CN112300126A

CN112300126A - Heterocyclic DNA-PK inhibitors

Info

Publication number: CN112300126A
Application number: CN201910698620.XA
Authority: CN
Inventors: 刘斌; 陈博
Original assignee: Shandong Xuanzhu Pharma Co Ltd
Current assignee: Shandong Xuanzhu Pharma Co Ltd
Priority date: 2019-07-31
Filing date: 2019-07-31
Publication date: 2021-02-02

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a heterocyclic DNA-PK inhibitor compound, pharmaceutically acceptable salts and isomers thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salts and the isomers thereof, a method for preparing the compound, the pharmaceutically acceptable salts and the stereoisomers thereof, and applications of the compound, the pharmaceutically acceptable salts and the isomers thereof.

Description

Heterocyclic DNA-PK inhibitors

Technical Field

Background

Cancer is a malignant disease which is difficult to treat all over the world, has high treatment difficulty and high mortality rate, brings heavy burden to patients and families, and is a main disease affecting the health of residents in China. In recent years, the incidence of cancer in our country has increased significantly, the mortality rate has also gradually increased, and cancer prevention and treatment face a severe situation.

Currently, radiotherapy and chemotherapy are the most effective means of treating cancer, while radiotherapy is the most effective non-surgical treatment of malignancies. Radiation and a considerable number of anticancer drugs can act directly or indirectly on DNA or DNA metabolic processes, resulting in DNA damage, of which DNA Double Strand Break (DSB) is the most lethal for cancer cells. After DNA damage, a series of cellular responses such as damaged DNA repair can be initiated, and the repair results in the improvement of cancer cell survival, which is one of the mechanisms of tumor cells resisting to radiotherapy and chemotherapy. If a DNA double strand break is not repaired in time and integrity, cancer cells die as a result of apoptosis or/and mitotic disturbances. Therefore, by inhibiting the repair of such DNA damage, the sensitivity of cancer cells to radiotherapy and chemotherapy can be improved, and the proliferation of cells can be inhibited.

In human and other higher eukaryote cells, DSB is repaired mainly by DNA-Dependent Protein Kinase (DNA-PK) dominated DNA non-homologous end joining (NHEJ), which repairs damaged DNA and maintains cell activity and genome stability. NHEJ repair is primarily involved in G1/S phase DNA damage repair and does not require DNA end-joining templates. NHEJ repair requires an economic coordination of many proteins and signaling pathways. The core component of NHEJ includes the heterodimer of Ku70/80 subunits, and a catalytic subunit DNA-dependent protein kinase (DNA-PKcs), which together constitute an active DNA-PK enzyme complex. DNA-PKcs belongs to the phosphatidylinositol 3 kinase (PI3K) superfamily member, a serine/threonine protein kinase; it also includes ATM, ATR, mTOR and 4 PI3K isomers. When DNA-PK binds to a DNA break, its kinase activity is activated. The important function of Ku is to combine with the end of DNA, recruit DNA-PKcs, and the two compose DNA-PK holoenzyme and activate DNA-PKcs; activated DNA-PKcs directs the Artemis protein (an endonuclease) to bind to the damaged site, DNA end-breaking is performed by virtue of its ribozyme activity to facilitate ligation repair, then the XRCC 4/DNA-ligase IV complex is recruited by the activated DNA-PKcs, and finally the broken DNA double-stranded end is targeted and ligated by DNA-ligase IV to complete repair. XRCC4 is a protein that forms a complex with DNA-ligase IV and increases the activity of DNA-ligase IV. DNA-PKcs present 40 amino acid residues that can be autophosphorylated, with the most typical autophosphorylation sites occurring at Ser2056(POR cluster) and Thr2609(ABCDE cluster). NHEJ is thought to develop through three key steps: recognition of DSB-binding of Ku70/80 to incomplete DNA ends recruits two molecules of DNA-PKcs to the adjacent side of the DSB; performing DNA processing to remove the end-pointed non-ligatable ends or other forms of damage; finally, the DNA ends are ligated.

Tumor cells are more sensitive to DNA-PK because they have a higher basal level of endogenous replication stress (oncogene-induced replication stress) and DNA damage, and the DNA repair mechanisms are less efficient in tumor cells.

At present, the development of the high-efficiency and good-selectivity DNA-PK inhibitor has important clinical significance, can synergistically enhance the efficacy of radiotherapy and chemotherapy, effectively inhibit the growth of tumors, and simultaneously can effectively reduce the damage to normal cells and reduce side effects.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a heterocyclic compound which has a novel structure and a good inhibition effect on DNA-PK. Further, such compounds may be used to increase the sensitivity of a subject to radiation therapy and/or one or more anti-cancer agents. Further, the compounds can be used in combination with radiotherapy and/or one or more anticancer agents for the treatment of benign tumors or cancer.

The technical scheme of the invention is as follows:

in one aspect, the present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, or an isomer thereof,

wherein the content of the first and second substances,

X₁、X₂、X₃、X₄、X₅independently selected from CH or N;

y is selected from-CH₂-, -C (O) -, -O-, -NH-, -S-, -S (O) -or-S (O)₂-；

The ring A and the ring B are independently selected from 6-10 membered optionally substituted by substituentAryl or 5-10 membered heteroaryl, said substituents being selected from halogen, amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy, halo C_1-6Alkylthio, hydroxy C_1-6Alkoxy, hydroxy C_1-6Alkylthio, amino C_1-6Alkoxy or amino C_1-6An alkylthio group;

R¹selected from halogen, amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy, halo C_1-6Alkylthio, hydroxy C_1-6Alkoxy, hydroxy C_1-6Alkylthio, amino C_1-6Alkoxy or amino C_1-6An alkylthio group;

ring C is selected from morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrofuranyl, 4, 5-dihydroimidazolyl, piperazinyl, optionally substituted,

Pyrimidinyl, pyridinyl, hexahydropyrimidinyl, hexahydropyridazinyl or imidazolyl; the substituent is selected from halogen, hydroxyl, sulfydryl, oxo, amino, nitro, cyano and C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy or halo C_1-6An alkylthio group;

m is selected from 0, 1,2 or 3.

In certain embodiments, ring A, ring B are independently selected from phenyl optionally substituted with substituents, 5-6 membered unitA cyclic heteroaryl group; the substituent is selected from halogen, amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, halo C_1-4Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio, halo C_1-4Alkoxy or halo C_1-4An alkylthio group.

In certain embodiments, ring a, ring B are independently selected from phenyl or 5-6 membered nitrogen containing monocyclic heteroaryl optionally substituted with a substituent; the substituent is selected from halogen, amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, halo C_1-4Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio, halo C_1-4Alkoxy or halo C_1-4An alkylthio group.

In certain preferred embodiments, ring a is selected from phenyl or 5-6 membered nitrogen containing monocyclic heteroaryl optionally substituted with substituents; the substituent is selected from halogen, amino and C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio, halo C_1-4Alkoxy or halo C_1-4An alkylthio group.

In certain preferred embodiments, ring B is selected from phenyl or 5-6 membered nitrogen containing monocyclic heteroaryl optionally substituted with a substituent; the substituent is selected from halogen, amino and C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio, halo C_1-4Alkoxy or halo C_1-4An alkylthio group.

In certain embodiments, ring a, ring B are independently selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl optionally substituted with a substituent; the substituents are selected from the group consisting of halogen, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

In certain preferred embodiments, ring a is selected from pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, optionally substituted with substituents; the substituents are selected from halogen, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

In certain preferred embodiments, ring B is selected from pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, optionally substituted with substituents; the substituents are selected from halogen, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

In certain preferred embodiments, R¹Selected from halogen, amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio, halo C_1-4Alkoxy or halo C_1-4An alkylthio group.

In certain preferred embodiments, R¹Selected from the group consisting of halogen, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

In certain embodiments, ring C is selected from morpholinyl, piperazinePyridyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrofuranyl, 4, 5-dihydroimidazolyl, piperazinyl, thienyl, etc,

Pyrimidinyl, pyridinyl, hexahydropyrimidinyl or hexahydropyridazinyl.

In certain embodiments, X₁Is N; x₂、X₃、X₄、X₅Independently selected from CH or N;

y is selected from-CH₂-, -C (O) -, -O-, -NH-or-S-; ring a, ring B are independently selected from pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl optionally substituted with a substituent; the substituents are selected from halogen, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy;

R¹selected from the group consisting of halogen, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy;

ring C is selected from morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrofuranyl, 4, 5-dihydroimidazolyl, piperazinyl, pyridyl, piperazinyl, etc,

Hexahydropyrimidyl or hexahydropyridazinyl;

m is selected from 0, 1 or 2.

y is selected from-CH₂-, -O-, -NH-or-S-;

ring a, ring B are independently selected from pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl optionally substituted with substituents; the substituents are selected from fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;

R¹selected from fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;

ring C is selected from morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, 4, 5-dihydroimidazolyl, piperazinyl,

Hexahydropyrimidyl or hexahydropyridazinyl;

m is selected from 0, 1 or 2.

In certain preferred embodiments, Y is selected from-O-, -NH-, or-S-.

In certain preferred embodiments, ring a is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, optionally substituted with a substituent; the substituents are selected from fluoro, chloro, bromo, iodo, amino, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

In certain preferred embodiments, ring B is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.

In certain preferred embodiments, R¹Selected from fluorine, chlorine, bromine, iodine, methyl, ethylAlkyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

In certain preferred embodiments, ring C is selected from morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, 4, 5-dihydroimidazolyl, piperazinyl,

The technical solutions of the present invention can be combined with each other to form a new technical solution, and the formed new technical solution is also included in the scope of the present invention.

In certain embodiments, the compound of formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof is selected from the group consisting of

In another aspect, the present invention also provides a pharmaceutical preparation, which contains the compound described in the aforementioned general formula (I) or (II), its pharmaceutically acceptable salt or its isomer, and one or more pharmaceutically acceptable excipients, and can be any pharmaceutically acceptable dosage form. Pharmaceutically acceptable excipients are substances which are non-toxic, compatible with the active ingredient and otherwise biologically suitable for use in the organism. The choice of a particular excipient will depend on the mode of administration or disease type and state used to treat a particular patient.

In certain embodiments, the pharmaceutical formulations described above may be administered to a patient or subject in need of such treatment by oral, parenteral, rectal, or pulmonary administration, among others. For oral administration, the pharmaceutical composition can be prepared into oral preparations, for example, conventional oral solid preparations such as tablets, capsules, pills, granules and the like; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, the pharmaceutical preparations can also be prepared into injections, including injections, sterile powders for injection, and concentrated solutions for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding suitable additives according to the properties of the medicine. For rectal administration, the pharmaceutical composition may be formulated as a suppository or the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalation formulation, aerosol, powder spray, or the like.

In another aspect, the present invention also relates to the use of the compound of the aforementioned general formula (I) or (II), a pharmaceutically acceptable salt thereof or an isomer thereof for the preparation of a medicament for the prevention and/or treatment of diseases such as benign tumors or cancers, including carcinoma in situ and metastatic cancers, in combination with radiotherapy and/or one or more anticancer agents.

Furthermore, the invention also relates to the application of a pharmaceutical preparation containing the compound shown in the general formula (I) or (II), the pharmaceutically acceptable salt thereof or the isomer thereof in preparing a medicament, wherein the medicament can be used together with radiotherapy and/or one or more anticancer agents to prevent and/or treat diseases such as benign tumors or cancers, and the cancers comprise carcinoma in situ and metastatic carcinoma.

In another aspect, the present invention also relates to the use of a compound of the aforementioned general formula (I) or (II), a pharmaceutically acceptable salt thereof, or an isomer thereof for the preparation of a medicament for sensitizing cancer cells to an anticancer agent and/or ionizing radiation.

Further, the invention also relates to application of a pharmaceutical preparation containing the compound shown in the general formula (I) or (II), the pharmaceutically acceptable salt thereof or the isomer thereof in preparing a medicament for sensitizing cancer cells to anticancer agents and/or ionizing radiation.

The ionizing radiation refers to the radiation of various energy rays received by a patient during the radiotherapy process.

In another aspect, the present invention also provides a pharmaceutical composition comprising a compound of the foregoing general formula (I) or (II), a pharmaceutically acceptable salt or isomer thereof, and one or more second therapeutically active agents selected from the group consisting of anti-cancer agents, including mitotic inhibitors, alkylating agents, anti-metabolites, DNA chimerics, anti-tumor antibiotics, growth factor inhibitors, signaling inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal agents, angiogenesis inhibitors, cell growth inhibitors, targeting antibodies, HMG-CoA reductase inhibitors, and prenyl protein transferase inhibitors.

In certain embodiments, the second therapeutically active agent can be a drug that reduces or reduces one or more side effects of a compound of the invention when used to treat a disease in a subject, or can enhance the efficacy of a compound of the invention.

In certain embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients, as described above.

In another aspect, the present invention also relates to the use of a pharmaceutical composition containing a compound of the aforementioned general formula (I) or (II), a pharmaceutically acceptable salt thereof, or an isomer thereof, for the preparation of a medicament for the prevention and/or treatment of diseases such as benign tumors or cancer, including carcinoma in situ and metastatic cancer, in combination with radiotherapy and/or one or more anticancer agents.

Further, the invention also relates to application of a pharmaceutical composition containing the compound shown in the general formula (I) or (II), the pharmaceutically acceptable salt thereof or the isomer thereof in preparing a medicament for sensitizing cancer cells to anticancer agents and/or ionizing radiation.

In another aspect, the present invention also relates to the use of a pharmaceutical composition containing the compound of the aforementioned general formula (I) or (II), its pharmaceutically acceptable salt or its isomer, in the preparation of a medicament for treating and/or preventing diseases such as benign tumor or cancer, including carcinoma in situ and metastatic carcinoma.

In another aspect, the present invention also provides a method for treating a disease associated with DNAPK overactivation, the method comprising administering to a patient in need thereof an effective amount of a compound described by the aforementioned general formula (I) or (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, the aforementioned pharmaceutical preparation or pharmaceutical composition; the disease associated with DNAPK over-activation is selected from benign tumors or cancers, including carcinoma in situ and metastatic carcinoma.

In another aspect, the present invention also provides a method for enhancing the sensitivity of a patient to an anticancer agent or radiation therapy, which comprises administering to a patient in need thereof an effective amount of a compound described by the aforementioned general formula (I) or (II), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, the aforementioned pharmaceutical preparation or pharmaceutical composition; the anti-cancer agent is as described above.

By "effective amount" is meant a dosage of a drug that prevents, alleviates, retards, inhibits or cures a condition in a subject. The size of the administered dose is determined by the administration mode of the drug, the pharmacokinetics of the medicament, the severity of the disease, the individual physical signs (sex, weight, height, age) of the subject, and the like.

In the present invention, unless otherwise defined, scientific and technical terms used herein have meanings commonly understood by those skilled in the art, however, in order to better understand the present invention, definitions of some terms are provided below. To the extent that the definitions and explanations of terms provided herein do not conform to the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.

The "halogen" as referred to herein means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

"C" according to the invention_1-6Alkyl "denotes straight or branched alkyl having 1 to 6 carbon atoms, including for example" C_1-4Alkyl group "," C_1-3Alkyl group "," C_1-2Alkyl group "," C_2-6Alkyl group "," C_2-5Alkyl group "," C_2-4Alkyl group "," C_2-3Alkyl group "," C_3-6Alkyl group "," C_3-5Alkyl group "," C_3-4Alkyl "and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. "C" according to the invention_1-4Alkyl "means C_1-6Specific examples of the alkyl group having 1 to 4 carbon atoms.

"C" according to the invention_1-6Alkoxy "means" C_1-6alkyl-O- ", said" C_1-6Alkyl "is as defined above. "C" according to the invention_1-4Alkoxy "means" C_1-4alkyl-O- ", said" C_1-4Alkyl "is as defined above.

"C" according to the invention_1-6Alkylthio "means" C_1-6alkyl-S- ", said" C_1-6Alkyl "is as defined above. "C" according to the invention_1-4Alkylthio "means" C_1-4alkyl-S- ", said" C_1-4Alkyl "is as defined above.

The "hydroxy group C" of the present invention_1-6Alkyl, amino C_1-6Alkyl, halo C_1-6Alkyl "means C_1-6One or more hydrogens of the alkyl group are each replaced by one or more hydroxyl groups, amino groups or halogens. C_1-6Alkyl is as previously defined

The "hydroxy group C" of the present invention_1-6Alkoxy, amino C_1-6Alkoxy, halo C_1-6Alkoxy "means" C_1-6One or more hydrogens of "alkoxy" are replaced with one or more hydroxy, amino, or halogen.

The "hydroxy group C" of the present invention_1-6Alkylthio, amino C_1-6Alkylthio, halo C_1-6Alkyl sulfideThe radical "means" C_1-6Alkylthio "is one in which one or more hydrogens are replaced with one or more hydroxy, amino, or halogen.

"C" according to the invention_1-6Alkylamino radical, di (C)_1-6Alkyl) amino "means independently C_1-6alkyl-NH-),

The "6-to 10-membered aryl" as referred to in the present invention includes "6-to 8-membered monocyclic aryl" and "8-to 10-membered fused ring aryl".

The "6-to 8-membered monocyclic aryl" as referred to herein means a monocyclic aryl group containing 6 to 8 ring carbon atoms, examples of which include, but are not limited to: phenyl, cyclooctatetraenyl, and the like; phenyl is preferred.

The "8-to 10-membered fused ring aryl" as referred to herein means an unsaturated aromatic cyclic group having 8 to 10 ring carbon atoms, formed by two or more cyclic structures sharing two adjacent atoms with each other, and is preferably a "9-to 10-membered fused ring aryl", and specific examples thereof are naphthyl and the like.

The "5-to 10-membered heteroaryl" as used herein includes "5-to 8-membered monocyclic heteroaryl" and "8-to 10-membered fused heteroaryl".

The "5-to 8-membered monocyclic heteroaryl group" according to the present invention means a monocyclic cyclic group having aromaticity, which contains 5 to 8 ring atoms, at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. "5-to 8-membered monocyclic heteroaryl" includes, for example, "5-to 7-membered monocyclic heteroaryl", "5-to 6-membered nitrogen-containing monocyclic heteroaryl", "6-membered nitrogen-containing monocyclic heteroaryl", and the like, in which the heteroatom contains at least one nitrogen atom, for example, contains only 1 or 2 nitrogen atoms, or contains one nitrogen atom and 1 or 2 other heteroatoms (for example, oxygen atom and/or sulfur atom), or contains 2 nitrogen atoms and 1 or 2 other heteroatoms (for example, oxygen atom and/or sulfur atom). Specific examples of "5-to 8-membered monocyclic heteroaryl" include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepinyl, 1, 3-diazacycloheptenyl, azepinyl, and the like. The "5-6 membered monocyclic heteroaryl" refers to a specific example containing 5 to 6 ring atoms in a 5-8 membered heteroaryl.

The "8-to 10-membered fused heteroaryl group" as used herein refers to an unsaturated aromatic cyclic structure having 8 to 10 ring atoms (at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom) formed by two or more cyclic structures sharing two adjacent atoms with each other. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. Including "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", etc., which can be fused in a benzo-5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, etc.; specific examples include, but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furothiophene, pyrazoloxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolinyl, acridinyl, phenanthridinyl, pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, and the like.

The "3-to 10-membered cycloalkyl" described herein includes "3-to 7-membered monocyclic cycloalkyl" and "8-to 10-membered fused ring cycloalkyl".

The "3-7 membered monocyclic cycloalkyl" as used herein means a saturated or partially saturated monocyclic cyclic group having 3 to 7 ring atoms and having no aromaticity, and the "3-7 membered monocyclic cycloalkyl" as used herein includes "3-7 membered saturated monocyclic cycloalkyl" and "3-7 membered partially saturated monocyclic cycloalkyl". As the "3-7 membered monocyclic cycloalkyl group", preferred are "3-6 membered monocyclic cycloalkyl", "5-6 membered monocyclic cycloalkyl", "3-6 membered saturated monocyclic cycloalkyl", "3-4 membered nitrogen-containing monocyclic cycloalkyl", "3-4 membered saturated nitrogen-containing monocyclic cycloalkyl" and the like. Examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexene, etc.

The "8-to 10-membered fused ring cycloalkyl" as referred to herein means a saturated or partially saturated, nonaromatic cyclic group containing 8 to 10 ring atoms formed by two or more cyclic structures sharing two adjacent atoms with each other, and examples thereof include, but are not limited to:

and the like.

The "3-to 10-membered heterocyclic group" described in the present invention includes "3-to 7-membered heteromonocyclic group" and "8-to 10-membered fused heterocyclic group".

The "3-to 7-membered heteromonocyclic group" according to the present invention means a saturated or partially saturated and non-aromatic monocyclic cyclic group containing at least one hetero atom (e.g., 1,2,3, 4 or 5) which is a nitrogen atom, an oxygen atom and/or a sulfur atom and has 3 to 7 ring atoms, and optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo. The "3-7 membered heteromonocyclic group" described herein includes "3-7 membered saturated heteromonocyclic group" and "3-7 membered partially saturated heteromonocyclic group". The "3-to 7-membered heteromonocyclic group" is preferably "3-to 6-membered heteromonocyclic group", "5-to 6-membered heteromonocyclic group", "3-to 6-membered saturated heteromonocyclic group", "5-to 6-membered saturated heteromonocyclic group", "3-to 4-membered nitrogen-containing heteromonocyclic group", "5-to 6-membered saturated nitrogen-containing heteromonocyclic group", or the like. Specific examples thereof include, but are not limited to: aziridinyl, 2H-aziridinyl, diazacyclopropenyl, 3H-diazacyclopropenyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, piperidonyl, piperazinyl, morpholinyl and the like.

The "8-to 10-membered fused heterocyclic group" as used herein means a saturated or partially saturated, nonaromatic cyclic group containing 8 to 10 ring atoms, at least one of which may be an aromatic ring but the whole fused ring may not have aromaticity, which is formed by two or more cyclic structures sharing two adjacent atoms with each other, wherein one of the ring atoms may be an aromatic ring, and the fused ring may have no aromaticity, and the heteroatom may be a nitrogen atom, an oxygen atom and/or a sulfur atom, and optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo. Specific examples thereof include, but are not limited to: pyrrolidinyl cyclopropyl, cyclopenta aziridinyl, pyrrolidinyl cyclobutyl, pyrrolidinyl piperidinyl, pyrrolidinyl piperazinyl, pyrrolidinyl morpholinyl, piperidino morpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, pyrimido tetrahydropyranyl, tetrahydroimidazo [4,5-c ] pyridinyl, 3, 4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, benzo [ d ] [1,3] dioxolyl, 2H-chromenyl, 2H-chromen-2-onyl, 4H-chromenyl, 4H-chromen-4-onyl, 4H-1, 3-benzoxazinyl, and the like.

The "oxo" group in the present invention means that when the substituted position is a carbon atom, a nitrogen atom or a sulfur atom, the carbon atom, the nitrogen atom or the sulfur atom may be oxo-substituted to form C O, N ═ O, S ═ O or SO₂The structure of (1).

The "optionally substituted with a substituent" in the present invention means that one or more hydrogen atoms on the substituted group may be "substituted" or "unsubstituted" with one or more substituents.

The "anticancer agent" of the present invention refers to an agent having a certain therapeutic effect on tumors, including, but not limited to, mitotic inhibitors, alkylating agents, antimetabolites, DNA chimerics, antitumor antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal drugs, angiogenesis inhibitors, cell growth inhibitors, targeting antibodies, HMG-CoA reductase inhibitors, prenyl protein transferase inhibitors, and the like; the tumor includes benign tumor and cancer.

The chemotherapy is the abbreviation of chemical drug therapy, and achieves the purpose of treatment mainly by using chemical therapeutic drugs to kill cancer cells.

The "radiotherapy" in the invention refers to a tumor treatment method, i.e. tumor radiotherapy, which mainly uses radioactive rays to perform local tumor treatment, wherein the "radioactive rays" include alpha, beta and gamma rays generated by radioactive isotopes, and x rays, electron beams, proton beams and other particle beams generated by various x-ray treatment machines or accelerators.

"pharmaceutically acceptable salt" as used herein refers to an acidic functional group (e.g., -COOH, -OH, -SO) present in a compound₃H, etc.) with a suitable inorganic or organic cation (base), including salts with alkali or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and salts of basic functional groups present in the compounds (e.g., -NH2, etc.) with suitable inorganic or organic anions (acids), including salts with inorganic or organic acids (e.g., carboxylic acids, etc.).

"isomers" as used herein refers to compounds of the present invention when they contain one or more asymmetric centers and thus may be present as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention may have asymmetric centers that each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. The compounds of the present invention, if they contain an olefinic double bond, include cis-isomers and trans-isomers, unless otherwise specified. The compounds of the invention may exist in tautomeric (one of the functional group isomers) forms having different points of attachment of hydrogen through one or more double bond shifts, e.g., a ketone and its enol form are keto-enol tautomers. The compounds of the present invention contain a spiro ring structure, and substituents on the ring may be present on both sides of the ring to form the opposite cis (cis) and trans (trans) isomers, depending on the steric structure of the ring. Each tautomer and mixtures thereof are included within the scope of the present invention. All enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of the compounds are included within the scope of the present invention.

The compounds of the invention may be prepared by enantiospecific synthesis or by resolution from a mixture of enantiomers in such a way as to give the individual enantiomers. Conventional resolution techniques include resolving mixtures of enantiomers of the starting material or the final product using various well-known chromatographic methods.

When the stereochemistry of the disclosed compounds is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure by weight relative to the other stereoisomers. When a single isomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. The optical purity wt% is the ratio of the weight of an enantiomer to the weight of the enantiomer plus the weight of its optical isomer.

In another aspect, the present invention also provides a process for the preparation of a compound of formula (I) according to the invention:

the preparation method of the compound of the general formula (I) comprises the following steps:

wherein X' is selected from F, Cl, Br, I; corresponding to X₁-X₅、R₁Ring a, ring B, ring C, Y, m are as previously defined. The method comprises the following steps:

(a) reacting the intermediate 1 with trifluoromethanesulfonic anhydride to generate an intermediate 2;

(b) the intermediate 2 and boric acid or boric acid ester compound have Suzuki coupling reaction, and then undergo reduction reaction and/or deprotection group (when a protection group exists) reaction to generate an intermediate 3;

(c) and reacting the intermediate 3 with the intermediate 4 under alkaline conditions to generate the compound of the general formula (I).

The second preparation method of the compound with the general formula (I):

wherein X' is selected from F, Cl, Br, I; m is selected from boric acid or boric acid ester; corresponding to X₁-X₅、R₁Ring a, ring B, ring C, Y, m are as previously defined. The method comprises the following steps:

(c) reacting the intermediate 3 with the intermediate 4 under alkaline conditions to generate an intermediate 5;

(d) the intermediate 5 is subjected to cyclization reaction to generate a compound shown in a general formula (I); or the intermediate 5 reacts with hydroxylamine hydrochloride under alkaline condition, and then the compound with the general formula (I) is generated through cyclization reaction.

In the above first and second preparation methods, all reactions can be performed in a conventional solvent, including but not limited to DMSO, DMF, acetonitrile, methanol, ethanol, tetrahydrofuran, toluene, dimethyl ether, dichloromethane, chloroform, dichloroethane, 1, 4-dioxane, trifluoroacetic acid, and water, and a single organic solvent or a mixed solvent of two or more solvents can be used in the reaction process. Alternatively, if a certain reactant is a liquid, the reaction may be carried out in the absence of another solvent.

The alkaline condition is a condition containing organic base or inorganic base, and the organic base is independently selected from pyridine, triethylamine, N-dimethylaniline, sodium methoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-butoxide, potassium acetate, N-diisopropylethylamine and the like; preferably an inorganic base independently selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium acetate, sodium acetate, potassium phosphate, sodium phosphate and the like.

The acidic condition refers to a condition containing organic acid or inorganic acid, and the organic acid is independently selected from formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, tartaric acid and the like; the inorganic acid is independently selected from hydrochloric acid, concentrated sulfuric acid, hydrobromic acid, hydrofluoric acid, nitric acid, nitrous acid, boric acid, and the like.

The palladium catalyst is independently selected from Pd (PPh)₃)₄、PdCl₂(PPh₃)₂、PdCl₂(MeCN)₂、Pd(dppf)Cl₂、Ph₂P(CH₂)₂PPh₂(dppe)、Ph₂P(CH₂)₃PPh₂(dppp)、Pd₂(dba)₃Palladium chloride, palladium acetate, palladium triphenylphosphine, and the like.

The "boric acid or borate compound" refers to an organic compound containing boric acid or borate in the structure.

The "reduction reaction" refers to a reaction in which a substance (molecule, atom or ion) obtains an electron or a close electron pair. Including, but not limited to, hydrogenation of unsaturated bonds.

The term "cyclization" refers to a reaction process for forming a new carbocyclic or heterocyclic ring, including intramolecular and intermolecular cyclization. The "cyclization" according to the invention is preferably an intermolecular cyclization to form a heterocyclic ring.

In the present invention, the compounds and intermediates of the present invention can be isolated and purified using methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds may include, but are not limited to: chromatography on a solid support (e.g., silica gel, alumina or silica derivatized with alkylsilanes), thin layer chromatography, distillation at various pressures, vacuum sublimation, trituration, for example, as described below: "Vogel's Textbook of Practical Organic Chemistry",5th edition (1989), Furniss et al, pub. Longman Scientific & Technical, Essex CM 202 JE, England.

It is understood that the chemical reaction, if involving reactive groups such as-NH-which need not participate in the reaction₂The reactive groups-OH, -COOH, etc. can be protected prior to the next reaction by methods known to those skilled in the art, including but not limited to, the formation of esters, amides, alkylamines, ethers, etc. of the reactive groups. Common methods of carboxyl protection include, but are not limited to, ester formation with aliphatic or aromatic alcohols, amide or hydrazide formation with amines or hydrazines. Common amino protecting groups include, but are not limited to: (1) alkoxycarbonyl amino-protecting groups such as benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenyl methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsiloxyethoxycarbonyl (Teoc), and the like; (2) acyl amino groups such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o- (p) nitrobenzenesulfonyl (Ns), pivaloyl and the like; (3) alkyl amino protecting groups, trityl (Trt), 2, 4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB), benzyl (Bn), and the like. Common hydroxyl protecting groups include, but are not limited to, silyl ether protecting groups, benzyl ether protecting groups, alkoxymethyl ethers or alkoxy-substituted methyl ethers, acetyl, benzoyl, pivaloyl and the like. After the reaction of the protecting group is finished, a deprotection reaction can be performed by methods known to those skilled in the art, and the deprotection conditions include but are not limited to deprotection under acidic conditions, deprotection under basic conditions, catalytic hydrogenation deprotection, and the like; the acidic and basic conditions are as defined above.

The raw materials and/or intermediates directly used in the preparation method of the present invention can be commercially or self-prepared, and the intermediate can be obtained by a person skilled in the art according to a known conventional chemical reaction preparation method, and the preparation method thereof is also within the protection scope of the present invention.

Advantageous effects of the invention

1. The compound, the pharmaceutically acceptable salt thereof or the stereoisomer thereof has excellent DNA-PK inhibitory effect, has good pharmacokinetic property in organisms, has lasting effect and high bioavailability, and can enhance the sensitivity of cancer cells to radiotherapy and/or one or more anticancer agents.

2. The compound, the pharmaceutically acceptable salt thereof or the stereoisomer thereof has better therapeutic effect on benign tumors and cancers.

3. The compound of the invention has simple preparation process, high medicine purity, stable quality and easy large-scale industrial production.

Detailed description of the preferred embodiments

The technical solutions of the present invention will be described below in conjunction with the specific embodiments, and the above-mentioned contents of the present invention will be further described in detail, but it should not be understood that the scope of the above-mentioned subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Abbreviations:

DME, dimethyl ether; DPPF: 1,1' -bis (diphenylphosphino) ferrocene; xanthphos 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene; TFA is trifluoroacetic acid; pd (dppf) Cl₂1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; pd (PPh)₃)₂Cl₂Bis-triphenylphosphine palladium dichloride; DCM is dichloromethane; MeOH: methanol; PE is petroleum ether; EA: ethyl acetate; py: pyridine; tf₂O: trifluoromethanesulfonic anhydride; THF: tetrahydrofuran; CDI: n' N-carbonyldiimidazole

Preparation example one: preparation of 8- (1- ((2 '-methyl- [4,5' -bipyrimidinyl ]) -6-yl) amino) propyl-2-yl) quinoline-4-carbonitrile

Preparation of 1.6-chloro-2 '-methyl-4, 5' -bipyrimidine

(2-Methylpyrimidin-5-yl) boronic acid (2.4g,17 m)mol), 4, 6-dichloropyrimidine (6.4g,43mmol), Pd (PPh)₃)₄(2g,1.7mmol), cesium carbonate (11g,34mmol), in DME (100mL) and water (10mL), N₂And reacting at 90 ℃ for 8h under protection. After the reaction, the product was spin-dried and separated by C18 reverse phase column (water/acetonitrile, acetonitrile 20% to 60%) to obtain the product (2.0g, yield 56.8%).

Preparation of 2.8-methoxyquinoline-4-carbonitrile

Coupling 4-bromo-8-methoxyquinoline (5.0g,21mmol), Zn (CN)₂(2.94g,25mmol)，Pd₂(dba)₃(0.96g,1.05mmol), DPPF (1.1g,2.1mmol), neutralized water (5mL), N in 1, 4-dioxane (50mL)₂And reacting for 4 hours at 100 ℃ under the protection condition. After the reaction was complete, the solvent was evaporated to dryness, water (30mL) was added, DCM was extracted three times (3 × 50mL), the organic phases were combined and purified over anhydrous Na₂SO₄Drying, filtering, spin-drying, and forward column chromatography (PE: EA ═ 5:1) to give the product (3.1g, yield 80.0%).

Preparation of 3.8-hydroxyquinoline-4-carbonitrile

8-Methoxyquinoline-4-carbonitrile (2.5g,14mmol) was dissolved in 1, 2-dichloroethane (40mL) and BBr was added dropwise₃(1M,28mL) in dichloromethane, and reacted at 80 ℃ for 4 h. After the reaction, methanol (20mL) was added dropwise and the mixture was spin-dried to obtain a crude product (7.1 g).

Preparation of 4.4-Cyanoquinolin-8-yl triflate

8-Hydroxyquinoline-4-carbonitrile (1.1g,6.5mmol), Py (5.1g,65mmol) was dissolved in DCM (50mL) and Tf was added dropwise at 0 deg.C₂O (9.2g,32.5mmol), after addition, was reacted at 0 ℃ for 1 h. After the reaction is finished, spin-dryingThe product was obtained by C18 reverse column separation (water/acetonitrile, acetonitrile 70% to 90%) (468mg, yield 23.8%).

5. Preparation of tert-butyl (2- (4-cyanoquinolin-8-yl) allyl) carbamate

4-Cyanoquinolin-8-yl trifluoromethanesulfonate (468mg,1.55mmol), tert-butyl (2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) allyl) carbamate (571mg,2.0mmol), Pd (dppf) Cl₂(117mg,0.16mmol)，Na₂CO₃(329mg,3.1mmol), dissolved in 1, 4-dioxane (15mL) and water (1mL), N₂Reacting for 3 hours at 100 ℃ under protection. After the reaction was completed, the reaction mixture was spin-dried and subjected to C18 reverse phase column separation (water/acetonitrile, acetonitrile 50% to 80%) to obtain the product (300mg, yield 62.7%).

6. Preparation of tert-butyl (2- (4-cyanoquinolin-8-yl) propyl) carbamate

Tert-butyl (2- (4-cyanoquinolin-8-yl) allyl) carbamate (300mg,0.97mmol), Pd/C (100mg) was dissolved in methanol (12mL), H₂Reacting for 24 hours at 25 ℃ under the atmosphere. After the reaction is finished, suction filtration is carried out, and the filtrate is dried in a rotary manner and is directly used for the next step.

Preparation of 8- (1-aminopropyl-2-yl) quinoline-4-carbonitrile

Tert-butyl (2- (4-cyanoquinolin) -8-yl) propyl) carbamate (crude from above) was dissolved in DCM (5mL), and reacted with TFA (5mL) dropwise at 15 ℃ for 3 h. After the reaction was completed, the reaction mixture was spin-dried and subjected to C18 reverse column separation (water/acetonitrile, acetonitrile 50% to 100%) to obtain the product (100mg, yield 48.8%).

Preparation of 8- (1- ((2 '-methyl- [4,5' -bipyrimidinyl ]) -6-yl) amino) propyl-2-yl) quinoline-4-carbonitrile

8- (1-aminopropyl-2-yl) quinoline-4-carbonitrile (100mg,0.47mmol), 6-chloro-2 '-methyl-4, 5' -bipyrimidine (97mg,0.47mmol), Na₂CO₃(149mg,1.41mmol), dissolved in THF (10mL) and water (0.5mL), reacted at 80 ℃ for 12 h. After the reaction was completed, the reaction mixture was spin-dried and separated by C18 reverse column (water/acetonitrile, acetonitrile 50% to 100%) to obtain the product (100mg, yield 55.4%).

Example 1: preparation of 2 '-methyl-N- (2- (4-morpholinoquinolin-8-yl) propyl) - [4,5' -pyrimidin-6-amine (Compound 1)

Preparation of 4- (8-methoxyquinolin-4-yl) morpholine

4-bromo-8-methoxyquinoline (2.0g,8.4mmol) was dissolved in ethanol (50mL), morpholine (2.2g,25.2mmol) was added, and the reaction was completed at 80 ℃ for 4 h. The ethanol was concentrated off, DCM was dissolved and the organic phase was washed with water. The organic phase was concentrated by drying to give the objective compound (1.9g, yield 92.7%).

Preparation of 7-bromo-4-morpholinoquinolin-8-ol

4- (8-Methoxyquinolin-4-yl) morpholine (1.2g,4.9mmol) was dissolved in DCM (100mL) and BBr was added dropwise at-20 deg.C₃(12.3g,49.0mmol), after addition, the temperature was raised to 25 ℃ and stirred for 12 h. The reaction was quenched with MeOH and purified by C18 column concentration (MeOH 0% to 50%) to afford crude title compound (1.6 g).

Preparation of 3.4-morpholinoquinolin-8-ol

7-bromo-4-morpholinoquinolin-8-ol (1.0g,3.2mmol) was dissolved in THF (50mL), n-BuLi (2.6mL,6.4mmol) was added dropwise at 0 deg.C, and after the addition, the temperature was raised to 20 deg.C for 2 h. Quenched with water and purified on a C18 column (MeOH ═ 0% to 50%) to afford the title compound (550mg, yield 67.4%).

Preparation of 4.4-morpholinoquinolin-8-yl trifluoromethanesulfonate

4-Morpholinoquinolin-8-ol (500mg,2.2mmol) in DCM (50mL) was added pyridine (348mg,4.4mmol), Tf at-20 deg.C₂O (930.6mg,3.3mmol), after addition, the reaction was completed at 15 ℃ for 2 h. Concentration and purification on silica gel (DCM: MeOH ═ 20:1) afforded the title compound (800mg, yield 92.4%).

5. Preparation of tert-butyl (2- (4-morpholinoquinolin-8-yl) allyl) carbamate

4-Morpholinoquinolin-8-yl trifluoromethanesulfonate (600mg,1.7mmol), tert-butyl (2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) allyl) carbamate (805.9mg,2.5mmol), Pd (dppf) Cl₂(124.4mg,0.17mmol)，Na₂CO₃(351.9mg,3.3mmol) was dissolved in 1, 4-dioxane (50mL), water (5mL) was added, and N was added after completion of addition₂Reacting for 12h at 100 ℃ under protection. Diluted with water, extracted with EA, and purified by dry concentration on a C18 column (MeOH 0% to 65%) to afford the title compound (400mg, yield 65.4%).

6. Preparation of tert-butyl (2- (4-morpholinoquinolin-8-yl) propyl) carbamate

Tert-butyl (2- (4-morpholinoquinolin-8-yl) allyl) carbamate (400mg,1.1mmol) was dissolved in methanol (50mL), Pd/C (200mg) was added, and after the addition, the reaction was hydrogenated at 20 ℃ for 12 hours. Celite was filtered and the filtrate was concentrated to give the title compound (390mg, yield 97.0%).

Preparation of 2- (4-Morpholinoquinolin-8-yl) propan-1-amine

Tert-butyl (2- (4-morpholinoquinolin-8-yl) propyl) carbamate (390mg,1.1mmol) was dissolved in DCM (25mL), TFA (5mL) was added, and after addition, reaction was carried out at 20 ℃ for 2 h. The concentrated solvent was used directly in the next step.

Preparation of 2 '-methyl-N- (2- (4-morpholinoquinolin-8-yl) propyl) - [4,5' -pyrimidin-6-amine

2- (4-Morpholinoquinolin-8-yl) propan-1-amine (crude, 1.1mmol), 6-chloro-2 '-methyl-4, 5' -bipyrimidine (237.9mg,1.2mmol), Na₂CO₃(222.6mg,2.1mmol) was dissolved in THF (50mL) and water (10mL) and after addition, the reaction was carried out at 80 ℃ for 12 h. The solvent was concentrated, diluted with water and DCM, the organic phases combined and dried to give the crude product which was purified on a large plate (DCM: MeOH ═ 20:1) to afford the title compound (6.4mg, crude 290mg remaining).

Molecular formula C₂₅H₂₇N₇O molecular weight 441.5LC-MS (M/e):442.0(M + H)⁺)

¹H-NMR(400MHz,CDCl₃)δ:9.10-9.15(m,2H),78.84(d,J＝4.8Hz 1H),8.56(s,1H),7.94(d,J＝8.4Hz 1H),7.62(d,J＝6.8Hz 1H),7.47(t,J＝8.0Hz 1H),6.95(d,J＝4.8Hz 1H),6.11-6.51(m,1H),4.59(d,J＝6.8Hz 1H),3.95-4.01(m,4H),3.68-3.74(m,1H),3.49(s,1H),3.16-3.26(m,4H),2.80(s,3H),1.52(d,J＝7.2Hz 3H).

Example 2: preparation of 2 '-methyl-N- (2- (3-morpholinoquinolin-8-yl) propyl) - [4,5' -bipyrimidine ] -6-amine (Compound 3)

Preparation of 4- (8-methoxyquinolin-3-yl) morpholine

3-bromo-8-methoxyquinoline (1g,4.22mmol), morpholine (440mg,5.3mmol), Pd (PPh)₃)₂Cl₂(59.2mg,0.08mmol), xanthphos (92.4mg,0.16mmol), potassium acetate (603mg,6.63mmol) were dissolved in 1, 4-dioxane (20mL), reacted at 100 ℃ for 6 hours, extracted with water (20mL), EA (3 × 20mL), the organic phases were combined, spun dry, and purified by column chromatography (dichloromethane: methanol 15:1) to give the desired product (900mg, 87% yield).

Preparation of 7-bromo-3-morpholinoquinolin-8-ol

4- (8-Methoxyquinolin-3-yl) morpholine (900mg,3.69mmol) was dissolved in dichloromethane (25mL) and BBr was added at 20 deg.C₃(1.85g,7.38mmol), reaction for 0.5 h, addition of water 50mL, extraction with dichloromethane (3 × 50mL), combination of organic phases, concentration, medium pressure preparation (acetonitrile: water 80:20) to afford the title product (495mg, 43.7% yield).

Preparation of 3.3-morpholinoquinolin-8-ol

Under the protection of nitrogen, 7-bromo-3-morpholinoquinolin-8-ol (495mg,1.6mmol) was dissolved in tetrahydrofuran (25mL) at 0 ℃, an n-hexane solution containing n-butyllithium (2.5M,2.9mL,3.2mmol) was added, the reaction was quenched with water (50mL), EA (3X 100mL) was extracted, the organic phases were combined, and the crude product (350mg) was spin-dried directly in the next step.

Preparation of 4.3-morpholinoquinolin-8-yl trifluoromethanesulfonate

3-Morpholinoquinolin-8-ol (350mg) was dissolved in dichloromethane (20mL), pyridine (237mg,3mmol), trifluoromethanesulfonic anhydride (246mg,3mmol) were added at 0 deg.C, the reaction was stirred for 6h, quenched with water (20mL), extracted with dichloromethane (3X 100mL), the organic phases were combined, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate ═ 1:1) to give the desired product (150mg, 25.9% yield in two steps).

5. Preparation of tert-butyl (2- (3-morpholinoquinolin-8-yl) allyl) carbamate

3-Morpholinoquinolin-8-yl trifluoromethanesulfonate (150mg,0.41mmol), tert-butyl (2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) allyl) carbamate (176.1mg,0.62mmol), Pd (dppf) Cl₂(29.2mg,0.04mmol), sodium carbonate (86.9mg,0.82mmol) were dissolved in 1, 4-dioxane/water (10mL/1mL), stirred at 100 ℃ for 2h, water (10mL), ethyl acetate (3 x 30mL) extracted, the organic phases combined and concentrated to give the crude product (150mg) which was directly used in the next step.

6. Preparation of tert-butyl (2- (3-morpholinoquinolin-8-yl) propyl) carbamate

Tert-butyl (2- (3-morpholinoquinolin-8-yl) allyl) carbamate (150mg) was dissolved in methanol (5mL) under a hydrogen atmosphere, Pd/C (30mg) was added thereto, the reaction was carried out at 20 ℃ for 6 hours, and the mixture was filtered through celite to obtain a crude product (150mg) which was directly used in the next step.

Preparation of 2- (3-morpholinoquinolin-8-yl) propan-1-amine

Tert-butyl (2- (3-morpholinoquinolin-8-yl) propyl) carbamate (150mg) was dissolved in dichloromethane (5mL) at 20 deg.C, trifluoroacetic acid (456mg,4mmol) was added, stirring was carried out for 6h, and the solvent was evaporated to dryness to give the crude product (50mg) which was directly used in the next step.

Preparation of 2 '-methyl-N- (2- (3-morpholinoquinolin-8-yl) propyl) - [4,5' -bipyrimidine ] -6-amine

2- (3-morpholinoquinolin-8-yl) propan-1-amine (40mg), 6-chloro-2 '-methyl-4, 5' -bipyrimidine (33.0mg,0.16mmol), sodium carbonate (31.3mg,0.2mmol) were dissolved in tetrahydrofuran/water (5mL/1mL), reacted at 80 ℃ for 2 hours, water (5mL) was added, ethyl acetate (3 x 10mL) was extracted, the organic phases were combined, concentrated, and prepared at high pressure (acetonitrile: water ═ 60:40) to give the product (2mg, four-step yield 1.1%).

Molecular formula C₂₅H₂₇N₇O molecular weight 441.2LC-MS (M/e) 442.2(M + H)⁺)

¹H-NMR(400MHz,CDCl₃)δ:9.18(s,2H),8.88(s,1H),8.58(s,1H),7.62-7.57(m,1H),7.47-7.46(m,2H),7.35-7.34(m,1H),5.90(s,1H),4.52(s,1H),3.97-3.95(m,4H),3.75-3.70(m,1H),3.35-3.33(m,5H),2.80(s,3H),1.53(d,J＝6.8Hz,3H)。

Example 3: preparation of 3- (8- (1- ((2 '-methyl- [4,5' -bipyrimidin ] -6-yl) amino) propan-2-yl) quinolin-4-yl) -1,2, 4-oxadiazol-5 (4H) -one (Compound 5)

Preparation of N ' -hydroxy-8- (1- ((2' -methyl- [4,5' -bipyrimidin ] -6-yl) amino) propan-2-yl) quinolin-4-carboxamidine

8- (1- ((2 '-methyl- [4,5' -bipyrimidin ] -6-yl) amino) propan-2-yl) quinoline-4-carbonitrile (860mg,2.3mmol), sodium hydrogencarbonate (580mg,6.9mmol), hydroxylamine hydrochloride (941.3mg,13.5mmol) were added to ethanol (30mL) and water (20mL) and reacted at 90 ℃ for 6 hours, and the system was purified by silica gel column chromatography (DCM: MeOH ═ 20:1) to give a crude product (600 mg).

Preparation of 3- (8- (1- ((2 '-methyl- [4,5' -bipyrimidin ] -6-yl) amino) propan-2-yl) quinolin-4-yl) -1,2, 4-oxadiazol-5 (4H) -one

N ' -hydroxy-8- (1- ((2' -methyl- [4,5' -bipyrimidin ] -6-yl) amino) propan-2-yl) quinoline-4-carboxamidine (550mg,1.3mmol) was added to 1, 4-dioxane (10mL), triethylamine (394.7mg,3.9mmol) and CDI (258.5mg,1.6mmol) were added, the reaction was carried out at 90 ℃ under microwave for 30 minutes, the system was subjected to silica gel column chromatography (DCM: MeOH ═ 10:1) to give a crude product (120mg), then subjected to C18 reverse phase column chromatography (water: MeOH ═ 1:1) to give a crude product (80mg), and finally purified over silica gel large plate (DCM: MeOH ═ 10:1) to give a product (50mg, yield 8.7%).

The molecular formula is as follows: c₂₃H₂₀N₈O₂Molecular weight: 440.5LC-MS (M/e): 440.9(M + H)⁺)

¹HNMR(400MHz,DMSO-d₆):9.31-9.01(m,3H),8.60-8.45(m,2H),7.91-7.80(m,2H),7.72-7.61(m,2H),6.95(s,1H),4.59-4.51(m,1H),3.85-3.60(m,2H),2.72(s 3H),1.50-1.38(m,3H).

Example 4: preparation of N- (2- (4- (4, 5-dihydro-1H-imidazol-2-yl) quinolin-8-yl) propyl) -2 '-methyl- [4,5' -bipyrimidine ] -6-amine (Compound 7)

8- (1- ((2 '-methyl- [4,5' -bipyrimidin ] -6-yl) amino) propyl-2-yl) quinoline-4-carbonitrile (90mg,0.24mmol), trichloroisocyanuric acid (5.6mg,0.024mmol) and ethylenediamine (2.5mL) were reacted at 110 ℃ for 4 hours under microwave. After the reaction was complete, the product was isolated by spin drying under high pressure (5mg, 5% yield).

Molecular formula C₂₄H₂₄N₈Molecular weight 424.2LC-MS (M/e) 425.2(M + H)⁺)

¹H-NMR(400MHz,CDCl₃)δ:8.99-9.07(m,3H),8.55-8.59(m,2H),7.72-7.73(d,J＝4Hz,2H),7.60(m,1H),6.50-6.70(m,1H),5.84(m,1H),4.65-4.67(m,1H),4.20-4.25(m,2H),3.67-3.80(m,4H),2.85(s,3H),1.59-1.61(m,3H)。

Experimental protocol

An exemplary experimental scheme of a portion of the compounds of the invention is provided below to show the advantageous activity and advantageous technical effects of the compounds of the invention. It should be understood, however, that the following experimental protocols are only illustrative of the present disclosure and are not intended to limit the scope of the present disclosure.

Experimental example 1 in vitro cytological Activity of Compounds of the invention

Abbreviations

EDTA: ethylenediaminetetraacetic acid

DMSO, DMSO: dimethyl sulfoxide

Tris (Tris): tris (hydroxymethyl) aminomethane

Brij-35: polyoxyethylene lauryl ether

DTT: dithiothreitol

And (3) testing the sample: the structural formula and the preparation method of the compound are shown in the examples.

Experimental reagent:

name (R)	Brand
		ADP-Glo Kinase Assay	Promege
DNA-PK	Promege

The experimental method comprises the following steps:

1. 1-fold kinase buffer solution is prepared

1) 1-fold kinase buffer

40mM Tris,pH 7.5

0.0055％Brij-35

20mM MgCl₂

0.05mM DTT

2. Compound preparation

1) The initial concentration of the compound to be detected was 1. mu.M, and the concentration was set to 100-fold, that is, 100. mu.M. Mu.l of 10mM compound was taken and 198. mu.l of 100% DMSO was added to prepare a 100. mu.M solution of the compound. 100 μ l of 100-fold compound was added to the second well of the 96-well plate, and 60 μ l of 100% DMSO was added to the other wells. Mu.l of compound from the second well was added to the third well and diluted sequentially 3-fold further down for a total of 10 concentrations.

2) Transfer the highest concentration (400nM) of 100. mu.l of 100% DMSO and the positive control Wortmannin to two empty wells as Max and Min wells, respectively.

3) Echo was used to transfer 50nl of compound to 384-well plates.

3. Preparing 2-fold concentration kinase solution

1) A2-fold DNA-PK kinase solution was prepared using a 1-fold kinase buffer.

2) Transfer 2.5. mu.l of 2-fold enzyme solution to 384-well reaction wells.

3) Shaking, mixing, and standing at room temperature.

4. Preparing substrate solution with 2 times concentration

1) A2-fold substrate solution was prepared using 1-fold kinase buffer.

2) Transfer 2.5. mu.l of 2-fold substrate solution to 384-well reaction wells to initiate the reaction.

3) Oscillating and mixing.

5. Kinase reaction and termination

1) The 384 well plates were capped and incubated at 28 ℃ for 3 hours.

2) Transfer 5. mu.l ADP-Glo reagent and incubate at 28 ℃ for 2 hours.

6. Detection of reaction results

1) The reaction was stopped by transferring 10. mu.l of the kinase detection reagent to reaction wells of a 384-well plate.

2) Rest for 30 minutes at room temperature.

7. Data reading

Sample values were read at Envision.

8. Inhibition rate calculation

1) Data is copied from Envision.

2) This was converted to inhibition data.

Percent inhibition is (max-conversion)/(max-min) 100. where max refers to the conversion rate of the DMSO control, min refers to the conversion rate of the no enzyme control, and conversion refers to the conversion rate at each concentration of test compound.

3) Data were imported into MS Excel and curve-fitted using XLFit Excel add-in version 5.4.0.8.

The experimental results are as follows:

TABLE 1 in vitro enzymatic Activity data for Compounds of the invention

And (4) experimental conclusion:

the result shows that the compound has better inhibition effect on the activity of DNA-PK kinase.

Claims

1. A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof or an isomer thereof,

wherein the content of the first and second substances,

X₁、X₂、X₃、X₄、X₅independently selected from CH or N;

y is selected from-CH₂-, -C (O) -, -O-, -NH-, -S-, -S (O) -or-S (O)₂-；

Ring A and ring B are independently selected from 6-10 membered aryl or 5-10 membered hetero optionally substituted by substituentsAryl, the substituent is selected from halogen, amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy, halo C_1-6Alkylthio, hydroxy C_1-6Alkoxy, hydroxy C_1-6Alkylthio, amino C_1-6Alkoxy or amino C_1-6An alkylthio group;

m is selected from 0, 1,2 or 3.

2. The compound, pharmaceutically acceptable salt thereof, or isomer thereof according to claim 1,

ring A and ring B are independently selected from phenyl optionally substituted by substituent, 5-6 membered monocyclic heteroaryl; the substituent is selected from halogen, amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, halo C_1-4Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio, halo C_1-4Alkoxy or halo C_1-4An alkylthio group;

preferably, ring a, ring B are independently selected from phenyl optionally substituted with a substituent or a 5-6 membered nitrogen containing monocyclic heteroaryl.

3. The compound, pharmaceutically acceptable salt thereof, or isomer thereof according to claim 1 or 2,

ring a, ring B are independently selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl optionally substituted with a substituent; the substituents are selected from the group consisting of halogen, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

4. The compound, a pharmaceutically acceptable salt thereof, or an isomer thereof according to any one of claims 1 to 3,

Pyrimidinyl, pyridinyl, hexahydropyrimidinyl or hexahydropyridazinyl.

5. The compound, a pharmaceutically acceptable salt thereof, or an isomer thereof according to any one of claims 1 to 4,

X₁is N; x₂、X₃、X₄、X₅Independently selected from CH or N;

y is selected from-CH₂-, -C (O) -, -O-, -NH-or-S-;

ring a, ring B are independently selected from pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl optionally substituted with a substituent; the substituents are selected from halogen, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy;

Hexahydropyrimidyl or hexahydropyridazinyl;

m is selected from 0, 1 or 2.

6. The compound, pharmaceutically acceptable salt thereof, or isomer thereof according to any one of claims 1-5,

X₁is N; x₂、X₃、X₄、X₅Independently selected from CH or N;

y is selected from-CH₂-, -O-, -NH-or-S-;

Hexahydropyrimidyl or hexahydropyridazinyl;

m is selected from 0, 1 or 2.

7. The compound of claim 1, a pharmaceutically acceptable salt thereof, or an isomer thereof, selected from the group consisting of:

8. a pharmaceutical formulation comprising a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof or an isomer thereof, characterized by comprising one or more pharmaceutically acceptable excipients, in any pharmaceutically acceptable dosage form.

9. A pharmaceutical composition comprising a compound of any one of claims 1-7, a pharmaceutically acceptable salt thereof, or an isomer thereof, characterized by comprising one or more second therapeutically active agents selected from the group consisting of anti-cancer agents including mitotic inhibitors, alkylating agents, anti-metabolites, DNA chimerics, anti-tumor antibiotics, growth factor inhibitors, signaling inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal drugs, angiogenesis inhibitors, cell growth inhibitors, targeting antibodies, HMG-CoA reductase inhibitors, and prenyl protein transferase inhibitors.

10. Use of a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt or isomer thereof, a pharmaceutical formulation according to claim 8, or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for use in combination with radiotherapy and/or one or more anti-cancer agents for the prevention and/or treatment of benign tumours or cancers, including carcinoma in situ and metastatic carcinoma.

11. Use of a compound of any one of claims 1-7, a pharmaceutically acceptable salt or isomer thereof, a pharmaceutical formulation of claim 8, or a pharmaceutical composition of claim 9 for the manufacture of a medicament for sensitizing cancer cells to an anti-cancer agent and/or radiation therapy.

12. Use of a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt or isomer thereof, a pharmaceutical formulation according to claim 8, or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the treatment and/or prophylaxis of benign tumours or cancers, including carcinoma in situ and metastatic cancers.

13. A kit, comprising:

(a) an effective amount of one or more compounds of any one of claims 1-7, a pharmaceutically acceptable salt thereof, or an isomer thereof,

and (b) an effective amount of one or more other anti-cancer agents.

14. A process for the preparation of a compound of formula (I) comprising the steps of:

(b) the intermediate 2 and boric acid or borate intermediate 2' undergo Suzuki coupling reaction, and then undergo reduction reaction and/or deprotection reaction to generate an intermediate 3;

(d) the intermediate 5 is subjected to cyclization reaction to generate a compound shown in a general formula (I); or the intermediate 5 reacts with hydroxylamine hydrochloride under alkaline condition, and then generates the compound with the general formula (I) through cyclization reaction;

wherein X' is selected from F, Cl, Br, I; m is selected from boric acid or boric acid ester; corresponding to X₁-X₅、R₁Ring a, ring B, ring C, Y, m are as defined in any one of claims 1 to 8; the reaction processes involved in the above preparation methods can be carried out in conventional solvents.