[go: up one dir, main page]

CN111909144A - Quinazoline DNA-PK inhibitor - Google Patents

Quinazoline DNA-PK inhibitor Download PDF

Info

Publication number
CN111909144A
CN111909144A CN202010384243.5A CN202010384243A CN111909144A CN 111909144 A CN111909144 A CN 111909144A CN 202010384243 A CN202010384243 A CN 202010384243A CN 111909144 A CN111909144 A CN 111909144A
Authority
CN
China
Prior art keywords
amino
alkyl
hydroxy
pharmaceutically acceptable
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
CN202010384243.5A
Other languages
Chinese (zh)
Inventor
刘斌
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shandong Xuanzhu Pharma Co Ltd
Original Assignee
Shandong Xuanzhu Pharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong Xuanzhu Pharma Co Ltd filed Critical Shandong Xuanzhu Pharma Co Ltd
Publication of CN111909144A publication Critical patent/CN111909144A/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

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

Description

Quinazoline DNA-PK inhibitor
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a quinazoline DNA-PK inhibitor compound, pharmaceutically acceptable salts or isomers thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salts or the isomers thereof, a method for preparing the compound, the pharmaceutically acceptable salts or the isomers thereof, and application of the compound, the pharmaceutically acceptable salts or the isomers thereof.
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 cancer 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 XRCC 4/DNA-ligase iv complexes are recruited by the activated DNA-PKcs, and finally the broken DNA double-stranded ends are 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 invention aims to provide a quinazoline compound which is novel in structure and has 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,
Figure BDA0002483317350000021
wherein,
each X1Each independently selected from-CH2-、-CHR7-、-C(O)-、-O-、-NR7-, -S-, -S (O) -or-S (O)2-；
X2、X3Each independently is selected from CH or N;
y is selected from CH and CR4Or N;
ring A is selected from 6-10 membered aryl or 5-10 membered heteroaryl;
R1、R2、R3each R4、R5、R6Each independently selected from hydrogen, halogen, hydroxyl, sulfhydryl, oxo, amino, nitro, cyano and C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy, halo C1-6Alkylthio, hydroxy C1-6Alkoxy, hydroxy C1-6Alkylthio, amino C1-6Alkoxy or amino C1-6An alkylthio group;
each R7Each independently selected from hydrogen, halogen, hydroxy, amino, carbonyl, oxo, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkoxy or C1-6Alkylcarbonyl group, each R7The substituted positions may be the same ring atom or different ring atoms, and R6And R7Not hydrogen at the same time;
m, n and q are respectively and independently selected from 1,2,3, 4 or 5;
p is selected from 1,2 or 3.
In certain embodiments, ring a is selected from phenyl, 5-6 membered monocyclic heteroaryl;
in certain embodiments, ring a is selected from phenyl or 5-6 membered nitrogen containing monocyclic heteroaryl.
In certain embodiments, ring a is selected from a 5-6 membered monocyclic heteroaryl group containing 1-2 nitrogen atoms.
In certain embodiments, ring a is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.
In certain embodiments, ring a is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.
In certain embodiments, ring a is selected from pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.
In certain embodiments, the compound, pharmaceutically acceptable salt thereof, or isomer thereof, has the structure shown in formula (II) below:
Figure BDA0002483317350000041
X1is selected from-CH2-, -O-, -NH-or-S-;
X2、X3each independently is selected from CH or N;
y is selected from CH and CR4Or N;
R1、R2、R3each independently selected from hydrogen, halogen, hydroxyl, sulfhydryl, oxo, amino, cyano, C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy or halo C1-6An alkylthio group;
each R4Each independently selected from halogen, hydroxyl, amino, nitro, cyano, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy or halo C1-6An alkoxy group;
R5、R6each independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano and C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkoxy or amino C1-6An alkoxy group;
each R7Each independently selected from hydrogen, halogen, hydroxy, amino, carbonyl, oxo, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkoxy or C1-6Alkylcarbonyl group, each R7The substituted positions may be the same ring atom or different ring atoms, and R6And R7Not hydrogen at the same time;
m, n and q are respectively and independently selected from 1,2 or 3.
In certain embodiments, the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof, has a structure according to the following general formula (IIa):
Figure BDA0002483317350000051
wherein R is1、R3Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, mercapto, oxo, amino, cyano, methyl, ethyl, propyl, isopropyl, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, methylthio, ethoxy, ethylthio, propoxy, isopropoxy, propylthio, isopropylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylthio, difluoromethylthio, or trifluoromethylthio;
each R4Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
R5selected from hydrogen, fluorine, chlorine, hydroxyl, amino, nitro or cyano;
R6selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
m and n are respectively and independently selected from 1 or 2.
In certain embodiments, X1Is selected from-CH2-, -O-, -NH-or-S-;
X2、X3each independently is selected from CH or N;
y is selected from CH and CR4Or N;
R1selected from fluoro, chloro, bromo, iodo, hydroxy, mercapto, oxo, amino, methyl, ethyl, methylamino, dimethylamino, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy or trifluoromethoxy;
R3selected from fluoro, chloro, bromo, iodo, hydroxy, amino, cyano, methyl, ethyl, methylamino, ethylamino, dimethylamino, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy, trifluoromethoxy, methylthio, ethylthio, or trifluoromethylthio;
each R4Each independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy;
R5selected from hydrogen, fluorine, chlorine, hydroxyl, amino, nitro or cyano;
R6selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl and propylAlkyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, or trifluoromethoxy;
m and n are respectively and independently selected from 1 or 2.
In certain embodiments, X1Selected from-O-, -NH-or-S-.
In certain embodiments, X2Is N.
In certain embodiments, Y is selected from CH, CR4Or N;
each R4Each independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, trifluoromethyl, methoxy or trifluoromethoxy.
In certain embodiments, m, n are each independently selected from 1 or 2.
In certain embodiments, R1Selected from fluoro, chloro, hydroxy, mercapto, oxo, amino, methyl, ethyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy or trifluoromethoxy;
in certain embodiments, R3Selected from fluoro, chloro, bromo, iodo, hydroxy, amino, methyl, ethyl, methylamino, ethylamino, dimethylamino, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy or trifluoromethoxy, methylthio, ethylthio or trifluoromethylthio;
in certain embodiments, R5Selected from hydrogen, fluorine, chlorine, hydroxyl, amino, nitro or cyano.
In certain embodiments, R6Selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy or trifluoromethoxy.
In certain embodiments, R6Selected from fluoro, chloro, bromo, iodo, hydroxy, amino, methyl, ethyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy.
In certain embodiments, the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof, has a structure represented by the following general formula (IIb):
Figure BDA0002483317350000061
wherein R is1、R3Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, mercapto, oxo, amino, cyano, methyl, ethyl, propyl, isopropyl, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, ethylthio, propylthio, isopropylthio, monofluoromethylthio, difluoromethylthio, or trifluoromethylthio;
each R4Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
R5selected from hydrogen, fluorine, chlorine, hydroxyl, amino, nitro or cyano;
each R7Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, carbonyl, oxo, methyl, ethyl, propyl, isopropyl, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy, and at least one R is7Is not hydrogen;
m, n and q are respectively and independently selected from 1 or 2.
In certain embodiments, each R is7Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, carbonyl, oxo, methyl, ethyl, propyl, isopropyl, methylamino, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy, and at least one R7Is not hydrogen.
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) or (II), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof is selected from the group consisting of
Figure BDA0002483317350000071
Figure BDA0002483317350000081
Figure BDA0002483317350000091
Figure BDA0002483317350000101
In another aspect, the present invention also provides a pharmaceutical preparation, which contains the compound described in the aforementioned general formula (I), (II), (IIa) or (IIb), 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 a compound of the aforementioned general formula (I), (II), (IIa) or (IIb), a pharmaceutically acceptable salt thereof or an isomer thereof, 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 diseases such as benign tumors or cancer, including carcinoma in situ and metastatic cancer.
Furthermore, the invention also relates to the application of a pharmaceutical preparation containing the compound shown in the general formula (I), (II), (IIa) or (IIb), the pharmaceutically acceptable salt or the isomer thereof in preparing a medicament, and 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, wherein the cancers comprise carcinoma in situ and metastatic cancers.
In another aspect, the present invention also relates to the use of a compound of the aforementioned general formula (I), (II), (IIa) or (IIb), a pharmaceutically acceptable salt thereof or an isomer thereof for the preparation of a medicament for sensitizing cancer cells to anticancer agents and/or ionizing radiation.
Furthermore, the invention also relates to the application of a pharmaceutical preparation containing the compound shown in the general formula (I), (II), (IIa) or (IIb), the pharmaceutically acceptable salt 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 relates to the use of a compound of the aforementioned general formula (I), (II), (IIa) or (IIb), a pharmaceutically acceptable salt thereof or an isomer thereof, for the preparation of a medicament for the treatment and/or prevention of diseases such as benign tumors or cancers, including carcinoma in situ and metastatic cancers.
Furthermore, the invention also relates to the application of a pharmaceutical preparation containing the compound shown in the general formula (I), (II), (IIa) or (IIb), the pharmaceutically acceptable salt or the isomer thereof in preparing a medicament, wherein the medicament can be used for treating and/or preventing diseases such as benign tumors or cancers, and the cancers comprise carcinoma in situ and metastatic cancers.
In another aspect, the present invention also provides a pharmaceutical composition comprising a compound of the foregoing general formula (I), (II), (IIa) or (IIb), a pharmaceutically acceptable salt thereof, or an isomer thereof, and one or more second therapeutically active agents selected from the group consisting of anti-cancer agents, including mitotic inhibitors, alkylating agents, antimetabolites, DNA chimerics, antitumor 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 comprising a compound of the aforementioned general formula (I), (II), (IIa) or (IIb), a pharmaceutically acceptable salt thereof or an isomer thereof, in 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 diseases such as benign tumors or cancer, including carcinoma in situ and metastatic carcinoma.
Furthermore, the invention also relates to the application of a pharmaceutical composition containing the compound shown in the general formula (I), (II), (IIa) or (IIb), the pharmaceutically acceptable salt 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 comprising a compound of the aforementioned general formula (I), (II), (IIa) or (IIb), a pharmaceutically acceptable salt thereof or an isomer thereof, for the preparation of a medicament for the treatment and/or prevention of diseases such as benign tumors or cancers, including carcinoma in situ and metastatic cancers.
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 of formula (I), (II), (IIa) or (IIb) as described above, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, a pharmaceutical formulation or a pharmaceutical composition as described above; 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), (II), (IIa) or (IIb), 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 invention1-6Alkyl "denotes straight or branched alkyl having 1 to 6 carbon atoms, including for example" C1-4Alkyl group "," C1-3Alkyl group "," C1-2Alkyl group "," C2-6Alkyl group "," C2-5Alkyl group "," C2-4Alkyl group "," C2-3Alkyl group "," C3-6Alkyl group "," C3-5Alkyl group "," C3-4Alkyl "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 invention1-4Alkyl "means C1-6Specific examples of the alkyl group having 1 to 4 carbon atoms.
"C" according to the invention1-6Alkoxy "means" C1-6alkyl-O- ", said" C1-6Alkyl "is as defined above. "C" according to the invention1-4Alkoxy "means" C1-4alkyl-O- ", said" C1-4Alkyl "is as defined above.
"C" according to the invention1-6Alkylthio "means" C1-6alkyl-S- ", said" C1-6Alkyl "is as defined above. "C" according to the invention1-4Alkylthio "means" C1-4alkyl-S- ", said" C1-4Alkyl "is as defined above.
The "hydroxy group C" of the present invention1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl "means C1-6One or more hydrogens of the alkyl group are each replaced by one or more hydroxyl groups, amino groups or halogens. C1-6Alkyl is as previously defined
The "hydroxy group C" of the present invention1-6Alkoxy, amino C1-6Alkoxy, halo C1-6Alkoxy "means" C1-6One or more hydrogens of "alkoxy" are replaced with one or more hydroxy, amino, or halogen.
The "hydroxy group C" of the present invention1-6Alkylthio, amino C1-6Alkylthio, halo C1-6Alkylthio "means" C1-6Alkylthio "is one in which one or more hydrogens are replaced with one or more hydroxy, amino, or halogen.
"C" according to the invention1-6Alkylamino radical, di (C)1-6Alkyl) amino "means independently C1-6alkyl-NH-),
Figure BDA0002483317350000131
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 "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 term "optionally substituted" as used herein means both the case where one or more hydrogen atoms on a substituent may be "substituted" or "unsubstituted" by one or more substituents.
"R" according to the invention6And R7Not simultaneously being hydrogen "means R6And each R7Not being simultaneously hydrogen, i.e. R6And each R7In which at least one is not hydrogen, in particular, R6Not hydrogen or at least one R7Is not hydrogen.
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 the invention:
a process for the preparation of a compound of formula (I):
Figure BDA0002483317350000161
wherein X, X' is independently selected from F, Cl, Br, I; e is selected from boric acid or boric acid ester; corresponding to X1-X3、R1-R7A, Y, m, n, p, q are as defined above.
The intermediate 1 and the diboron pinacol ester react under the alkaline condition and the action of a palladium catalyst to generate an intermediate 2.
And reacting the intermediate 2 and the intermediate 3 under the conditions of alkaline condition, palladium catalyst action and inert gas protection to generate the compound of the general formula (I).
In the above preparation method, all reactions can be carried out in a conventional solvent, including but not limited to DMSO, DMF, acetonitrile, methanol, tetrahydrofuran, toluene, DMF, dimethyl ether, dichloromethane, chloroform, 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 refers to the condition containing organic base or inorganic base, the organic base includes but is not limited to pyridine, triethylamine, N-dimethylaniline, sodium methoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-butoxide, potassium acetate, N-diisopropylethylamine and the like; preferred inorganic bases include, but are not limited to, 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.
Such palladium catalysts include, but are not limited to: 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 inert gas includes, but is not limited to, nitrogen, argon, and the like.
The "diboron" is also called "pinacol ester diborate" or "pinacol ester diborate".
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 reaction2OH, -COOH, etc., by protecting the active group by methods known to those skilled in the art including, but not limited to, ester, amide, alkylamine formation of the active groupEthers, and the like. 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, the protecting group can be deprotected by a method 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, hydrogenation deprotection, and the like.
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:
AIBN azobisisobutyronitrile; TMSCN is trimethylsilyl cyanide; DIEA is N, N-diisopropylethylamine; pd2(dba)3Tris (dibenzylideneacetone) dipalladium (0); xanthphos 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene; TFA is trifluoroacetic acid; rt: peak retention time by liquid chromatography.
Preparation example one: preparation of (5-bromo-2-chloro-4-fluorophenyl) (6-methoxypyridazin-3-yl) methanol
1.1 preparation of bromo-5- (bromomethyl) -4-chloro-2-fluorobenzene
Figure BDA0002483317350000181
1-bromo-4-chloro-2-fluoro-5-methylbenzene (20.0g,89.5mmol), NBS (15.9g,89.5mmol), AIBN (1.47g,9.0mmol) were dissolved in CCl4(400mL) and reacted at 80 ℃ for 3 h. The solvent was concentrated and purified by silica gel column (petroleum ether: ethyl acetate ═ 50:1) to give the title compound (24.5g, yield 91.4%).
2.2 preparation of 2- (5-bromo-2-chloro-4-fluorophenyl) acetonitrile
Figure BDA0002483317350000182
1-bromo-5- (bromomethyl) -4-chloro-2-fluorobenzene (24.5g,87.7mmol), K2CO3(13.5g,98.0mmol) was dissolved in acetonitrile (150mL), TMSCN (12.2g,122.5mmol) was added, and after the addition, the reaction was carried out at 80 ℃ for 24 hours. The title compound (11.8g, 58.2% yield) was purified by washing with 2N aqueous NaOH, extracting with ethyl acetate, and concentrating the organic phase on a silica gel column (petroleum ether: ethyl acetate: 10: 1).
Preparation of 2- (5-bromo-2-chloro-4-fluorophenyl) -2- (6-methoxypyridazin-3-yl) acetonitrile
Figure BDA0002483317350000191
KOH (2.3g,40.2mmol) was dissolved in DMF (15mL), and the mixture was stirred at 20 ℃ for 30min, 2- (5-bromo-2-chloro-4-fluorophenyl) acetonitrile (5.0g,20.1mmol) was dissolved in DMF (5mL) and added to the reaction mixture, and the mixture was stirred at 20 ℃ for 30min, and 3-chloro-6-methoxypyridazine (1.8g,12.6mmol) was added thereto, and then the reaction was carried out at 50 ℃ for 2 h. Cooled to 20 ℃, poured into saturated brine, extracted with ethyl acetate, dried and concentrated, and purified by C18 column (acetonitrile 0-80%) to give the title compound (930mg, yield 21.0%).
Preparation of (5-bromo-2-chloro-4-fluorophenyl) (6-methoxypyridazin-3-yl) methanone
Figure BDA0002483317350000192
2- (5-bromo-2-chloro-4-fluorophenyl) -2- (6-methoxypyridazin-3-yl) acetonitrile (930mg,2.6mmol) was dissolved in acetonitrile (30mL), KOt-Bu (394.0mg,2.6mmol) was added, stirring was carried out at 20 ℃ for 20min, the temperature was reduced to 0 ℃ and H was added dropwise2O2(0.6mL,5.7mmol), after the addition, stirring at 0 ℃ for 30min, raising the temperature to 20 ℃ and reacting for 2 h. The mixture was diluted with water and extracted with ethyl acetate, and the extract was purified by organic phase drying and concentrating silica gel column (petroleum ether: ethyl acetate 1:1) to give the title compound (510mg, yield 56.6%).
Preparation of (5-bromo-2-chloro-4-fluorophenyl) (6-methoxypyridazin-3-yl) methanol
Figure BDA0002483317350000193
(5-bromo-2-chloro-4-fluorophenyl) (6-methoxypyridazin-3-yl) methanone (400mg,1.16mmol) was dissolved in methanol (15mL) and NaBH was added portionwise4(194.4mg,5.12mmol), after the addition was completed, the reaction was carried out at 25 ℃ for 2 hours. Addition of saturated NH4Diluted with aqueous Cl, extracted with ethyl acetate, the organic phases combined and dried, and purified on silica gel column (dichloromethane: methanol ═ 20:1) to afford the title compound (300mg, yield 74.6%).
Preparation example two: preparation of (R) -4- (4-chloroquinazolin-7-yl) -3-methylmorpholine
Preparation of 1, 7-bromo-4-chloroquinazoline
Figure BDA0002483317350000201
7-Bromoquinazolin-4 (3H) -one (10.0g,44.0mmol) was dissolved in POCl3(50mL), DIEA (2.8g,22.0mmol) was added and the reaction was completed at 115 ℃ for 3 hours. The solvent was concentrated to give the title compound (10.0g), which was used directly in the next step.
Preparation of 7-bromo-4- ((4-methoxybenzyl) oxy) quinazoline
Figure BDA0002483317350000202
NaH (60%) (993.6mg,24.8mmol) was dissolved in toluene (100mL), p-methoxybenzyl alcohol (2.9g,20.7mmol) was added, and after addition, stirring was performed at 20 ℃ for 1 h. 7-bromo-4-chloroquinazoline (5.0g, crude product) was added in portions and reacted at 20 ℃ for 12 hours. Quenched with water, extracted with ethyl acetate, the organic phases combined and dried, concentrated and purified on silica gel column (petroleum ether: ethyl acetate 2:1) to give the title compound (6.0g, 77.9% yield over two steps).
Preparation of (R) -4- (4- ((4-methoxybenzyl) oxy) quinazolin-7-yl) -3-methylmorpholine
Figure BDA0002483317350000203
Coupling (7-bromo-4- ((4-methoxybenzyl) oxy) quinazoline (500mg,1.45mmol), (R) -3-methylmorpholine (176.3mg,1.74mmol), Pd2(dba)3(137.4mg,0.15mmol), XantPhos (173.6mg,0.3mmol), t-BuONa (278.7mg,2.9mmol) in toluene (25mL), N2Reacting for 12h at 80 ℃ under protection. Diluted with water, extracted with ethyl acetate, and purified with silica gel column (petroleum ether: ethyl acetate 1:1) to give the title compound (320mg, yield 60.4%).
Preparation of (R) -7- (3-methylmorpholino) quinazolin-4 (3H) -one
Figure BDA0002483317350000204
(R) -4- (4- ((4-methoxybenzyl) oxy) quinazolin-7-yl) -3-methylmorpholine (320mg,0.88mmol) was dissolved in TFA (10mL) and reacted at 20 ℃ for 12 h. The solvent was concentrated and purified by C18 column (acetonitrile ═ 0% to 60%) to give the title compound (120mg, yield 56.1%).
Preparation of (R) -4- (4-chloroquinazolin-7-yl) -3-methylmorpholine
Figure BDA0002483317350000211
(R) -7- (3-Methylmorpholino) quinazolin-4 (3H) -one (120mg,0.45mmol) was dissolved in POCl3(10mL), DIEA (31.6mg,0.24mmol) was added, the reaction was carried out at 115 ℃ for 3h, the solvent was concentrated, and the product was purified on a large plate (petroleum ether: ethyl acetate ═ 1:1) to give the title compound (100mg, yield 77.6%).
Preparation example three: preparation of 4- (4-chloro-8-fluoroquinazolin-7-yl) morpholine
Preparation of 1.7-bromo-8-fluoroquinazolin-4 (3H) -one
Figure BDA0002483317350000212
2-amino-4-bromo-3-fluorobenzoic acid (5g,21.36mmol) was dissolved in formamide (20mL) and N2After completion of the reaction at 160 ℃ for 4 hours under protection, ice water (100mL) was added, and the mixture was filtered to give the compound (4.81g, yield: 93.0%).
Preparation of 2.7-bromo-4-chloro-8-fluoroquinazoline
Figure BDA0002483317350000213
7-bromo-8-fluoroquinazolin-4 (3H) -one (3g,12.39mmol) was dissolved in POCl3(25mL), DIEA (0.8g,6.2mmol) was added at 20 ℃ and the mixture was heated to 120 ℃ for reaction for 6 hoursAfter the reaction was completed, the reaction mixture was cooled to room temperature, 100mL of water was added, and extracted with ethyl acetate (3 × 150mL) and concentrated to obtain a crude compound (3.8 g).
Preparation of 3.7-bromo-8-fluoro-4- ((4-methoxybenzyl) oxy) quinazoline
Figure BDA0002483317350000221
P-methoxybenzyl alcohol (1.71g,12.39mmol) was dissolved in toluene (10mL), NaH (60%, 0.59g,14.87mmol) was added, the reaction was allowed to react at 20 ℃ for 1 hour, the reaction was added dropwise to a toluene solution (20mL) of 7-bromo-4-chloro-8-fluoroquinazolin (3.8g crude) and stirring was continued for 2 hours. Water (50mL) was added, EA (3 × 150mL) was extracted, the organic phases were combined, spin dried, and purified by column chromatography (petroleum ether: ethyl acetate: 10:1) to give the desired product (1.89g, 42.2% yield over two steps).
Preparation of 4- (8-fluoro-4- ((4-methoxybenzyl) oxy) quinazolin-7-yl) morpholine
Figure BDA0002483317350000222
Under a nitrogen atmosphere, 7-bromo-8-fluoro-4- ((4-methoxybenzyl) oxy) quinazoline (200mg,0.55mmol), morpholine (57.4mg,0.66mmol), Pd2(dba)3(50.38mg,0.055mmol), xanthphos (57.0mg,0.11mmol), sodium tert-butoxide (105.6mg,1.1mmol) were dissolved in 1, 4-dioxane (10mL), reacted at 100 ℃ for 6 hours, water (10mL) was added, ethyl acetate (3 x 50mL) was extracted, the organic phases were combined, spin-dried, and column chromatographed (petroleum ether: ethyl acetate 1:1) to obtain the desired product (181mg, 88.8% yield).
Preparation of 5.8-fluoro-7-morpholinoquinazolin-4 (3H) -one
Figure BDA0002483317350000223
4- (8-fluoro-4- ((4-methoxybenzyl) oxy) quinazolin-7-yl) morpholine (100mg,0.27mmol) was dissolved in trifluoroacetic acid (2mL), stirred at 20 ℃ for 6 hours, evaporated to dryness and prepared at medium pressure (acetonitrile: water ═ 90:10) to give the product (41mg, 60.7% yield).
Preparation of 4- (4-chloro-8-fluoroquinazolin-7-yl) morpholine
Figure BDA0002483317350000224
8-fluoro-7-morpholinoquinazolin-4 (3H) -one (40mg,0.16mmol) was dissolved in POCl3To (5mL) was added DIEA (10.3mg,0.08mmol) at 20 ℃, heated to 120 ℃ and reacted for 6 hours, after completion of the reaction, cooled to room temperature, the solvent was evaporated to dryness, and purified by column chromatography (dichloromethane: methanol ═ 20:1) to give the product (22mg, yield 51.3%).
Preparation example four: preparation of 4- (4-chloroquinazolin-7-yl) morpholin-3-one
Preparation of 4- (4- ((4-methoxybenzyl) oxy) quinazolin-7-yl) morpholin-3-one
Figure BDA0002483317350000231
Coupling (7-bromo-4- ((4-methoxybenzyl) oxy) quinazoline (300mg,0.87mmol), morpholin-3-one (105.8mg,1.05mmol), Pd2(dba)3(79.7mg,87.0μmol)，XantPhos(100.7mg,0.17mmol)，Cs2CO3(595.5mg,1.74mmol) was dissolved in toluene (10mL), N2Reacting for 3 hours at 80 ℃ under protection. Diluted with water, extracted with ethyl acetate, and purified by C18 column (acetonitrile ═ 0-80%) to give the title compound (100mg, yield 31.4%).
Preparation of 4- (4-oxo-3, 4-dihydroquinazolin-7-yl) morpholin-3-one
Figure BDA0002483317350000232
4- (4- ((4-methoxybenzyl) oxy) quinazolin-7-yl) morpholin-3-one (210mg,0.6mmol) was dissolved in TFA (10mL) and reacted at 20 ℃ for 2 h. The solvent was concentrated and purified by C18 column (acetonitrile ═ 0% to 50%) to give the title compound (130mg, yield 95.7%).
Preparation of 4- (4-chloroquinazolin-7-yl) morpholin-3-one
Figure BDA0002483317350000233
4- (4-oxo-3, 4-dihydroquinazolin-7-yl) morpholin-3-one (140mg,0.57mmol) was dissolved in POCl3(10mL), DIEA (39.6mg,0.29mmol) was added, the reaction was completed at 115 ℃ for 3h, the solvent was concentrated, and the product was purified on a large plate (dichloromethane: methanol ═ 20:1) to obtain the title compound (80mg, yield 53.3%).
Example 14 preparation of- (4- (4-chloro-2-fluoro-5- (hydroxy (6-methoxypyridazin-3-yl) methyl) phenyl) quinazolin-7-yl) morpholin-3-one (Compound 1)
Preparation of (2-chloro-4-fluoro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) (6-methoxypyridazin-3-yl) methanol
Figure BDA0002483317350000241
The reaction mixture was washed with (5-bromo-2-chloro-4-fluorophenyl) (6-methoxypyridazin-3-yl) methanol (100mg,0.29mmol), diboron (88.1mg,0.35mmol), Pd (PPh)3)2Cl2(6.1mg, 8.7. mu. mol), KOAc (85.3mg,0.87mmol) was dissolved in 1, 4-dioxane (5mL) to complete the addition, N2Reacting for 3h at 130 ℃ under protection. Used directly in the next step.
Preparation of 4- (4- (4-chloro-2-fluoro-5- (hydroxy (6-methoxypyridazin-3-yl) methyl) phenyl) quinazolin-7-yl) morpholin-3-one
Figure BDA0002483317350000242
Under a nitrogen atmosphere, (2-chloro-4-fluoro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) (6-methoxypyridazin-3-yl) methanol (crude, 0.29mmol), 4- (4-chloroquinazolin-7-yl) morpholin-3-one (76.3mg,0.29mmol), Pd (PPh)3)2Cl2(6.1mg,8.7μmol)，Na2CO3(92.2mg,0.87mmol) was dissolved in 1, 4-dioxane (10mL),water (0.5mL) was added, and the reaction was completed at 130 ℃ for 2 hours. Dilution with water, extraction with ethyl acetate, organic phase dry concentration and large plate purification (dichloromethane: methanol ═ 20:1) followed by high pressure workup (acetonitrile ═ 0-60%) afforded the title compound (17.6mg, two step yield 12.3%).
Molecular formula C24H19ClFN5O4Molecular weight 495.1LC-MS (M/e) 496.1(M + H)+)
1H-NMR(400MHz,CDCl3):9.37(s,1H),7.97(d,J＝2.0Hz,1H),7.92(dd,J＝2.4Hz,1H),7.77-7.82(m,2H),7.38-7.43(m,2H),7.00(d,J＝8.8Hz,1H),6.45(s,1H),4.43(s,2H),4.13-4.15(m,5H),3.98-4.01(m,2H)
Example 2 preparation of (2-chloro-4-fluoro-5- (8-fluoro-7-morpholinoquinazolin-4-yl) phenyl) (6-methoxypyridazin-3-yl) methanol (Compound 2)
Preparation of (2-chloro-4-fluoro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) (6-methoxypyridazin-3-yl) methanol
Figure BDA0002483317350000251
(5-bromo-2-chloro-4-fluorophenyl) (6-methoxypyridazin-3-yl) methanol (41.5mg,0.12mmol), pinacol diboron (36.5mg,0.14mmol), Pd (PPh) under a nitrogen atmosphere3)2Cl2(2.5mg, 3.6. mu. mol), potassium acetate (35.3mg,0.36mmol) was dissolved in 1, 4-dioxane (5mL) and reacted at 130 ℃ for 6 hours for direct use in the next reaction.
Preparation of (2-chloro-4-fluoro-5- (8-fluoro-7-morpholinoquinazolin-4-yl) phenyl) (6-methoxypyridazin-3-yl) methanol
Figure BDA0002483317350000252
4- (4-chloro-8-fluoroquinazolin-7-yl) morpholine (22mg,0.08mmol), Pd (PPh) under nitrogen atmosphere3)2Cl2(1.75mg, 2.5. mu. mol), sodium carbonate (25.4mg,0.24mmol) was dissolved in the reaction flask of the previous step, water (0.5mL) was added,the reaction was carried out at 130 ℃ for 2 hours, and purified by column chromatography (dichloromethane: methanol ═ 20:1) to give the product (3.6mg, yield 8.7%).
Molecular formula C24H20ClF2N5O3Molecular weight 499.9LC-MS (M/e) 500.1(M + H)+)
1H-NMR(400MHz,CDCl3):9.19(s,1H),8.01(d,J＝8.0Hz,1H),7.71(d,J＝9.2Hz,1H),7.64-7.62(m,1H),7.58-7.53(m,1H),7.52-7.48(m,1H),7.17(d,J＝9.2Hz,1H),6.35(s,1H),4.07(s,3H),3.89-3.88(m,4H),3.50-3.49(m,4H).
Example 2-1 preparation of (S) - (2-chloro-4-fluoro-5- (8-fluoro-7-morpholinoquinazolin-4-yl) phenyl) (6-methoxypyridazin-3-yl) methanol (Compound 2-1) and (R) - (2-chloro-4-fluoro-5- (8-fluoro-7-morpholinoquinazolin-4-yl) phenyl) (6-methoxypyridazin-3-yl) methanol (Compound 2-2)
Figure BDA0002483317350000261
The splitting method comprises the following steps: high performance liquid chromatography
Splitting conditions are as follows:
type of chromatographic column CHIRALPAK IA(IA00CD-RF007)
Specification of chromatographic column 0.46cm I.D.×15cm L
Sample volume 5.0μl
Mobile phase MeOH
Flow rate of flow 1.0ml/min
Wavelength of light UV 214nm
Column temperature 35℃
HPLC equipment Aglient 1200
And (3) splitting results:
Figure BDA0002483317350000262
example 3 preparation of (2-chloro-4-fluoro-5- (7- ((S) -3-methylmorpholinyl) quinazolin-4-yl) phenyl) (6-methoxypyridazin-3-yl) methanol (Compound 4)
Preparation of (2-chloro-4-fluoro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) (6-methoxypyridazin-3-yl) methanol
Figure BDA0002483317350000271
(5-bromo-2-chloro-4-fluorophenyl) (6-methoxypyridazin-3-yl) methanol (100mg,0.29mmol), pinacol diboron (88.1mg,0.35mmol), Pd (PPh) under a nitrogen atmosphere3)2Cl2(6.1mg, 8.7. mu. mol), potassium acetate (85.3mg,0.87mmol) was dissolved in 1, 4-dioxane (5mL) and reacted at 130 ℃ for 6 hours for direct use in the next reaction.
Preparation of (2-chloro-4-fluoro-5- (7- ((S) -3-methylmorpholinyl) quinazolin-4-yl) phenyl) (6-methoxypyridazin-3-yl) methanol
Figure BDA0002483317350000272
Under a nitrogen atmosphere, (S) -4- (4-chloroquinazolin-7-yl) -3-methylmorpholine (76.3mg,0.29mmol), Pd (PPh)3)2Cl2(6.1mg, 8.7. mu. mol), sodium carbonate (92.2mg,0.87mmol) was dissolved in the reaction flask of the previous step, water (0.5mL) was added thereto, the reaction was carried out at 130 ℃ for 2 hours, and the product was purified by column chromatography (dichloromethane: methanol ═ 20:1) to obtain a product (5.3mg, yield 3.7%).
Molecular formula C25H23ClFN5O3Molecular weight 495.9LC-MS (M/e):496.2(M + H)+)
1H-NMR(400MHz,CDCl3):9.120(s,1H),7.738-7.720(d,J＝7.2Hz,1H),7.587-7.556(m,1H),7.386-7.329(m,2H),7.259-7.220(m,1H),7.168-7.162(d,J＝2.4Hz,1H),6.978-6.955(d,J＝9.2Hz,1H),6.414-6.404(s,1H),4.125-4.103(s,3H),4.095-4.069(m,2H),3.853-3.849(s,2H),3.711-3.703(m,1H),3.472-3.470(m,1H),3.347(m,1H),1.281-1.264(d,J＝6.8Hz,3H).
Example 4 preparation of (2-chloro-4-fluoro-5- (7- ((R) -3-methylmorpholino) quinazolin-4-yl) phenyl) (6-methoxypyridazin-3-yl) methanol (Compound 3)
Preparation of (2-chloro-4-fluoro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) (6-methoxypyridazin-3-yl) methanol
Figure BDA0002483317350000281
The reaction mixture was washed with (5-bromo-2-chloro-4-fluorophenyl) (6-methoxypyridazin-3-yl) methanol (50mg,0.14mmol), diboron (44.0mg,0.0.17mmol), Pd (PPh)3)2Cl2(3.0mg, 4.3. mu. mol), KOAc (42.3mg,0.43mmol) in 1, 4-dioxane (5mL) and, when addition is complete, N2Reacting for 3h at 130 ℃ under protection. Used directly in the next step.
Preparation of (2-chloro-4-fluoro-5- (7- ((R) -3-methylmorpholino) quinazolin-4-yl) phenyl) (6-methoxypyridazin-3-yl) methanol
Figure BDA0002483317350000282
(2-chloro-4-fluoro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) (6-methoxypyridazin-3-yl) methanol (crude, 0.14mmol), (R) -4- (4-chloroquinazolin-7-yl) -3-methylmorpholine (36.8mg,0.14mmol), Pd (PPh) under nitrogen3)2Cl2(3.01mg,4.3μmol)，Na2CO3(45.6mg,0.43mmol), dissolved in 1, 4-dioxane (5mL), added with water (0.5mL) and reacted at 130 ℃ for 3 h. Dilution with water, extraction with ethyl acetate, and organic phase dry concentration large plate purification (dichloromethane: methanol ═ 20:1) afforded the title compound (19.6mg, two step yield 27.4%).
Molecular formula C25H23ClFN5O3Molecular weight 495.1LC-MS (M/e) 496.1(M + H)+)
1H-NMR(400MHz,CDCl3):9.17(s,1H),7.78(d,J＝7.6Hz 1H),7.61-7.64(m,1H),7.31-7.44(m,2H),7.22-7.27(m,1H),7.01-7.03(m,1H),6.46(s,1H),4.18(s,3H),4.12-4.15(m,2H),3.90(s,2H),3.75-3.76(m,1H),3.52-3.55(m,1H),3.40-3.41(m,2H),1.28-1.35(m,3H).
Example 5 preparation of (2-chloro-5- (7- (2, 2-difluoromorpholino) quinazolin-4-yl) -4-fluorophenyl) (6-methoxypyridazin-3-yl) methanol (Compound 5)
1. Preparation of 7- (2, 2-difluoromorpholino) quinazolin-4-ol
Figure BDA0002483317350000291
2, 2-difluoro-4- (4- ((4-methoxybenzyl) oxy) quinazolin-7-yl) morpholine (250mg,0.65mmol) was dissolved in dichloroethane (9mL), TFA (148mg,1.3mmol) was added and the reaction was allowed to proceed at 30 ℃ for 1.5h, after completion of the reaction, spin-dried and isolated by normal phase preparative separation (dichloromethane: methanol ═ 5:1) to give crude product (280 mg).
2. Preparation of 4- (4-chloroquinazolin-7-yl) -2, 2-difluoromorpholine
Figure BDA0002483317350000292
7- (2, 2-Difluoromolino) quinazolin-4-ol (230mg crude) was dissolved in POCl3(20mL), DIEA (0.2mL) was added dropwise and the mixture was reacted at 110 ℃ for 18 hours. After the reaction was completed, the product was obtained by spin-drying and preparative chromatography using reverse phase C18 (water: acetonitrile: 3:1 to 1:1) (64mg, 42.3% yield in two steps).
3. Preparation of (2-chloro-4-fluoro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) (6-methoxypyridazin-3-yl) methanol
Figure BDA0002483317350000293
(5-bromo-2-chloro-4-fluorophenyl) (6-methoxypyridazin-3-yl) methanol (150mg,0.44mmol), pinacol diboron (222mg,0.88mmol), Pd (PPh)3)2Cl2(12mg,0.018mmol), potassium acetate (129mg,1.3mmol), dissolved in 1, 4-dioxane (10mL), N2And reacting at 90 ℃ for 5 hours under protection. After the reaction was completed, it was used in the next step.
4. Preparation of (2-chloro-5- (7- (2, 2-difluoromorpholino) quinazolin-4-yl) -4-fluorophenyl) (6-methoxypyridazin-3-yl) methanol
Figure BDA0002483317350000301
4- (4-Chloroquinazolin-7-yl) -2, 2-difluoromorpholine (55mg,0.19mmol), (2-chloro-4-fluoro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) (6-methoxypyridazin-3-yl) methanol (crude in the above step), Pd (PPh)3)2Cl2(12mg,0.018mmol)，Na2CO3(140mg,1.3mmol), dissolved in 1, 4-dioxane (5mL), added water (1mL), N2Reacting at 90 ℃ for 10h under protection, drying by spinning after the reaction is finished, and separating by high-pressure preparative chromatography (acetonitrile/water is 50-70%) to obtain a pure product (4mg, crude product 12 mg).
Molecular formula C24H19ClF3N5O3Molecular weight 517.9LC-MS (M/e):518.1(M + H)+)
1H-NMR(400MHz,CDCl3):9.20(s,1H),7.77-7.79(d,1H,J＝8.0Hz),7.65-7.70(m,1H),7.34-7.47(m,2H),7.24(s,1H),6.97-6.99(d,1H,J＝8.0Hz),6.42(s,1H),5.20(s,1H),4.28-4.31(t,2H),4.13(s,3H),3.75-3.79(t,2H),3.60(s,2H)。
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:
Figure BDA0002483317350000302
Figure BDA0002483317350000311
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. Preparation of 2 Xkinase 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. Preparation of 2 Xsubstrate solution
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
Figure BDA0002483317350000321
And (4) experimental conclusion:
the result shows that the compound has better inhibition effect on the activity of DNA-PK kinase.

Claims (14)

1. A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof or an isomer thereof,
Figure FDA0002483317340000011
wherein,
each X1Each independently selected from-CH2-、-CHR7-、-C(O)-、-O-、-NR7-, -S-, -S (O) -or-S (O)2-；
X2、X3Each independently is selected from CH or N;
y is selected from CH and CR4Or N;
ring A is selected from 6-10 membered aryl or 5-10 membered heteroaryl;
R1、R2、R3each R4、R5、R6Each independently selected from hydrogen, halogen, hydroxyl, sulfhydryl, oxo, amino, nitro, cyano and C1-6Alkyl radical, C1-6Alkyl radicalAmino, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy, halo C1-6Alkylthio, hydroxy C1-6Alkoxy, hydroxy C1-6Alkylthio, amino C1-6Alkoxy or amino C1-6An alkylthio group;
each R7Each independently selected from hydrogen, halogen, hydroxy, amino, carbonyl, oxo, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkoxy or C1-6Alkylcarbonyl group, each R7The substituted positions may be the same ring atom or different ring atoms, and R6And R7Not hydrogen at the same time;
m, n and q are respectively and independently selected from 1,2,3, 4 or 5;
p is selected from 1,2 or 3.
2. The compound, pharmaceutically acceptable salt thereof, or isomer thereof according to claim 1,
ring A is selected from phenyl, 5-6 membered monocyclic heteroaryl;
preferably, ring A is selected from phenyl or 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 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, thienyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl.
4. The compound, a pharmaceutically acceptable salt thereof, or an isomer thereof according to any one of claims 1 to 3, having a structure represented by the following general formula (II):
Figure FDA0002483317340000021
X1is selected from-CH2-, -O-, -NH-or-S-;
X2、X3each independently is selected from CH or N;
y is selected from CH and CR4Or N;
R1、R2、R3each independently selected from hydrogen, halogen, hydroxyl, sulfhydryl, oxo, amino, cyano, C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy or halo C1-6An alkylthio group;
each R4Each independently selected from halogen, hydroxyl, amino, nitro, cyano, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy or halo C1-6An alkoxy group;
R5、R6each independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano and C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkoxy or amino C1-6An alkoxy group;
each R7Each independently selected from hydrogen, halogen, hydroxy, amino, carbonyl, oxo, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkoxy or C1-6Alkylcarbonyl group, each R7Substituted positionMay be the same ring atom or different ring atoms, and R6And R7Not hydrogen at the same time;
m, n and q are respectively and independently selected from 1,2 or 3.
5. The compound of claim 4, a pharmaceutically acceptable salt thereof, or an isomer thereof, having a structure represented by the following general formula (IIa):
Figure FDA0002483317340000031
wherein R is1、R3Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, mercapto, oxo, amino, cyano, methyl, ethyl, propyl, isopropyl, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, methylthio, ethoxy, ethylthio, propoxy, isopropoxy, propylthio, isopropylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylthio, difluoromethylthio, or trifluoromethylthio;
each R4Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
R5selected from hydrogen, fluorine, chlorine, hydroxyl, amino, nitro or cyano;
R6selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
m and n are respectively and independently selected from 1 or 2.
6. The compound, pharmaceutically acceptable salt thereof, or isomer thereof according to claim 5,
X1is selected from-CH2-, -O-, -NH-or-S-;
X2、X3each independently is selected from CH or N;
y is selected from CH and CR4Or N;
R1selected from fluoro, chloro, bromo, iodo, hydroxy, mercapto, oxo, amino, methyl, ethyl, methylamino, dimethylamino, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy or trifluoromethoxy;
R3selected from fluoro, chloro, bromo, iodo, hydroxy, amino, cyano, methyl, ethyl, methylamino, ethylamino, dimethylamino, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy, trifluoromethoxy, methylthio, ethylthio, or trifluoromethylthio;
each R4Each independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy;
R5selected from hydrogen, fluorine, chlorine, hydroxyl, amino, nitro or cyano;
R6selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, or trifluoromethoxy;
m and n are respectively and independently selected from 1 or 2.
7. The compound of claim 4, a pharmaceutically acceptable salt thereof, or an isomer thereof, having a structure represented by the following general formula (IIb):
Figure FDA0002483317340000041
wherein R is1、R3Each independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, sulfydryl, oxo, amino and cyanogenA group, methyl, ethyl, propyl, isopropyl, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, methylthio, ethoxy, ethylthio, propoxy, propylthio, isopropoxy, isopropylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylthio, difluoromethylthio, or trifluoromethylthio;
each R4Each independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
R5selected from hydrogen, fluorine, chlorine, hydroxyl, amino, nitro or cyano;
each R7Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, carbonyl, oxo, methyl, ethyl, propyl, isopropyl, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy, and at least one R is7Is not hydrogen;
m, n and q are respectively and independently selected from 1 or 2.
8. The compound of claim 1, a pharmaceutically acceptable salt thereof, or an isomer thereof, selected from the group consisting of:
Figure FDA0002483317340000042
Figure FDA0002483317340000051
Figure FDA0002483317340000061
Figure FDA0002483317340000071
9. a pharmaceutical formulation comprising a compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein the pharmaceutical formulation comprises one or more pharmaceutically acceptable excipients, and wherein the pharmaceutical formulation is in any pharmaceutically acceptable dosage form.
10. A pharmaceutical composition comprising a compound of any one of claims 1-8, a pharmaceutically acceptable salt thereof, or an isomer thereof, 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 agents, angiogenesis inhibitors, cell growth inhibitors, targeting antibodies, HMG-CoA reductase inhibitors, and prenyl protein transferase inhibitors.
11. Use of a compound of any one of claims 1 to 8, a pharmaceutically acceptable salt or isomer thereof, a pharmaceutical formulation of claim 9, or a pharmaceutical composition of claim 10 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 tumors or cancers, including carcinoma in situ and metastatic cancers.
12. Use of a compound of any one of claims 1-8, a pharmaceutically acceptable salt or isomer thereof, a pharmaceutical formulation of claim 9, or a pharmaceutical composition of claim 10 for the manufacture of a medicament for sensitizing cancer cells to an anti-cancer agent and/or radiation therapy.
13. Use of a compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt or isomer thereof, a pharmaceutical formulation according to claim 9, or a pharmaceutical composition according to claim 10 for the manufacture of a medicament for the treatment and/or prophylaxis of benign tumours or cancers, including carcinoma in situ and metastatic cancers.
14. A kit, comprising:
(a) an effective amount of one or more compounds of any one of claims 1-8, pharmaceutically acceptable salts thereof, or isomers thereof,
and (b) an effective amount of one or more other anti-cancer agents.
CN202010384243.5A 2019-05-10 2020-05-09 Quinazoline DNA-PK inhibitor Withdrawn CN111909144A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910387017 2019-05-10
CN201910387017X 2019-05-10

Publications (1)

Publication Number Publication Date
CN111909144A true CN111909144A (en) 2020-11-10

Family

ID=73238123

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010384243.5A Withdrawn CN111909144A (en) 2019-05-10 2020-05-09 Quinazoline DNA-PK inhibitor

Country Status (1)

Country Link
CN (1) CN111909144A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114072396A (en) * 2019-06-27 2022-02-18 南京明德新药研发有限公司 Quinoline and cinnoline derivatives as DNA-PK inhibitors
WO2022143671A1 (en) * 2020-12-28 2022-07-07 南京明德新药研发有限公司 Crystal form of morpholine-substituted benzopyrimidine compound and preparation method therefore
CN116669741A (en) * 2021-01-05 2023-08-29 山东轩竹医药科技有限公司 polycyclic kinase inhibitors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102803227A (en) * 2010-03-16 2012-11-28 默克专利有限公司 Morpholinylquinazolines
CN103068803A (en) * 2010-08-28 2013-04-24 默克专利股份公司 Imidazo[4,5-c]quinolines as DNA-PK inhibitors
US20140045869A1 (en) * 2012-04-24 2014-02-13 Vertex Pharmaceuticals Incorporated Dna-pk inhibitors
CN105358552A (en) * 2013-05-11 2016-02-24 默克专利股份公司 Arylquinazolines

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102803227A (en) * 2010-03-16 2012-11-28 默克专利有限公司 Morpholinylquinazolines
CN103068803A (en) * 2010-08-28 2013-04-24 默克专利股份公司 Imidazo[4,5-c]quinolines as DNA-PK inhibitors
US20140045869A1 (en) * 2012-04-24 2014-02-13 Vertex Pharmaceuticals Incorporated Dna-pk inhibitors
CN105358552A (en) * 2013-05-11 2016-02-24 默克专利股份公司 Arylquinazolines

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114072396A (en) * 2019-06-27 2022-02-18 南京明德新药研发有限公司 Quinoline and cinnoline derivatives as DNA-PK inhibitors
CN114072396B (en) * 2019-06-27 2024-02-02 南京明德新药研发有限公司 Quinoline and cinnoline derivatives as DNA-PK inhibitors
WO2022143671A1 (en) * 2020-12-28 2022-07-07 南京明德新药研发有限公司 Crystal form of morpholine-substituted benzopyrimidine compound and preparation method therefore
CN116670128A (en) * 2020-12-28 2023-08-29 南京明德新药研发有限公司 Crystal form of morpholine-substituted benzopyrimidine compound and preparation method thereof
CN116669741A (en) * 2021-01-05 2023-08-29 山东轩竹医药科技有限公司 polycyclic kinase inhibitors
CN116669741B (en) * 2021-01-05 2025-07-22 山东轩竹医药科技有限公司 Polycyclic kinase inhibitors

Similar Documents

Publication Publication Date Title
CN112300132A (en) Aryl quinazoline DNA-PK inhibitor
CN112574179B (en) DNA-PK inhibitors
CN112300126A (en) Heterocyclic DNA-PK inhibitors
CN112047948B (en) Kras mutant inhibitors
CN109715634B (en) Fused bicyclic inhibitors of the MENIN-MLL interaction
CN106986863B (en) DNA-PK inhibitors
US20240092794A1 (en) Novel prmt5 inhibitors
CN111171049B (en) Tyrosine kinase inhibitors and uses thereof
EP4514473B1 (en) Heterocyclic compounds as modulators of bcl6 as ligand directed degraders
CN111909144A (en) Quinazoline DNA-PK inhibitor
JP2019524646A (en) Cyanoindoline derivatives as NIK inhibitors
CN105884695B (en) Heterocyclic derivatives species tyrosine kinase inhibitor
WO2020215998A1 (en) Pyrimido five-membered heterocyclic compound and use thereof as mutant idh2 inhibitor
CN120152972A (en) Thiadiazole derivatives and their compositions and uses
CN113549092A (en) Tricyclic kinase inhibitors
CN112574211B (en) Heterocyclic kinase inhibitors
CN119998291A (en) Pyrazole derivatives, pharmaceutical compositions and applications
CN111909147B (en) DNA-PK inhibitors
US12441725B2 (en) ISO-citrate dehydrogenase (IDH) inhibitor
CN113372345B (en) Deuterated heterocyclic kinase inhibitors
CN114149457B (en) Benzo [ c ] [1,2] oxaborole-1 (3H) -alcohol compound and application thereof
CN114249753A (en) Triazolopyridine kinase inhibitors
CN113087724B (en) Isothiazolopyrimidinone compounds, pharmaceutical compositions containing the same and uses thereof
CN113493471A (en) Heteroaromatic kinase inhibitors
CN117024424A (en) Pyrrolopyridine derivatives and their preparation methods and uses

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WW01 Invention patent application withdrawn after publication
WW01 Invention patent application withdrawn after publication

Application publication date: 20201110