或其异构体，
和(b)有效量的一种或多种抗癌剂。
本发明所述的“抗癌剂”是指对肿瘤具有一定治疗作用的药剂，包括但不限于有丝分裂抑制剂、烷化剂、抗代谢物、DNA嵌合剂、抗肿瘤抗生素、生长因子抑制剂、信号传导 抑制剂、细胞周期抑制剂、酶抑制剂、类维生素A受体调控剂、蛋白酶体抑制剂、拓扑异构酶抑制剂、生物应答调节剂、激素类药物、血管再生抑制剂、细胞生长抑制剂、靶向抗体、HMG-CoA还原酶抑制剂和异戊二烯基蛋白质转移酶抑制剂等。
本发明所述的肿瘤包括良性肿瘤和癌症。
本发明所述的“有效量”是指能够预防、减轻、延缓、抑制或治愈受试者病症的药物剂量。给药剂量的大小与药物给药方式、药剂的药代动力学、疾病的严重程度、受试者的个性体征(性别、体重、身高、年龄)等相关。
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员通常理解的含义，然而为了更好地理解本发明，下面提供了部分术语的定义。当本发明所提供的术语的定义和解释与本领域技术人员所通常理解的含义不符的时候，以本发明所提供的术语的定义和解释为准。
本发明所述的“卤素”是指氟原子、氯原子、溴原子或碘原子。
本发明所述的“C 1-6烷基”表示直链或支链的含有1-6个碳原子的烷基，包括例如“C 1-4烷基”、“C 1-3烷基”、“C 1-2烷基”、“C 2-6烷基”、“C 2-5烷基”、“C 2-4烷基”、“C 2-3烷基”、“C 3-6烷基”、“C 3-5烷基”、“C 3-4烷基”等，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。本发明所述的“C 1-4烷基”指C 1-6烷基中的含有1-4个碳原子的具体实例。
本发明所述的“C 1-6烷氧基”是指“C 1-6烷基-O-”，所述的“C 1-6烷基”如前文所定义。本发明所述的“C 1-4烷氧基”是指“C 1-4烷基-O-”，所述的“C 1-4烷基”如前文所定义。
本发明所述的“C 1-6烷硫基”是指“C 1-6烷基-S-”，所述的“C 1-6烷基”如前文所定义。本发明所述的“C 1-4烷硫基”是指“C 1-4烷基-S-”，所述的“C 1-4烷基”如前文所定义。
本发明所述的“羟基C 1-6烷基、氨基C 1-6烷基、卤代C 1-6烷基”是指C 1-6烷基中的一个或多个(例如，1个、2个、3个、4个或5个)氢分别被一个或多个(例如，1个、2个、3个、4个或5个)羟基、氨基或卤素所取代。C 1-6烷基如前文所定义。
本发明所述“羟基C 1-6烷氧基、氨基C 1-6烷氧基、卤代C 1-6烷氧基”是指“C 1-6烷氧基”中的一个或多个(例如，1个、2个、3个、4个或5个)氢被一个或多个(例如，1个、2个、3个、4个或5个)羟基、氨基或卤素所取代。
本发明所述“羟基C 1-6烷硫基、氨基C 1-6烷硫基、卤代C 1-6烷硫基”是指“C 1-6烷硫基”中的一个或多个(例如，1个、2个、3个、4个或5个)氢被一个或多个(例如，1个、2个、3个、4个或5个)羟基、氨基或卤素所取代。
本发明所述的“C 1-6烷基氨基、二(C 1-6烷基)氨基”分别是指C 1-6烷基-NH-、
Figure PCTCN2021088926-appb-000022
本发明所述的“C 1-6烷基羰基”是指C 1-6烷基-C(O)-。
本发明所述的“3-8元环烷基”是指含有3-8个环原子的饱和或部分饱和的且不具有芳香性的单环环状基团，本发明所述的“3-8元环烷基”包括“3-8元饱和环烷基”和“3-8元部分饱和环烷基”，例如是“3-6元环烷基”、“3-6元饱和环烷基”、“5-6元环烷基”、“5-6元饱和环烷基”等。其实例包括但不限于：环丙基、环丁基、环戊基、环己基或环己烯基等。
本发明所述的“3-8元杂环基”是指含有至少一个(例如，含有1个、2个、3个、4个或5个)杂原子的且环原子数为3-8个的饱和或部分饱和的且不具有芳香性的单环环状基团，所述杂原子为氮原子、氧原子和/或硫原子，任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被一个或两个氧原子氧代。本发明所述的“3-8元杂环基”包括“3-8元饱和杂环基”和“3-8元部分饱和杂环基”。所述“3-8元杂环基”例如是“3-6元杂环基”、“3-6元饱和杂环基”、“3-5元杂环基”、“3-5元饱和杂环基”、“5-6元杂环基”、“5-6元饱和杂环基”等。其具体实例包括但不仅限于：氮杂环丙烷基、2H-氮杂环丙烷基、二氮杂环丙烷基、3H-二氮杂环丙烯基、氮杂环丁烷基、氧杂环丙基、氧杂环丁烷基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,4-二氧杂环己二烯基、四氢呋喃基、二氢吡咯基、四氢吡咯烷基、四氢吡唑烷基、四氢咪唑烷基、4,5-二氢咪唑基、吡唑烷基、4,5-二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、噻唑烷基、四氢吡喃基、四氢噻喃基、1,1-二氧代四氢噻喃基、哌啶基、四氢吡啶基、哌啶酮基、四氢吡啶酮基、二氢哌啶酮基、哌嗪基、六氢嘧啶基、吗啉基等。
本发明所述的“CR 2”、“CR 3R 4”、“NR 5”、“CR 6”分别指以下结构：
Figure PCTCN2021088926-appb-000023
Figure PCTCN2021088926-appb-000024
本发明所述“每一X 6”是指当n为2或3时，多个X 6中每一个X 6独立地选自上述技术方案中所描述的基团。
本发明所述“任选被取代基取代”是指被取代的基团上的一个或多个(例如，1个、2 个、3个、4个或5个)氢原子被一个或多个(例如，1个、2个、3个、4个或5个)取代基“取代”或者“不取代”的两种情形。
本发明所述的“化疗”是化学药物治疗的简称，主要通过使用化学治疗药物杀灭癌细胞达到治疗的目的。
本发明所述的“放疗”是指一种肿瘤治疗方法，即肿瘤放射治疗，主要利用放射线进行肿瘤局部治疗，所述的“放射线”包括放射性同位素产生的α、β、γ射线和各类x射线治疗机或加速器产生的x射线、电子线、质子束及其他粒子束等。
本发明所述的“药学上可接受的盐”是指化合物中存在的酸性官能团(例如-COOH、-OH、-SO 3H等)与适当的无机或者有机阳离子(碱)形成的盐，包括与碱金属或碱土金属形成的盐、铵盐、与含氮有机碱形成的盐；以及化合物中存在的碱性官能团(例如-NH 2等)与适当的无机或者有机阴离子(酸)形成的盐，包括与无机酸或有机酸(例如羧酸等)形成的盐。
本发明所述的“异构体”是指本发明化合物可含有一个或多个不对称中心，因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物可以有不对称中心，这类不对称中心各自独立地产生两个光学异构体。本发明的范围包括所有可能的光学异构体和它们的混合物。本发明所述的化合物若含有烯烃双键，除非特别说明，包括顺式异构体和反式异构体。本发明所述的化合物可以以互变异构体(官能团异构体的一种)形式存在，其通过一个或多个双键位移而具有不同的氢的连接点，例如，酮和它的烯醇形式是酮-烯醇互变异构体。本发明化合物含有环状结构，受环的立体空间结构的影响，环上的取代基可存在于环两侧从而形成相对的顺式(cis)和反式(trans)异构体。各互变异构体及其混合物都包括在本发明的范围中。所有化合物的对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等，均包括在本发明范围中。
本发明化合物可通过对映体特异性合成或从对映异构体混合物拆分以得到个别对映异构体的形式制备。常规拆分技术包括使用各种众所周知的色谱方法拆分起始物质或最终产物的对映异构体的混合物。
当公开的化合物的立体化学通过结构命名或描绘时，命名或描绘的立体异构体相对于其他立体异构体为至少60％重量、70％重量、80％重量、90％重量、99％重量或99.9％重量纯。当单一异构体通过结构命名或描绘时，所描绘或命名的对映异构体为至少60％重量、70％重量、80％重量、90％重量、99％重量或99.9％重量纯。光学纯度重量％为对映异构体的重量与对映异构体重量加上其光学异构体的重量比率。
发明的有益效果
本发明取得了以下一个或多个有益效果：
1、本发明化合物、其药学上可接受的盐或其异构体具有优异的DNA-PK抑制作用，其在生物体内具有良好的药代动力学性质，作用持久，生物利用度高，能够增强癌细胞对放疗和/或一种或多种抗癌剂的敏感性。
2、本发明化合物、其药学上可接受的盐或其异构体对良性肿瘤和癌症具有较好的治疗作用，且肝微粒体稳定性高。
3、本发明化合物制备工艺简单，药品纯度高，质量稳定，易于进行大规模工业生产。
具体实施方案
下面将结合具体实施方式对本发明技术方案进行描述，对本发明的上述内容作进一步的详细说明，但不应将此理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
缩写：
BrettPhos Pd G3：甲磺酸(2-二环己基膦基-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2-氨基-1,1'-联苯-2-基)钯(II)；DMA:N,N-二甲基乙酰胺；DCM:二氯甲烷；MeOH：甲醇；EA:乙酸乙酯；TEA:三乙胺；DIEA(DIPEA)：N,N-二异丙基乙胺；TLC：薄层色谱；DMF：N,N-二甲基甲酰胺；DMSO：二甲基亚砜；THF:四氢呋喃；TBAF:四丁基氟化铵；DPPA:叠氮磷酸二苯酯；mCPBA：间氯过氧苯甲酸；TBDPS:叔丁基二苯基硅基醚。
实施例一：N-(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-6H-咪唑并[2,1-f]嘌呤-2-胺(化合物3)的制备
1、2-((2-氯-9-(四氢-2H-吡喃-4-基)-9H-嘌呤-8-基)氨基)乙-1-醇的制备
Figure PCTCN2021088926-appb-000025
将2,8-二氯-9-(四氢-2H-吡喃-4-基)-9H-嘌呤(500mg,1.8mmol)加入DMA(20mL)中，再加入乙醇胺(336mg,5.5mmol)，后在70℃下反应2小时。体系降至20℃，加入水(40mL)和EA(80mL)，萃取分液，有机相浓缩经硅胶柱层析(DCM:MeOH＝15:1)提纯得产物(480mg，产率89.6％)。
2、2-氯-N-(2-氯乙基)-9-(四氢-2H-吡喃-4-基)-9H-嘌呤-8-胺的制备
Figure PCTCN2021088926-appb-000026
将2-((2-氯-9-(四氢-2H-吡喃-4-基)-9H-嘌呤-8-基)氨基)乙-1-醇(450mg,1.5mmol)加入到三氯氧膦(5mL)的反应瓶中，在110℃下反应2小时。体系降至20℃，后慢慢加入饱和碳酸钠溶液，调节pH到8，后加入EA(30mL)萃取分液，有机相无水硫酸钠干燥，有机相浓缩经硅胶柱层析(DCM:MeOH＝20:1)提纯得产物(400mg，产率84.3％)。
3、2-氯-9-(四氢-2H-吡喃-4-基)-7,9-二氢-6H-咪唑并[2,1-f]嘌呤的制备
Figure PCTCN2021088926-appb-000027
将2-氯-N-(2-氯乙基)-9-(四氢-2H-吡喃-4-基)-9H-嘌呤-8-胺(200mg,0.63mmol)，KI(53mg,0.32mmol)，三乙胺(128mg,1.3mmol)，加入甲苯(10mL)中，后110℃下反应6小时。体系浓缩经硅胶柱层析(DCM:MeOH＝35:1)得产物(168mg，产率95.3％)。
4、N-(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-6H-咪唑并[2,1-f]嘌呤-2-胺的制备
Figure PCTCN2021088926-appb-000028
将2-氯-9-(四氢-2H-吡喃-4-基)-7,9-二氢-6H-咪唑并[2,1-f]嘌呤(100mg,0.36mmol)，7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-胺(63.7mg,0.43mmol)，碳酸铯(352.0mg,1.08mmol)和BrettPhos Pd G3(32.7mg,0.036mmol)溶于二氧六环(10mL)中，然后体系在N 2环境下100℃反应4小时，后体系浓缩，经硅胶柱层析(DCM:MeOH＝20:1)，得产物粗品(80mg)，后经硅胶制备TLC大板(DCM:MeOH＝20:1)提纯得目标化合物(30mg，产率21.3％)。
分子式：C 19H 21N 9O 分子量：391.4 LC-MS(M/e)：391.9(M+H)
1HNMR(400MHz,DMSO-d 6):δ9.16(s,1H),8.49(s,1H),8.34(s,1H),7.67 (s,1H),7.64(s,1H),4.48-4.38(m,1H),4.07-4.01(m,2H),3.95-3.91(m,2H),3.75-3.68(m,2H),3.48-3.41(m,2H),2.49-2.41(m,2H),2.35(s,3H),1.72-1.66(m,2H).
实施例二：N-(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-9-(四氢-2H-吡喃-4-基)-9H-咪唑[2,1-f]嘌呤-2-胺(化合物4)的制备
1、2-氯-9-(四氢-2H-吡喃-4-基)-9H-咪唑并[2,1-f]嘌呤的制备
Figure PCTCN2021088926-appb-000029
将2-氯-9-(四氢-2H-吡喃-4-基)-9H-嘌呤-8-胺(800mg,3.1mmol)，氯乙醛(742mg,9.45mmol)，加入DMA(20mL)中，后100℃下反应18小时。后体系降至20℃，加入EA(80mL)和水(40mL)，萃取分液，有机相浓缩经硅胶柱层析(DCM:MeOH＝15:1)得粗品(1.2g)，后经反相C18柱提纯(水/甲醇＝1/1)得粗品(200mg)，后经制备TLC大板提纯(DCM:MeOH＝15:1)得产物(130mg，收率15.1％)。
2、N-(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-9-(四氢-2H-吡喃-4-基)-9H-咪唑[2,1-f]嘌呤-2-胺的制备
Figure PCTCN2021088926-appb-000030
将2-氯-9-(四氢-2H-吡喃-4-基)-9H-咪唑并[2,1-f]嘌呤(100mg,0.36mmol)，7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-胺(80mg,0.54mmol)，碳酸铯(351.9mg,1.1mmol)和BrettPhos Pd G3(33mg,0.036mmol)溶于二氧六环(10mL)中，然后体系在N 2环境下100℃反应2小时，后体系降至20℃浓缩，经硅胶柱层析(DCM:MeOH＝30:1)，得产物粗品(110mg)，后加入甲醇(2mL)超声析出固体(70mg)，后经硅胶制备大板(DCM:MeOH＝30:1)提纯，得目标化合物(35mg，产率25.0％)。
分子式：C 19H 19N 9O 分子量：389.4 LC-MS(M/e)：389.9(M+H)
1HNMR(400MHz,DMSO-d 6):δ9.14(s,1H),9.00(s,1H),8.66(s,1H),8.39 (s,1H),7.72(s,1H),7.68(d,J＝1.6Hz,1H),7.03(d,J＝1.6Hz,1H),4.75-4.65(m,1H),4.05-3.97(m,2H),3.48-3.41(m,2H),2.60-2.50(m,2H),2.39(s,3H),1.86-1.78(m,2H).
实施例三：N-(7-甲基-[1,2,4]三唑[1,5-a]吡啶-6-基)-8-(四氢-2H-吡喃-4-基)-8H-异恶唑[4',5':4,5]吡咯[2,3-d]嘧啶-6-胺(化合物1)的制备
1、5-溴-2-氯-7H-吡咯[2,3-d]嘧啶的制备
Figure PCTCN2021088926-appb-000031
将对2-氯-7H-吡咯[2,3-d]嘧啶(6.1g,40mmol)溶于DMF(70mL)中，加入N-溴代丁二酰亚胺(7.8g,44mmol)，25℃下反应3小时，加入水(70mL)，抽滤收集固体，固体经乙腈(70mL)打浆抽滤收集固体，旋干得到产物(7.4g,收率80.1％)。
2、5-溴-2-氯-7-(四氢-2H-吡喃-4-基)-7H-吡咯[2,3-d]嘧啶的制备
Figure PCTCN2021088926-appb-000032
5-溴-2-氯-7H-吡咯[2,3-d]嘧啶(7.4g,31.8mmol)、四氢吡喃-4-醇(6.5g,63.6mmol)和三苯基膦(16.7g,63.6mmol)溶于四氢呋喃(200mL)中，缓慢滴加偶氮二甲酸二异丙酯(12.9g,63.6mmol)，加毕35℃反应16小时，反应液旋干柱层析(乙酸乙酯/石油醚＝0-15％)得到产物(7.1g,收率70.5％)。
3、5-溴-2,6-二氯-7-(四氢-2H-吡喃-4-基)-7H-吡咯[2,3-d]嘧啶的制备
Figure PCTCN2021088926-appb-000033
5-溴-2-氯-7-(四氢-2H-吡喃-4-基)-7H-吡咯[2,3-d]嘧啶(5.5g,17.4mmol)和N-氯代丁二酰亚胺(2.8g,20.8mmol)溶于1,2-二氯乙烷(200mL)中，80℃反应6小时，降温至30℃，饱和碳酸氢钠(100mL x 2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液旋干，结晶(二氯甲烷：石油醚＝20mL:100mL)得到产物(4.2g,收率68.9％)
4、2,6-二氯-7-(四氢-2H-吡喃-4-基)-7H-吡咯[2,3-d]嘧啶-5-甲醛的制备
Figure PCTCN2021088926-appb-000034
将5-溴-2,6-二氯-7-(四氢-2H-吡喃-4-基)-7H-吡咯[2,3-d]嘧啶(4.2g,12mmol)溶于四氢呋喃(80mL)中，氮气保护下-78℃下加入正丁基锂(2.5M,2.7mL,13.2mmol)，-78℃搅拌30min，加入N,N-二甲基甲酰胺(2.0g,24mmol)，-78℃搅拌30min，将反应液倒入饱和氯化铵(80mL)中淬灭，乙酸乙酯(100mL)萃取，有机相用饱和食盐水(50mL x 2)洗涤，无水硫酸钠干燥，浓缩，柱层析(乙酸乙酯/石油醚＝30％-50％)纯化得到产物(600mg,收率16.7％)。
5、2,6-二氯-7-(四氢-2H-吡喃-4-基)-7H-吡咯[2,3-d]嘧啶-5-甲醛肟的制备
Figure PCTCN2021088926-appb-000035
将2,6-二氯-7-(四氢-2H-吡喃-4-基)-7H-吡咯[2,3-d]嘧啶-5-甲醛(600mg,2mmol)、盐酸羟胺(278mg,4mmol)与醋酸钾(392mg,4mmol)溶于乙腈(10mL)中，25℃反应3小时，乙酸乙酯(20mL)萃取，食盐水(30mL)洗涤，无水硫酸钠干燥，浓缩得到产物(600mg,收率95.2％)。
6、6-氯-8-(四氢-2H-吡喃-4-基)-8H-异恶唑[4',5':4,5]吡咯[2,3-d]嘧啶的制备
Figure PCTCN2021088926-appb-000036
将2,6-二氯-7-(四氢-2H-吡喃-4-基)-7H-吡咯[2,3-d]嘧啶-5-甲醛肟(600mg,1.9mmol)与60％氢化钠(76mg,1.9mmol)溶于四氢呋喃(10mL)中，氮气保护下60℃反应1小时，95％乙醇(1mL)淬灭，旋干，中压反相C18柱纯化(甲醇/水＝0-40％)得到产物(100mg,收率18.9％)。
7、N-(7-甲基-[1,2,4]三唑[1,5-a]吡啶-6-基)-8-(四氢-2H-吡喃-4-基)-8H-异恶唑[4',5':4,5]吡咯[2,3-d]嘧啶-6-胺的制备
Figure PCTCN2021088926-appb-000037
6-氯-8-(四氢-2H-吡喃-4-基)-8H-异恶唑[4',5':4,5]吡咯[2,3-d]嘧啶(55mg,0.20mmol)、7-甲基-[1,2,4]三唑[1,5-a]吡啶-6-胺(59mg,0.40mmol)、碳酸铯(195mg,0.6mmol)与甲磺酸(2-二环己基膦基-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2-氨基-1,1'-联苯-2-基)钯(II)(18mg,0.02mmol)溶于1,4-二氧六环(3mL)中，氮气鼓气5分钟，微波100℃下反应1小时，降温至30℃，抽滤，滤液浓缩柱层析(甲醇/二氯甲烷＝15％)得到产物(17.3mg,收率22.5％)。
分子式：C 19H 18N 8O 2 分子量：390.4 LC-MS(M/e)：390.9(M+H +)
1HNMR(400MHz,DMSO-d6):δ:9.24-9.21(m,2H),8.41(s,1H),7.76(s,1H),7.47(s,1H),4.50-4.40(m,1H),3.95-3.85(m,2H),3.10-3.00(m,2H),2.60-2.45(m,2H),2.36(s,3H),1.55-1.45(m,2H).
实施例四：N-(7-甲基-[1,2,4]三氮唑[1,5-a]吡啶-6-基)-8-(四氢-2H-吡喃-4-基)-8H-异噻唑[4’,5’:4,5]吡咯[2,3-d]嘧啶-6-胺(化合物2)的制备
1、2-氯-6-巯基-7-(四氢-2H-吡喃-4-基)-7H-吡咯[2,3-d]嘧啶-5-甲醛的制备
Figure PCTCN2021088926-appb-000038
2,6-二氯-7-(四氢-2H-吡喃-4-基)-7H-吡咯[2,3-d]嘧啶-5-甲醛(0.30g,1.0mmol)溶于甲醇(8mL)、四氢呋喃(8mL)和水(2mL)的混合溶剂中，加入NaHS(0.17g,3.0mmol)，25℃反应4小时后，减压除去有机溶剂，含水反应液直接用于下一步反应。
2、2-氯-5-亚胺甲基-7-(四氢-2H-吡喃-4-基)-7H-吡咯[2,3-d]嘧啶-6-硫醇的制备
Figure PCTCN2021088926-appb-000039
2-氯-6-巯基-7-(四氢-2H-吡喃-4-基)-7H-吡咯[2,3-d]嘧啶-5-甲醛的上步反应溶液加入30％浓氨水(10mL)，于20℃下搅拌反应38小时，反应液直接用于下一步反应。
3、6-氯-8-(四氢-2H-吡喃-4-基)-8H-异噻唑[4’,5’:4,5]吡咯[2,3-d]嘧啶的制备
Figure PCTCN2021088926-appb-000040
向2-氯-5-亚胺甲基-7-(四氢-2H-吡喃-4-基)-7H-吡咯[2,3-d]嘧啶-6-硫醇的上步反应溶液中滴加含碘(0.80g,3.2mmol)的四氢呋喃溶液(2mL)，20℃搅拌1小时，1小时后，减压除去溶剂，反相C18柱纯化(水:甲醇＝1:4)得产物(35mg,三步收率11.9％)
4、N-(7-甲基-[1,2,4]三氮唑[1,5-a]吡啶-6-基)-8-(四氢-2H-吡喃-4-基)-8H-异噻唑[4’,5’:4,5]吡咯[2,3-d]嘧啶-6-胺的制备
Figure PCTCN2021088926-appb-000041
将6-氯-8-(四氢-2H-吡喃-4-基)-8H-异噻唑[4’,5’:4,5]吡咯[2,3-d]嘧啶(65mg,0.22mmol)、7-甲基-[1,2,4]三氮唑[1,5-a]吡啶-6-胺(66mg,0.45mmol)、碳酸铯(230mg,0.71mmol)和Brettphos Pd G3(20mg,0.022mmol)溶于二氧六环(6mL)中，N 2保护下100℃下反应16小时，减压除去溶剂，反相C18柱(水：甲醇＝4:6)纯化得产物粗品，该粗品进一步经制备TLC板分离(甲醇：二氯甲烷＝1:10)得产物(1.7mg,收率1.9％)。
分子式：C 19H 18N 8OS 分子量：406.1 LC-MS(M/e)：406.9(M+H +)
1HNMR(400MHz,CDCl 3):δ:9.80(s,1H),8.89(s,1H),8.69(s,1H),8.29(s,1H),7.61(s,1H),7.02(s,1H),5.12-5.05(m,1H),4.24-4.14(m,2H),3.73(t,J＝12Hz,2H),2.55(s,3H),2.27-2.17(m,2H),2.10-2.01(m,2H).
实施例五：9-(4,4-二氟环己基)-N-(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-9H-咪唑并[2,1-f]嘌呤-2-胺(化合物6)的制备
1、2-氯-4-((4,4-二氟环己基)氨基)嘧啶-5-羧酸乙酯的制备
Figure PCTCN2021088926-appb-000042
将2,4-二氯嘧啶-5-羧酸乙酯(6.0g，27.1mmol)，4,4-二氟环己胺盐酸盐(4.7g，27.3mmol)和N,N-二异丙基乙胺(9.0g,69.7mmol)溶于乙腈(100.0mL)中，体系在20℃下反应4小时，浓缩后残余物进行柱层析(乙酸乙酯：石油醚＝15％)得化合物(7.7g，收率为88.8％)。
2、2-氯-4-((4,4-二氟环己基)氨基)嘧啶-5-羧酸的制备
Figure PCTCN2021088926-appb-000043
将2-氯-4-((4,4-二氟环己基)氨基)嘧啶-5-羧酸乙酯的(3.0g，27.1mmol)溶于THF(30.0mL)和水(30.0mL)的混合体系中，体系在20℃下加入氢氧化锂(800.0mg,19.0mmol)反应2.0小时，浓缩后调pH至3-4后析出固体，然后进行过滤得化合物(2.6g，收率为95.2％)。
3、2-氯-9-(4,4-二氟环己基)-7,9-二氢-8H-嘌呤-8-酮的制备
Figure PCTCN2021088926-appb-000044
将2-氯-4-((4,4-二氟环己基)氨基)嘧啶-5-羧酸(2.6g,8.9mmol)、叠氮磷酸二苯酯(2.5g,9.1mmol)和三乙胺(900.0mg,8.9mmol)溶于DMA(30.0mL)中，体系在25℃下反应1.0小时后，升至115℃继续反应16小时。反应结束后降至25℃，缓慢倒入冰水(100.0mL)中，过滤后将固体干燥得化合物(2.8g)。
4、2,8-二氯-9-(4,4-二氟环己基)-9H-嘌呤的制备
Figure PCTCN2021088926-appb-000045
将2-氯-9-(4,4-二氟环己基)-7,9-二氢-8H-嘌呤-8-酮(1.0g,3.5mmol)和N,N-二异丙基乙胺(930.0mg,7.2mmol)溶于三氯氧磷(15.0mL)中，体系在150℃下微波反应2.5小时，反应结束后浓缩调体系pH至7，然后用DCM(100.0mL)进行萃取，有机相干燥，过滤，滤液浓缩柱层析得产物(600.0mg，收率为56.6％)。
5、2-氯-9-(4,4-二氟环己基)-9H-嘌呤-8-胺的制备
Figure PCTCN2021088926-appb-000046
将2,8-二氯-9-(4,4-二氟环己基)-9H-嘌呤(1.2g)溶于DMSO(20.0mL)中，体系通入氨气后在70℃下反应1.5小时，反应结束后倒入水(100.0mL)中，过滤后干燥固体并进行柱层析(MeOH:DCM＝8％)得化合物(800.0mg，收率为71.4％)。
6、2-氯-9-(4,4-二氟环己基)-9H-咪唑并[2,1-f]嘌呤的制备
Figure PCTCN2021088926-appb-000047
将2-氯-9-(4,4-二氟环己基)-9H-嘌呤-8-胺(550mg,1.91mmol)和氯乙醛(1.1g,14.0mmol)溶于DMA(10.0mL)中，体系在110℃下微波反应1.0小时，反应结束后倒入水(100.0mL)中用饱和碳酸氢钠调pH至7，再用乙酸乙酯(200.0mL)进行萃取，有机相干燥并进行柱层析(EA:PE＝60％)得产物(180mg，收率为30％)。
7、9-(4,4-二氟环己基)-N-(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-9H-咪唑并[2,1-f]嘌呤-2-胺的制备
Figure PCTCN2021088926-appb-000048
将2-氯-9-(4,4-二氟环己基)-9H-咪唑并[2,1-f]嘌呤(230mg,0.737mmol)、碳酸铯(550.0mg,1.688mmol)、BrettPhos Pd G3(70.0mg,0.077mmol)和7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-胺(120.0mg,0.809mmol)溶于二氧六环(10.0mL)中，体系在N 2，110℃下反应3.0小时，浓缩后进行柱层析(甲醇:二氯甲烷＝10％)纯化得粗品(120.0mg)，然后再进行反相柱层析(H 2O:MeOH＝59％)纯化得产物(55mg，收率为17.6％)。
分子式:C 20H 19F 2N 9 分子量:423.4 LC-MS(M/e):423.9(M+H +)
1H-NMR(400MHz,CDCl 3)δ:9.68(s,1H),8.82(s,1H),8.45(s,1H),7.60(s,1H),7.37(s,1H),7.15(s,1H),6.81(s,1H),4.80-4.66(m,1H),2.88-2.81(m,2H),2.68(s,3H),2.41-2.32(s,2H),2.15-2.02(m,2H),2.01-1.92(m,2H).
实施例六：5-(4,4-二氟环己基)-N-(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-7,8-二氢-5H-咪唑[1,2-e]嘌呤-2-胺(化合物9)的制备
1、2-((2-氯-9-(4,4-二氟环己基)-9H-嘌呤-8-基)氨基)乙-1-醇的制备
Figure PCTCN2021088926-appb-000049
将2,8-二氯-9-(4,4-二氟环己基)-9H-嘌呤(614.2mg,2.0mmol)溶于DMA(6.0mL)中，向体系中加入DIEA(516.8mg,4.0mmol)、乙醇胺(244.4mg,4.0mmol)，然后升温至80℃反应2.0小时，加水(20.0mL)，用乙酸乙酯(20mL)萃取，有机相浓缩进行柱层析(DCM:MOH＝15:1)得产物(510.0mg，收率：76.9％)。
2、2-氯-N-(2-氯乙基)-9-(4,4-二氟环己基)-9H-嘌呤-8-胺的制备
Figure PCTCN2021088926-appb-000050
将2-((2-氯-9-(4,4-二氟环己基)-9H-嘌呤-8-基)氨基)乙-1-醇(470.0mg,1.4mmol)中加入三氯氧磷(5.0mL)，体系在110℃反应2.0小时后进行浓缩，加水(20.0mL)，用乙酸乙酯(20mL)萃取，得产物(450.0mg，收率：90.7％)。
3、2-氯-5-(4,4-二氟环己基)-7,8-二氢-5H-咪唑并[1,2-e]嘌呤的制备
Figure PCTCN2021088926-appb-000051
将2-氯-N-(2-氯乙基)-9-(4,4-二氟环己基)-9H-嘌呤-8-胺(430mg,1.2mmol)溶于甲苯(10.0mL)中，加入KI(99.6mg,0.6mmol)、三乙胺(242.9mg,2.4mmol)，110℃下反应6.0小时后浓缩，加水(20.0mL)，用EA(20mL)萃取，旋干有机相得产物(360.0mg，收率：93.5％)。
4、5-(4,4-二氟环己基)-N-(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-7,8-二氢-5H-咪唑[1，2-e]嘌呤-2-胺的制备
Figure PCTCN2021088926-appb-000052
将2-氯-5-(4,4-二氟环己基)-7,8-二氢-5H-咪唑并[1,2-e]嘌呤(250.0mg,0.8mmol)，7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-胺(118.6mg,0.8mmol)，碳酸铯(521.3mg,1.6mmol)和BrettPhos Pd G3(72.7mg,0.08mmol)中加入1,4-二氧六环(5.0mL)中，体系在N 2环境下100℃反应3.0小时后进行浓缩，经柱层析(MeOH:DCM＝1:20)得产物(58.0mg，收率：17.1％)。
分子式：C 20H 21F 2N 9 分子量：425.5 LC-MS(M/e)：425.9(M+H +)
1HNMR(400MHz,CD 3OD):δ9.18(s,1H),8.30(s,1H),7.66(s,1H),7.61(s,1H),4.20-4.32(m,1H),4.09-4.19(m,2H),3.69-3.90(m,2H),2.47-2.61(m,2H),2.46(s,3H),2.09-2.19(m,2H),1.95-2.05(m,2H),1.83-1.92(m,2H).
实施例七：N-(7-甲基-[1,2,4]三唑[1,5-a]吡啶-6-基)-9-(四氢-2H-吡喃-4-基)-9H-[1,2,4]三唑[3,4-f]嘌呤-7-胺(化合物10)的制备
1、2-氯-8-肼基-9-(四氢-2H-吡喃-4-基)-9H-嘌呤的制备
Figure PCTCN2021088926-appb-000053
2,8-二氯-9-(四氢-2H-吡喃-4-基)-9H-嘌呤(200mg,0.73mmol)溶于四氢呋喃(4mL)，加入水合肼(50％,2mL),25℃反应1h，浓缩柱层析(甲醇/二氯甲烷＝5％)得到产物(180mg,收率91.5％)。
2、7-氯-9-(四氢-2H-吡喃-4-基)-9H-[1,2,4]三唑并[3,4-f]嘌呤的制备
Figure PCTCN2021088926-appb-000054
2-氯-8-肼基-9-(四氢-2H-吡喃-4-基)-9H-嘌呤(180mg,0.67mmol)、原甲酸三乙酯(298mg,2.01mmol)溶于1,4-二氧六环(3mL)，110℃下反应6小时，降温至30℃，浓缩柱层析(甲醇/二氯甲烷＝4％)得到产物(120mg,收率64.3％)。
3、N-(7-甲基-[1,2,4]三唑[1,5-a]吡啶-6-基)-9-(四氢-2H-吡喃-4-基)-9H-[1,2,4]三唑[3,4-f]嘌呤-7-胺的制备
Figure PCTCN2021088926-appb-000055
7-氯-9-(四氢-2H-吡喃-4-基)-9H-[1,2,4]三唑并[3,4-f]嘌呤(120mg,0.44mmol)、7-甲基-[1,2,4]三唑[1,5-a]吡啶-6-胺(127mg,0.88mmol)、碳酸铯(418mg,1.32mmol)与甲磺酸(2-二环己基膦基-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2-氨基-1,1'-联苯-2-基)钯(II)(39.8mg,0.044mmol)溶于1,4-二氧六环(3mL)中，氮气鼓气5分钟，微波100℃下反应1小时，降温至30℃，抽滤，滤液浓缩柱层析(甲醇/二氯甲烷＝8％)得到产物(60mg,收率35.7％)。
分子式：C 18H 18N 10O 分子量：390.4 LC-MS(M/e)：390.9(M+H +)
1HNMR(400MHz,DMSO-d6):δ:9.21(s,1H),9.09(s,1H),8.97(s,1H),8.72(s,1H),8.39(s,1H),7.73(s,1H),4.70-4.60(m,1H),4.07-3.99(m,2H),3.50-3.40(m,2H),2.50-2.40(m,2H),2.37(s,3H),1.95-1.85(m,2H).
实施例八：(1r,4r)-4-(2-((7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基)-9H-咪唑并[2,1-f]嘌呤-9-基)环己-1-醇(化合物5)的制备
1N-((1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2-氯-5-硝基嘧啶-4-胺的制备
Figure PCTCN2021088926-appb-000056
-78℃下，将(1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基-1-胺(4.9g,13.9mmol)缓慢滴加入含有2,4-二氯-5-硝基嘧啶(2.7g,13.9mmol)和DIPEA(5mL)的二氯甲烷(50mL)中，-78℃反应30分钟，然后缓慢升温至30℃反应15小时。减压除去溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝4:1)得目标化合物(5.0g，收率：70.4％)。
2、N 4-((1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2-氯嘧啶-4,5-二胺的制备
Figure PCTCN2021088926-appb-000057
将5％含量的铂碳(600mg)加入至含有N-((1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2-氯-5-硝基嘧啶-4-胺(4.0g,7.8mmol)的乙酸乙酯(30mL)中，氢气氛围中30℃反应14小时，将反应液过滤，滤液直接减压旋干得到目标化合物粗品(3.7g),未进一步纯化，直接用于下一步反应中。
3、9-((1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2-氯-7,9-二氢-8H-嘌呤-8-硫酮的制备
Figure PCTCN2021088926-appb-000058
将N 4-((1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2-氯嘧啶-4,5-二胺(2.2g粗品)和乙基黄原酸钾(2.6g,16.2mmol)加入至无水乙醇(30mL)中，80℃反应10小时，降至室温，减压除去溶剂，向残留物中加入水(400mL)，用4M盐酸水溶液调节pH至4，二氯甲烷萃取3次，合并后的二氯甲烷经水洗，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶柱层析(乙酸乙酯:石油醚＝3:1)得目标化合物(2.0g，两步收率82％)。
4、9-((1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2,8-二氯-9H-嘌呤酮的制备
Figure PCTCN2021088926-appb-000059
将9-((1R,4R)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2-氯-7,9-二氢-8H-嘌呤-8-硫酮(2.0g,3.8mmol)加入到氯化亚砜(15mL)和DMF(1mL)的混合溶液中，80℃反应1小时。降至室温，减压除去溶剂，用乙酸乙酯重新溶解残留物后，饱和碳酸氢钠溶液调节pH至碱性，分液，乙酸乙酯相经水洗，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶柱层析(乙酸乙酯:石油醚＝2:1)得目标化合物(1.3g，收率：65.09％)。
5、9-((1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2-氯-9H-嘌呤-8-胺的制备
Figure PCTCN2021088926-appb-000060
氨气通入含有9-((1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2,8-二氯-9H-嘌呤酮(1.25g,2.4mmol)的DMSO(10mL)中，70℃反应3小时。降至室温，将反应液缓慢滴加至冰水中，析出白色固体，过滤，滤饼用水洗涤3次，减压干燥得目标化合物(1.05g，收率：86.44％)。
6、9-((1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2-氯-9H-咪唑并[2,1-f]嘌呤的制备
Figure PCTCN2021088926-appb-000061
将9-((1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2-氯-9H-嘌呤-8-胺(1.0g,2.0mmol)，溴代乙醛缩二乙醇(3.12g,15.8mmol)和碳酸钾(1.64g,11.9mmol)加入至1,4-二氧六环(20mL)中，100℃反应5小时。降至室温，过滤，滤液减压浓缩，残留物经硅胶柱层析(二氯甲烷:甲醇＝30:1)得目标化合物(520mg，收率：49.0％)。
7、9-((1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-N-(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-9H-咪唑并[2,1-f]嘌呤-2-胺的制备
Figure PCTCN2021088926-appb-000062
含有9-((1r,4r)-4-((叔丁基二苯基)氧基)环己基)-2-氯-9H-咪唑并[2,1-f]嘌呤(210mg,0.4mmol)，7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-胺(110mg,0.74mmol)，BrettPhos Pd G3(36mg,0.04mmol)和碳酸铯(482mg,1.48mmol)的1,4-二氧六环(10mL)中，100℃反应4小时。降至室温，过滤，滤液减压浓缩，残留物经硅胶柱层析(二氯甲烷:甲醇＝20:1)得目标化合物(140mg，收率：54.5％)。
8、(1r,4r)-4-(2-((7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基)-9H-咪唑并[2,1-f]嘌呤-9-基)环己-1-醇的制备
Figure PCTCN2021088926-appb-000063
将TBAF(3mL)滴加入含有9-((1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-N-(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-9H-咪唑并[2,1-f]嘌呤-2-胺(80mg,0.12mmol)的THF(4mL)中，50℃反应5小时。降至室温，加入饱和氯化铵溶液淬灭反应，二氯甲烷萃取三次，二氯甲烷层经水洗，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶制备TLC板纯化(二氯甲烷:甲醇＝10:1)和反相柱纯化(甲醇:水＝4:1)得目标化合物(16mg，收率：33.0％)。
分子式:C 20H 21N 9O 分子量:403.5 LC-MS(M/e):403.9(M+H +)
1H-NMR(400MHz,DMSO-d 6)δ:9.15(s,1H),8.93(s,1H),8.64(s,1H),8.37(s,1H),7.70(s,1H),7.65(s,1H),7.00(s,1H),4.75(m,1H),4.41(m,1H),2.48(s,3H),2.35(m,2H),1.96(m,2H),1.84(m,2H),1.31(m,2H)。
实施例九：4-(2-((7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基)-9H-咪唑并[2,1-f]嘌呤-9-基)四氢-2H-硫代吡喃1,1-二氧化物(化合物7)的制备
1、2-氯-4-((四氢-2H-硫代吡喃-4-基)氨基)嘧啶-5-羧酸乙酯的制备
Figure PCTCN2021088926-appb-000064
将2,4-二氯嘧啶-5-羧酸乙酯(5g,22.6mmol),四氢-2H-硫代吡喃-4-胺盐酸盐(3.4g,22.6mmol)溶于乙腈(110mL)中，加入碳酸钾(7.8g,56.5mmol)，25℃下反应8h，LCMS检测反应完成，反应液倒入水中，有固体析出，抽滤得产品(6.5g，收率95.3％)。
2、2-氯-4-((四氢-2H-硫代吡喃-4-基)氨基)嘧啶-5-羧酸的制备
Figure PCTCN2021088926-appb-000065
将2-氯-4-((四氢-2H-硫代吡喃-4-基)氨基)嘧啶-5-羧酸乙酯(6.5g,21.6mmol),溶于四氢呋喃(35mL)和水(35mL)中，加入氢氧化锂(1.8g,43.2mmol)，25℃下反应3h，LCMS检测反应完成，稀盐酸(3M)调pH至6-7，有固体析出，抽滤得产品(5.5g，收率92.9％)。
3、2-氯-9-(四氢-2H-硫代吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮的制备
Figure PCTCN2021088926-appb-000066
将2-氯-4-((四氢-2H-硫代吡喃-4-基)氨基)嘧啶-5-羧酸(3.6g,13.1mmol),溶于DMA(80mL)中，加入DPPA(3.6g,13.1mmol)和三乙胺(1.3g,13.1mmol),氮气保护110℃下反应16h，LCMS检测反应完成，倒入水中有固体析出，抽滤得产品(1.2g，收率33.8％)。
4、2,8-二氯-9-(四氢-2H-硫代吡喃-4-基)-9H-嘌呤的制备
Figure PCTCN2021088926-appb-000067
将2-氯-9-(四氢-2H-硫吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮(1.1g,4.1mmol)溶于POCl 3(10mL)中，加入DIEA(1.6g,12.3mmol)，150℃下微波反应3h，LCMS检测反应完成，反应液旋干，倒入水中有固体析出，抽滤得产品(1g，收率84.4％)。
5、2-氯-9-(四氢-2H-硫代吡喃-4-基)-9H-嘌呤-8-胺的制备
Figure PCTCN2021088926-appb-000068
将2,8-二氯-9-(四氢-2H-硫吡喃-4-基)-9H-嘌呤(1g,3.46mmol)溶于氨的异丙醇溶 液(3.5M,20mL)中70℃下反应16h，LCMS检测反应完成，反应液旋干，硅胶柱层析(MeOH:DCM＝1:10)分离得产品(480mg，收率51.4％)。
6、2-氯-9-(四氢-2H-硫代吡喃-4-基)-9H-咪唑并[2,1-f]嘌呤的制备
Figure PCTCN2021088926-appb-000069
将2-氯-9-(四氢-2H-硫代吡喃-4-基)-9H-嘌呤-8-胺(480mg,1.78mmol)，溴乙醛缩乙二醇(2.8g,14.3mmol)和碳酸钾(1.4g,10.7mmol)溶于二氧六环(15mL)中，100℃反应8h，LCMS检测反应完成，反应液倒入水(50mL)中，DCM萃取，硅胶柱层析分离(MeOH:DCM＝1:10)得产品(180mg，收率34.3％)。
7、N-(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-9-(四氢-2H-硫代吡喃-4-基)-9H-咪唑[2,1-f]嘌呤-2-胺的制备
Figure PCTCN2021088926-appb-000070
将2-氯-9-(四氢-2H-硫代吡喃-4-基)-9H-咪唑并[2,1-f]嘌呤(180mg,0.61mmol),7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-胺(83mg,0.56mmol)，Brettphos Pd G3(54mg,0.06mmol)和碳酸铯(475mg,1.44mmol)溶于二氧六环(18mL)中，氮气保护，100℃下反应4h，LCMS检测反应完成，旋干，硅胶柱层析分离得产品(110mg,收率44.4％)。
8、4-(2-((7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基)-9H-咪唑并[2,1-f]嘌呤-9-基)四氢-2H-硫代吡喃1,1-二氧化物的制备
Figure PCTCN2021088926-appb-000071
将N-(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-9-(四氢-2H-硫代吡喃-4-基)-9H-咪唑[2,1-f]嘌呤-2-胺(110mg,0.27mmol)溶于DCM(15mL)中，加入mCPBA(140mg,0.81mmol)25℃下反应2h，LCMS检测反应完成。饱和碳酸氢钠水溶液洗，DCM萃取，有机相旋干，粗品经反相色谱柱纯化(MeOH:H 2O＝0-60％)得产品(18.9mg，收率16.0％)。
分子式:C 19H 19N 9O 2S 分子量:437.5 LC-MS(M/e):438.2(M+H +)
1H-NMR(400MHz,CDCL 3)δ:9.67(s,1H),8.51(s,1H),8.30(s,1H),7.63(s,1H), 7.39(s,1H),7.17(s,1H),6.85(s,1H),4.80-4.90(m,1H),3.25-3.40(m,6H),2.55(s,3H),2.40–2.50(m,2H).
实施例十：(1r,4r)-4-(2-((7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基)-6,7-二氢-9H-咪唑[2,1-f]嘌呤-9-基)环己-1-醇(化合物8)的制备
1、2-((9-((1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2-氯-9H-嘌呤-8-基)氨基)乙-1-醇的制备
Figure PCTCN2021088926-appb-000072
9-((1r，4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2,8-二氯-9H-嘌呤(1.5g,2.9mmol)溶于DMA(50mL)，加入乙醇胺(696.4mg,11.5mmol)，加毕，70℃反应1小时。LCMS检测反应结束。倒入冰水中，乙酸乙酯萃取，有机相干燥，浓缩，得目标化合物(1.4g，收率：87.7％)。
2、9-((1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2-氯-N-(2-氯乙基)-9H-嘌呤-8-胺的制备
Figure PCTCN2021088926-appb-000073
将2-((9-((1r，4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2-氯-9H-嘌呤-8-基)氨基)乙-1-醇(2.0g,3.6mmol)溶于二氯甲烷(100mL)中，0℃下滴加二氯亚砜(867.0mg,7.2mmol)，加毕，升温至40℃反应2小时。LCMS检测反应结束。0℃下加甲醇淬灭反应，二氯甲烷萃取，有机相加水洗，有机相干燥，浓缩，硅胶柱纯化(石油醚:乙酸乙酯＝2:1)，得目标化合物(2.0g，收率:97.7％)。
3、9-((1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2-氯-7,9-二氢-6H-咪唑并[2,1-f]嘌呤的制备
Figure PCTCN2021088926-appb-000074
将9-((1r，4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2-氯-N-(2-氯乙基)-9H-嘌呤-8-胺(2.0g,3.5mmol)溶于甲苯(50mL)，加入三乙胺(1.1g,10.5mmol)，碘化 钾(292.4mg,1.8mmol)，加毕，升温至110℃反应13小时。LCMS检测反应结束。浓缩溶剂，残留物经硅胶柱层析(纯乙酸乙酯)得目标化合物(1.3g，收率69.5％)。
4、9-((1r,4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-N-(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-7,9-二氢-6H-咪唑并[2,1-f]嘌呤-2-胺的制备
Figure PCTCN2021088926-appb-000075
将9-((1r，4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-2-氯-7,9-二氢-6H-咪唑并[2,1-f]嘌呤(1.0g,1.9mmol)和7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-胺(417.3mg,2.8mmol)溶于1,4-二氧六环(40mL)，加入碳酸铯(1.2g,3.8mmol)，Brettphos Pd G3(172.5mg,0.19mmol)，加毕，氮气保护下100℃反应3小时。LCMS检测反应结束。降至室温，减压除去溶剂，残留物经硅胶柱层析(二氯甲烷:甲醇＝20:1)得目标化合物(1.1g，收率：89.9％)。
5、(1r,4r)-4-(2-((7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基)-6,7-二氢-9H-咪唑[2,1-f]嘌呤-9-基)环己-1-醇的制备
Figure PCTCN2021088926-appb-000076
将TBAF(3.4mL,3.4mmol)滴加入含有9-((1r，4r)-4-((叔丁基二苯基甲硅烷基)氧基)环己基)-N-(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-7,9-二氢-6H-咪唑并[2,1-f]嘌呤-2-胺(1.1g,1.7mmol)的THF(20mL)中，50℃反应4小时。LCMS检测反应结束。降至室温，浓缩溶剂，乙酸乙酯溶解，有机相水洗，干燥，浓缩，反相C18柱纯化(乙腈/水＝0-100％)得目标化合物(315mg，收率：45.5％)。
分子式:C 20H 23N 9O 分子量:405.5 LC-MS(M/e):406.3(M+H +)
1H-NMR(400MHz,DMSO-d 6)δ:9.13(s,1H),8.63(br,1H),8.35(s,1H),7.86(br,1H),7.68(s,1H),4.65(m,1H),4.07-4.14(m,3H),3.79-3.91(m,2H),3.15(m,1H),2.37(s,3H),2.15-2.30(m,2H),1.85-1.95(m,2H),1.70-1.82(m,2H),1.19-1.28(m,2H).
实施例十一：6-甲基-N-(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-9-(四氢-2H-吡 喃-4-基)-9H-咪唑[2,1-f]嘌呤-2-胺(化合物12)的制备
1、2-氯-6-甲基-9-(四氢-2H-吡喃-4-基)-9H-咪唑并[2,1-f]嘌呤的制备
Figure PCTCN2021088926-appb-000077
将2-氯-9-(四氢-2H-吡喃-4-基)-9H-嘌呤-8-胺(507mg,2.0mmol)，2-溴-1,1-二乙氧基丙烷(2.11g,10.0mmol)，加入到含乙腈(20mL)的封管中，后125℃下反应16小时。合并另一批次一起处理(共1.014g)，体系浓缩经硅胶柱层析(DCM/MeOH＝40/1)，旋干得粗品1.0g，后经反相C18柱提纯(水/MeOH＝2/8)，得粗品(300mg)。
2、6-甲基-N-(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-9-(四氢-2H-吡喃-4-基)-9H-咪唑[2,1-f]嘌呤-2-胺的制备
Figure PCTCN2021088926-appb-000078
向2-氯-6-甲基-9-(四氢-2H-吡喃-4-基)-9H-咪唑并[2,1-f]嘌呤(300mg粗品)和7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-胺(148.1mg,1.0mmol)的1,4-二氧六环(10mL)溶液中，加入Brettphos Pd G3(90.7mg,0.10mmol)和碳酸铯(651.6mg,2.0mmol)，用氮气置换气体3次，后微波下105℃下反应2h。浓缩除去溶剂，后经硅胶柱层析纯化(DCM/MeOH＝15/1)，得到产物(100mg，收率24.8％)。
分子式:C 20H 21N 9O 分子量:403.5 LC-MS(M/e):404.3(M+H +)
1H-NMR(400MHz,CDCl 3)δ:9.76(s,1H),8.46(s,1H),8.27(s,1H),7.60(s,1H),6.81(s,1H),4.84-4.72(m,1H),4.22-4.15(m,2H),3.65-3.55(m,2H),2.90-2.79(m,2H),2.59-2.57(m,6H),1.93-1.87(m,2H).
实施例十二：2-((7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基)-9-(四氢-2H-吡喃-4-基)-6H-咪唑并[2,1-f]嘌呤-7(9H)-酮(化合物13)的制备
1、2-氯-9-(四氢-2H-吡喃-4-基)-6H-咪唑并[2,1-f]嘌呤-7(9H)-酮的制备
Figure PCTCN2021088926-appb-000079
将2-氯-9-(四氢-2H-吡喃-4-基)-9H-嘌呤-8-胺(507mg,2mmol)，碳酸钾(829.2mg, 6.0mmol)加入乙腈(80mL)中，然后加入氯乙酰氯(677.4mg,6.0mmol)，体系在85℃下反应18小时。最后体系减压抽滤，滤液浓缩经硅胶柱层析(DCM:MeOH＝50:1)纯化，得产物(350mg，收率59.8％)。
2、2-((7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基)-9-(四氢-2H-吡喃-4-基)-6H-咪唑并[2,1-f]嘌呤-7(9H)-酮的制备
Figure PCTCN2021088926-appb-000080
将2-氯-9-(四氢-2H-吡喃-4-基)-6H-咪唑并[2,1-f]嘌呤-7(9H)-酮(150mg,0.51mmol)，7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-胺(113.9mg,0.77mmol)，碳酸铯(332.3mg,1.0mmol)和BrettPhos Pd G3(23mg,0.025mmol)溶于1,4-二氧六环(10mL)中，然后体系在N 2环境下90℃反应2小时，后体系降至20℃浓缩，经硅胶柱层析(DCM:MeOH＝10:1)纯化，得粗品(70mg)，后再经硅胶TLC大板提纯(DCM:MeOH＝10:1)得产物(45mg，收率21.8％)。
分子式：C 19H 19N 9O 2 分子量：405.4 LC-MS(M/e)：405.9(M+H +)
1HNMR(400MHz,CDCl 3):δ9.67(s,1H),8.28(s,1H),8.17(s,1H),7.61(s,1H),6.81(s,1H),4.80-4.68(m,1H),4.39(s,2H),4.20-4.13(m,2H),3.58-3.51(m,2H),2.83-2.72(m,2H),2.53(s,3H),1.91-1.84(m,2H).
实施例十三：2-((7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基)-10-(四氢-2H-吡喃-4-基)嘧啶并[2,1-f]嘌呤-8(10H)-酮(化合物14)的制备
1、2-氯-10-(四氢-2H-吡喃-4-基)嘧啶并[2,1-F]嘌呤-8-(10H)-酮的制备
Figure PCTCN2021088926-appb-000081
将2-氯-9-(四氢-2H-吡喃-4-基)-9H-嘌呤-8-胺(600.0mg,2.4mmol)、三乙胺(242.9mg,2.4mmol)溶于甲苯(10.0mL)中，25℃搅拌15分钟，加入(E)-1,1,1-三氯-4-乙氧基-3-烯-2-酮(522.0mg,2.4mmol)，110℃搅拌10小时。过滤，滤液旋干溶剂经硅胶柱层析提纯(DCM/MeOH＝40/1)，得产物(290.0mg,收率40.1％)。
2、2-((7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基)-10-(四氢-2H-吡喃-4-基)嘧啶并[2,1-f]嘌呤-8(10H)-酮的制备
Figure PCTCN2021088926-appb-000082
将2-氯-10-(四氢-2H-吡喃-4-基)嘧啶并[2,1-F]嘌呤-8-(10H)-酮(222.0mg,0.7mmol)溶于1,4-二氧六环(5mL)中，加入7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-胺(118.6mg,0.8mmol)，Brettphos Pd G3(63.6mg,0.07mmol)，碳酸铯(456.1mg,1.4mmol)，氮气保护100℃搅拌2小时。反相柱层析(MeOH、H 2O)得产物(5.9mg,收率1.9％)。
分子式:C 20H 19N 9O 2 分子量:417.4 LC-MS(M/e):417.9(M+H +)
1H-NMR(400MHz,CDCl 3)δ:9.40(s,1H),9.09-9.04(d,2H),8.40(s,1H),8.03-8.02(d,1H),7.75(s,1H),6.22-6.20(d,1H),4.89-4.83(m,1H),4.01-3.91(m,2H),3.45-3.35(m,2H),2.70-2.59(m,2H),2.38(s,3H),1.95-1.75(m,2H).
实验方案
以下提供本发明部分化合物的示例性实验方案，以显示本发明化合物有利活性和有益技术效果。但是应当理解，下述实验方案仅仅是对本发明内容的示例，而不是对本发明范围的限制。
实验例1 本发明化合物的体外酶学活性
缩写
EDTA：乙二胺四乙酸
DMSO：二甲基亚砜
Tris：三羟甲基氨基甲烷
Brij-35：月桂醇聚氧乙烯醚
DTT：二硫苏糖醇
供试品：本发明化合物，其结构式、制备方法见实施例。
实验试剂：
名称 品牌
ADP-Glo Kinase Assay Promege
DNA-PK Promege
实验方法：
1.配制1倍的激酶缓冲液
1)由以下物质或溶液配制1倍激酶缓冲液：
40mM Tris,pH 7.5；
0.0055％Brij-35；
20mM MgCl 2；
0.05mM DTT。
2.化合物配制
1)化合物的检测起始浓度为1μM，配制成100倍浓度，即100μM。取2μl 10mM化合物，加入198μl 100％DMSO，配制成100μM化合物溶液。在96孔板上第二个孔中加入100μl的100倍的化合物，其他孔加入60μl的100％DMSO。从第二孔中取30μl化合物加入第三孔中，依次往下做3倍稀释，共稀释10个浓度。
2)转移100μl 100％DMSO和阳性对照wortmannin的最高浓度(400nM)分别到两个空的孔中作为Max孔和Min孔。
3)使用Echo转移50nl化合物到384孔板中。
3.配制2x激酶溶液
1)使用1倍激酶缓冲液配制2倍DNA-PK激酶溶液。
2)转移2.5μl 2倍酶溶液到384孔板反应孔中。
3)振荡，混匀，室温下静置。
4.配制2x底物溶液
1)使用1倍激酶缓冲液配制2倍底物溶液。
2)转移2.5μl 2倍底物溶液到384孔板反应孔中起始反应。
3)振荡，混匀。
5.激酶反应和终止
1)将384孔板盖上盖子，于28℃下孵育3小时。
2)转移5μl ADP-Glo reagent，于28℃下孵育2小时。
6.反应结果的检测
1)转移10μl激酶检测试剂到384孔板反应孔中终止反应。
2)室温下静止30分钟。
7.数据读取
在Envision读取样品数值。
8.抑制率计算
1)从Envision上复制数据。
2)把其转化成抑制率数据。
抑制百分数＝(max-conversion)/(max-min)*100.其中max是指DMSO对照的转化率，min是指无酶活对照的转化率，conversion是指测试化合物各浓度下的转化率。
3)将数据进行曲线拟合得IC 50值。
实验结果：
表1本发明化合物体外酶学活性数据
Figure PCTCN2021088926-appb-000083
实验结论：
结果表明，本发明化合物对DNA-PK激酶活性有较好的抑制作用。
实验例2 本发明化合物在不同种属中的肝微粒体代谢稳定性实验
供试品：本发明化合物，自制，其化学名称和制备方法见各化合物的制备实施例。
实验材料：
食蟹猴混合肝微粒体购自瑞德肝脏疾病研究中心(上海有限公司)，批号为：ZXBZ，肝微粒体蛋白浓度为20mg·mL -1。
人、Beagle犬、SD大鼠的混合肝微粒体均购自Corning，批号分别为：38292、9259006、9259001。肝微粒体蛋白浓度均为20mg·mL -1。
实验启动因子β-NADPH购于Solarbio公司；pH7.4的磷酸盐缓冲液(PBS)由本实验室自制。
供试品溶液制备：
精密称取供试品粉末适量，加入适量的二甲基亚砜(DMSO)溶解到1mM，再用甲醇稀释20倍到50μM的工作液。
实验方法:
表2.肝微粒体代谢稳定性实验温孵体系组成
Figure PCTCN2021088926-appb-000084
实验操作步骤：
(1)按照上面表2“实验温孵体系组成”的比例，每个化合物取100mM PBS 5.85mL，20mM MgCl 2溶液0.585mL及H 2O 3.57mL，制备温孵体系混合溶液1(不含微粒体、供试品和β-NADPH)。该实验同时进行实验孵育体系的阳对药维拉帕米(在各试验种属肝微粒体中均易被代谢)以证明肝微粒体酶活性正常。
(2)从-80℃冰箱中取出肝微粒体(20mg蛋白/mL)，置于37℃水浴恒温振荡器上预温孵3min。
(3)每个化合物每个种属取1.9mL温孵体系混合溶液1，加入56μL不同种属的微粒体，制备温孵体系混合溶液2(不含供试品和β-NADPH)。
(4)样品组(含微粒体和β-NADPH)：取616μL温孵体系混合溶液2，加入14μL浓度为50μM的供试品工作溶液，加入70μL 10mM的β-NADPH工作溶液。混匀，复样。取样时间点为0min，5min，10min，20min，30min，60min。该样品组用于评价化合物经由β-NADPH介导的代谢稳定性。
(5)对照组(含微粒体，不含β-NADPH，以水代替β-NADPH)：取264μL温孵体系混合溶液2，加入6μL浓度为50μM的供试品工作溶液，加入30μL水。混匀，复样。取样时间点为0min和60min。该阴性对照组用于评价化合物在肝微粒体孵育体系中是否存在非β-NADPH介导的代谢。
(6)于各个预定时间点从孵育样品管中取样50μL，加入至终止样品管(内含300μL冷的终止剂，含内标甲苯磺丁脲50ng/mL的乙腈溶液)，涡旋，终止反应。
(7)涡旋10min后，离心5min(12000rpm)。
(8)取上清液100μL，加入100μL水，涡旋混匀，LC-MS/MS进样分析。
数据分析：
通过下面公式中供试品与内标峰面积的比值转化成剩余量百分比。
Figure PCTCN2021088926-appb-000085
实验结果：
表3本发明化合物肝微粒体稳定性结果
Figure PCTCN2021088926-appb-000086
实验结论：
本发明化合物在人、猴、犬及大鼠肝微粒体中具有良好的稳定性。
实验例3 本发明化合物的SD大鼠体内药代动力学实验
供试品：本发明实施例化合物，自制，其化学名称和制备方法见制备实施例。
受试动物：SD大鼠，雄性，体重190-210g，3只/组。
供试品溶液制备：
空白溶媒(1)的配制方法：称取28g HP-β-CD，加入适量注射用水溶解，再用注射用水定容到100mL，涡旋混匀，即得28％HP-β-CD。
空白溶媒(2)的配制方法：称取20g HPC，缓慢加入500mL搅拌着的纯化水中，再加入1mL吐温80，搅拌至澄清透明，定容到1000mL，搅拌均匀，即得2％HPC+0.1％吐温80。
IV(静脉推注)给药：
取本发明实施例化合物(适量)，加入DMA(3％-10％，v/v)，涡旋溶解，然后加入PEG400(3％-10％，v/v)，涡旋混匀，最后加入空白溶媒(1)(适量)，涡旋混匀，50℃保温20min，制备得适宜浓度(可为1mg/mL)的澄清溶液，作为测试化合物的IV 给药溶液。
PO(灌胃)给药：
称取本发明实施例化合物(适量)，置于组织研磨器中，加入空白溶媒(2)(适量)，以1200转/分钟的转速研磨均匀，得浓度为10mg/mL的混悬药液，取上述混悬液(适量)，置于离心管中，加入空白溶媒(2)(适量)，涡旋混匀，制备得适宜浓度(可为0.4mg/mL)的混悬药液，作为测试化合物的PO给药药液。
实验方法
IV给药剂量为2mg/kg，给药浓度为1mg/mL，给药体积为2mL/kg。
PO给药剂量为4mg/kg，给药浓度为0.4mg/mL，给药体积为10mL/kg。
IV采血时间点：给药后0.083、0.25、0.5、1、2、4、6、8、24h。
PO给药采血时间点：给药后0.167、0.5、1、2、4、6、8、24h。
每个时间点通过尾静脉采集全血约100μL，放置到含有EDTA-K 2抗凝剂的抗凝管中，在4℃条件下8000转/分钟离心6分钟得到血浆样品，血浆于-80℃冰箱冻存，待分析。
血浆样品分析
采用蛋白沉淀法：取血浆样品20μL，加入内标(含甲苯磺丁脲50ng/mL的乙腈溶液)200μL，涡旋10min后，然后4000转/分钟离心20分钟，取上清液100μL，再加入100μL水，涡旋混匀3min后，LC-MS/MS分析。
实验结果及结论
经测试发现，本发明化合物具有良好的药代动力学性质，且具有较高的暴露量和生物利用度。
尽管本发明的具体实施方式已经得到详细的描述，但本领域技术人员将理解：根据已经公开的所有教导，可以对细节进行各种修改和变动，并且这些改变均在本发明的保护范围之内。

Claims (17)

  1. 通式(I)所示的化合物、其药学上可接受的盐或其异构体，
    Figure PCTCN2021088926-appb-100001
    其中，
    X 1、X 2、X 3、X 4分别独立地选自CR 2或N；
    X 5选自C、CH或N；
    每一X 6、X 7、X 8分别独立地选自CR 3R 4、NR 5、CR 6、N、O或S；
    Y 1、Y 2、Y 3、Y 4分别独立地选自CH或N；
    环A选自任选被1-3个取代基取代的3-8元环烷基或3-8元杂环基，所述取代基选自卤素、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基羰基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、羟基C 1-6烷氧基、羟基C 1-6烷硫基、氨基C 1-6烷氧基、氨基C 1-6烷硫基；
    R 1、R 2、R 3、R 4、R 5、R 6分别独立地选自H、卤素、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、羟基C 1-6烷氧基、羟基C 1-6烷硫基、氨基C 1-6烷氧基、氨基C 1-6烷硫基；
    虚键---为化学键或不存在，且相邻的虚键不同时为化学键；
    n选自1、2或3。
  2. 如权利要求1所述的化合物、其药学上可接受的盐或其异构体，其中，
    环A选自任选被1-2个取代基取代的3-6元环烷基或3-6元杂环基；所述取代基选自卤素、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、C 1-6烷基羰基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、卤代C 1-6烷氧基或卤代C 1-6烷硫基；
    优选地，环A选自任选被1-2个取代基取代的3-6元饱和环烷基或3-6元饱和杂环基。
  3. 如权利要求1-2任一项所述的化合物、其药学上可接受的盐或其异构体，其中，
    环A选自任选被1-2个取代基取代的环丙基、环丁基、环戊基、环己基、氧杂环丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢噻吩基、四氢吡咯烷基、四氢吡唑烷基、四氢咪唑烷基、四氢吡喃基、四氢噻喃基、哌啶基、哌嗪基、六氢嘧啶基或吗啉基；所述取代基选自卤素、羟基、氨基、硝基、氰基、甲基、乙基、丙基、异丙基、甲基氨基、二甲基氨基、甲基羰基、一氟甲基、二氟甲基、三氟甲基、羟基甲基、氨基甲基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、一氟甲氧基、二氟甲氧基、三氟甲氧基或三氟甲硫基。
  4. 如权利要求1-3任一项所述的化合物、其药学上可接受的盐或其异构体，其中，
    R 1、R 2分别独立地选自H、卤素、羟基、氨基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、卤代C 1-6烷氧基或卤代C 1-6烷硫基；
    R 3、R 4、R 6分别独立地选自H、卤素、羟基、氨基、C 1-6烷基或卤代C 1-6烷基；
    R 5选自氢、C 1-6烷基或卤代C 1-6烷基。
  5. 如权利要求1-4任一项所述的化合物、其药学上可接受的盐或其异构体，其中，
    R 1、R 2分别独立地选自H、卤素、羟基、氨基、硝基、氰基、甲基、乙基、丙基、异丙基、三氟甲基、甲氧基、乙氧基、三氟甲氧基、甲硫基、乙硫基或三氟甲硫基；
    R 3、R 4、R 6分别独立地选自H、卤素、羟基、氨基、甲基、乙基、丙基、异丙基、三氟甲基或三氟乙基；
    R 5选自氢、甲基、乙基、丙基、异丙基、三氟甲基或三氟乙基。
  6. 如权利要求1-5任一项所述的化合物、其药学上可接受的盐或其异构体，其中，
    X 1、X 2、X 4均为N；X 3选自CH或N；X 5选自C或N；
    每一X 6、X 7、X 8分别独立的选自CR 3R 4、NR 5、CR 6、N、O或S；
    Y 1、Y 2、Y 4分别为N，Y 3为CH或N；
    环A选自任选被1-2个取代基取代的环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢噻吩基、四氢吡咯烷基、四氢吡喃基、四氢噻喃基、哌啶基、哌嗪基或吗啉基；所述取代基选自氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、甲基羰基、三氟甲基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、三氟甲氧基或三氟甲硫基；
    R 1选自H、氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、三氟甲基、甲氧基、乙氧基或三氟甲氧基；
    R 3、R 4、R 6分别独立地选自H、氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基或三氟甲基；
    R 5选自H、甲基、乙基、丙基、异丙基或三氟甲基；
    虚键---为化学键或不存在，且相邻的虚键不同时为化学键；
    n选自1或2。
  7. 如权利要求1-2或4-5任一项所述的化合物、其药学上可接受的盐或其异构体，其中，环A为任选被1-3个取代基取代的3-8元杂环基，其为至少含有一个杂原子的且环原子数为3-8个的饱和或部分饱和的且不具有芳香性的单环环状基团，所述杂原子为硫原子，任选地，环状结构中硫原子可以被氧原子氧代；
    优选地，环A选自任选被1-2个取代基取代的
    Figure PCTCN2021088926-appb-100002
    Figure PCTCN2021088926-appb-100003
    所述取代基选自卤素、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、C 1-6烷基羰基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、卤代C 1-6烷氧基或卤代C 1-6烷硫基。
  8. 如下所示的化合物、其药学上可接受的盐或其异构体：
    Figure PCTCN2021088926-appb-100004
    Figure PCTCN2021088926-appb-100005
  9. 通式(IIb)所示的化合物、其药学上可接受的盐或其异构体，
    Figure PCTCN2021088926-appb-100006
    其中，X 5、每一X 6、X 8、R 1、R 3、R 4、R 5、R 6如权利要求1-6任一项所述定义，
    X 7为羰基；
    环A选自任选被1-3个取代基取代的3-8元环烷基、3-8元杂环基、
    Figure PCTCN2021088926-appb-100007
    Figure PCTCN2021088926-appb-100008
    所述取代基选自卤素、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基羰基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、羟基C 1-6烷氧基、羟基C 1-6烷硫基、氨基C 1-6烷氧基、氨基C 1-6烷硫基；
    虚键---为化学键或不存在，且相邻的虚键不同时为化学键；
    n选自1、2或3。
  10. 如权利要求9所述的化合物、其药学上可接受的盐或其异构体，选自如下化合物：
    Figure PCTCN2021088926-appb-100009
  11. 含有权利要求1-10任一项所述的化合物、其药学上可接受的盐或其异构体的药物制剂，其特征在于，包含一种或多种药学上可接受的赋形剂，该药物制剂为药学上可接受的任一剂型。
  12. 含有权利要求1-10任一项所述的化合物、其药学上可接受的盐或其异构体的药物组合物；任选地，所述药物组合物还包含一种或多种第二治疗活性剂，所述的第二治疗活性剂选自抗癌剂，包括有丝分裂抑制剂、烷化剂、抗代谢物、DNA嵌合剂、抗肿瘤抗生素、生长因子抑制剂、信号传导抑制剂、细胞周期抑制剂、酶抑制剂、类维生素A受体调控剂、蛋白酶体抑制剂、拓扑异构酶抑制剂、生物应答调节剂、激素类药物、血管再生抑制剂、细胞生长抑制剂、靶向抗体、HMG-CoA还原酶抑制剂和异戊二烯基蛋白质转移酶抑制剂。
  13. 权利要求1-10任一项所述的化合物、其药学上可接受的盐或其异构体在制备用于预防和/或治疗良性肿瘤或癌症的药物中的用途，所述的癌症包括原位癌和转移的癌症；
    任选地，所述化合物、其药学上可接受的盐或其异构体与放疗和/或一种或多种抗癌剂联用。
  14. 权利要求1-10任一项所述的化合物、其药学上可接受的盐或其异构体在制备用于使癌细胞对于抗癌剂和/或放疗敏感的药物中的用途。
  15. 一种试剂盒，包含：
    (a)有效量的一种或多种权利要求1-10任一项所述的化合物、其药学上可接受的盐或其异构体，
    和(b)有效量的一种或多种抗癌剂。
  16. 通式(I)所示的化合物、其药学上可接受的盐或其异构体的制备方法，包括以下步骤：
    Figure PCTCN2021088926-appb-100010
    1)中间体1经过一步或多步反应环合成中间体2；
    2)中间体2和中间体3经过偶联反应得到式(I)化合物，
    其中，X、X'、X”分别独立地选自卤素、氨基或羟基；X 1、X 2、X 3、X 4、X 5、X 6、X 7、X 8、Y 1、Y 2、Y 3、Y 4、R 1、R 2、R 3、R 4、R 5、R 6、环A、n和虚键---如权利要求1-10任一项所述。
  17. 通式(III)所示的化合物、其药学上可接受的盐或其异构体，
    Figure PCTCN2021088926-appb-100011
    其中，X选自卤素、氨基或羟基；
    X 1、X 2、X 3、X 4、X 5、X 6、X 7、X 8、R 2、R 3、R 4、R 5、R 6、环A、n和虚键---如权利要求1-10任一项所述。
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