CN112574211B - Heterocyclic kinase inhibitors - Google Patents

Heterocyclic kinase inhibitors Download PDF

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CN112574211B
CN112574211B CN202011036883.3A CN202011036883A CN112574211B CN 112574211 B CN112574211 B CN 112574211B CN 202011036883 A CN202011036883 A CN 202011036883A CN 112574211 B CN112574211 B CN 112574211B
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amino
pharmaceutically acceptable
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acceptable salt
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CN112574211A (en
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刘斌
陈博
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Shandong Xuanzhu Pharma Co Ltd
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Xuanzhu Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention belongs to the technical field of medicine, and particularly relates to a compound of general formula (I)The heterocyclic DNA-PK kinase inhibitor compound, pharmaceutically acceptable salt and isomer thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salt and the isomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt and the isomer thereof, and application of the compound, the pharmaceutically acceptable salt and the isomer thereof.

Description

Heterocyclic kinase inhibitors
Technical Field
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 isomers thereof, and applications of the compound, the pharmaceutically acceptable salts and 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 cells can be inhibited.
In human and other higher eukaryotes, DSB repair is mainly performed by DNA-Dependent Protein Kinase (DNA-PK) dominated DNA non-homologous end joining (NHEJ), thereby repairing damaged DNA and maintaining cellular activity and genomic 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 heterodimer of the Ku70/80 subunit and the catalytic subunit DNA-dependent protein kinase (DNA-PKcs), together, constitute an active DNA-PK enzyme complex.
DNA-PKcs belongs to the phosphatidylinositol 3 kinase (PI3K) superfamily member, is a serine/threonine protein kinase; the PI3K superfamily 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 a high-efficiency and good-selectivity DNA-PK inhibitor has important clinical significance, can synergistically enhance the effects 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. Furthermore, the compounds can be used for preventing and/or treating benign tumors or cancers by combining with radiotherapy and/or one or more anticancer agents.
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 BDA0002705332420000021
wherein the content of the first and second substances,
X1、X2、X3、X4、X5each independently selected from C (R) or N;
Y1、Y2、Y3、Y4、Y5each independently selected from C (R') or N;
x is selected from-CR4R5-、-C(O)-、-O-、-NR4-, -S-, -S (O) -or-S (O)2-；
Y is selected from O or S;
ring A is selected from 6-10 membered aryl or 5-10 membered heteroaryl optionally substituted with a substituent selected from halogen, hydroxy, amino, nitro, cyano, C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl radicalHydroxy group 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, amino C1-6Alkylthio, optionally substituted by C1-6Alkyl, halogen, hydroxy, amino substituted C3-6Cycloalkyl, optionally substituted by C1-6Alkyl, halogen, hydroxy, amino substituted C3-6A heterocyclic group;
each R, each R', R1Each independently selected from H, 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 radical, C1-6Alkylthio, halo C1-6Alkoxy, halo C1-6Alkylthio, hydroxy C1-6Alkoxy, hydroxy C1-6Alkylthio, amino C1-6Alkoxy, amino C1-6Alkylthio, optionally substituted by C1-6Alkyl, halogen, hydroxy, amino substituted C3-6Cycloalkyl, optionally substituted by C1-6Alkyl, halogen, hydroxy, amino substituted C3-6A heterocyclic group;
R2is selected from C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, -NR3R6、-O-R3or-S-R3；
R3、R6Each independently selected from H, C1-6Alkyl radical, C3-6Cycloalkyl, C3-6Heterocyclyl, wherein said alkyl, cycloalkyl, heterocyclyl is optionally substituted by C1-6Alkyl, halogen, hydroxy, amino substitution;
R4、R5each independently selected from H, C1-6Alkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclyl, wherein said alkyl, cycloalkyl, heterocyclyl is optionally substituted by C1-6Alkyl, halogen, hydroxy, amino substitution;
m is selected from 0, 1,2 or 3.
In certain embodiments, Y is selected from S.
In certain embodiments, Y is selected from O.
In certain embodiments, ring a is selected from phenyl, 5-8 membered monocyclic heteroaryl optionally substituted with substituents; the substituent is selected from halogen, amino, nitro, 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.
In certain embodiments, ring a is selected from phenyl, 5-6 membered monocyclic heteroaryl, optionally substituted with substituents; the substituent is selected from halogen, amino, nitro, 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.
In certain embodiments, ring a is selected from phenyl or 5-6 membered monocyclic heteroaryl.
In certain embodiments, ring a is selected from phenyl or 5-6 membered monocyclic heteroaryl substituted with a substituent; the substituent is selected from halogen, amino, nitro, 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.
In certain embodiments, ring a is 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, 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.
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 phenyl or 5-6 membered nitrogen containing monocyclic heteroaryl substituted with a substituent; the substituent is selected from halogen, amino, nitro, 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.
In certain embodiments, ring a is 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 embodiments, ring a is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.
In certain embodiments, ring a is selected from phenyl, 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, hydroxymethyl, aminomethyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, ring a is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.
In certain embodiments, each R', R1Each independently selected from H, halogen, amino, nitro, cyano, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halogeno C1-6Alkoxy, halo C1-6An alkylthio group.
In certain embodiments, R1Selected from the group consisting of H, fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, each R, R' is independently selected from H, fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethylthio.
In certain embodiments, each R is independently selected from H, fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethylthio; each R' is H.
In certain embodiments, R2Is selected from C1-6Alkyl, halo C1-6Alkyl, -NH-R3、-O-R3or-S-R3；
R3Selected from H, C1-6Alkyl, said alkyl being optionally substituted by C1-6Alkyl, halogen, hydroxyl and amino substitution.
In certain embodiments, R2Selected from methyl,Ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -NH-R3、-O-R3or-S-R3；
R3Selected from H, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, X1、X2、X3、X4、X5Each independently selected from CH or N.
In certain embodiments, X1Is C (R), X2、X3、X4、X5Each independently selected from C (R) or N; each R is independently selected from H, fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethylthio.
In certain embodiments, X1Is CH, X2、X3、X4、X5Each independently selected from CH or N.
In certain embodiments, X1Is N; x2、X3、X4、X5Each independently selected from C (R) or N; each R is independently selected from H, fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethylthio.
In certain embodiments, X1Is N; x2、X3、X4、X5Each independently selected from CH or N.
In certain embodiments, X3Is N; x1、X2、X4、X5Each independently selected from C (R) or N; each R is independently selected from H, fluorine, chlorine, bromine, iodine, amino and nitreA group, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethylthio.
In certain embodiments, X4Is N; x1、X2、X3、X5Each independently selected from C (R) or N; each R is independently selected from H, fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethylthio.
In certain embodiments, X5Is N; x2、X2、X3、X4Each independently selected from C (R) or N; each R is independently selected from H, fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethylthio.
In certain embodiments, X1Is N; x5Is N; x2、X3、X4Each independently selected from C (R) or N; each R is independently selected from H, fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethylthio.
In certain embodiments, X1Is N; x4Is N; x2、X3、X5Each independently selected from C (R) or N; each R is independently selected from H, fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, and trifluoromethylFluoromethoxy or trifluoromethylthio.
In certain embodiments, X1Is N; x3Is N; x2、X4、X5Each independently selected from C (R) or N; each R is independently selected from H, fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethylthio.
In certain embodiments, X2Is N; x5Is N; x1、X3、X4Each independently selected from C (R) or N; each R is independently selected from H, fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethylthio.
In certain embodiments, X3Is N; x4Is N; x1、X2、X5Each independently selected from C (R) or N; each R is independently selected from H, fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethylthio.
In certain embodiments, X1Is N; x2Is C (R); x3、X4、X5Each independently selected from C (R) or N; each R is independently selected from H, fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethylthio.
In certain embodiments, X1Is N; x2Is CH; x3、X4、X5Each independently selected from CH or N.
In certain embodiments, X2Is C (R); x1、X3、X4、X5Each independently selected from C (R) or N; each R is independently selected from H, fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethylthio.
In certain embodiments, X2Is CH; x1、X3、X4、X5Each independently selected from CH or N.
In certain embodiments, X3Is C (R); x1、X2、X4、X5Each independently selected from C (R) or N; each R is independently selected from H, fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethylthio.
In certain embodiments, X3Is CH; x1、X2、X4、X5Each independently selected from CH or N.
In certain embodiments, Y1、Y2、Y3、Y4、Y5Each independently selected from CH or N.
In certain embodiments, Y1Is N; y is2Is CH; y is3、Y4、Y5Each independently selected from CH or N.
In certain embodiments, Y1、Y2、Y3、Y4、Y5Each independently selected from CH or N, and Y1-Y5Only one of them is N, and the others are CH.
In certain embodiments, Y1Is N; y is2、Y3、Y4、Y5Are both CH.
In certain embodiments, X is selected from-CR4R5-、-C(O)-、-O-、-NR4-, -S-, -S (O) -or-S (O)2-； R4、R5Each independently selected from H, C1-6Alkyl, wherein the alkyl is optionally substituted by C1-6Alkyl, halogen, hydroxyl and amino substitution.
In certain embodiments, X is selected from-CR4R5-、-C(O)-、-O-、-NR4-, -S-, -S (O) -or-S (O)2-； R4、R5Each independently selected from H, methyl, ethyl, propyl, isopropyl, trifluoromethyl, hydroxymethyl, aminomethyl.
In certain embodiments, X is selected from-CH2-, -O-, -NH-or-S-.
In some embodiments of the present invention, the substrate is,
X1、X2、X3、X4、X5each independently selected from C (R) or N;
Y1、Y2、Y3、Y4、Y5each independently selected from CH or N;
x is selected from-CH2-, -O-, -NH-or-S-;
ring a is selected from phenyl, 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, hydroxymethyl, aminomethyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
each R is independently selected from H, fluoro, chloro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
R1selected from fluorine, chlorine, bromine, iodine, amino, nitro, cyano, methyl, ethyl, propyl, isopropylA fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy group;
R2selected from the group consisting of methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -NH-R3、- O-R3or-S-R3；
R3Selected from H, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl;
m is selected from 0, 1 or 2.
In some embodiments of the present invention, the substrate is,
X1、X2、X3、X4、X5each independently selected from CH or N;
Y1、Y2、Y3、Y4、Y5each independently selected from CH or N;
x is selected from-CH2-, -O-, -NH-or-S-;
ring a is selected from phenyl, 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, hydroxymethyl, aminomethyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, 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;
R2selected from the group consisting of methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -NH-R3、- O-R3or-S-R3；
R3Selected from H, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl;
m is selected from 0, 1 or 2.
In some embodiments of the present invention, the substrate is,
X1、X2、X3、X4、X5each independently selected from CH or N;
Y1is N, Y2Is CH, Y3、Y4、Y5Each independently selected from CH or N;
x is selected from-CH2-, -O-, -NH-or-S-;
ring a is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl;
R1selected from fluoro, chloro, bromo, iodo, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
R2selected from the group consisting of methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -NH-R3、- O-R3or-S-R3；
R3Selected from methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
m is selected from 0, 1 or 2.
In certain embodiments, the compound of formula (I), a pharmaceutically acceptable salt thereof, or an isomer thereof, further has a structure as shown in formula (II),
Figure BDA0002705332420000081
wherein, X1、X2、X3、X4、X5、Y1、Y2X, Y, ring A, R1、R4、R5R, R' are as previously definedThe method is as follows.
In certain embodiments, the compound of formula (I), a pharmaceutically acceptable salt thereof, or an isomer thereof, further has a structure as shown in formula (III),
Figure BDA0002705332420000082
wherein, X1、X2、X3、X4、X5X, Y, ring A, R1、R4、R5R is as defined above.
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, or an isomer thereof, is selected from the compounds shown in table 1 below:
TABLE 1
Figure BDA0002705332420000083
Figure BDA0002705332420000091
Figure BDA0002705332420000101
In certain embodiments, the compound of formula (I), a pharmaceutically acceptable salt thereof, or an isomer thereof, is selected from the compounds shown in table 2 below:
TABLE 2
Figure BDA0002705332420000102
Figure BDA0002705332420000111
In certain embodiments, the compound of formula (I), a pharmaceutically acceptable salt thereof, or an isomer thereof, is selected from the compounds shown in table 3 below:
TABLE 3
Figure BDA0002705332420000112
Figure BDA0002705332420000121
Figure BDA0002705332420000131
Figure BDA0002705332420000141
Figure BDA0002705332420000151
In another aspect, the present invention also provides a pharmaceutical preparation, which contains the compound described in the above general formulas (I), (II), (III), its pharmaceutically acceptable salt or its isomer, and one or more pharmaceutically acceptable excipients, and the pharmaceutical preparation 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 above-described pharmaceutical formulations 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 above pharmaceutical preparations may 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), (II), (III), a pharmaceutically acceptable salt thereof, or an isomer thereof, in the preparation of a medicament for preventing and/or treating diseases such as benign tumors or cancers in combination with radiotherapy and/or one or more anticancer agents, including carcinoma in situ and metastatic cancers.
Furthermore, the invention also relates to the application of a pharmaceutical preparation containing the compounds of the general formulas (I), (II) and (III), the pharmaceutically acceptable salts thereof or the isomers thereof in preparing a medicament for preventing and/or treating diseases such as benign tumors or cancers, wherein the medicament can be combined with radiotherapy and/or one or more anticancer agents, and the cancers comprise carcinoma in situ and metastatic cancers.
In another aspect, the present invention also relates to the use of the compound of the aforementioned general formulas (I), (II), (III), 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 radiotherapy.
Furthermore, the invention also relates to application of a pharmaceutical preparation containing the compounds of the general formulas (I), (II) and (III), pharmaceutically acceptable salts thereof or isomers thereof in preparing a medicament for sensitizing cancer cells to anticancer agents and/or radiotherapy.
In another aspect, the present invention also provides a pharmaceutical composition comprising a compound of the foregoing general formula (I), (II), (III), 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, 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 the compound of the aforementioned general formula (I), (II), (III), a pharmaceutically acceptable salt thereof, or an isomer thereof, in the preparation of a medicament for preventing and/or treating diseases such as benign tumors or cancers, which can be combined with radiotherapy and/or one or more anticancer agents, including carcinoma in situ and metastatic cancers.
Furthermore, the invention also relates to application of a pharmaceutical composition containing the compounds of the general formulas (I), (II) and (III), pharmaceutically acceptable salts thereof or isomers thereof in preparing a medicament for sensitizing cancer cells to anticancer agents and/or radiotherapy.
In another aspect, the present invention also provides a method for treating diseases 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 formulae (I), (II), (III), a pharmaceutically acceptable salt thereof, or an isomer 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 represented by the aforementioned general formula (I), (II), (III), a pharmaceutically acceptable salt thereof or an isomer thereof, the aforementioned pharmaceutical preparation or pharmaceutical composition; the anti-cancer agent is as described above.
In another aspect, the present invention also provides a kit comprising:
(a) an effective amount of one or more compounds of the general formulas (I), (II) and (III), pharmaceutically acceptable salts thereof or isomers thereof,
and (b) an effective amount of one or more anti-cancer agents.
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 related to the administration mode of the drug, the pharmacokinetics of the medicament, the severity of the disease, the individual 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 and 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 by one or more hydroxy, amino or halogenAnd (4) substitution.
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 BDA0002705332420000181
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, and examples thereof include phenyl and the like.
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. "5-8 membered monocyclic heteroaryl" includes, for example, "5-7 membered monocyclic heteroaryl", "5-6 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 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, and the like. The "5-6 membered monocyclic heteroaryl" refers to a specific example containing 5 to 6 ring atoms in the 5-8 membered monocyclic 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-to 10-membered fused heteroaryl", "8-to 9-membered fused heteroaryl", and the like, which may be fused in a benzo-5-6-membered heteroaryl, 5-6-membered heteroaryl and 5-6-membered heteroaryl, and the like; 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.
"C" according to the invention3-6Cycloalkyl "refers to a saturated or partially saturated monocyclic ring group containing 3 to 6 ring atoms and having no aromaticity, as defined in the present invention by" C3-6Cycloalkyl "includes" C3-6Saturated cycloalkyl radicals "and" C3-6Partially saturated cycloalkyl radicals "Preferably "C3-4Cycloalkyl group "," C5-6Cycloalkyl group "," C3-5Cycloalkyl groups "and the like. Examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexene, etc.
"C" according to the invention3-6The heterocyclic group "means a saturated or partially saturated and non-aromatic monocyclic cyclic group containing at least one hetero atom (e.g., containing 1,2,3, 4 or 5) which is a nitrogen atom, an oxygen atom and/or a sulfur atom and has 3 to 6 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. "C" according to the invention3-6Heterocyclyl "includes" C3-6Saturated heterocyclic radicals "and" C3-6Partially saturated heterocyclyl ". Said "C3-6Heterocyclyl "preferably" C3-4Heterocyclic group "," C3-5Heterocyclic group "," C5-6Heterocyclyl "and the like. Specific examples thereof include, but are not limited to: aziridinyl, 2H-aziridinyl, diazaziridinyl, 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, piperidyl, tetrahydropyridinyl, piperidonyl, tetrahydropyridinonyl, dihydropiperidonyl, piperazinyl, morpholinyl and the like.
The term "optionally substituted with a substituent" as used herein refers to both the case where one or more hydrogen atoms on a substituted group are "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, 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 means that the compounds of the present invention contain one or more asymmetric centers and thus are available 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 a disclosed compound 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:
Figure BDA0002705332420000201
wherein Hal, Hal 'and Hal' are respectively and independently selected from F, Cl, Br and I; corresponding to X1-X5、Y1-Y5、X、Y、 R1、R2Ring A, m is as previously defined. The method comprises the following steps:
(a) reacting the intermediate 1 with pinacol diboron under the conditions of a catalyst and alkalinity to generate an intermediate 2;
(b) the intermediate 2 and the intermediate 3 are subjected to Suzuki coupling reaction under the action of a catalyst to generate an intermediate 4;
(c) and reacting the intermediate 4 and the intermediate 5 under alkaline conditions to generate the compound of the general formula (I), wherein Y is O.
(d) The compound (Y is O) in the general formula (I) reacts under the action of a Lawson reagent to generate the compound (Y is S) in 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, ethanol, tetrahydrofuran, toluene, dimethyl ether, dichloromethane, chloroform, dichloroethane, 1, 4-dioxane, trifluoroacetic acid, and water, and a single 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 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 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)3Chlorine, chlorinePalladium oxide, palladium acetate, palladium triphenylphosphine, and the like.
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, by the methods 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 protecting carboxyl groups 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 aboveAnd (5) defining.
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 or the isomer 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 isomer 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:
EDCI: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; DMAP: 4-dimethylaminopyridine; DCM is dichloromethane; MeOH: methanol; TFA is trifluoroacetic acid; pd (dppf)2Cl21,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; THF: tetrahydrofuran; lawson's reagent: 2, 4-bis (p-methoxyphenyl) -1, 3-dithia-2, 4-diphosphetane-2, 4 sulfide; EA: ethyl acetate; PE: petroleum ether; pd (PPh)3)2Cl2: bis (triphenylphosphine) palladium dichloride; NMP: n-methyl pyrrolidone; DIPEA is N, N-diisopropylethylamine; tf2O: trifluoromethanesulfonic anhydride; HATU: 2- (7-azabenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate;DIEA: n, N-diisopropylethylamine; SFC: supercritical fluid chromatography; p-TsOH: p-toluenesulfonic acid; b is2pin2: pinacol ester bisboronic acid.
Preparation example one: preparation of 8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carboxamide
1. Preparation of 8- (3- ((tert-butoxycarbonyl) amino) prop-1-en-2-yl) quinoline-4-carboxylic acid
Figure BDA0002705332420000221
Tert-butyl (2- (4-cyanoquinolin-8-yl) allyl) carbamate (1.2g,3.9mmol), KOH (0.87g,15.5 mmol) was dissolved in ethanol (30mL), water (10mL), and reacted at 110 ℃ for 10 h. After the reaction, adjusting pH to 5-6 with dilute hydrochloric acid, adding water (20mL), EA extracting for three times (3X 30mL), combining organic phases, and passing through anhydrous Na2SO4Drying, filtering and spin-drying to obtain the product (770mg, yield 60.3%).
2. Preparation of tert-butyl (2- (4- (methylcarbamoyl) quinolin-8-yl) allyl) carbamate
Figure BDA0002705332420000231
8- (3- ((tert-butoxycarbonyl) amino) prop-1-en-2-yl) quinoline-4-carboxylic acid (770mg), methylamine hydrochloride (317mg, 4.70mmol), EDCI (893mg,4.70mmol), DMAP (862mg,7.05mmol) were dissolved in DCM (20mL) and reacted at 25 ℃ for 2 h. After the reaction, water (20mL) is added, extraction is carried out for three times, organic phases are combined and are treated by anhydrous Na2SO4Drying, filtering, spin-drying, and reverse C18 separation (acetonitrile/water, acetonitrile 30% -50%) to obtain 800mg crude product.
3. Preparation of tert-butyl (2-4- (methylcarbamoyl) quinolin-8-yl) propyl) carbamate
Figure BDA0002705332420000232
Will (2- (4- (methyl)Carbamoyl) quinolin-8-yl) allyl) carbamic acid tert-butyl ester (800mg crude from above) was dissolved in methanol (20mL), Pd/C (200mg), H was added2Reacting for 1h at 25 ℃ under the environment. After the reaction was complete, suction filtration was performed, the filtrate was dried by spin drying, and forward separation (DCM: MeOH ═ 20:1) gave the product (646mg, 80.5% yield over two steps).
4. Preparation of 8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carboxamide
Figure BDA0002705332420000233
Tert-butyl (2- (4- (methylcarbamoyl) quinolin-8-yl) propyl) carbamate (646mg) was dissolved in DCM (10mL), and TFA (6mL) was added dropwise and reacted at 25 ℃ for 1 h. After the reaction, the crude product (1.03 g) was obtained by spin-drying.
Preparation example two: preparation of 6- (6-chloropyrimidin-4-yl) pyrazolo [1,5-a ] pyrimidine
1. Preparation of 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] pyrimidine
Figure BDA0002705332420000234
Reacting 6-bromo-pyrazolo [1, 5-a)]Pyrimidine (900mg,4.5mmol), pinacol diboron (2.3g,9.1mmol), Pd (dppf)2Cl2(90.0mg,0.12mmol), potassium acetate (900.0mg,9.2mmol) were dissolved in toluene (30mL), and after the addition, the reaction was carried out at 90 ℃ under nitrogen for 3 hours, and the reaction solution was used directly for the next reaction.
2. Preparation of 6- (6-chloropyrimidin-4-yl) pyrazolo [1,5-a ] pyrimidine
Figure BDA0002705332420000241
Mixing 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a]To the pyrimidine reaction solution were added sodium carbonate (1.4g,13.2mmol), 4, 6-dichloropyrimidine (990.0mg,6.6mmol), Pd (dppf)2Cl2(90.0mg,0.12mmol), toluene (5.0mL)) And water (5.0 mL). After the addition, the reaction was carried out at 100 ℃ for 3 hours. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography (MeOH: DCM ═ 1:20) to obtain the objective compound (540mg, crude product).
Preparation example three: preparation of (R) -8- (1-aminopropan-2-yl) -N-methylquinoline-4-carboxamide hydrochloride
1. Preparation of tert-butyl (2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) allyl) carbamate
Figure BDA0002705332420000242
To N-tert-butoxycarbonylaminopropyne (150.0g,967.7mmol), B at 0 deg.C2(Pin)2(300.0g, 1181.1 mmol), CuCl (10.0g,100.8mmol), t-BuONa (15.0g,156.1mmol), and P (t-Bu)3MeOH (75.0mL,1875.0mmol) was slowly added dropwise to a suspension of (25.0g,123.6 mmol) in 3.0L of toluene, and after the addition was complete, the system was warmed to 20 ℃ and stirred for 16 h. Silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) gave the crude compound (330.0 g) which was used directly in the next step.
2. Preparation of tert-butyl (2- (4-hydroxyquinolin-8-yl) allyl) carbamate
Figure BDA0002705332420000243
A mixture containing 4-hydroxy-8-bromoquinoline (150.0g,669.6mmol), tert-butyl (2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) allyl) carbamate (288.0g,1014.1mmol), Pd (dppf) Cl2(15.0g,20.5mmol), and Na2CO3A suspension of (144.0g,1358.5mmol) 1, 4-dioxane (1.9L) and water (0.2L) was stirred at 100 ℃ for 16h and tert-butyl (2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) allyl) carbamate (90.0g) and Pd (dppf) Cl were added2(12.0g), stirring was continued at 100 ℃ for 16 hours. Direct silica gel column chromatography (dichloromethane: methanol ═ 20:1) afforded the crude compound (120.0g) which was used directly in the next step.
3. Preparation of tert-butyl (2- (4-hydroxyquinolin-8-yl) propyl) carbamate
Figure BDA0002705332420000251
A suspension (1.5L) of tert-butyl (2- (4-hydroxyquinolin-8-yl) allyl) carbamate in methanol containing (100.0g,333.3mmol) and 10% Pd/C (50.0g) was stirred under hydrogen at 40 ℃ for 4 hours, filtered through Celite, and the solvent was spin-dried to obtain the product (86.0g, yield: 85.4%).
4. Preparation of 8- (1- (((tert-butoxycarbonyl) amino) prop-2-yl) quinolin-4-yl trifluoromethanesulfonate
Figure BDA0002705332420000252
To a solution of tert-butyl (2- (4-hydroxyquinolin-8-yl) propyl) carbamate (86.0g,284.8mmol) and pyridine (111.8g,1415.2mmol) in 1.0L of dichloromethane at-20 deg.C was slowly added Tf dropwise2O (120.4g,427.0mmol), and after the addition was complete, the mixture was stirred at-20 ℃ for 20 min. The reaction was quenched by addition of saturated aqueous citric acid (500mL), and the organic phase was separated, dried over anhydrous sodium sulfate, and spin-dried to give the product (120.0g, yield: 97.0%).
5. Preparation of tert-butyl (2- (4-cyanoquinolin-8-yl) propyl) carbamate
Figure BDA0002705332420000253
8- (1- (((tert-butoxycarbonyl) amino) propan-2-yl) quinolin-4-yl trifluoromethanesulfonate (120.0g,276.5mmol), Zn (CN)2(40.8g,347.5mmol) and Pd (PPh)3)4A suspension (1.4L) of (16.8g,14.5mmol) in methanol was stirred at 100 ℃ for 12 hours under nitrogen. The solvent was dried, water (500.0mL) was added, extraction was performed with ethyl acetate (500.0mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography over silica gel (petroleum ether: ethyl acetate: 10:1) gave the product (76.0g, yield: 88.4%).
6. Preparation of 8- (1- ((tert-butoxycarbonyl) amino) propan-2-yl) quinoline-4-carboxylic acid
Figure BDA0002705332420000254
A mixture of tert-butyl (2- (4-cyanoquinolin-8-yl) propyl) carbamate (76.0g,243.6mmol) and KOH (136.8g, 2442.9mmol) in ethanol (800.0mL) and water (280.0mL) was stirred at 120 ℃ for 12 hours. The pH was adjusted to 5 to 6 with dilute hydrochloric acid to precipitate a solid, which was then filtered to obtain the product (41.0g, yield: 50.9%).
7. Preparation of (R) - (2- (2- (4- (methylcarbamoyl) quinolin-8-yl) propyl) carbamic acid tert-butyl ester
Figure BDA0002705332420000261
8- (1- ((tert-butoxycarbonyl) amino) propan-2-yl) quinoline-4-carboxylic acid (37.7g,114.0mmol), HATU (86.9 g,228.0mmol), MeNH2A suspension (500.0mL) of HCl (15.4g,228.0mmol) and DIEA (29.4g,228.0mmol) in dichloromethane was stirred at 10 ℃ for 16 h. Water (500.0mL) was added, extracted with dichloromethane (500.0mL x 3), and the organic phases were combined and dried over anhydrous sodium sulfate. Silica gel column chromatography (dichloromethane: methanol 60: 1-20: 1) to obtain crude product, beating the crude product with ethyl acetate to obtain racemate (23.9g), and SFC separation (column model: CHIRALPAX AY-H (AYH0 CE-vc0010.46cm i.d. 25cm L), mobile phase: n-hexane/ethanol 90:10(V: V), peak time: 16.928min) to obtain target compound (12g, yield: 30.6%).
8. Preparation of (R) -8- (1-aminopropan-2-yl) -N-methylquinoline-4-carboxamide hydrochloride
Figure BDA0002705332420000262
Tert-butyl (2- (4- (methylcarbamoyl) quinolin-8-yl) propyl) carbamate (3.0g, 8.7mmol) was dissolved in a solution of hydrogen chloride in 1, 4-dioxane (30.0mL) and stirred at 20 ℃ for 1.5 hours. Spin dry to give the crude product (2.6g) which was used directly in the next step.
The first embodiment is as follows: preparation of N-methyl-8- (1- ((6- (pyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carboxamide (Compound 2)
Figure BDA0002705332420000263
6- (6-Chloropyrimidin-4-yl) pyrazolo [1,5-a ] pyrimidine (240.0mg,1.0mmol), sodium carbonate (1.0g,9.4mmol) and 8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carboxamide (350.0mg, crude) were dissolved in a mixed system of THF (30mL) and water (7.4 mL), stirred at 80 ℃ for 16h and then subjected to column chromatography by concentration (MeOH: DCM ═ 1:20) to give the title compound (150.0mg, yield 34.2%).
Molecular formula C24H22N8O molecular weight 438.5 LC-MS (M/e):439.2(M + H)+)
1H-NMR(400MHz,DMSO-d6)δ:9.80-9.41(m,1H),9.00-8.99(m,1H),8.67-8.65(s,1H), 8.61-8.41(s,1H),8.40-8.30(s,1H),8.05-7.95(m,1H),7.86-7.72(s,1H),7.71-7.61(m,2H), 7.51-7.62(s,1H),6.82-6.71(s,1H),4.68-4.45(s,1H),3.92-3.65(s,2H),2.90-2.85(s,3H), 1.45-1.39(s,3H)。
Example two: preparation of N-methyl-8- (1- ((6- (pyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carbothioamide (Compound 7)
Figure BDA0002705332420000271
N-methyl-8- (1- ((6- (pyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carboxamide (37.5mg,0.08mmol), lawson's reagent (212mg,0.52mmol) was dissolved in THF (8mL), reacted at 75 ℃ for 16h and concentrated column chromatography (MeOH: DCM ═ 1:20) afforded the title compound (20.0mg, 54.9% yield).
Molecular formula C24H22N8Molecular weight of S454.6 LC-MS (M/e):455.2(M + H)+)
1H-NMR(400MHz,CDCl3-d6)δ:9.80-9.51(s,1H),9.10-8.90(s,2H),8.47-8.35(s,1H), 8.31-8.21(s,1H),7.92-7.85(m,1H),7.67-7.55(m,1H),7.51-7.32(m,2H),6.78-6.61(s,1H), 7.31-6.12(s,2H),4.55-4.39(s,1H),3.89-4.73(s,2H),3.52-3.35(s,3H),1.62-1.45(s,3H)。
Example three: preparation of N-methyl-8- (1- ((6- (pyrrolo [1,2-a ] pyrimidin-3-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carboxamide (Compound 1)
1. Preparation of 5-bromo-2-propynyl pyrimidine
Figure BDA0002705332420000272
2, 5-dibromopyrimidine (9.0g,38.1mmol), tributylstannyl propiolate (16.3g,49.6mmol), Pd (PPh)3)2Cl2(5.3g,7.6mmol) in 1, 4-dioxane (90mL), N2And reacting at 80 ℃ for 3h under protection. After the reaction is finished, adding saturated NaOH solution and saturated NaHCO3The solution was stirred for 30min, water (50mL) was added, EA extracted three times (3 x 100mL), the organic phases were combined and passed over anhydrous Na2SO4Drying, filtering, spin-drying, and normal phase preparative chromatography (EA: PE ═ 1:5) gave the product (4.0g, yield 53.5%).
2. Preparation of 3-bromopyrrolo [1,2-a ] pyrimidines
Figure BDA0002705332420000273
5-bromo-2-propynyl pyrimidine (4.5g,22.9mmol), CuCl (0.5g,4.6mmol), TEA (7.0g,69.0mmol), DMA (80mL), N2Reacting for 5 hours at 140 ℃ under protection. After the reaction was complete, water (50mL) was added, EA was extracted three times (3X 50mL), the organic phases were combined and passed over anhydrous Na2SO4Drying, filtration, spin-drying and normal phase chromatography (EA: PE ═ 1:10) gave the product (960mg, 21.3% yield).
3. Preparation of 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [1,2-a ] pyrimidine
Figure BDA0002705332420000281
Reacting 3-bromopyrrolo [1,2-a ]]Pyrimidine (900mg,4.6mmol), pinacol ester bisoborate (2.3g,9.2 mmol), Pd (PPh)3)2Cl2(323mg,0.5mmol), potassium acetate (1.35g,13.8mmol), dissolved in 1, 4-dioxane (20ml), N2And reacting at 90 ℃ for 3h under protection. After the reaction was completed, it was used in the next step.
4. Preparation of 3- (6-chloropyrimidin-4-yl) pyrrolo [1,2-a ] pyrimidine
Figure BDA0002705332420000282
Reacting 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [1,2-a ]]Pyrimidine (6mL of the reaction solution from the previous step), Pd (PPh)3)2Cl2(98mg,0.1mmol)，Na2CO3(487mg,4.6mmol), dissolved in 1, 4-dioxane (20mL), added water (1mL), N2And reacting at 100 ℃ for 12h under protection. After the reaction was completed, spin-dried, and subjected to normal phase preparative chromatography (EA: PE ═ 1:3) to obtain a product (340 mg).
5. Preparation of N-methyl-8- (1- ((6- (pyrrolo [1,2-a ] pyrimidin-3-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carboxamide
Figure BDA0002705332420000283
Reacting 3- (6-chloropyrimidin-4-yl) pyrrolo [1,2-a]Pyrimidine (100mg,0.4mmol), 8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carboxamide trifluoroacetate (153mg crude), Na2CO3(364mg,3.4mmol) was added to a mixed solution of THF (5mL) and water (2.5mL) and reacted at 85 ℃ for 12 h. After the reaction was complete, the product was spun dry and separated on silica gel (DCM: MeOH: 20:1) to give the title compound (8 mg).
Molecular formula C25H23N7O has a molecular weight of 437.5 LC-MS(M/e):438.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:9.35(s,1H),9.00(s,1H),8.66(s,1H),8.47(s,1H), 7.99-8.01(d,1H,J＝8.0Hz),7.79(s,1H),7.55-7.67(m,4H),6.91(s,1H),6.57(s,1H),4.54(s, 1H),3.63(s,2H),2.87-2.88(d,3H,J＝8.0Hz),1.40(s,3H)。
Example four: preparation of (R) -N-methyl-8- (1- ((6- (pyrrolo [1,2-a ] pyrimidin-3-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carboxamide (Compound 1-1)
Figure BDA0002705332420000291
Reacting 3- (6-chloropyrimidin-4-yl) pyrrolo [1,2-a]Pyrimidine (97.0mg, crude), (R) -8- (1-aminopropan-2-yl) -N-methylquinoline-4-carboxamide hydrochloride (60.0mg, crude), Na2CO3(268.0mg,2.5mmol), dissolved in THF (8mL), and water (0.5mL) was added, after which the reaction was carried out at 80 ℃ for 12 h. After the reaction was complete, spin-dry, add water (10mL), extract three times (3 x 30mL) with DCM: MeOH: 10:1, combine the organic phases, anhydrous Na2SO4Drying, filtration, spin-drying and separation on silica gel (DCM: MeOH ═ 20:1) gave the title compound (33 mg).
Molecular formula C25H23N7O molecular weight 437.5 LC-MS (M/e):438.2(M + H)+)
1H-NMR(400MHz,DMSO-d6)δ:9.30(s,1H),8.97(s,1H),8.70(s,1H),8.47(s,1H), 7.96-7.80(d,1H,J＝8.0Hz),7.52-7.75(m,5H),7.00(s,1H),6.53(s,1H),4.50(s,1H),3.73(s, 2H),2.84-2.85(d,3H,J＝4.0Hz),1.20(s,3H)。
Example five: preparation of (R) -N-methyl-8- (1- ((6- (pyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carboxamide (Compound 2-1)
Figure BDA0002705332420000292
(R) -8- (1-aminopropan-2-yl) -N-methylquinoline-4-carboxamide hydrochloride (170.0mg,0.61mmol), 6- (6-chloropyrimidin-4-yl) pyrazolo [1,5-a ] pyrimidine (223.0mg,0.96mmol), sodium carbonate (245.0mg,2.3mmol) were dissolved in a mixture of THF (11.0mL) and water (3.3mL), the system was reacted at 80 ℃ for 16 hours, concentrated, and the residue was subjected to column chromatography (dichloromethane: methanol ═ 20:1)) to obtain a compound (135.0mg, yield: 50.5%).
Molecular formula C24H22N8O molecular weight 438.5 LC-MS (M/e):439.2(M + H)+)
1H-NMR(400MHz,DMSO)δ:9.48-8.97(m,3H),8.65(s,1H),8.49(s,1H),8.31(s,1H), 7.99-7.96(m,1H),7.96-7.62(m，3H),7.60-7.5(m 1H),7.5-6.99(m,1H),6.99-6.80(s,1H), 4.52(s,1H),3.82-3.45(m,2H),2.86-2.98(m,3H),1.37(s,3H)。
Example six: preparation of (R) -8- (1- ((6- (imidazo [1,5-a ] pyrimidin-3-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carboxamide (Compound 3-1)
1. Preparation of 5-bromo-2- (bromomethyl) pyrimidine
Figure BDA0002705332420000301
5-bromo-2-methylpyrimidine (20.0g,115.6mmol), NBS (20.0g,112.4mmol), BPO (2.0g) was dissolved in carbon tetrachloride (350.0 mL). The system is reacted for 20 hours at 80 ℃, and after the reaction is finished, the crude product is cooled and filtered and is directly subjected to the next reaction.
2. Preparation of (5-bromopyrimidin-2-yl) methylamine
Figure BDA0002705332420000302
The crude product obtained in the above step was dissolved in methanol (100.0mL), and then slowly dropped into ammonia (100.0mL), reacted at 25 ℃ for 2 hours, after completion of the reaction, concentrated, and the residue was subjected to column chromatography (dichloromethane: methanol 10:1) to obtain a crude compound (8.7g, crude yield in two steps: 40.1%).
3. Preparation of N- ((5-bromopyrimidin-2-yl) methyl) formamide
Figure BDA0002705332420000303
Formic acid (20.0mL) was added to acetic anhydride (20.0mL), the system was reacted at 50 ℃ for 5 hours, then (5-bromopyrimidin-2-yl) methylamine (7.0g,37.2mmol) was added to the system and the reaction was continued at 50 ℃ for 16 hours, after the reaction was completed, concentration was performed, and the residue was subjected to column chromatography (dichloromethane: methanol ═ 20:1) to give a crude compound (1.3g, crude yield: 16.3%).
4. Preparation of 3-bromoimidazo [1,5-a ] pyrimidines
Figure BDA0002705332420000304
N- ((5-bromopyrimidin-2-yl) methyl) formamide (1.3g,6.0mmol) was dissolved in phosphorus oxychloride (10.0mL), then the system was reacted at 110 ℃ for 1.5 hours, after the reaction was completed, concentrated, and the residue was subjected to column chromatography (dichloromethane: methanol ═ 20:1) to give a crude compound, which was then subjected to reverse phase column chromatography (methanol: water ≈ 35%) to give a crude compound (750mg, crude yield 63.1%).
5. Preparation of 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) imidazo [1,5-a ] pyrimidine
Figure BDA0002705332420000305
Reacting 3-bromoimidazo [1,5-a ]]Pyrimidine (500.0mg,2.5mmol) was dissolved in dioxane (10.0mL), potassium acetate (500.0mg,5.1mmol) and pinacol diboron (1.3g,5.1mmol), Pd (dppf) Cl were added2(50.0mg) and reacting at 90 ℃ for 6 hours, and after the reaction is finished, cooling to 25 ℃ to directly carry out the next reaction on the system.
6. Preparation of 3- (6-chloropyrimidin-4-yl) imidazo [1,5-a ] pyrimidine
Figure BDA0002705332420000311
To a solution containing 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) imidazo [1,5-a]To the reaction solution of pyrimidine (crude in the above step, 2.5mmol) was added sodium carbonate (800.0mg,151.0mmol), 4, 6-dichloropyrimidine (560.0mg,3.8mmol), water (2.0mL), Pd (dppf) Cl2(50.0 mg). After the reaction was completed at 90 ℃ for 40 minutes, the reaction was filtered, concentrated, and the residue was subjected to column chromatography (dichloromethane: methanol ═ 50:1) to give a crude compound (250.0mg, crude yield in two steps: 43.1%).
7. Preparation of (R) -8- (1- ((6- (imidazo [1,5-a ] pyrimidin-3-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carboxamide
Figure BDA0002705332420000312
(R) -8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carboxamide hydrochloride (120.0mg,0.43mmol), 3- (6-chloropyrimidin-4-yl) imidazo [1,5-a ] pyrimidine (100.0mg,0.43mmol) and sodium carbonate (230.0mg,2.2mmol) were dissolved in a mixture of THF (10.0mL) and water (2.0mL), and after the system was reacted at 80 ℃ for 16 hours, it was concentrated, and the residue was subjected to reverse phase column chromatography (methanol: water: acetic acid ═ 4:10: 0.5%) to obtain a compound (10.0mg, yield: 5.3%).
Molecular formula C24H22N8O molecular weight 438.5 LC-MS (M/e):439.2(M + H)+)
1H-NMR(400MHz,DMSO-d6)δ:9.37(s,1H),8.99(s,1H),8.98-8.67(m,2H),8.67-8.45 (m,2H),8.01-7.99(m,1H),7.96-7.56(m,5H),7.57-6.93(m,1H),4.53(s,1H),3.80-3.67(s, 2H),2.88(m,3H),1.39(s,3H)。
Example seven: preparation of N-methyl-8- (1- ((6- (pyrrolo [1,2-a ] pyrimidin-3-yl ] pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carbothioamide (Compound 6)
1. Preparation of tert-butyl (2- (4- (methylaminomethionyl) quinolin-8-yl) propyl) carbamate
Figure BDA0002705332420000321
Tert-butyl (2- (4- (methylcarbamoyl) quinolin-8-yl) propyl) carbamate (340mg,1.0mmol), lawson's reagent (809mg,2.0mmol) was dissolved in THF (20mL) and reacted at 70 ℃ for 6 h. After the reaction was complete, water (40mL) was added, EA extracted three times (3 × 80mL), the organic phases were combined, filtered, spun-dried and separated by silica gel column (PE: EA ═ 1:1) to give the crude product (600 mg).
2. Preparation of 8- (1-aminopropyl-2-yl) -N-methylquinoline-4-thiocarboxamide trifluoroacetate
Figure BDA0002705332420000322
Tert-butyl (2- (4- (methylaminomethionyl) quinolin-8-yl) propyl) carbamate (550mg crude) was dissolved in DCM (10mL), added TFA (4mL), and reacted at 25 ℃ for 2 h. After the reaction was complete, it was spun dry and chromatographed reverse phase C18 (50% methanol/water) to give the crude product (200 mg).
3. Preparation of N-methyl-8- (1- ((6- (pyrrolo [1,2-a ] pyrimidin-3-yl ] pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carbothioamide
Figure BDA0002705332420000323
Reacting 3- (6-chloropyrimidin-4-yl) pyrrolo [1,2-a]Pyrimidine (50mg,0.2mmol), 8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carbothioamide trifluoroacetate (78mg crude), Na2CO3(89mg,0.8mmol), dissolved in THF (5mL), and water (1mL) was added to react at 80 ℃ for 24 h. After the reaction was completed, spin-dried, and subjected to preparative high-pressure chromatography (acetonitrile: water: 1:4) to obtain the objective compound (10 mg).
Molecular formula C25H23N7Molecular weight of S453.6 LC-MS (M/e):454.2(M + H)+)
1H-NMR(400MHz,CD3OD)δ:9.14(s,1H),8.90(s,1H),8.49(s,1H),8.40(s,1H),7.90- 7.92(d,1H,J＝8.0Hz),7.75-7.76(d,1H,J＝4.0Hz),7.56-7.60(t,1H),7.52(s,1H),7.37(s,1H), 7.07(s,1H),6.80(s,1H),6.62(s,1H),4.63(s,2H),3.82(s,1H),3.20(s,3H),1.51(s,3H)。
Example eight: preparation of (R) -8- (1- ((6- (imidazo [1,2-a ] pyrimidin-6-yl ] pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carbothioamide (Compound 9-1)
1. Preparation of 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) imidazo [1,2-a ] pyrimidine
Figure BDA0002705332420000331
To 6-bromoimidazo [1,2-a ]]To a solution of pyrimidine (1.00g,5.05mmol) in 1, 4-dioxane (15mL) was added pinacol diboron (2.56g,10.1mmol), Pd (dppf) Cl2(0.37g,0.51mmol) and KOAc (0.99g, 10.1mmol), N2Reacting for 3 hours at 90 ℃ under protection. The reaction solution was cooled to 20 ℃ and used directly in the next step.
2. Preparation of 6- (6-chloropyrimidin-4-yl) imidazo [1,2-a ] pyrimidine
Figure BDA0002705332420000332
To the reaction mixture from the above step were added water (5mL), 4, 6-dichloropyrimidine (1.10g,5.57mmol), Pd (dppf) Cl2(0.37g,0.51mmol) and Na2CO3(1.60g,15.1mmol) and reacted at 90 ℃ for 3 h. The solvent was concentrated, extracted with water (50mL) and ethyl acetate (3 x 50mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (MeOH: DCM ═ 1:20) to give the title compound (240mg, yield 20%).
3. Preparation of (R) - (2- (4- (methylaminomethionyl) quinolin-8-yl) propyl) carbamic acid tert-butyl ester
Figure BDA0002705332420000333
To a solution of (R) - (tert-butyl 2- (2- (4- (methylcarbamoyl) quinolin-8-yl) propyl) carbamate (100mg,0.29 mmol) in THF (5mL) was added lawson's reagent (235mg,0.58mmol), reacted at 70 ℃ for 5h, the solvent was concentrated, extracted with water (15mL) and ethyl acetate (15mL), the organic phase was washed 2 times with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, concentrated, and purified using a preparation plate (PE: EA ═ 1:3) to obtain the objective compound (95mg, yield 91%).
4. Preparation of (R) -8- (1-aminopropan-2-yl) -N-methylquinoline-4-thiocarboxamide hydrochloride
Figure BDA0002705332420000341
To a solution of (R) - (2- (4- (methylaminomethionyl) quinolin-8-yl) propyl) carbamic acid tert-butyl ester (95mg,0.26mmol) in DCM (2mL) was added HCl (4M in 1, 4-dioxane) (3mL) and reacted at 20 ℃ for 1 h. The solvent was removed by concentration. The crude was used directly in the next step (90mg crude).
5. Preparation of (R) -8- (1- ((6- (imidazo [1,2-a ] pyrimidin-6-yl ] pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carbothioamide
Figure BDA0002705332420000342
To 6- (6-chloropyrimidin-4-yl) imidazo [1,2-a]THF/H of pyrimidine (126mg, 0.54mmol) and (R) -8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carbothioamide hydrochloride (crude from above)2Na was added to an O (3:1) (6mL) solution2CO3(289mg,2.70mmol), reaction at 80 ℃ for 18 h. Concentrate to remove the solvent, extract with water (5mL) and ethyl acetate (3 x 10mL), dry concentrate the organic phase on a large plate (DCM: MeOH ═ 10:1), purify on a C18 column (MeCN/H)2O ═ 0 to 50%), yielding the product (24.5mg, two-step yield 20.7%).
Molecular formula C24H22N8Molecular weight of S454.6 LC-MS (M/e):455.2(M + H)+)
1H NMR(400MHz,DMSO-d6)δ:10.75(s,1H),9.55(s,1H),8.97-8.90(m,2H),8.47(s, 1H),7.99(s,1H),7.78-7.58(m,5H),7.36(s,1H),6.94(brs,1H),4.49(s,2H),3.74-3.70(m, 1H),3.20(d,J＝4.4Hz,3H),1.35(m,3H)。
Example nine: preparation of N-methyl-8- (1- ((6- (pyrrolo [1,2-a ] pyrimidin-3-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carbothioamide (Compound 6-1)
Figure BDA0002705332420000343
Reacting 3- (6-chloropyrimidin-4-yl) pyrrolo [1,2-a]Pyrimidine (70mg, crude), (R) -8- (1-aminopropan-2-yl) -N-methylquinoline-4-carbothioamide hydrochloride (109mg, crude), Na2CO3(191mg,1.8mmol) was added to a mixed solution of THF (6mL) and water (1mL) and reacted at 80 ℃ for 12 h. After the reaction was completed, the reaction was spun off, and separated by silica gel plate (DCM: MeOH ═ 20:1) to obtain the objective compound (60 mg).
Molecular formula C25H23N7Molecular weight of S453.6 LC-MS (M/e):454.2(M + H)+)
1H-NMR(400MHz,DMSO-d6)δ:9.20(s,1H),8.90(s,1H),8.47(s,1H),8.37(s,1H), 7.89-7.90(d,1H,J＝4.0Hz),7.72-7.77(d,1H,J＝20.0Hz),7.53-7.57(t,1H),7.49(s,1H),7.42 (s,1H),7.04(s,1H),6.75(s,1H),6.55(s,1H),4.58(s,1H),3.76-3.93(m,2H),3.30(s,3H), 1.15(s,3H)。
Example ten: preparation of (R) -N-methyl-8- (1- ((6- (pyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-thiocarboxamide (compound 7-1)
Figure BDA0002705332420000351
(R) -N-methyl-8- (1- ((6- (pyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carboxamide (50.0mg,0.11mmol) was dissolved in tetrahydrofuran (5.0mL), a lawson's reagent (230.0mg,0.56mmol) was added, the system was reacted at 75 ℃ for 6 hours, the reaction was completed, concentration was performed, and the residue was subjected to column chromatography (dichloromethane: methanol ═ 20:1)) to obtain a compound (35.0mg, yield: 70%).
Molecular formula C24H22N8Molecular weight of S454.6 LC-MS (M/e):456.2(M + H)+)
1H-NMR(400MHz,DMSO)δ:10.78(s,1H),9.81-9.18(m,1H),9.09-8.91(m,2H),8.51- 8.41(m,1H),8.40-8.25(m,1H),7.88-7.51(m,4H),7.45-7.35(m,1H),7.05-6.79(m,1H),4.52 (s,1H),3.82-3.45(m,2H),3.3-3.2(m,3H),1.37(s,3H)。
Example eleven: preparation of (R) -8- (1- ((6- (imidazo [1,5-a ] pyrimidin-3-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carbothioamide (Compound 8-1)
Figure BDA0002705332420000352
3- (6-Chloropyrimidin-4-yl) imidazo [1,5-a ] pyrimidine (193.0mg,0.83mmol), (R) -8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carbothioamide hydrochloride (90.0mg,0.3mmol), DIEA (220.0mg,1.7mmol) were dissolved in NMP (6.5mL), the system was subjected to microwave reaction at 120 ℃ for 2 hours, and after completion of the reaction, the crude compound was obtained by reverse phase column chromatography (methanol: water: 70%), followed by column chromatography (dichloromethane: methanol 20:1) to obtain a product (14.0mg, yield: 10.3%).
Molecular formula C24H22N8Molecular weight of S454.6 LC-MS (M/e):455.2(M + H)+)
1H-NMR(400MHz,DMSO)δ:10.78(s,1H),9.43-9.28(m,1H),8.92-8.851(m,1H), 8.75-8.35(m,3H),7.89-6.8(m,7H),4.52(s,1H),3.82-3.45(m,2H),3.3-3.2(m,3H),1.37(s, 3H)。
Example twelve: preparation of 8- (1- ((6- (imidazo [1,2-a ] pyridin-7-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carboxamide (Compound 15)
1. Preparation of 7-bromoimidazo [1,2-a ] pyridines
Figure BDA0002705332420000361
2-amino-4-bromo-pyridine (4.30g,25mmol), chloroacetaldehyde (9.80g,50mmol) were dissolved in H2In O (50mL), the mixture was stirred at 100 ℃ for 5 hours. Cooling to 10 deg.C, adding saturated Na2CO3The pH was adjusted to greater than 7 with aqueous solution, extracted with DCM (100mL) and the organic phases combined. The organic phase was dried over anhydrous sodium sulfate and chromatographed on silica gel (PE/EA ═ 3/7) to give the product (4.06g, 82.9% yield).
2. Preparation of imidazo [1,2-a ] pyridin-7-ylboronic acids
Figure BDA0002705332420000362
Reacting 7-bromoimidazo [1,2-a ]]Pyridine (4.06g,20.7mmol) was dissolved in 1, 4-dioxane (200mL), and pinacol diboron (5.36g,21.1mmol), Pd (dppf) Cl, was added2(731mg,1.0mmol), potassium acetate (6.10g,62.1 mmol), heating to 90 ℃ under the protection of nitrogen for reaction for 16 hours, cooling to 15 ℃ when the reaction is completed, filtering, and concentrating the filtrate for the next reaction.
3. Preparation of 7- (6-chloropyrimidin-4-yl) imidazo [1,2-a ] pyridine
Figure BDA0002705332420000363
Imidazo [1, 2-a)]Pyridin-7-ylboronic acid (crude from above) was dissolved in 1, 4-dioxane (100mL) and 4, 6-dichloropyrimidine (4.59g,31mmol), Pd (dppf) Cl was added2(731mg,1.0mmol), cesium carbonate (13.50g,41.4 mmol), H2O (10 mL). After the addition of nitrogen protection, the temperature is raised to 100 ℃ for reaction for 18 hours, the reaction is finished, and the system is directly dried by spinning and purified by silica gel column chromatography (PE/EA is 1/1) to obtain the product (350mg, the total yield of the two steps is 7.4%).
4. Preparation of 8- (1- ((6- (imidazo [1,2-a ] pyridin-7-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carboxamide
Figure BDA0002705332420000371
7- (6-Chloropyrimidin-4-yl) imidazo [1,2-a]Pyridine (300mg,1.3 mm)ol) THF (10mL), H2O (2mL) was dissolved, 8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carboxamide trifluoroacetate (100mg,0.41 mmol), anhydrous sodium carbonate (87mg,0.82mmol) were added and the reaction was carried out at 80 ℃ for 20 hours, the solvent was dried and the reaction solution was filtered through a filter and filtered18Purifying by column chromatography (H)2O/acetonitrile 2/3) to give the product (30mg, 16.6% yield).
Molecular formula C25H23N7O molecular weight 437.5 LC-MS (M/e):438.2(M + H)+)
1H-NMR(400MHz,CDCl3)δ:9.08-9.07(d,1H,J＝4Hz),8.44(s,1H),8.16-8.11(m,2H), 7.72-7.55(m,4H),7.52-7.45(m,2H),6.23-5.96(m,2H),4.47(s,1H),3.97-3.94(m,1H),3.83- 3.79(m,1H),3.04-3.03(d,3H,J＝4Hz),1.59-1.57(d,3H,J＝8Hz)。
Example thirteen: preparation of (R) -8- (1- ((6- (imidazo [1,2-a ] pyridin-7-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carboxamide (Compound 15-1)
Figure BDA0002705332420000372
7- (6-Chloropyrimidin-4-yl) imidazo [1,2-a]Pyridine (60mg,0.21mmol) was added THF (10mL), H2O (2mL) was dissolved, and then (R) -8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carboxamide hydrochloride (260mg,1.13mmol), anhydrous sodium carbonate (67mg,0.63mmol) were added, reacted at 70 ℃ for 16.6 hours, and the solvent was purified by silica gel column chromatography (DCM/MeOH-20/1) to give the product (45mg, yield 47.9%).
Molecular formula C25H23N7O molecular weight 437.5 LC-MS (M/e):438.2(M + H)+)
1H-NMR(400MHz,CDCl3)δ:9.09-9.08(d,1H,J＝4Hz),8.44(s,1H),8.12-8.09(m,2H), 7.69(s,2H),7.62(s,2H),7.52-7.43(m,2H),5.86-5.66(m,2H),4.45(s,1H),4.03-3.98(m,1H), 3.83-3.77(m,1H),3.03-3.02(d,3H,J＝4Hz),1.59-1.57(d,3H,J＝8Hz)。
Example fourteen: preparation of (R) -8- (1- ((6- (3-fluoropyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carboxamide (Compound 16-1)
1. Preparation of 6-bromo-3-fluoropyrazolo [1,5-a ] pyrimidines
Figure BDA0002705332420000381
6-Bromopyrazolo [1,5-a ] pyrimidine (5.0g, 25.3mmol), 1-chloromethyl-4-fluoro-1, 4-diazobicyclo 2.2.2 octane bis (tetrafluoroborate) salt (9.0g,25.4mmol) were dissolved in acetonitrile (50.0mL), and acetic acid (10.0mL) was added. The reaction was carried out at 70 ℃ for 16 hours, after completion, concentration and column chromatography (ethyl acetate: n-heptane 20:1) gave the crude product (1.5g, crude yield 27.3%).
2. Preparation of 3-fluoro-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] pyrimidine
Figure BDA0002705332420000382
Reacting 6-bromo-3-fluoropyrazolo [1,5-a ]]Pyrimidine (1.5g,7.0mmol) was dissolved in dioxane (10.0mL), potassium acetate (1.7g,17.3mmol) and pinacol diboron (4.4g,17.3mmol), Pd (dppf) Cl were added2(300.0mg) and reacting at 90 ℃ for 6 hours, and after the reaction is finished, cooling to 25 ℃ to directly carry out the next reaction by the system.
3. Preparation of 6- (6-chloropyrimidin-4-yl) -3-fluoropyrazolo [1,5-a ] pyrimidine
Figure BDA0002705332420000383
To a solution containing 3-fluoro-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) imidazo [1,5-a]To the reaction mixture of pyrimidine (crude from the previous step) was added sodium carbonate (2.2g,20.8mmol), 4, 6-dichloropyrimidine (1.5g,10.1mmol), water (8.0mL), Pd (dppf) Cl2(20.0 mg). The reaction was continued at 90 ℃ for 5 hours, after which time it was filtered, concentrated and the residue was chromatographed (dichloromethane: methanol 50:1) to give the crude compound (250.0mg, 14 crude yield in two steps).3％)。
4. Preparation of (R) -8- (1- ((6- (3-fluoropyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carboxamide
Figure BDA0002705332420000384
(R) -8- (1-Aminoprop-2-yl) -N-methylquinoline-4-carboxamide hydrochloride (120.0mg,0.43mmol), 3- (6-chloropyrimidin-4-yl) imidazo [1,5-a ] pyrimidine (100.0mg,0.43mmol), sodium carbonate (220.0mg,2.1mmol) were dissolved in a mixture of THF (15.0mL) and water (2.0mL), the system was reacted at 80 ℃ for 10 hours, concentrated, and the residue was subjected to column chromatography (dichloromethane: methanol ═ 50:1) to give a crude product, which was then washed with methanol to give a product (20.4mg, yield: 10.4%).
Molecular formula C24H21FN8O molecular weight 456.5 LC-MS (M/e):457.2(M + H)+)
1H-NMR(400MHz,DMSO)δ:9.68-9.37(m,1H),9.09-8.90(m,2H),8.68-8.57(m,1H), 8.57-8.35(s,1H),8.01-7.99(m,1H),7.89-7.61(m,3H),7.57-7.51(s,1H),7.57-6.81(m,1H), 4.53(s,1H),3.90-3.67(s,2H),2.88(m,3H),1.39(s,3H)。
Example fifteen: preparation of (R) -N-methyl-8- (1- ((6- (2-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carboxamide (Compound 17-1)
1. Preparation of 6-bromo-2-methylpyrazolo [1,5-a ] pyrimidine
Figure BDA0002705332420000391
3-methyl-1H-pyrazol-5-amine (7.2g,72mmol) was added to acetonitrile (100mL) and, after complete dissolution, 2-bromomalondialdehyde (10.8g,72mmol) was slowly added to the solution, followed by addition of p-toluenesulfonic acid (1.2g,7.2mmol), reaction at 65 ℃ for 1 hour, TLC detection (Rf ═ 0.6, PE: EA ═ 5:1), spin-drying, and column separation (PE: EA ═ 5:1) to give the title compound (0.9g, yield 6%).
2. Preparation of 2-methyl-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrazolo [1,5-a ] pyrimidine
Figure BDA0002705332420000392
Reacting 6-bromo-2-methylpyrazolo [1,5-a ]]Pyrimidine (500mg,2.4mmol) was added to 30mL dioxane, potassium acetate (691mg,7.2mmol), Pd (dppf) Cl was added2(175mg,0.24mmol), pinacol bisborate (1.2g, 4.8mmol), heating to 100 ℃ under the protection of nitrogen for 4 hours, monitoring the reaction by LC-MS, and directly reacting the system in the next step.
3. Preparation of 6- (6-chloropyrimidin-4-yl) -2-methylpyrazolo [1,5-a ] pyrimidine
Figure BDA0002705332420000393
The system (2) was cooled to 10 ℃ and water (3mL), 4, 6-dichloropyrimidine (360mg, 2.4mmol), Pd (dppf) Cl, was added to the reaction mixture2(73mg,0.1mmol) and Na2CO3(636mg,6mmol), reaction at 90 ℃ for 3 h. The solvent was concentrated, 40mL of water and 50mL of ethyl acetate were added for extraction, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (MeOH: DCM ═ 1:20) to give the title compound (150mg, yield 35%).
4. Preparation of (R) -N-methyl-8- (1- ((6- (2-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carboxamide
Figure BDA0002705332420000401
Reacting 6- (6-chloropyrimidin-4-yl) -2-methylpyrazolo [1,5-a ]]Pyrimidine (150mg, 0.61mmol) in THF/H2To a solution of O (3/1) (8mL), Na was added2CO3(323mg,3.1mmol), and (R) -8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carboxamide hydrochloride (170mg,0.61mmol) was added and reacted at 80 ℃ for 18 h. Concentrating to remove solvent, purifying with C18 column (MeOH 0-60%), and making into final productThe crude was purified (MeOH: DCM ═ 1:15) to give the title compound (37.0mg, yield 13%).
Molecular formula C25H24N8O molecular weight 452.5 LC-MS (M/e):453.0(M + H)+)
1H-NMR(400MHz,DMSO-d6)δ:9.38-9.61(m,1H),8.97-9.35(m,2H),8.70(s,1H), 8.50(m,1H),8.01(s,1H),7.88-7.55(m,4H),7.36(s,1H),6.94(s,1H),4.41-4.61(m,1H),3.97- 3.76(m,2H),2.87(d,J＝4.4Hz,3H),2.46(s,3H),1.38(s,3H)。
Example sixteen: preparation of (R) -8- (1- ((6- (3-fluoro-2-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carboxamide (18-1)
1. Preparation of 6-bromo-3-fluoro-2-methylpyrazolo [1,5-a ] pyrimidine
Figure BDA0002705332420000402
6-bromo-2-methylpyrazolo [1,5-a ] pyrimidine (500mg,2.4mmol) was dissolved in acetonitrile (50mL), and 1-chloromethyl-4-fluoro-1, 4-diazobicyclo 2.2.2 octane bis (tetrafluoroborate) salt (1.3g,3.6mmol) was added to react at 10 ℃ for 4 hours. The solvent was concentrated and purified by silica gel column (PE: EA ═ 5:1) to obtain the objective compound (200mg, yield: 36.8%).
2. Preparation of 3-fluoro-2-methyl-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] pyrimidine
Figure BDA0002705332420000403
Reacting 6-bromo-3-fluoro-2-methylpyrazolo [1,5-a ]]Pyrimidine (200.0mg,0.87mmol), pinacol bisborate (332.8mg,1.3mmol), Pd (dppf) Cl2(31.8mg, 43.5. mu. mol), Potassium acetate (255.8mg,2.6mmol) was dissolved in 1, 4-dioxane (10mL), and after addition, N was added2The reaction is carried out for 3h at 90 ℃ under protection and is directly used in the next step.
3. Preparation of 6- (6-chloropyrimidin-4-yl) -3-fluoro-2-methylpyrazolo [1,5-a ] pyrimidine
Figure BDA0002705332420000411
The reaction system in the previous step was supplemented with 4, 6-dichloropyrimidine (193.7mg,1.3mmol), Pd (dppf) Cl2(31.8mg, 43.5μmol)，Na2CO3(275.6mg,2.6mmol), water (2mL), after addition, N2The reaction was carried out at 90 ℃ for 1 hour under protection, and the reaction mixture was purified by a concentrated solvent silica gel column (PE: EA. RTM. 4:1) to obtain the objective compound (120mg, two-step yield: 52.2%).
4. Preparation of (R) -8- (1- ((6- (3-fluoro-2-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carboxamide
Figure BDA0002705332420000412
Reacting 6- (6-chloropyrimidin-4-yl) -3-fluoro-2-methylpyrazolo [1,5-a ]]Pyrimidine (60.0mg,0.23mmol), (R) -8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carboxamide hydrochloride (58.0mg,0.21mmol), Na2CO3(121.5mg,1.2mmol) was dissolved in THF (5mL) and water (1mL), reacted at 80 ℃ for 16h, and purified by silica gel column (DCM: MeOH ═ 20:1) as a concentrated solvent to obtain the objective compound (21.0mg, yield: 21.2%).
Molecular formula C25H23FN8O molecular weight 470.5 LC-MS (M/e):471.2(M + H)+)
1H-NMR(400MHz,CDCl3)δ:9.30-9.52(m,1H),8.97-9.16(m,2H),8.66(d,J＝4.4Hz, 1H),8.45-8.53(m,1H),7.97(d,J＝8.0Hz,1H),7.62-7.75(m,3H),7.52(s,1H),6.94-7.36(m, 1H),4.52(s,1H),3.36-3.77(m,2H),2.84(d,J＝4.8Hz,3H),2.39(s,3H),1.36(s,3H)。
Example seventeen: preparation of (R) -N-methyl-8- (1- ((6- (3-methylimidazo [1,2-a ] pyridin-7-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carboxamide (Compound 28-1)
1. Preparation of 7-bromo-3-methylimidazo [1,2-a ] pyridines
Figure BDA0002705332420000413
To a solution of 2-bromo-1, 1-dimethoxypropane (1.90g,10.4mmol) in dioxane/water (4:1) (8mL) was added HCl (4M in 1, 4-dioxane) (1 mL). The reaction mixture was reacted at 90 ℃ for 1 hour. The pH was adjusted to about 8 with saturated sodium bicarbonate, and 2-amino-4-bromopyridine (0.90g,5.2mmol) was added and reacted at 100 ℃ for 1h with microwave. The product was concentrated to remove dioxane, and filtered to obtain the desired product (0.34g, yield 31%).
2. Preparation of 3-methyl-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) imidazo [1,2-a ] pyridine
Figure BDA0002705332420000421
To 7-bromo-3-methylimidazo [1,2-a ]]Pyridine (210mg,1mmol) in 1, 4-dioxane (15mL) was added pinacol diboron (508mg,2mmol), Pd (dppf) Cl2(73mg,0.1mmol) and KOAc (294mg, 3mmol), N2Reacting for 16h at 80 ℃ under protection. The reaction solution was cooled to 20 ℃ and used directly in the next step.
3. Preparation of 7- (6-chloropyrimidin-4-yl) -3-methylimidazo [1,2-a ] pyridine
Figure BDA0002705332420000422
To the reaction mixture obtained in the above step were added water (2mL), 4, 6-dichloropyrimidine (223mg,1.5mmol), Pd (dppf) Cl2(73mg,0.1mmol) and Na2CO3(318mg,3mmol), and reacted at 80 ℃ for 3 h. The solvent was concentrated, and the crude product was purified by column chromatography (MeOH: DCM ═ 1:20) to give the title compound (150mg, two-step yield 61%).
4. Preparation of (R) -N-methyl-8- (1- ((6- (3-methylimidazo [1,2-a ] pyridin-7-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carboxamide
Figure BDA0002705332420000423
To 7- (6-chloropyrimidin-4-yl) -3-methylimidazo [1,2-a ]]Pyridine (64mg,0.26mmol) and (R) -8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carboxamide hydrochloride (crude) in THF/H2Na was added to an O (3:1) (6mL) solution2CO3(289mg,2.7mmol), reaction at 80 ℃ for 18 h. The solvent was removed by concentration and the crude product was purified by C18 column (MeOH: 0-60%) to give a crude product with a purity of 82% and purified by preparative plate (MeOH: DCM: 1:15) to give the title compound (14.0mg, 12% yield over two steps).
Molecular formula C26H25N7O molecular weight: 451.5 LC-MS (M/e):452.2(M + H)+)
1H NMR(400MHz,MeOD)δ:8.93(s,1H),8.38-8.21(m,2H),8.17(s,1H),8.00(d,J＝8.0 Hz,1H),7.76(d,J＝6.8Hz 1H),7.60(d,J＝8.0Hz,1H),7.55-7.40(m,3H),7.28-6.60(br,1H), 4.55-4.55(m,2H),3.85-3.70(m,1H),3.00(s,3H),2.54(s,3H),1.48(d,J＝6.0Hz,3H)。
Example eighteen: preparation of (R) -N-methyl-8- (1- ((6- (2-methylimidazol [1,2-a ] pyridin-7-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carboxamide (29-1)
1. Preparation of 7-bromo-2-methylimidazo [1,2-a ] pyridine
Figure BDA0002705332420000431
P-toluenesulfonic acid (209.4mg,1.22mmol), 1-bromo-2, 2-dimethoxypropane (5.59g,30.50mmol), 4-bromopyridin-2-amine (1.08g,6.24mmol) were dissolved in water (20mL), reacted at 100 ℃ for 16 hours, cooled to 30 ℃, adjusted to PH 8 with saturated sodium carbonate solution, extracted with ethyl acetate (30mL), washed with organic phase saturated brine (15mL), dried over anhydrous sodium sulfate, and concentrated by column chromatography (ethyl acetate/petroleum ether ═ 30%) to give the product (600mg, 46%).
2. Preparation of 2-methyl-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxin-2-yl) imidazo [1,2-a ] pyridine
Figure BDA0002705332420000432
7-bromo-2-methylimidazo [1,2-a ] pyridine (600mg,2.8mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (102.5mg,0.14mmol), potassium acetate (824.4mg,8.4mmol) and bis-pinacolato borate (1.4g,5.6mmol) were dissolved in 1, 4-dioxane (10mL) and reacted at 80 ℃ for 16 hours under nitrogen protection, and the reaction solution was directly used in the next step.
3. Preparation of 7- (6-chloropyrimidin-4-yl) -2-methylimidazo [1,2-a ] pyridine
Figure BDA0002705332420000433
The reaction solution of 2-methyl-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxin-2-yl) imidazo [1,2-a ] pyridine obtained in the above step, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (102.5mg,0.14mmol), potassium carbonate (773mg,5.6mmol) and 4, 6-dichloropyrimidine (625.7mg,4.2mmol) were dissolved in 1, 4-dioxane (20mL) and water (5mL), reacted at 100 ℃ for 16 hours under nitrogen protection, cooled to 30 ℃, filtered to collect a filtrate, and the filtrate was concentrated by column chromatography (ethyl acetate: petroleum ether: methanol ═ 19:20:1) to obtain a product (200mg, 29%)
4. Preparation of (R) -N-methyl-8- (1- ((6- (2-methylimidazol [1,2-a ] pyridin-7-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carboxamide
Figure BDA0002705332420000434
7- (6-chloropyrimidin-4-yl) -2-methylimidazo [1,2-a ] pyridine (75.4mg,0.3mmol), (R) -8- (1-aminopropan-2-yl) -N-methylquinoline-4-carboxamide hydrochloride (57.5mg,0.2mmol), sodium carbonate (63.6mg,0.6mmol) were dissolved in tetrahydrofuran (2mL) and water (1mL), reacted at 80 ℃ for 16 hours, cooled to 30 ℃, extracted with ethyl acetate (20mL), the organic phase was washed with saturated brine (10mL x 3), dried over anhydrous sodium sulfate, and concentrated by column chromatography (methanol/dichloromethane ═ 5%) to give the product (17mg, 18%).
The molecular formula is as follows: c26H25N7O molecular weight: 451.5 LC-MS (M/e):452.2(M + H)+)
1HNMR(400MHz,CDCl3):δ:9.10-9.00(m,1H),8.45-8.35(m,1H),8.15-8.05(m,1H), 8.05-7.95(m,1H),7.75-7.55(m,2H),7.55-7.29(m,3H),5.85-5.65(m,2H),4.50-4.30(m,1H), 4.10-3.90(m,1H),3.90-3.70(m,1H),3.03(s,3H),2.51(s,3H),1.58(d,J＝7.2Hz,3H)。
Example nineteenth: preparation of (R) -8- (1- ((6- (3-fluoro-2-methylimidazo [1,2-a ] pyridin-7-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carboxamide (Compound 43-1)
1. Preparation of 7- (6-chloropyrimidin-4-yl) -3-fluoro-2-methylimidazo [1,2-a ] pyridine
Figure BDA0002705332420000441
7- (6-Chloropyrimidin-4-yl) -2-methylimidazo [1,2-a ] pyridine (120mg,0.5mmol) was dissolved in tetrahydrofuran (2mL), cooled to 0 deg.C, added with sodium hydride (60%, 30mg,0.75mmol), reacted for 0.5h, added with 1-chloromethyl-4-fluoro-1, 4-diazobicyclo 2.2.2 octane bis (tetrafluoroborate) salt (354mg,1mmol), reacted at 64 deg.C for 16h, and concentrated by column chromatography (ethyl acetate/petroleum ether ═ 30%) to give the product (90mg, 70%).
2. Preparation of (R) -8- (1- ((6- (3-fluoro-2-methylimidazo [1,2-a ] pyridin-7-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carboxamide
Figure BDA0002705332420000442
7- (6-chloropyrimidin-4-yl) -3-fluoro-2-methylimidazo [1,2-a ] pyridine (90mg,0.34mmol), (R) -8- (1-aminopropan-2-yl) -N-methylquinoline-4-carboxamide hydrochloride (81.5mg,0.3mmol), sodium carbonate (63.6mg,0.6mmol) were dissolved in tetrahydrofuran (2mL) and water (1mL), reacted at 80 ℃ for 16 hours, cooled to 30 ℃, extracted with ethyl acetate (20mL), the organic phase was washed with saturated brine (10mL × 3), dried over anhydrous sodium sulfate, and concentrated by column chromatography (methanol/dichloromethane ═ 5%) to give the product (11.3mg, 7%).
The molecular formula is as follows: c26H24FN7O molecular weight: 469.5 LC-MS (M/e): 470.2(M + H)+)
1HNMR(400MHz,DMSO-d6):δ:9.20-8.90(m,1H),8.80-8.65(m,1H),8.60-8.25(m, 2H),8.25-7.95(m,2H),7.85-7.30(m,5H),7.05-6.95(m,1H),4.60-4.40(m,1H),3.90-3.60 (m,2H),2.87(d,J＝4.0,3H),2.35(s,3H),1.38(s,3H)。
Example twenty: preparation of (R) -8- (1- ((6- (3-fluoroimidazo [1,2-a ] pyridin-7-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carboxamide (Compound 30-1)
1. Preparation of 7-bromoimidazo [1,2-a ] pyridines
Figure BDA0002705332420000451
4-Bromopyridin-2-amine (1.0g,5.8mmol) was dissolved in water (10mL), chloroacetaldehyde (40%) (2.8g,14.5 mmol) was added, the reaction was carried out at 100 ℃ for 4 hours, and Na was added2CO3After adjusting pH to 10, dichloromethane extraction, organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography (DCM: MeOH: 20:1) was performed to obtain the product (1.0g, yield: 88%).
2. Preparation of 7-bromo-3-fluoroimidazo [1,2-a ] pyridine
Figure BDA0002705332420000452
7-bromoimidazo [1,2-a ] pyridine (1.0g,5.1mmol) was dissolved in THF (30mL), 60% NaH (244.0mg,6.1mmol) was added at-5 deg.C, 1-chloromethyl-4-fluoro-1, 4-diazobicyclo 2.2.2 octane bis (tetrafluoroborate) salt (3.6g,10.2mmol) was added after 20min, the temperature was raised to 60 deg.C, reaction was carried out for 16 hours, water was added, EA was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography was carried out (EA: PE ═ 1:1), to obtain a product (470.0mg, yield: 43%).
3. Preparation of 3-fluoro-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) imidazo [1,2-a ] pyridine
Figure BDA0002705332420000453
Reacting 7-bromo-3-fluoroimidazo [1,2-a ]]Pyridine (450.0mg,2.1mmol) was dissolved in dioxane (50mL) and bis-pinacolato borate (723.0mg,3.2mmol), Pd (dppf) Cl was added2(146.0mg,0.2mmol)，KOAc(617.0mg, 6.3mmol)，N2Under the condition, the reaction is carried out for 3 hours at the temperature of 90 ℃, and after the temperature is reduced to 10 ℃, the reaction system is directly used for the next step.
4. Preparation of 7- (6-chloropyrimidin-4-yl) -3-fluoroimidazo [1,2-a ] pyridine
Figure BDA0002705332420000454
Reacting 3-fluoro-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) imidazo [1,2-a]After the pyridine (reaction system above) was supplemented with water (5mL), 4, 6-dichloropyrimidine (477.0mg,3.2mmol), Pd (dppf) Cl was added2(146.0mg,0.2 mmol)，Na2CO3(668.0mg,6.3mmol)，N2The reaction mixture was concentrated by column chromatography (DCM: MeOH: 20:1) at 90 ℃ for 2 hours to give the product (200.0mg, two-step yield: 38%).
5. Preparation of (R) -8- (1- ((6- (3-fluoroimidazo [1,2-a ] pyridin-7-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carboxamide
Figure BDA0002705332420000461
Reacting 7- (6-chloropyrimidin-4-yl) -3-fluoroimidazo [1,2-a]Pyridine (50.0mg,0.2mmol) was dissolved in THF (8mL) and water (1mL), Na was added2CO3(64.0mg,0.6mmol), (R) -8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carboxamide hydrochloride (56.0mg,0.2mmol), reacted at 80 ℃ for 16 hours, and the reaction solution was concentrated by column chromatography (DCM: MeOH ═ 20:1) to give the product (20.0mg, yield: 22%).
The molecular formula is as follows: c25H22FN7O molecular weight: 455.5 LC-MS (M/e):456.2(M + H)+)
1HNMR(400MHz,MeOD)δ:8.91-9.10(br,1H),8.44(s,1H),8.24-8.38(br,1H),8.03- 8.05(m,2H),7.81(d,J＝6.8Hz,1H),7.64(t,J＝8Hz,1H),7.45-7.56(br,2H),7.31-7.45(br, 1H),6.72-6.98(br,1H),4.58-4.69(m,1H),3.81-3.94(m,2H),3.01(s,3H),1.41-1.46(m,3H)。
Example twenty one: preparation of (R) -N-methyl-8- (1- ((6- ([1,2,4] triazolo [4,3-a ] pyridin-7-pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carboxamide (Compound 42-1)
1. Preparation of [1,2,4] triazolo [4,3-a ] pyridin-7-ylboronic acids
Figure BDA0002705332420000462
Reacting 7-bromo- [1,2,4]Triazolo [4,3-a]Pyridine (800mg,4.0mmol), pinacol bisborate (2.1g,8.1 mmol), Pd (PPh)3)2Cl2(292mg,0.4mmol), potassium acetate (1.2g,12.1mmol), dissolved in 1, 4-dioxane (10mL), N2And reacting at 90 ℃ for 12h under protection. After the reaction was completed, it was used in the next step.
2. Preparation of 7- (6-chloropyrimidin-4-yl) - [1,2,4] triazolo [4,3-a ] pyridine
Figure BDA0002705332420000463
Will [1,2,4]]Triazolo [4,3-a]pyridin-7-Ylboronic acid (crude from above), 4, 6-dichloropyrimidine (715mg,4.9mmol), Pd (PPh)3)2Cl2(292mg,0.4mmol)，Na2CO3(1.3g,12.0mmol), dissolved in 1, 4-dioxane (30mL), added water (10mL), N2Under protection, the mixture reacts for 12 hours at 80 ℃, after the reaction is finished, the crude product is obtained by silica gel column separation (DCM: MeOH: 20:1), and then the crude product is pulped by methanol, filtered and dried by spinning to obtain 150mg of the product, wherein the yield of the two steps is 16.1%.
3. Preparation of (R) -N-methyl-8- (1- ((6- ([1,2,4] triazolo [4,3-a ] pyridin-7-pyrimidin) -4-yl) amino) propan-2-yl) quinoline-4-carboxamide
Figure BDA0002705332420000471
Mixing 7- (6-chloropyrimidin-4-yl) - [1,2,4]]Triazolo [4,3-a]Pyridine (41mg,0.2mmol), (R) -8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carboxamide hydrochloride (50mg, crude), Na2CO3(72mg,0.7mmol) was added to a mixed solvent of THF (5mL) and water (0.5mL) and reacted at 85 ℃ for 12h, after completion of the reaction, dried, added with water (10mL), extracted three times (3X 10mL) with a mixed solvent of dichloromethane/methanol (DCM: MeOH ═ 10:1), the organic phases were combined and Na anhydrous2SO4Drying, filtration, spin-drying and separation on silica gel (DCM: MeOH ═ 10:1) gave the title compound (10.5mg, 13.6% yield).
Molecular formula C24H22N8O molecular weight 438.5 LC-MS (M/e):439.2(M + H)+)
1H-NMR(400MHz,CD3OD)δ:9.23(s,1H),8.94(s,1H),8.56(s,1H),8.43(s,1H),8.21 (s,1H),8.00-8.02(d,1H,J＝8.0Hz),7.75-7.77(d,1H,J＝8.0Hz),7.58-7.62(t,1H),7.50(s,2H), 6.87(s,1H),4.56-4.60(m,1H),3.79-3.91(m,2H),2.99(s,3H),1.48(s,3H)。
Example twenty two: preparation of (R) -8- (1- ((6- (3-fluoropyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carbothioamide (Compound 51-1)
Figure BDA0002705332420000472
(R) -8- (1- ((6- (3-fluoropyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carboxamide (35.0mg,0.077mmol), Lawson's reagent (140.0mg,0.346mmol) were dissolved in tetrahydrofuran (25mL) and reacted at 70 ℃ for 16 hours, and the residue was subjected to column chromatography (dichloromethane: methanol ═ 15:1) after concentration to give a product (27.0 mg, yield 74.2%).
Molecular formula C24H21FN8S molecular weight 472.6 LC-MS (M/e):473.1(M + H)+)
1H-NMR(400MHz,DMSO-d6)δ:10.77(s,1H),9.69-9.35(m,1H),9.31-9.02(m,1H), 8.91(s,1H),8.61-8.35(m,2H),7.96-7.32(m,5H),7.09-6.75(m 1H),4.52(s,1H),3.82-3.65 (m,2H),3.31-3.28(m,3H),1.37(s,3H)。
Example twenty three: preparation of (R) -N-methyl-8- (1- ((6- (2-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-thiocarboxamide (Compound 52-1)
Figure BDA0002705332420000481
Reacting 6- (6-chloropyrimidin-4-yl) -2-methylpyrazolo [1,5-a ]]Pyrimidine (50mg,0.23mmol) in THF/H2Na was added to an O (3:1) (6mL) solution2CO3(111mg,1.05mmol) of (R) -8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carbothioamide hydrochloride (62mg,0.21mmol) was added and the reaction was allowed to proceed at 80 ℃ for 18 h. Concentrate to remove the solvent and purify the crude by C18 column (MeOH/H)2O ═ 0-60%), and purified using prep. plate (MeOH: DCM ═ 1:15) to afford the title compound (14mg, yield 14%).
Molecular formula C25H24N8Molecular weight of S468.6 LC-MS (M/e):469.2(M + H)+)
1H-NMR(400MHz,DMSO-d6)δ:10.77(s,1H),9.38-9.61(m,1H),8.97-9.35(m,1H), 8.70(s,1H),8.50(m,1H),8.01(s,1H),7.79-7.60(m,4H),7.38(s,1H),6.94(s,1H),4.41-4.61 (m,1H),3.97-3.76(m,2H),3.06(d,J＝16Hz,3H),2.44(s,3H),1.36(s,3H)。
Example twenty-four: preparation of (R) -8- (1- ((6- (3-fluoro-2-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carbothioamide (Compound 53-1)
Figure BDA0002705332420000482
(R) -8- (1- ((6- (3-fluoro-2-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carboxamide (40mg, 85.1. mu. mol) was dissolved in THF (20mL), Lawson's reagent (162.5mg,0.42mmol) was added, reaction was completed at 80 ℃ for 12h, and concentrated solvent Pre-TLC purification (DCM: MeOH ═ 20:1) gave the title compound (30.0mg, yield: 72.5%).
Molecular formula C25H23FN8Molecular weight of S486.6 LC-MS (M/e):487.2(M + H)+)
1H-NMR(400MHz,CDCl3)δ:10.76(d,J＝3.6Hz,1H),9.31-9.59(m,1H),8.92-9.17(m, 2H),8.49(s,1H),7.60-7.80(m,4H),6.95-7.38(m,2H),4.52(m,1H),3.52-3.80(m,2H),3.21 (d,J＝4.4Hz,3H),2.45(s,3H),1.36(s,3H)。
Example twenty-five: preparation of (R) -8- (1- ((6- (imidazo [1,2-a ] pyridin-7-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carbothioamide (Compound 55-1)
1. Preparation of (R) - (2- (4- (methylaminomethionyl) quinolin-8-yl) propyl) carbamic acid tert-butyl ester
Figure BDA0002705332420000491
Tert-butyl (R) - (2- (2- (4- (methylcarbamoyl) quinolin-8-yl) propyl) carbamate (500mg,1.46 mmol) was dissolved in THF (10mL), lawson's reagent (1.18g,2.92mmol) was added, the mixture was stirred at 70 ℃ for 18 hours, and the mixture was purified by silica gel column chromatography (PE/EA ═ 7/3) on a dry basis to give the product (400mg, 76.4% yield).
2. Preparation of (R) -8- (1-aminopropan-2-yl) -N-methylquinoline-4-thiocarboxamide
Figure BDA0002705332420000492
Tert-butyl (R) - (2- (4- (methylaminomethionyl) quinolin-8-yl) propyl) carbamate (400mg,1.1mmol) was dissolved in HCl (1, 4-dioxane solution) (10mL), reacted at 10 ℃ for 1 hour, dried, methanol (10mL) was added and pH adjusted to greater than 7 with saturated sodium bicarbonate solution, extracted with EA (50mL), and the organic phase was dried to give the product (260mg, 90.1% yield).
3. Preparation of (R) -8- (1- ((6- (imidazo [1,2-a ] pyridin-7-yl) pyrimidin-4-yl) amino) propan-2-yl) -N-methylquinoline-4-carbothioamide
Figure BDA0002705332420000493
7- (6-Chloropyrimidin-4-yl) imidazo [1,2-a]Pyridine (80mg,0.35mmol) was added to THF (15mL), H2O (3mL) was dissolved, and then (R) -8- (1-aminopropyl-2-yl) -N-methylquinoline-4-thiocarboxamide (60mg, 0.23mmol), anhydrous sodium carbonate (49mg,0.46mmol) were added to react at 70 ℃ for 20 hours, and the resulting mixture was purified by silica gel column chromatography using a rotary solvent (PE/EA ═ 1/2), to obtain a product (64mg, yield 61.0%).
Molecular formula C25H23N7Molecular weight of S453.6 LC-MS (M/e):454.2(M + H)+)
1H-NMR(400MHz,CDCl3)δ:9.00-8.99(d,1H,J＝4Hz),8.42(s,1H),8.10-8.07(m,2H), 7.67(s,2H),7.59-7.36(m,5H),5.76-5.56(m,2H),4.45(m,1H),4.03-3.98(m,1H),3.83-3.77 (m,1H),3.44-3.43(d,3H,J＝4Hz),1.57-1.55(d,3H,J＝8Hz)。
Example twenty-six: preparation of (R) -N-methyl-8- (1- ((6- (3-methylimidazo [1,5-a ] pyridin-7-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carboxamide (Compound 41-1)
1. (4-bromopyridin-2-yl) methylamine
Figure BDA0002705332420000501
4-bromopyridine-2-carbonitrile (8.0g,43.7mmol) was added to tetrahydrofuran (100mL) and, after complete dissolution, BH3-THF (264mL,264mmol) was slowly added dropwise to the solution and reacted at 25 deg.C for 17 hours, LC-MS monitored the reaction was complete, carefully quenched with methanol (100mL) and spun dry to give the crude title compound (0.9g, crude) which was used in the next step without purification.
2. 7-bromo-3-methylimidazo [1,5-a ] pyridines
Figure BDA0002705332420000502
(4-bromopyridin-2-yl) methylamine (1.31g,6.9mmol) was added to acetic anhydride (6mL), p-TsOH (1.2g, 6.9mmol) was added, stirring was carried out at 100 ℃ for 4 hours, the reaction was monitored by LC-MS for completion, cooling was carried out to room temperature, the reaction solution was poured into water (30mL), the pH was adjusted to 7 with 20% NaOH, dichloromethane was extracted (20mL × 3), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (EA: PE ═ 2:1) to obtain the objective compound (400mg, yield: 27.1%).
3. 3-methyl-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) imidazo [1,5-a ] pyridine
Figure BDA0002705332420000503
Reacting 7-bromo-3-methylimidazo [1,5-a ]]Pyridine (300mg,1.4mmol) was added to dioxane (20mL), potassium acetate (403mg,4.2mmol), Pd (dppf) Cl was added2(102mg,0.14mmol), pinacol bisborate (702mg, 2.8mmol), heating to 100 ℃ under the protection of nitrogen for 4 hours, monitoring the reaction by LC-MS, and directly reacting the system in the next step.
4. Preparation of 7- (6-chloropyrimidin-4-yl) -3-methylimidazo [1,5-a ] pyridine
Figure BDA0002705332420000504
The reaction mixture was cooled to 10 ℃ in the system (3), and water (5mL), 4, 6-dichloropyrimidine (271mg, 1.8mmol), Pd (dppf) Cl and the like were added to the reaction mixture2(102mg,0.14mmol) and Na2CO3(296mg,2.8mmol) and reacted at 100 ℃ for 8 h. The solvent was concentrated, water (40mL) and ethyl acetate (50mL) were added for extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (MeOH: DCM ═ 1:20) to give the objective compound (98mg, yield: 28.7%).
5. (R) -N-methyl-8- (1- ((6- (3-methylimidazo [1,5-a ] pyridin-7-yl) pyrimidin-4-yl) amino) propan-2-yl) quinoline-4-carboxamide
Figure BDA0002705332420000511
7- (6-Chloropyrimidin-4-yl) -3-methylimidazo [1,5-a]Pyridine (88mg, 0.36mmol) in THF/H2To a solution of O (3/1) (10mL), Na was added2CO3(190mg,1.8mmol), add (R) -8- (1-aminopropyl-2-yl) -N-methylquinoline-4-carboxamide hydrochloride (100mg,0.36mmol) and react at 80 ℃ for 18 h. The solvent was removed by concentration, and the crude product was purified by C18 column (MeOH: 0-60%) and then by preparative plate (MeOH: DCM: 1:15) to obtain the objective compound (12.0mg, yield: 7.4%).
Molecular formula C26H25N7O molecular weight: 451.5 LC-MS (M/e):452.2(M + H)+)
1H-NMR(400MHz,DMSO-d6)δ:9.05(s,1H),8.95(s,1H),8.77(s,1H),8.33-845(m, 2H),8.01(s,1H),7.94(s,1H),7.88-7.55(m,4H),6.90-7.12(m,1H),4.41-4.61(m,1H),3.97- 3.76(m,2H),2.87(s,3H),2.63(s,3H),1.38(s,3H)
Other compounds of the invention were prepared by reference to the preparation of the above examples, as shown in table 4 below:
TABLE 4
Figure BDA0002705332420000512
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 shown in tables 1 to 3 of the invention are shown in the examples.
The 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 times, 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:
the compounds shown in tables 1 to 3 of the invention have the inhibitory activity of 1nM-200nM on DNA-PK kinase, can effectively inhibit the activity of the DNA-PK kinase, and are effective DNA-PK kinase inhibitors, and specific examples are shown in Table 5.
TABLE 5 in vitro enzymatic Activity data for Compounds of the invention
Figure BDA0002705332420000531
Figure BDA0002705332420000541
Experimental example 2: liver microsome metabolic stability test of the compound of the invention in different species
And (3) testing the sample: the chemical name and the preparation method of the compound are shown in the preparation examples of each compound.
Experimental materials:
cynomolgus monkey mixed liver microsomes were purchased from the research center for liver disease of reed (shanghai ltd) under the batch number: ZXBZ, liver microsomal protein concentration 20 mg/mL-1(ii) a Human mixed liver microsomes were purchased from corning corporation under the cat # 452117, lot # 38294, and a liver microsomes protein concentration of 20 mg/mL-1(ii) a Beagle mixed liver microsomes were purchased from XenoTech under lot number: 1410114, the concentration of liver microsomal protein is 20 mg/mL-1。
The experimental promoter beta-NADPH is purchased from Solarbio; phosphate Buffered Saline (PBS) pH7.4 was prepared by the laboratory.
Preparing a test solution:
a proper amount of test powder is precisely weighed, a proper amount of dimethyl sulfoxide (DMSO) is added to dissolve the test powder to 1mM, and the test powder is diluted by 20 times to 50 mu M of working solution by using methanol.
The experimental method comprises the following steps:
TABLE 6 liver microsome metabolic stability experiment incubation system composition
Figure BDA0002705332420000542
The experimental operation steps are as follows:
(1) according to the above Table 6 "composition of the Experimental incubation System", 5.85 mL of 100mM PBS and 20mM MgCl were used for each compound2Solution 0.585mL and H2O3.57 mL, and a mixed solution 1 (not containing microsomes, a sample and. beta. -NADPH) for incubation was prepared. The positive pair drug verapamil of the experimental incubation system was also performed to demonstrate normal liver microsomal enzyme activity.
(2) Liver microsomes (20mg protein/mL) were removed from the-80 ℃ freezer and placed on a 37 ℃ water bath constant temperature shaker for pre-incubation for 3 min.
(3) For each compound, 1.9mL of mixed solution 1 of incubation system was taken for each species, and 56. mu.L of microsomes of different species was added to prepare mixed solution 2 of incubation system (containing no test substance and. beta. -NADPH).
(4) Sample set (microsome and β -NADPH containing): and adding 14 mu L of the test sample working solution with the concentration of 50 mu M into 616 mu L of the mixed solution 2 of the incubation system, and adding 70 mu L of 10mM beta-NADPH working solution. Mixing, and repeating the steps. The sampling time points are 0min, 5min, 10min, 20min, 30min and 60 min. This sample set was used to evaluate the metabolic stability of compounds mediated via β -NADPH.
(5) Control group (microsome-containing, no β -NADPH, water instead of β -NADPH): 264 mu L of the mixed solution 2 of the incubation system is taken, 6 mu L of the working solution of the test article with the concentration of 50 mu M is added, and 30 mu L of water is added. Mixing, and repeating the steps. Sampling time points were 0min and 60 min. This negative control group was used to evaluate whether compounds present non- β -NADPH mediated metabolism in the liver microsome incubation system.
(6) At each predetermined time point, 50 μ L of sample was taken from the incubation sample tube, added to a stop sample tube (containing 300 μ L of cold stop reagent, containing 50ng/mL acetonitrile as internal standard of tolbutamide), vortexed, and the reaction was stopped.
(7) After vortexing for 10min, centrifuge for 5min (12000 rpm).
(8) Taking 100 mu L of supernatant, adding 100 mu L of water, mixing uniformly by vortex, and carrying out LC-MS/MS sample injection analysis.
And (3) data analysis:
the percent residual was converted by the ratio of the peak area of the test article to the internal standard in the following equation.
Figure BDA0002705332420000551
The experimental results are as follows:
TABLE 7 hepatic microsome stability results for compounds of the invention
Figure BDA0002705332420000552
And (4) experimental conclusion:
the compounds of the invention have good stability in human, monkey and dog liver microsomes.

Claims (14)

1. A compound represented by the general formula (III), a pharmaceutically acceptable salt thereof or an isomer thereof,
Figure FDA0003520290120000011
wherein the content of the first and second substances,
X1、X3、X4、X5each independently selected from C (R) or N;
X2selected from C (R);
x is selected from-NR4-；
Y is selected from O or S;
ring a is selected from pyrimidinyl;
each R is independently selected from H, halogen, hydroxyl, amino 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, hydroxyC1-6Alkylthio, amino C1-6Alkoxy, amino C1-6An alkylthio group;
R1is methyl;
R4is H.
2. The compound, pharmaceutically acceptable salt thereof, or isomer thereof according to claim 1,
y is selected from S.
3. The compound, pharmaceutically acceptable salt thereof, or isomer thereof according to claim 1,
y is selected from O.
4. The compound, pharmaceutically acceptable salt thereof, or isomer thereof according to claim 1,
each R is independently selected from H, halogen, amino, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkoxy, halo C1-6An alkylthio group;
R1is methyl.
5. The compound, a pharmaceutically acceptable salt thereof, or an isomer thereof according to claim 1,
each R is independently selected from H, fluoro, chloro, bromo, iodo, amino, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethylthio;
R1is methyl.
6. The compound, pharmaceutically acceptable salt thereof, or isomer thereof according to claim 1,
X1、X3、X4、X5each independently selected from C (R) or N;
X2is selected fromC(R)；
X is-NH-;
ring a is selected from pyrimidinyl;
each R is independently selected from H, fluoro, chloro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
R1is methyl.
7. The compound, pharmaceutically acceptable salt thereof, or isomer thereof according to claim 1,
X1、X3、X4、X5each independently selected from CH or N;
X2is selected from CH;
x is selected from-NH-;
ring a is selected from pyrimidinyl;
R1is methyl.
8. The compound, a pharmaceutically acceptable salt thereof, or an isomer thereof according to claim 1, wherein X1Is N, X2Is CH, X3、X4、X5Each independently selected from CH or N.
9. A compound, a pharmaceutically acceptable salt thereof, or an isomer thereof as described below:
Figure FDA0003520290120000021
Figure FDA0003520290120000031
Figure FDA0003520290120000032
Figure FDA0003520290120000041
Figure FDA0003520290120000051
Figure FDA0003520290120000052
Figure FDA0003520290120000061
Figure FDA0003520290120000071
Figure FDA0003520290120000081
10. a pharmaceutical formulation comprising a compound according to any one of claims 1 to 9, 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.
11. A pharmaceutical composition comprising a compound of any one of claims 1-9, 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.
12. Use of a compound according to any one of claims 1 to 9, a pharmaceutically acceptable salt or isomer thereof, a pharmaceutical formulation according to claim 10, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the prevention and/or treatment of benign tumours or cancers, including in situ and metastatic cancers, in combination with radiotherapy and/or one or more anti-cancer agents.
13. Use of a compound of any one of claims 1-9, a pharmaceutically acceptable salt or isomer thereof, a pharmaceutical formulation of claim 10, or a pharmaceutical composition of claim 11, in the manufacture of a medicament for sensitizing cancer cells to an anti-cancer agent and/or radiation therapy.
14. A kit, comprising:
(a) an effective amount of one or more compounds of any one of claims 1-9, a pharmaceutically acceptable salt thereof, or an isomer thereof,
and (b) an effective amount of one or more anti-cancer agents.
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