CN116917288A - 7, 9-dihydro purine derivative and pharmaceutical application thereof - Google Patents

7, 9-dihydro purine derivative and pharmaceutical application thereof Download PDF

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CN116917288A
CN116917288A CN202280015449.8A CN202280015449A CN116917288A CN 116917288 A CN116917288 A CN 116917288A CN 202280015449 A CN202280015449 A CN 202280015449A CN 116917288 A CN116917288 A CN 116917288A
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陈俐娟
杨壮
叶昊宇
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Chengdu Zeiling Biomedical Technology Co ltd
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom

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Abstract

The invention discloses a 7, 9-dihydro purine derivative and pharmaceutical application thereof. Specifically provided are compounds of formula I, or pharmaceutically acceptable salts thereof, or stereoisomers thereof. Experiments show that the compound provided by the invention has good inhibitory activity on DNA-PK, in particular to compounds CLJ1, 4, 8, 15, 22-25, 56 and 59, and the inhibitory activity is even better than that of the known DNA-PK inhibitor AZD-7648. The compound provided by the invention has wide application prospect in preparing DNA-PK inhibitor. The invention provides a new choice for the anti-tumor drug sensitizer, the radiotherapy sensitizer and the drug for treating tumor, and also provides a new choice for the method for treating tumor.

Description

7, 9-dihydro purine derivative and pharmaceutical application thereof Technical Field
The invention belongs to the field of chemical medicines, and particularly relates to a 7, 9-dihydropyridine derivative and pharmaceutical application thereof.
Background
Cancer is the most deadly disease affecting human health and life, and research on how to effectively anticancer is the goal of continuous efforts of scientists. The existing methods and medicines for treating cancers are numerous, and effective methods comprise means such as surgery, radiotherapy, medicine treatment and the like. The modes of treating cancer include modes of directly killing cancer cells, regulating body immunity and the like, wherein specific action mechanisms of directly killing cancer cells include direct damage to DNA, inhibition of DNA synthesis, inhibition of protein synthesis and the like. Radiotherapy and a lot of anticancer drugs all reach the purpose of treating cancer through direct damage DNA's mode, and damage DNA can trigger the organism to repair damaged DNA, repair damaged DNA can in turn improve cancer cell's survival for cancer cell produces the resistance. Therefore, if repair of DNA damage can be suppressed, the sensitivity of cancer cells can be improved.
Among DNA damage, DNA double strand breaks (DNA double strand break, DSB) are the most serious, one of the main causes of gene mutation and chromosome breakage, and have an important influence on tumorigenesis and development. Whereas repair of DSBs is mainly by DNA non-homologous end joining (nonhomologous end joining, NHEJ) dominated by DNA-dependent protein kinases (DNA-dependent protein kinase, DNA-PK). Thus, inhibiting the function and activity of DNA-PK is an effective way to inhibit DSB repair and increase the sensitivity of tumor cells to radiation and antitumor drugs.
DNA-PK is a complex consisting of catalytic subunits DNA-PKcs and Ku70/80 heterodimers, ku70 and Ku80 (also known as Ku 86) encoded by the XRCC6 and XRCC5 genes, respectively, in humans, with strong affinity for the free end of DNA, which heterodimers recognize DSBs and recruit kinase subunits DNA-PKcs. At present, the role of DNA-PK inhibitors in radiotherapy sensitization and chemotherapy sensitization has been demonstrated. For example, boeckman et al have found that the mechanism by which cisplatin promotes cell radiosensitization is primarily by preventing NHEJ repair of DSB by preventing DNA-PKcs from phosphorylating the protein of interest. Therefore, the DNA-PK inhibitor has important clinical value for improving the tumor treatment effect as a radiotherapy sensitizer and an anti-tumor drug sensitizer.
In addition, the study also shows that the DNA-PK inhibitor can directly inhibit the proliferation of tumor cells, and has an anti-tumor effect when used alone. Studies have demonstrated that inhibition of Ku70 or DNA-PKcs expression can lead to a retardation of cervical cancer cell growth.
DNA-PK inhibitors reported so far include AZD-7648, KU-57788, NU-7441, NU-7026 and the like. Among them, AZD-7648 (CAS: 2230820-11-6) is a potent and highly selective DNA-PK inhibitor developed by the company Aspirin. The study shows that AZD-7648 can enhance DNA damage induced by radiotherapy and doxorubicin chemotherapy. Furthermore, the team has demonstrated that the combination of AZD-7648 with the PARP inhibitor Olaparib increases the instability of the cell genome in the case of ATM defects, thus inhibiting cell growth and promoting apoptosis. The study also shows that AZD-7648 can also enhance the curative effect of Olaparib in a xenograft PDX tumor model and continuously inhibit tumor growth.
However, AZD-7648 has room for further improvement in DNA-PK inhibitory activity, and has significant inhibitory activity against the PI3K family subtype, and in addition, the PK properties of AZD-7648 have relatively low oral exposure, and the half-life and clearance rate need to be further improved. Therefore, the compound which has more excellent inhibition activity on DNA-PK and more balanced in-vivo and in-vitro properties is developed, and has important clinical application value and social benefit.
Disclosure of Invention
The invention aims to provide a 7, 9-dihydropyridine derivative and application thereof in preparing DNA-PK inhibitors.
The invention provides a compound shown in a formula I, or pharmaceutically acceptable salt or stereoisomer thereof:
wherein R is 1 Is LR (L) 5 L is C 1～4 Alkylene, NH or none, R 5 Selected from the group consisting of a substituted or unsubstituted 3-to 6-membered saturated heterocyclic group, a substituted or unsubstituted 3-to 6-membered saturated cycloalkyl group, a substituted or unsubstituted bridged cycloalkyl group, and a substituted or unsubstituted C 1～6 Alkyl, said substituents being selected from C 1～6 Alkyl, SO 2 R 6 、COR 6 Halogen, hydroxy; r is R 6 Selected from halogenated or unsubstituted C 1～6 Alkyl, halogenated or unsubstituted 3-to 6-membered saturated cycloalkyl;
R 2 selected from C 1～6 Alkyl, 3-6 membered saturated heterocyclic group, 3-6 membered saturated cycloalkyl;
x is NH or none;
ring A is
Wherein M is 1 、M 2 、M 3 、M 4 、M 5 Each independently selected from CH or N;
m is an integer of 1 to 5, R 3 Each independently selected from substituted or unsubstituted C 1～5 Alkyl, substituted or unsubstituted 5-to 6-membered heteroaryl, substituted or unsubstituted 5-to 6-membered aryl; the substituents are each independently selected from halogenated or unsubstituted C 1～5 Alkyl, C 1～5 Alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, SO 2 R 7 、COR 7 Or two substituents are linked to form a ring; r is R 7 Selected from hydrogen or C 1～5 An alkyl group;
n is an integer of 1 to 4;
R 4 each independently selected from hydrogen, halogenated or unsubstituted C 1～6 Alkyl, halogenated or unsubstituted C 1～6 Alkoxy, cyano, nitro, halogen, COOR 8 、COR 8 、SO 2 R 8 Substituted or unsubstituted 5-to 6-membered heteroaryl, substituted or unsubstituted 5-to 6-membered aryl; the substituents are each independently selected from halogenated or unsubstituted C 1～5 Alkyl, R 8 Is C 1～6 An alkyl group;
y is selected from N or CH;
h is an integer of 0 to 2; r is R y Selected from C 1～6 An alkyl group.
Further, the method comprises the steps of,
R 1 is LR (L) 5 L is C 1～4 Alkylene, NH or none, R 5 Selected from the group consisting of a substituted or unsubstituted 3-to 6-membered saturated heterocyclic group, a substituted or unsubstituted 3-to 6-membered saturated cycloalkyl group, a substituted or unsubstituted bridged cycloalkyl group, said substituents being selected from the group consisting of C 1～6 Alkyl, SO 2 R 6 、COR 6 ；R 6 Selected from halogenated or unsubstituted C 1～6 Alkyl, halogenated or unsubstituted 3-to 6-membered saturated cycloalkyl;
R 2 selected from C 1～6 An alkyl group;
x is NH or none;
ring A is
Wherein M is 1 、M 2 、M 3 、M 4 、M 5 Each independently selected from CH or N;
m is an integer of 1 to 5, R 3 Each independently selected from substituted or unsubstituted C 1～5 Alkyl, substituted or unsubstituted 5-to 6-membered heteroaryl, substituted or unsubstituted 5-to 6-membered aryl; the substituents are each independently selected from halogenated or unsubstituted C 1～5 Alkyl, C 1～5 Alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, SO 2 R 7 An aldehyde group, or two substituents are joined to form a ring; r is R 7 Selected from C 1～5 An alkyl group;
n is an integer of 1 to 4;
R 4 each independently selected from hydrogen, halogenated or unsubstituted C 1～6 Alkyl, halogenated or unsubstituted C 1～6 Alkoxy, cyano, nitro, halogen, COOR 8 、COR 8 、SO 2 R 8 A substituted or unsubstituted 5-to 6-membered heteroaryl, each of said substituents being independently selected from C 1～5 Alkyl, R 8 Is C 1～6 An alkyl group.
Further, the method comprises the steps of,
the structure of the compound is shown as a formula II:
wherein R is 1 Is LR (L) 5 L is C 1～3 Alkylene, NH or none, R 5 Selected from the group consisting of a substituted or unsubstituted 3-to 6-membered saturated heterocyclic group, a substituted or unsubstituted 3-to 6-membered saturated cycloalkyl group, a substituted or unsubstitutedBridged cycloalkyl groups, said substituents being selected from C 1～5 Alkyl, SO 2 R 6 、COR 6 ；R 6 Selected from halogenated or unsubstituted C 1～5 Alkyl, halogenated or unsubstituted 3-to 6-membered saturated cycloalkyl;
R 2 selected from C 1～3 An alkyl group;
M 1 、M 2 、M 3 、M 4 、M 5 each independently selected from CH or N;
m is 2, wherein R 3 Is C 1～3 Alkyl, another R 3 Selected from substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-6 membered aryl; the substituents are each independently selected from halogenated or unsubstituted C 1～5 Alkyl, C 1～5 Alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, SO 2 R 7 An aldehyde group, or two substituents are joined to form a ring; r is R 7 Selected from C 1～5 An alkyl group.
Further, the method comprises the steps of,
the structure of the compound is shown as a formula III-a:
or the structure of the compound is shown as a formula III-b1 or a formula III-b 2:
or the structure of the compound is shown as a formula III-c1, a formula III-c2 or a formula III-c 3:
or, the structure of the compound is shown as a formula III-d:
or the structure of the compound is shown as a formula III-e1 or a formula III-e 2:
or, the structure of the compound is shown as a formula III-f:
wherein the R is 1 Selected from the following substituted or unsubstituted: wherein L is methylene, NH or none; the substituents are selected from C 1～3 Alkyl, SO 2 R 6 、COR 6 ；R 6 Selected from halogenated or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted cyclopropyl;
R a1 、R b1 、R b2 、R c1 、R c2 、R d1 、R e1 、R e2 、R f1 each independently selected from the group consisting of substituted or unsubstituted: the substituents are each independently selected from halogenated or unsubstituted C 1～3 Alkyl, C 1～3 Alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, SO 2 R 7 An aldehyde group, or two substituents are joined to form a ring; r is R 7 Selected from C 1～3 An alkyl group.
Further, the method comprises the steps of,
the structure of the compound is shown in a formula IV:
wherein R is 1 Is LR (L) 5 L is C 1～3 Alkylene, NH or none, R 5 Selected from the group consisting of a substituted or unsubstituted 3-to 6-membered saturated heterocyclic group, a substituted or unsubstituted 3-to 6-membered saturated cycloalkyl group, a substituted or unsubstituted bridged cycloalkyl group, said substituents being selected from the group consisting of C 1～5 Alkyl, SO 2 R 6 、COR 6 ；R 6 Selected from halogenated or unsubstituted C 1～5 Alkyl, halogenated or unsubstituted 3-to 6-membered saturated cycloalkyl;
R 2 selected from C 1～3 An alkyl group;
n is an integer of 1 to 4;
R 4 each independently selected from hydrogen, halogenated or unsubstituted C 1～5 Alkyl, halogenated or unsubstituted C 1～5 Alkoxy, cyano, nitro, halogen, COOR 8 、COR 8 、SO 2 R 8 Substituted byOr unsubstituted 5-to 6-membered heteroaryl, each of said substituents being independently selected from C 1～5 Alkyl, R 8 Is C 1～5 An alkyl group.
Further, the method comprises the steps of,
the structure of the compound is shown as a formula V:
wherein n is an integer of 1 to 2;
R 4 each independently selected from hydrogen, halogenated or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 Alkoxy, cyano, nitro, halogen, COOR 8 、COR 8 、SO 2 R 8 Substituted or unsubstitutedThe substituents are each independently selected from C 1～3 Alkyl, R 8 Is C 1～3 An alkyl group.
Further, the method comprises the steps of,
the compound is one of the following compounds:
further, the method comprises the steps of,
the compound is one of the following compounds:
the invention also provides application of the compound, or pharmaceutically acceptable salt or stereoisomer thereof in preparing DNA-PK inhibitor.
Further, the DNA-PK inhibitor is a drug for inhibiting damaged DNA repair of tumor cells.
Further, the DNA-PK inhibitor is an anti-tumor drug sensitizer, a radiotherapy sensitizer or a drug for treating tumors.
Further, the anti-tumor drug sensitizer is a chemotherapeutic drug sensitizer.
Further, the chemotherapeutic agent comprises cisplatin, doxorubicin, olaparib, bleomycin, doxorubicin, etoposide, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, MEDI4736, AZD1775, AZD 6758, AZD1390, or AZD0156.
Further, the tumor includes malignant tumor of blood system, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumor, gastric cancer, esophageal cancer, liver cancer, cholangiocellular carcinoma, colon cancer, rectal cancer, small intestine cancer, pancreatic cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, uterine cancer, vulval cancer, bladder cancer, renal cancer, squamous cell carcinoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, ewing's sarcoma, gastrointestinal stromal tumor, kaposi's sarcoma, rhabdomyosarcoma, neuroblastoma;
The malignant tumor of the blood system is preferably leukemia, multiple myeloma and lymphoma; the lung cancer is preferably non-small cell lung cancer, squamous cell carcinoma; the central nervous system tumor is preferably glioma, embryonic dysplastic neuroepithelial tumor, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma; the kidney cancer is preferably renal cell carcinoma, clear cell, renal eosinophil tumor.
The invention also provides an anti-tumor combined drug which contains the compound and the anti-tumor drug which are used for simultaneous or separate administration of the same or different specification unit preparations and a pharmaceutically acceptable carrier.
Further, the antitumor drug is a chemotherapeutic drug.
Further, the chemotherapeutic agent is cisplatin, doxorubicin, olaparib, bleomycin, doxorubicin, etoposide, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, MEDI4736, AZD1775, AZD 6758, AZD1390, or AZD0156.
The invention also provides an anti-tumor composition which consists of the compound and an anti-tumor drug.
Further, the antitumor drug is a chemotherapeutic drug.
Further, the chemotherapeutic agent is cisplatin, doxorubicin, olaparib, bleomycin, doxorubicin, etoposide, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, MEDI4736, AZD1775, AZD 6758, AZD1390, or AZD0156.
The invention also provides an anti-tumor medicament, which is characterized in that: the preparation is prepared by taking the compound, or pharmaceutically acceptable salt or stereoisomer thereof as an active ingredient and adding a pharmaceutically acceptable carrier.
The invention also provides a method for treating tumors, which comprises the step of combining the compound, or pharmaceutically acceptable salt or stereoisomer thereof with an anti-tumor drug or radiotherapy.
Further, the antitumor drug is a chemotherapeutic drug.
Further, the chemotherapeutic drug is cisplatin, doxorubicin, olaparib, bleomycin, doxorubicin, etoposide, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, MEDI4736 (Devalukumab), AZD1775, AZD6738, AZD1390, or AZD0156.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
The minimum and maximum values of the carbon atom content of the hydrocarbon groups are indicated by a prefix, e.g. prefix C a～b Alkyl means any alkyl group containing from "a" to "b" carbon atoms. For example, C 1～6 Alkyl refers to straight or branched chain alkyl groups containing 1 to 6 carbon atoms.
Halogen is fluorine, chlorine, bromine or iodine.
By "pharmaceutically acceptable" is meant that the carrier, vehicle, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising the pharmaceutical dosage form, and physiologically compatible with the recipient.
"salts" are acidic and/or basic salts formed with inorganic and/or organic acids and/or bases of a compound or stereoisomer thereof, and also include zwitterionic salts (inner salts) and also include quaternary ammonium salts, for example alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. Or by mixing the compound, or a stereoisomer thereof, with a suitable amount (e.g., equivalent) of an acid or base. These salts may be obtained by precipitation in solution and collected by filtration, or recovered after evaporation of the solvent, or by lyophilization after reaction in an aqueous medium.
The pharmaceutically acceptable salts of the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoric, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate salts of the compounds.
Bridged cycloalkyl refers to a polycyclic cycloalkyl group in which two rings share two non-adjacent carbon atoms.
"heterocyclyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic and carry at least one ring heteroatom (including but not limited to O, S or N). "saturated heterocyclyl" refers to a saturated heterocyclyl. For example, the "3-to 6-membered saturated heterocyclic group" means a saturated heterocyclic group having 3 to 6 ring atoms.
"cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be a single ring or multiple rings. "saturated cycloalkyl" refers to saturated cycloalkyl. For example, "3-to 6-membered saturated cycloalkyl" refers to a saturated cycloalkyl group having 3 to 6 ring carbon atoms.
"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings) but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be at a carbon atom on the ring with a conjugated pi-electron system. Aryl groups may be substituted or unsubstituted.
"heteroaryl" refers to a heteroaromatic group containing one to more heteroatoms. Heteroatoms as referred to herein include oxygen, sulfur and nitrogen. Such as furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted.
DNA-PK inhibitors refer to agents that inhibit DNA-PK-mediated DNA damage repair, as well as agents that inhibit DNA-PK expression.
The antitumor drugs include chemotherapy drugs, molecular targeting drugs, tumor immunity drugs and the like.
Chemotherapy is a method for treating tumors by using chemically synthesized drugs, and is one of the main means for treating tumors at present. The chemotherapeutic medicine refers to a medicine applied in chemotherapy, and the chemotherapeutic medicine can act on different links of growth and propagation of tumor cells to inhibit or kill the tumor cells.
Experiments show that the compound has good inhibitory activity on DNA-PK, in particular to compounds CLJ1, 4, 8, 15, 22-25, 56 and 59, and the inhibitory activity is even better than that of the known DNA-PK inhibitor AZD-7648.
The compound provided by the invention has wide application prospect in preparing DNA-PK inhibitor. The invention provides a new choice for the anti-tumor drug sensitizer, the radiotherapy sensitizer and the drug for treating tumor, and also provides a new choice for the method for treating tumor.
As is well known to those skilled in the art, DNA-PK inhibitors are used in combination with anti-tumor drugs cisplatin, doxorubicin, olapanib, bleomycin, doxorubicin, etoposide, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, MEDI4736, AZD1775, AZD6738, AZD1390 or AZD0156, etc. to enhance the therapeutic efficacy of anti-tumor drugs. Therefore, the compound provided by the invention is used in combination with the anti-tumor drugs, and provides a new choice for the anti-tumor drugs.
The present specification also relates to the use of such compounds and salts thereof for the treatment or prevention of DNA-PK mediated diseases, including cancer; meanwhile, the compounds of the invention have better inhibitory activity on proliferation of various tumor cells, and some compounds have better antiproliferative activity than AZD-7648.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
Example 1: preparation of CLJ1
Step a: preparation of intermediate M1
To an acetonitrile solution (250 mL) of ethyl 2, 4-dichloro-5-pyrimidinecarboxylate (10.00 g,1.0 eq) and 4-aminotetrahydropyran hydrochloride (6.23 g,1.0 eq) was added potassium carbonate (15.63 g,2.5 eq) in portions at ambient temperature, and reacted overnight at ambient temperature, after which the potassium carbonate was removed by suction after TLC showed the reaction, the filtrate was concentrated in vacuo and flash column chromatography using PE/EA system (3-10%) to give white powder M1 in about 70% yield. 1 H NMR(400MHz,Chloroform-d)δ8.66(d,J＝1.4Hz,1H),8.38(d,J＝7.8Hz,1H),4.43–4.26(m,3H),3.98(dt,J＝12.0,3.7Hz,2H),3.56(td,J＝11.5,2.2Hz,2H),2.07–1.95(m,2H),1.60(dtd,J＝12.4,10.8,4.3Hz,2H),1.38(td,J＝7.2,1.2Hz,3H).
Step b: preparation of intermediate M2
Slowly adding aqueous solution (90 mL) of lithium hydroxide (2.64 g,2 eq) into tetrahydrofuran solution (90 mL) of M1 (9 g,1 eq) at normal temperature, concentrating to remove tetrahydrofuran and part of water after TLC shows that the reaction is finished, slowly dripping 3M hydrochloric acid solution into the rest mixture under the condition of stirring at normal temperature, stopping dripping when pH test paper shows that the pH is about 5, collecting a large amount of precipitated solid by suction filtration and drying overnight to obtain white powder M2,can be used as the raw material for the next step without further purification. 1 H NMR(400MHz,DMSO-d 6 )δ8.59(d,J＝1.2Hz,1H),8.54(d,J＝7.7Hz,1H),4.17(dtt,J＝10.8,6.9,4.1Hz,1H),3.84(dt,J＝11.9,3.6Hz,2H),3.47(dd,J＝11.4,2.3Hz,2H),1.93–1.82(m,2H),1.60–1.49(m,2H).
Step c: preparation of intermediate M3
To a solution of M2 (8 g,1 eq) in N, N-dimethylformamide (125 mL) were added diphenyl azide phosphate (7.2 mL,1 eq) and triethylamine (4.3 mL,1 eq) at room temperature, nitrogen was pumped three times, and the temperature was raised to 80 ℃, TLC showed that after the reaction was completed, most of the N, N-dimethylformamide was removed by vacuum concentration, extraction was performed with an appropriate amount of ethyl acetate and a saturated ammonium chloride solution three times the volume of ethyl acetate, the organic layer was separated, concentrated in vacuo, and flash column chromatography was performed using PE/EA (10-100%) system to obtain intermediate M3 in 49% yield as a white powder. 1 H NMR(400MHz,DMSO-d 6 )δ8.13(s,1H),4.41(tt,J＝12.2,4.2Hz,1H),3.97(dd,J＝11.6,4.5Hz,2H),3.45(dd,J＝12.1,1.9Hz,2H),2.43(tt,J＝12.4,6.5Hz,2H),1.72–1.63(m,2H).
Step d: preparation method of intermediate M4
NaH (1.97 g,2 eq) is slowly added to an N, N-dimethylformamide solution (15 mL) of M3 (6.3 g,1 eq) in batches at the temperature of 0 ℃, the mixture is stirred for 20-30min at the temperature of 0 ℃, methyl iodide (4.62 mL,3 eq) of the N, N-dimethylformamide solution (5 mL) is slowly added dropwise, the temperature is slowly restored to the room temperature, after the TLC shows that the reaction is finished, a small amount of saturated saline is slowly added under an ice bath, after the mixed solution does not generate bubbles any more, a large amount of saturated saline is added, a large amount of solid is precipitated, the obtained solid is dried overnight in vacuum after suction filtration to obtain M4, white powder, and the yield is 90%; 1 H NMR(400MHz,DMSO-d 6 )δ8.36(s,1H),4.45(tt,J＝12.2,4.2Hz,1H),3.97(dd,J＝11.6,4.5Hz,2H),3.50–3.41(m,2H),3.36(s,3H),2.43(tt,J＝12.5,6.3Hz,2H),1.68(ddd,J＝12.3,4.3,1.8Hz,2H).
Step e: preparation of intermediate M5
To 2-bromo-4-methyl-5-aminopyridine (0.4 g,1 eq), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane)-2-yl) -1H-pyrazole (0.53 g,1.2 eq), potassium carbonate (0.98 g,3 eq), [1,1' -bis (diphenylphosphino) ferrocene]To a mixture of palladium dichloride (10%, 0.16 g) was added a mixed solution of dioxane (14 mL), ethanol (6 mL) and water (12 mL), nitrogen was pumped three times, the mixed solution was warmed to 70 ℃, the reaction was allowed to proceed for about 2h, tlc showed the end of the reaction, celite was pumped to remove insoluble solids, filtrate was concentrated, and PE/EA system (40-80%) was flash column chromatographed to give intermediate M5 as a pale yellow solid in 69% yield. 1 H NMR(400MHz,Chloroform-d)δ7.95(s,1H),7.84(s,1H),7.77(s,1H),7.15(s,1H),3.89(s,3H),2.16(s,3H).
Step f: preparation of the end product CLJ1
To a mixture of M4 (0.1 g,1 eq), M5 (0.084 g,1 eq), cesium carbonate (0.243 g,2 eq), tris (dibenzylidene-BASE acetone) dipalladium (0.051 g, 15%), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.065 g, 30%) was added 10mL dioxane, nitrogen was pumped three times, the mixture was warmed to 100 ℃, the reaction was allowed to proceed overnight, TLC showed that M4 was complete, 5mL ethyl acetate was added to the reaction, the insoluble solids were removed by filtration through celite, the filtrate was concentrated, and the PE/EA system (50-100%) was flash column chromatographed to give the final product CLJ1 as a light brown solid in 52% yield. 1 H NMR(400MHz,Chloroform-d)δ9.06(s,1H),7.88(d,J＝8.2Hz,2H),7.81(s,1H),7.29(s,1H),6.76(s,1H),4.49(tt,J＝12.2,4.2Hz,1H),4.09(dd,J＝11.6,4.4Hz,2H),3.90(s,3H),3.49(td,J＝12.2,1.9Hz,2H),3.35(s,3H),2.71(qd,J＝12.5,4.6Hz,2H),2.32(s,3H),1.74–1.65(m,2H).ESI-MS m/z:421.2[M+H] + .
Examples 2 to 25: preparation of CLJ2-CLJ25
The preparation of CLJ2-CLJ25 is identical to example 1, except that the-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazole used for preparing M5 is replaced by the corresponding boronate. The structure of CLJ2-CLJ25 is characterized as follows:
examples 26 to 32: preparation of CLJ26-CLJ32
CLJ26-CLJ32 was prepared in the same manner as in example 1, except that 2-bromo-4-methyl-5-aminopyridine from M5 was replaced with the corresponding amino compound and 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentan-2-yl) -1H-pyrazole was replaced with the corresponding borate. The characterization is as follows:
CLJ26, 1 H NMR(400MHz,DMSO-d 6 )δ12.96(s,1H),8.57(s,1H),8.09(s,1H),8.04(s,1H),7.87(d,J＝8.3Hz,1H),7.47(d,J＝8.3Hz,1H),4.39(ddt,J＝12.1,8.3,4.1Hz,1H),3.96(dd,J＝11.6,4.4Hz,2H),3.47–3.40(m,2H),3.29(s,3H),2.58–2.50(m,2H),2.45(s,3H),1.65(dd,J＝13.0,3.9Hz,2H).ESI-Ms m/z:407.1[M+H] +
CLJ27, 1 H NMR(400MHz,Chloroform-d)δ8.73(d,J＝2.6Hz,1H),8.57(d,J＝8.6Hz,1H),8.24(dd,J＝8.6,2.5Hz,1H),7.88(s,1H),7.55(d,J＝8.5Hz,1H),6.87–6.75(m,2H),4.55(tt,J＝12.2,4.2Hz,1H),4.18–4.07(m,2H),3.99(s,3H),3.59–3.50(m,2H),3.41(s,3H),2.77(qd,J＝12.6,4.7Hz,2H),2.67(s,3H),1.79–1.71(m,2H).ESI-Ms m/z:448.2[M+H] +
CLJ28, 1 H NMR(400MHz,Chloroform-d)δ8.30(d,J＝8.4Hz,1H),7.92–7.86(m,1H),7.53–7.46(m,1H),7.30(dd,J＝8.4,2.2Hz,1H),6.81(s,1H),6.28(t,J＝1.4Hz,1H),4.55(ddt,J＝12.2,8.0,4.3Hz,1H),4.13(dd,J＝11.8,4.5Hz,2H),3.91(d,J＝1.0Hz,3H),3.54(t,J＝12.0Hz,2H),3.40(d,J＝1.0Hz,3H),2.78(qd,J＝12.5,4.6Hz,2H),2.41(s,3H),1.74(dd,J＝13.1,4.0Hz,2H).ESI-MS m/z:420.2[M+H] + .
CLJ29， 1 H NMR(400MHz,Chloroform-d)δ8.27(d,J＝1.7Hz,1H),7.89(s,1H),7.79–7.72(m,2H),7.19(d,J＝7.8Hz,1H),7.10(dd,J＝7.8,1.8Hz,1H),6.80(s,1H),4.56(tt,J＝12.2,4.1Hz,1H),4.10(dd,J＝11.7,4.5Hz,2H),3.94(s,3H),3.53(td,J＝12.2,1.9Hz,2H),3.40(s,3H),2.78(qd,J＝12.5,4.6Hz,2H),2.35(s,3H),1.75(ddd,J＝12.3,4.2,1.8Hz,2H).ESI-MS m/z:420.4[M+H] + .
CL30， 1 H NMR(400MHz,Chloroform-d)δ8.64(d,J＝2.0Hz, 1H),8.31(d,J＝1.9Hz,1H),7.92(s,1H),7.86(s,1H),7.81(s,1H),6.84(s,1H),4.57(ddt,J＝12.3,8.4,4.1Hz,1H),4.12(dd,J＝11.8,4.5Hz,2H),3.95(s,3H),3.55(td,J＝12.2,1.9Hz,2H),3.42(s,3H),2.76(qd,J＝12.5,4.6Hz,2H),2.61(s,3H),1.76(dd,J＝13.3,3.9Hz,2H).ESI-MS m/z:420.2[M+H] + .
CLJ31， 1 H NMR(400MHz,Chloroform-d)δ8.58(s,1H),8.23(s,1H),8.08(s,1H),8.03(s,1H),7.98(s,1H),7.06(s,1H),4.61(tt,J＝12.3,4.1Hz,1H),4.16(dd,J＝11.7,4.8Hz,2H),3.94(s,3H),3.58(td,J＝12.1,1.8Hz,2H),3.43(s,3H),2.80(qd,J＝12.5,4.6Hz,2H),2.32(s,3H),1.79(dd,J＝13.2,4.2Hz,2H).ESI-MS m/z:420.2[M+H] + .
CLJ32， 1 H NMR(400MHz,Chloroform-d)δ9.32(s,1H),8.14(s,1H),8.06(s,1H),7.85(s,1H),6.63(s,1H),4.53(tt,J＝12.3,4.2Hz,1H),4.13(dd,J＝11.8,4.5Hz,2H),3.95(s,3H),3.53(td,J＝12.2,1.9Hz,2H),3.40(s,3H),2.82–2.69(m,2H),2.57(s,3H),1.77–1.66(m,2H).ESI-MS m/z:421.1[M+H] + .
example 33: preparation of CLJ33
The preparation of CLJ33 was identical to example 1, except that the 4-aminotetrahydropyran hydrochloride salt used to prepare M2 was replaced with memantine hydrochloride, and the subsequent intermediate was replaced accordingly.
EM1， 1 H NMR(400MHz,Chloroform-d)δ8.58(d,J＝2.0Hz,1H),8.35(s,1H),4.29(qd,J＝7.1,1.7Hz,2H),2.19–2.13(m,1H),2.02–1.97(m,2H),1.83(d,J＝11.6Hz,2H),1.66(d,J＝11.6Hz,2H),1.43–1.14(m,13H),0.83–0.78(m,2H).
EM3， 1 H NMR(400MHz,Chloroform-d)δ10.25(s,1H),8.14(s,1H),2.53–2.47(m,2H),2.35–2.26(m,3H),2.25–2.17(m,2H),1.51(dt,J＝12.4,2.8Hz,2H),1.37(dt,J＝12.3,2.5Hz,2H),1.31(dt,J＝12.4,2.4Hz,1H),1.22(dt,J＝12.5,2.1Hz,1H),0.94(s,6H).
EM4， 1 H NMR(400MHz,Chloroform-d)δ7.93(d,J＝1.1Hz,1H),3.35(d,J＝1.0Hz,3H),2.50–2.42(m,2H),2.32–2.22(m,3H),2.18(dt,J＝11.9,1.7Hz,2H),1.48(dt,J＝12.7,2.7Hz,2H),1.39–1.26(m,3H),1.19(dq,J＝12.5,1.9Hz,1H),0.91(d,J＝1.7Hz,6H).
CLJ33， 1 H NMR(400MHz,Chloroform-d)δ8.83(s,1H),7.86(d,J＝15.6Hz,2H),7.76(s,1H),7.30(s,1H),6.73(s,1H),3.93(s,3H),3.29(s,3H),2.35(d,J＝3.1Hz,2H),2.31(s,3H),2.24(d,J＝11.9Hz,2H),2.20–2.15(m,1H),2.11(d,J＝12.0Hz,2H),1.41(dd,J＝11.9,3.3Hz,2H),1.27(d,J＝12.8Hz,2H),1.22–1.08(m,2H),0.84(s,6H).ESI-MS m/z:499.2[M+H] +
Example 34: preparation of CLJ34
The preparation of CLJ34 was identical to example 1, except that the 4-aminotetrahydropyran hydrochloride salt used to prepare M2 was replaced with memantine hydrochloride, while intermediate M6 was replaced with FM2. The preparation method of FM2 comprises the following steps:
preparation of FM1
A solution of concentrated nitric acid (1.5 mL) in glacial acetic acid (5 mL) is slowly added dropwise to a solution of 3,4- (methylenedioxy) toluene (1 g) in glacial acetic acid (15 mL) at-5 ℃, the temperature is kept under stirring for 30min, the reaction solution is slowly warmed to room temperature, ice water is slowly added dropwise after TLC reaction is finished, a large amount of solid is separated out, the solid is dried overnight under vacuum after suction filtration, and the pale yellow solid is used for the next step without further treatment. 1 H NMR(400MHz,DMSO-d 6 )δ7.59(s,1H),7.05(s,1H),6.19(s,2H),2.47(s,3H).
Preparation of FM2
Hydrazine hydrate (1 mL) is slowly added dropwise into methanol solution of FM1 (1.2 g,1 eq) and palladium-carbon (10%) at normal temperature, reaction is carried out overnight at normal temperature, diatomite is filtered out after TLC shows that the reaction is finished, and a target product is obtained through vacuum concentration, namely a pale yellow solid, and is used for the next step without further treatment. 1 H NMR(400MHz,Chloroform-d)δ6.57(s,1H),6.28(s,1H),5.82(s,2H),3.49–3.22(m,2H),2.08(s,3H).
CLJ34， 1 H NMR(400MHz,Chloroform-d)δ7.76(s,1H),7.30(s,1H),6.68(s,1H),6.46(s,1H),5.90(s,2H),3.29(s,3H),2.41(d,J＝3.3Hz,2H),2.24(d,J＝12.0Hz,2H),2.21(s,3H),2.18(d,J＝12.1Hz,2H),1.47–1.41(m,2H),1.30(d,J＝12.5Hz,2H),1.27–1.20(m,2H),1.14(dt,J＝12.4,2.0Hz,1H),0.87(s,6H).ESI-MS m/z:462.2[M+H] +
Examples 35 to 45: preparation of CLJ35-CLJ45
The preparation of CLJ35-CLJ45 was identical to example 1, except that the 4-aminotetrahydropyran hydrochloride salt used to prepare M2 was replaced with memantine hydrochloride, and the subsequent intermediate was replaced accordingly. The structure and characterization of CLJ35-CLJ45 are shown below:
CLJ35， 1 H NMR(400MHz,Chloroform-d)δ9.04(d,J＝17.2Hz,1H),7.90(d,J＝7.7Hz,2H),7.81(d,J＝6.9Hz,1H),7.32(s,1H),6.71(d,J＝13.5Hz,1H),3.95(s,4H),3.38(d,J＝5.6Hz,3H),2.48(dq,J＝12.0,6.0Hz,1H),2.34(d,J＝3.9Hz,4H),1.91–1.81(m,2H),1.73(tt,J＝11.1,5.1Hz,3H),1.18–1.11(m,2H),0.97(dd,J＝7.0,4.6Hz,1H),0.76(d,J＝6.5Hz,3H).ESI-MS m/z:433.2[M+H] +
CLJ36， 1 H NMR(400MHz,Chloroform-d)δ8.94(s,1H),7.88(d,J＝3.8Hz,2H),7.82(s,1H),7.31(s,1H),6.79(s,1H),5.06(dtd,J＝9.9,7.4,5.7Hz,1H),4.19–3.97(m,4H),3.92(s,3H),3.36(s,3H),2.52(ddt,J＝13.1,7.8,5.4Hz,1H),2.31(s,3H),2.28–2.21(m,1H).ESI-MS m/z:407.1[M+H] +
CLJ37， 1 H NMR(400MHz,Chloroform-d)δ9.10(s,1H),7.91(s,2H),7.84(s,1H),7.33(s,1H),6.59(s,1H),4.00–3.93(m,5H),3.78(d,J＝7.2Hz,2H),3.40(s,3H),3.35(td,J＝11.7,2.2Hz,2H),2.35(s,3H),2.18(ddt,J＝11.3,7.8,3.9Hz,1H),1.62–1.54(m,2H),1.51–1.38(m,2H).ESI-MS m/z:435.2[M+H] +
CLJ38， 1 H NMR(400MHz,Chloroform-d)δ9.10(s,1H),7.91(s,2H),7.84(s,1H),7.33(s,1H),6.59(s,1H),4.00–3.93(m,5H),3.78(d,J＝7.2Hz,2H),3.40(s,3H),3.35(td,J＝11.7,2.2Hz,2H),2.35(s,3H),2.18(ddt,J＝11.3,7.8,3.9Hz,1H),1.62–1.54(m,2H),1.51–1.38(m,2H).ESI-MS m/z:377.1[M+H] +
CLJ39， 1 H NMR(400MHz,Chloroform-d)δ8.95(s,1H),7.91(s,2H),7.83(s,1H),7.32(s,1H),6.61(s,1H),4.82(d,J＝13.6Hz,1H),4.49(ddt,J＝12.2,8.1,4.2Hz,1H),3.94(s,4H),3.38(s,3H),3.16(td,J＝13.2,2.4Hz,1H),2.59(dtd,J＝21.3,12.6,3.4Hz,2H),2.45(td,J＝12.6,4.3Hz,1H),2.34(s,3H),2.09(s,3H),1.81(t,J＝13.5Hz,2H).ESI-MS m/z:498.1[M+H] +
CLJ40， 1 H NMR(400MHz,Chloroform-d)δ9.02(s,1H),7.89(d, J＝3.5Hz,2H),7.83(s,1H),7.32(s,1H),6.74(s,1H),4.40(tt,J＝12.2,4.0Hz,1H),4.00–3.94(m,2H),3.93(s,3H),3.37(s,3H),2.97(td,J＝12.5,2.3Hz,2H),2.73(qd,J＝12.6,4.2Hz,2H),2.35(s,4H),1.88–1.79(m,2H),1.13(dt,J＝6.9,3.4Hz,2H),0.96–0.88(m,2H).ESI-MS m/z:524.2[M+H] +
CLJ41， 1 H NMR(400MHz,Chloroform-d)δ9.31(s,1H),8.17(s,1H),7.96(s,1H),7.90(s,1H),7.52(s,1H),6.86(s,1H),4.85–4.78(m,1H),4.55(ddt,J＝12.2,8.0,4.2Hz,1H),3.96(s,4H),3.40(s,3H),3.24(dd,J＝13.4,2.6Hz,1H),2.70–2.63(m,1H),2.54(qd,J＝12.1,11.7,4.4Hz,2H),2.47(s,3H),2.12(s,3H),1.84(dd,J＝28.4,12.8Hz,2H).ESI-MS m/z:552.1[M+H] +
CLJ42， 1 H NMR(400MHz,DMSO-d 6 )δ8.60(d,J＝46.2Hz,1H),8.51(d,J＝5.6Hz,1H),8.16(s,1H),8.01(d,J＝5.0Hz,1H),7.91(s,1H),7.48(d,J＝2.9Hz,1H),4.55–4.40(m,2H),4.17(t,J＝17.1Hz,1H),3.87(s,3H),3.17(s,3H),2.74(t,J＝12.9Hz,1H),2.59(ddd,J＝13.9,10.5,8.3Hz,1H),2.29(dd,J＝12.3,4.7Hz,2H),2.22(d,J＝2.5Hz,3H),1.94–1.84(m,3H),1.78(d,J＝13.0Hz,2H),1.73–1.62(m,1H).ESI-MS m/z:524.2[M+H] +
CLJ43， 1 H NMR(400MHz,Chloroform-d)δ9.00(d,J＝11.8Hz,1H),7.91(d,J＝6.8Hz,2H),7.83(s,1H),7.34(s,1H),6.89–6.79(m,1H),4.83–4.62(m,2H),4.53(tt,J＝12.2,4.1Hz,1H),4.31(d,J＝13.9Hz,1H),3.95(s,3H),3.38(s,3H),3.31–3.16(m,3H),2.75–2.41(m,3H),2.36(s,3H),2.29–2.18(m,1H),1.86(dd,J＝38.3,12.8Hz,2H).ESI-MS m/z:506.2[M+H] +
CLJ44， 1 H NMR(400MHz,Chloroform-d)δ8.99(s,1H),7.90(d,J＝5.6Hz,2H),7.83(s,1H),7.34(s,1H),6.81(s,1H),4.77(d,J＝13.2Hz,1H),4.51(ddt,J＝12.1,8.2,4.2Hz,1H),4.37(d,J＝13.6Hz,1H),3.93(s,3H),3.37(s,3H),3.17(q,J＝7.3Hz,2H),2.60–2.45(m,2H),2.35(s,3H),1.91–1.72(m,3H),0.94(d,J＝7.9Hz,2H),0.71(s,2H).ESI-MS m/z:488.2[M+H] +
CLJ45， 1 H NMR(400MHz,Chloroform-d)δ8.93(s,1H),7.90(d,J＝2.1Hz,2H),7.82(s,1H),7.31(s,1H),6.70(s,1H),4.85–4.76(m,1H),4.47(tt,J＝12.1,4.1Hz,1H),3.92(s,4H),3.36(s,3H),3.14(td,J＝13.3,2.5Hz,1H),2.57(dtd,J＝21.4,12.7,3.5Hz,2H),2.46(d,J＝4.4Hz,1H),2.32(s,3H),2.06(s,3H),1.78(td,J＝13.7,7.6Hz,2H).ESI-MS m/z:462.2[M+H] +
examples 46 to 53, 59: preparation of CLJ46-CLJ54
The preparation of CLJ46-CLJ54 is identical to example 1, except that M5 is replaced by the corresponding commercially available secondary amine starting material. The structure and characterization of CLJ46-CLJ54 are as follows:
example 55: preparation of CLJ55
CLJ55 was prepared as in example 1, except that intermediate SM6 was replaced with GM3. The preparation method of GM3 comprises the following steps:
preparation of GM1
N, N-dimethylformamide dimethyl acetal (20 mL) is added into 3-methyl-4-nitrobenzamide (1 g), nitrogen is pumped three times after the mixture is dissolved, the temperature is raised to 85 ℃, stirring is kept for 3h, the reaction liquid is concentrated in vacuum after the TLC shows that the reaction is finished, yellow oily matter is obtained, glacial acetic acid (30 mL) is added at normal temperature, hydrazine hydrate (2.5 mL) is slowly added dropwise, a large amount of white solid is separated out, the temperature is raised to 90 ℃ and is stirred for 1h, the reaction liquid is dissolved, after TLC shows that the reaction is finished, vacuum concentration is carried out, a proper amount of diethyl ether is added, a large amount of white solid is separated out, and the solid is obtained through suction filtration and can be used for the next step without further purification. 1 H NMR(400MHz,DMSO-d 6 )δ8.63(s,1H),8.15–8.00(m,3H),2.59(s,3H).
Preparation of GM2
To a tetrahydrofuran solution of GM1 (1 g), 3, 4-dihydro-2H-pyran (1 mL) was added at one time, p-toluenesulfonic acid (0.1 g) was added under stirring at room temperature, stirring at room temperature was continued for 30min, TLC showed completion of the reaction, the reaction solution was concentrated, and PE/EA system flash column chromatography gave a white solid. 1 H NMR(400MHz,Chloroform-d)δ8.34(s,1H),8.13–8.01(m,3H),5.51(dd,J＝8.5,3.7Hz,1H),4.15–4.03(m,1H),3.81–3.69(m,1H),2.66(s,3H),2.21–2.02(m,3H),1.77–1.65(m,3H).
Preparation of GM3
To GM2 (1.3 g) and a proper amount of palladium-carbon methanol solution, slowly dropwise adding 1.5mL of hydrazine hydrate solution, sealing at normal temperature, reacting overnight, after TLC shows that the reaction is finished, removing palladium-carbon by suction filtration through diatomite, and concentrating in vacuum to obtain a target product, namely a white solid.
CLJ55， 1 H NMR(400MHz,Chloroform-d)δ8.32–8.25(m,2H),8.04–7.94(m,2H),7.89(s,1H),6.91(s,1H),5.48(dd,J＝7.5,4.7Hz,1H),4.54(tt,J＝12.2,4.1Hz,1H),4.13(dd,J＝11.6,4.9Hz,3H),3.80–3.70(m,1H),3.57–3.51(m,2H),3.39(s,3H),2.77(qd,J＝12.5,4.6Hz,2H),2.41(d,J＝2.1Hz,3H),2.25–1.96(m,4H),1.73(dt,J＝11.9,3.0Hz,4H).ESI-MS m/z:491.2[M+H] +
Example 56: preparation of CLJ56
To a methanol solution of CLJ44 (0.2 g) was added 0.5mL of concentrated hydrochloric acid, reacted overnight at room temperature, concentrated in vacuo, then added 10mL of water, slowly added with solid particles of sodium hydroxide, adjusted to pH about 8, extracted with 30mL of ethyl acetate, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow solid, CLJ55.
CLJ56， 1 H NMR(400MHz,DMSO-d 6 )δ8.33(s,1H),8.04(s,1H),7.82(s,2H),7.75(dd,J＝8.3,2.0Hz,1H),7.58(d,J＝8.3Hz,1H),4.40(ddt,J＝12.2,8.0,4.1Hz,1H),3.97(dd,J＝11.3,4.4Hz,2H),3.44–3.37(m,2H),3.29(s,3H),2.54(dd,J＝15.9,11.3Hz,2H),2.26(s,3H),1.70–1.63(m,2H).ESI-MS m/z:407.1[M+H] +
Example 57: preparation of CLJ57
CLJ57 was prepared as in example 1, except that intermediate SM6 was replaced with HM2. The preparation method of HM2 comprises the following steps:
preparation of HM1
To GM1 (1 eq) in N, N-dimethylformamide (5 mL) was added excess NaH (2 eq) under ice bath, stirred in ice bath for 30min, methyl iodide in N, N-dimethylformamide (5 mL) was slowly added dropwise, the reaction was allowed to proceed overnight, TLC showed that after the reaction was completed, saturated brine was slowly added under ice bath, a large amount of solids was precipitated, filtered off with suction, and the solids were dried overnight under vacuum. Can be used in the next step without further purification.
Preparation of HM2
1.2mL of hydrazine hydrate solution is slowly added dropwise into a methanol solution of HM1 (1 g) and a proper amount of palladium carbon, the reaction is carried out at normal temperature in a closed manner overnight, after TLC shows that the reaction is finished, the palladium carbon is removed by suction filtration through diatomite, and the target product is obtained by vacuum concentration. 1 H NMR(400MHz,
Chloroform-d)δ7.98(s,1H),7.80(d,J＝1.9Hz,1H),7.76(dd,J＝8.1,2.0Hz,1H),6.71(d,J＝8.2Hz,1H),3.92(s,3H),3.59(s,2H),2.21(s,3H).
CLJ57， 1 H NMR(400MHz,Chloroform-d)δ8.31(d,J＝8.5Hz,1H),8.04(s,1H),8.01–7.93(m,2H),7.90(d,J＝1.0Hz,1H),6.87(s,1H),4.54(tt,J＝12.3,4.3Hz,1H),4.17–4.10(m,2H),3.96(s,3H),3.53(t,J＝12.0Hz,2H),3.40(d,J＝1.0Hz,3H),2.78(qd,J＝12.5,4.6Hz,2H),2.41(s,3H),1.73(d,J＝10.7Hz,2H).ESI-MS m/z:421.2[M+H] +
Example 58: preparation of CLJ58
CLJ58 was prepared as in example 1, except that intermediate SM6 was replaced with FM2.
CLJ58， 1 H NMR(400MHz,Chloroform-d)δ7.81(s,1H),7.40(s, 1H),6.69(s,1H),6.46(s,1H),5.92(s,2H),4.50(tt,J＝12.2,4.2Hz,1H),4.11(dd,J＝11.7,4.6Hz,2H),3.57–3.47(m,2H),3.37(s,3H),2.75(qd,J＝12.5,4.6Hz,2H),2.23(s,3H),1.71(ddd,J＝12.2,4.3,1.9Hz,2H).ESI-MS m/z:384.1[M+H] +
Example 59: preparation of CLJ59
CLJ59 was prepared as in example 1, except that the 4-aminotetrahydropyran hydrochloride salt used to prepare M2 was replaced with 1-t-butoxycarbonyl-4-aminopiperidine, and the subsequent intermediate was substituted accordingly.
IM1， 1 H NMR(400MHz,Chloroform-d)δ8.65(s,1H),8.37(d,J＝7.8Hz,1H),4.33(q,J＝7.1Hz,2H),4.30–4.19(m,1H),3.99(s,2H),3.00(t,J＝12.3Hz,2H),2.03–1.91(m,2H),1.45(s,11H),1.36(t,J＝7.1Hz,3H).
IM2， 1 H NMR(400MHz,Chloroform-d)δ8.76(s,1H),8.60(d,J＝8.0Hz,1H),4.30(dp,J＝15.0,6.1,5.1Hz,1H),4.07(d,J＝13.5Hz,2H),3.00(t,J＝12.7Hz,2H),2.00(d,J＝12.7Hz,2H),1.47(s,11H).
IM3, 1 H NMR(400MHz,DMSO-d 6 )δ11.33(s,1H),8.04(s,1H),4.32(tt,1H),4.07(d,2H),2.79(s,2Hs),2.14-2.30(m,2H),1.61–1.73(m,2H),1.41(s,9H).
IM4, 1 H NMR(400MHz,Chloroform-d)δ8.00(s,1H),4.48(tt,J＝12.3,4.1Hz,1H),4.28(s,2H),3.43(s,3H),2.83(d,J＝11.4Hz,2H),2.52(qd,J＝12.6,4.5Hz,2H),1.75(s,2H),1.48(s,9H).
IM5, 1 H NMR(400MHz,Chloroform-d 6 )δ9.23(s,1H),8.78(s,1H),7.83(d,J＝1.5Hz,1H),7.24(s,1H),7.06(d,J＝1.6Hz,1H),4.73(s,1H),4.41(dt,J＝12.5,7.1Hz,2H),3.96(s,3H),3.26(s,3H),3.05(dt,J＝12.5,7.1Hz,2H),2.93(s,1H),2.87(q,J＝7.0Hz,1H),2.50(dt,J＝13.4,7.0Hz,2H),2.44(s,3H),1.65(dt,J＝13.0,7.1Hz,2H),1.47(s,9H).
Preparation of CLJ 59:
slowly dropwise adding 1.5mL of concentrated hydrochloric acid into a methanol solution of IM5 (1 g) at normal temperature, stirring overnight at normal temperature, after TLC (thin layer chromatography) shows that the reaction is finished, concentrating the reaction liquid in vacuum, adding water, slowly adding solid sodium hydroxide particles in batches, adjusting the pH to be about 8, adding ethyl acetate with the volume being three times that of water, extracting and separating to obtain an organic layerDrying over anhydrous sodium sulfate, and concentrating to obtain the target compound with light yellow brown color. 1 H NMR(400MHz,Chloroform-d)δ9.20(s,1H),7.96(s,1H),7.88–7.84(m,2H),7.31(s,1H),4.59–4.46(m,1H),3.95(s,3H), 3.54(d,J＝12.4Hz,2H),3.40(s,3H),3.00–2.80(m,4H),2.37(s,3H),2.00–1.90(m,2H)。
The beneficial effects of the invention are demonstrated by biological experimental examples below.
Experimental example 1: effect of Compounds on the enzymatic Activity of DNA-PK enzymes
1. Experimental method
Enzyme activity detection and IC 50 The calculation method comprises the following steps:
DNA-PK inhibition activity assay: the DNA-PK enzyme was incubated in a buffer containing 50 nGST-cMyc-p 53 and a given concentration of Mg/ATP assay and the reaction was initiated by the addition of a Mg/ATP mixture. After incubation for 30 minutes at room temperature, the reaction was stopped by adding an EDTA-containing stop solution. Finally, a detection buffer is added, which contains a d 2-labeled anti-GST monoclonal antibody and a Europium-labeled anti-phosphoSer 15 antibody against phosphorylated p 53. The plates were then read using time resolved fluorescence analysis. And determining a Homogeneous Time Resolved Fluorescence (HTRF) signal according to the formula htrf=10000× (Em 665nm/Em620 nm).
The enzyme activity data of each compound prepared in the examples of the present invention for DNA-PK enzyme at different concentrations was measured according to the above method, and the results are shown in Table 1; and calculating IC for inhibition of DNA-PK activity by a portion of the compounds 50 Values, results are shown in table 2. The known DNA-PK inhibitor AZD-7648 is used as a positive control.
2. Experimental results
Table 1 enzymatic Activity of Compounds against DNA-PK at various concentrations
IC for inhibiting DNA-PK enzyme by each Compound of Table 2 50 Value of
Cmpd DNA-PKIC 50 (nM) Cmpd DNA-PKIC 50 (nM)
AZD-7648 1 CLJ29 10
CLJ1 0.1 CLJ31 2
CLJ2 8 CLJ33 1
CLJ3 2 CLJ34 3
CLJ4 0.4 CLJ35 24
CLJ5 6 CLJ36 35
CLJ8 0.8 CLJ39 17
CLJ13 2 CLJ40 3
CLJ15 0.7 CLJ41 143
CLJ17 6 CLJ44 21
CLJ18 4 CLJ46 6
CLJ20 7 CLJ47 13
CLJ22 0.1 CLJ50 3
CLJ23 0.9 CLJ51 1
CLJ24 0.4 CLJ54 4
CLJ25 0.3 CLJ56 0.4
CLJ26 25 CLJ58 1
CLJ27 161 CLJ59 0.9
The experimental results in tables 1 and 2 show that the compounds provided by the invention have good inhibitory activity on DNA-PK. In particular, the compounds of the invention CLJ1, 4, 8, 15, 22-25, 56, 59, which inhibit DNA-PK IC 50 Is lower than the AZD-7648 known as DNA-PK inhibitor.
Experimental example 2: determination of cloning experiment inhibition rate of compound on radiation induced tumor cell sensitization
1. Experimental method
Cloning experiments:
(1) Inoculating cells: hct116 cells in the culture dish were collected in a centrifuge tube in an ultra clean bench and centrifuged at 1000rpmCells were resuspended in DMED complete medium for 3min and counted, plated at 400/well in 24-well plates at a volume of 500 μl per well. Place 24-well plate in 5% CO 2 Is cultured at a constant temperature of 37 ℃ for three days.
(2) And (3) drug treatment: and (3) treating the Hct116 cells for 1h according to the preset concentration of the compound to be tested, and then irradiating. The known DNA-PK inhibitor AZD-7648 is used as a positive control.
(3) And (3) irradiation: the cells after the drug treatment are irradiated under the condition of 2Gy, and the cells are put into a incubator for culturing for one week after the irradiation.
(4) Crystal violet staining: cell supernatants were removed from 24-well plates, cells were gently washed twice with PBS, slowly methanol was added and fixed at room temperature for 20min. The methanol was discarded, and the 24-well plate was placed on a laboratory bench to volatilize the methanol. Crystal violet was added for dyeing for 20min, crystal violet was recovered, and the 24-well plate was washed 3 times with ultrapure water.
(5) Photographing: photographs were taken using a chemiluminescent imaging system.
The cloning experiment results were analyzed by software image J for quantitative analysis. Then, after calculating the inhibition rate of each concentration of the compound on the cell clone formation, converting the compound treatment concentration into a logarithmic form, taking the logarithmic concentration as x and the inhibition rate as y, fitting a dose-response curve by using Graphpad prism 8.0 software, and fitting an IC 50 Values.
2. Experimental results
Table 3 determination of cloning experiments inhibition of compounds for radiation-induced tumor cell sensitization
Cloning experiments IC of compounds of table 4 for the sensitization of radiation-induced tumor cells 50 Measurement of values
From the results in tables 3 and 4, it can be seen that the compounds provided by the present invention are effective in inhibiting radiation-induced tumor cell sensitization; in particular, the compounds CLJ1, 22, 23, 31, 54 of the invention inhibit radiation-induced tumor cell sensitization IC 50 Is lower than the AZD-7648 known as DNA-PK inhibitor. The compounds provided by the invention can be used for preparing radiotherapy sensitizers.
Experimental example 3: pharmacokinetic properties of Compounds in vivo in rats
1. Experimental method
Weighing a proper amount of compound to be tested, adding a small amount of 1% DMSO for dissolving, and then adding physiological saline solution to prepare 1 mg.mL -1 To be administered. 6 SD rats (Chengdu laboratory animal Co., ltd., license number: SCXK 2020-030) were male rats, 200-250g each, each per day, 5 mg.kg -1 Intravenous administration, 5mg kg -1 Orally administered, blood samples were collected from each animal by cardiac puncture 0min before administration and 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h and 24h after administration and stored in a refrigerator (-20 ℃). Plasma was separated from the blood by centrifugation (4 ℃,4000g,15 min) and stored in a-80 ℃ freezer. The samples were tested by ultra high performance liquid chromatography (UFLC) system (SIL-30AC autosampler,LC-30AD chromatograph,CBM-20A communications bus module,CTO-20AC prominence column oven, shimadzu corporation, japan) and the plasma concentration data was analyzed by non-compartmental analysis.
2. Experimental results
Table 5 in vivo pharmacokinetic properties of Compounds
As can be seen from the results in table 5, the compounds provided by the present invention are superior to the known DNA-PK inhibitor AZD-7648 in terms of pharmacokinetic properties including exposure, half-life, clearance, etc., in particular, the compounds CLJ1, CLJ13, CLJ31, and have better bioavailability than the known DNA-PK inhibitor AZD-7648, in addition to the above parameters.
In summary, the invention provides 7, 9-dihydropyridine derivatives represented by formula I and pharmaceutical uses thereof. Experiments show that the compound provided by the invention has good inhibitory activity on DNA-PK, in particular to compounds CLJ1, 4, 8, 15, 22-25, 56 and 59, and the inhibitory activity is even better than that of the known DNA-PK inhibitor AZD-7648. The compound provided by the invention has wide application prospect in preparing DNA-PK inhibitor. The invention provides a new choice for the anti-tumor drug sensitizer, the radiotherapy sensitizer and the drug for treating tumor, and also provides a new choice for the method for treating tumor.

Claims (24)

  1. A compound of formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
    wherein R is 1 Is LR (L) 5 L is C 1～4 Alkylene, NH or none, R 5 Selected from the group consisting of a substituted or unsubstituted 3-to 6-membered saturated heterocyclic group, a substituted or unsubstituted 3-to 6-membered saturated cycloalkyl group, a substituted or unsubstituted bridged cycloalkyl group, and a substituted or unsubstituted C 1～6 Alkyl, said substituents being selected from C 1～6 Alkyl, SO 2 R 6 、COR 6 Halogen, hydroxy; r is R 6 Selected from halogenated or unsubstituted C 1～6 Alkyl, halogenated or unsubstituted 3-to 6-membered saturated cycloalkyl;
    R 2 selected from C 1～6 Alkyl, 3-6 membered saturated heterocyclic group, 3-6 membered saturated cycloalkyl;
    X is NH or none;
    ring A is
    Wherein M is 1 、M 2 、M 3 、M 4 、M 5 Each independently selected from CH or N;
    m is an integer of 1 to 5, R 3 Each independently selected from substituted or unsubstituted C 1～5 Alkyl, substituted or unsubstituted 5-to 6-membered heteroaryl, substituted or unsubstituted 5-to 6-membered aryl; the substituents are each independently selected from halogenated or unsubstituted C 1～5 Alkyl, C 1～5 Alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, SO 2 R 7 、COR 7 Or two substituents are linked to form a ring; r is R 7 Selected from hydrogen or C 1～5 An alkyl group;
    n is an integer of 1 to 4;
    R 4 each independently selected from hydrogen, halogenated or unsubstituted C 1～6 Alkyl, halogenated or unsubstituted C 1～6 Alkoxy, cyano, nitro, halogen, COOR 8 、COR 8 、SO 2 R 8 Substituted or unsubstituted 5-to 6-membered heteroaryl, substituted or unsubstituted 5-to 6-membered aryl; the substituents are each independently selected from halogenated or unsubstituted C 1～5 Alkyl, R 8 Is C 1～6 An alkyl group;
    y is selected from N or CH;
    h is an integer of 0 to 2; r is R y Selected from C 1～6 An alkyl group.
  2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
    R 1 is LR (L) 5 L is C 1～4 Alkylene, NH or none, R 5 Selected from the group consisting of a substituted or unsubstituted 3-to 6-membered saturated heterocyclic group, a substituted or unsubstituted 3-to 6-membered saturated cycloalkyl group, a substituted or unsubstituted bridged cycloalkyl group, said substituents being selected from the group consisting of C 1～6 Alkyl, SO 2 R 6 、COR 6 ；R 6 Selected from halogenated or unsubstituted C 1～6 Alkyl, halogenated or unsubstituted 3-to 6-membered saturated cycloalkyl;
    R 2 selected from C 1～6 An alkyl group;
    x is NH or none;
    ring A is
    Wherein M is 1 、M 2 、M 3 、M 4 、M 5 Each independently selected from CH or N;
    m is an integer of 1 to 5, R 3 Each independently selected from substituted or unsubstituted C 1～5 Alkyl, substituted or unsubstituted 5-to 6-membered heteroaryl, substituted or unsubstituted 5-to 6-membered aryl; the substituents are each independently selected from halogenated or unsubstituted C 1～5 Alkyl, C 1～5 Alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, SO 2 R 7 An aldehyde group, or two substituents are joined to form a ring; r is R 7 Selected from C 1～5 An alkyl group;
    n is an integer of 1 to 4;
    R 4 each independently selected from hydrogen, halogenated or unsubstituted C 1～6 Alkyl, halogenated or unsubstituted C 1～6 Alkoxy, cyano, nitro, halogen, COOR 8 、COR 8 、SO 2 R 8 A substituted or unsubstituted 5-to 6-membered heteroaryl, each of said substituents being independently selected from C 1～5 Alkyl, R 8 Is C 1～6 An alkyl group.
  3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: the structure of the compound is shown as a formula II:
    wherein R is 1 Is LR (L) 5 L is C 1～3 Alkylene, NH or none, R 5 Selected from the group consisting of a substituted or unsubstituted 3-to 6-membered saturated heterocyclic group, a substituted or unsubstituted 3-to 6-membered saturated cycloalkyl group, a substituted or unsubstituted bridged cycloalkyl group, said substituents being selected from the group consisting of C 1～5 Alkyl, SO 2 R 6 、COR 6 ；R 6 Selected from halogenated or unsubstituted C 1～5 Alkyl, halogenated or unsubstituted 3-to 6-membered saturated cycloalkyl;
    R 2 selected from C 1～3 An alkyl group;
    M 1 、M 2 、M 3 、M 4 、M 5 each independently selected from CH or N;
    m is 2, wherein R 3 Is C 1～3 Alkyl, another R 3 Selected from substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-6 membered aryl; the substituents are each independently selected from halogenated or unsubstituted C 1～5 Alkyl, C 1～5 Alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group,SO 2 R 7 An aldehyde group, or two substituents are joined to form a ring; r is R 7 Selected from C 1～5 An alkyl group.
  4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: the structure of the compound is shown as a formula III-a:
    or the structure of the compound is shown as a formula III-b1 or a formula III-b 2:
    or the structure of the compound is shown as a formula III-c1, a formula III-c2 or a formula III-c 3:
    or, the structure of the compound is shown as a formula III-d:
    or the structure of the compound is shown as a formula III-e1 or a formula III-e 2:
    or, the structure of the compound is shown as a formula III-f:
    wherein the R is 1 Selected from the following substituted or unsubstituted: wherein L is methylene, NH or none; the substituents are selected from C 1～3 Alkyl, SO 2 R 6 、COR 6 ；R 6 Selected from halogenated or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted cyclopropyl;
    R a1 、R b1 、R b2 、R c1 、R c2 、R d1 、R e1 、R e2 、R f1 each independently selected from the group consisting of substituted or unsubstituted: the substituents are each independently selected from halogenated or unsubstituted C 1～3 Alkyl, C 1～3 Alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, SO 2 R 7 An aldehyde group, or two substituents are joined to form a ring; r is R 7 Selected from C 1～3 An alkyl group.
  5. The compound of claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: the structure of the compound is shown in a formula IV:
    wherein R is 1 Is LR (L) 5 L is C 1～3 Alkylene, NH or none, R 5 Selected from the group consisting of a substituted or unsubstituted 3-to 6-membered saturated heterocyclic group, a substituted or unsubstituted 3-to 6-membered saturated cycloalkyl group, a substituted or unsubstituted bridged cycloalkyl group, said substituents being selected from the group consisting of C 1～5 Alkyl, SO 2 R 6 、COR 6 ；R 6 Selected from halogenated or unsubstituted C 1～5 Alkyl, halogenated or unsubstituted 3-to 6-membered saturated cycloalkyl;
    R 2 selected from C 1～3 An alkyl group;
    n is an integer of 1 to 4;
    R 4 each independently selected from hydrogen, halogenated or unsubstituted C 1～5 Alkyl, halogenated or unsubstituted C 1～5 Alkoxy, cyano, nitro, halogen, COOR 8 、COR 8 、SO 2 R 8 A substituted or unsubstituted 5-to 6-membered heteroaryl, each of said substituents being independently selected from C 1～5 Alkyl, R 8 Is C 1～5 An alkyl group.
  6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: the structure of the compound is shown as a formula V:
    wherein n is an integer of 1 to 2;
    R 4 each independently selected from hydrogen, halogenated or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 Alkoxy, cyano, nitro, halogen, COOR 8 、COR 8 、SO 2 R 8 Substituted or unsubstitutedThe substituents are each independently selected from C 1～3 Alkyl, R 8 Is C 1～3 An alkyl group.
  7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: the compound is one of the following compounds:
  8. a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: the compound is one of the following compounds:
  9. use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for the preparation of a DNA-PK inhibitor.
  10. Use according to claim 9, characterized in that: the DNA-PK inhibitor is a drug for inhibiting damaged DNA repair of tumor cells.
  11. Use according to claim 10, characterized in that: the DNA-PK inhibitor is an anti-tumor drug sensitizer, a radiotherapy sensitizer or a drug for treating tumors.
  12. Use according to claim 11, characterized in that: the anti-tumor drug sensitizer is a chemotherapeutic drug sensitizer.
  13. Use according to claim 12, characterized in that: the chemotherapeutic agent comprises cisplatin, doxorubicin, olapanib, bleomycin, doxorubicin, etoposide, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, MEDI4736, AZD1775, AZD 6758, AZD1390 or AZD0156.
  14. Use according to claim 11, characterized in that: the tumor comprises malignant tumor of blood system, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumor, gastric cancer, esophageal cancer, liver cancer, cholangiocellular carcinoma, colon cancer, rectal cancer, small intestine cancer, pancreatic cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, uterine cancer, vulval cancer, bladder cancer, renal cancer, squamous cell carcinoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, ewing's sarcoma, gastrointestinal stromal tumor, kaposi's sarcoma, rhabdomyosarcoma, neuroblastoma;
    The malignant tumor of the blood system is preferably leukemia, multiple myeloma and lymphoma; the lung cancer is preferably non-small cell lung cancer, squamous cell carcinoma; the central nervous system tumor is preferably glioma, embryonic dysplastic neuroepithelial tumor, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma; the kidney cancer is preferably renal cell carcinoma, clear cell, renal eosinophil tumor.
  15. An antitumor combination, characterized in that: comprising a compound according to any one of claims 1 to 8 and an antitumor agent for simultaneous or separate administration of the same or different specification unit preparations, together with a pharmaceutically acceptable carrier.
  16. A combination according to claim 15, wherein: the antitumor drug is a chemotherapeutic drug.
  17. A combination according to claim 16, wherein: the chemotherapeutic drug is cisplatin, doxorubicin, olapanib, bleomycin, doxorubicin, etoposide, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, MEDI4736, AZD1775, AZD 6758, AZD1390 or AZD0156.
  18. An anti-tumor composition, characterized in that: which consists of a compound according to any one of claims 1 to 8 and an antitumor agent.
  19. The composition of claim 18, wherein: the antitumor drug is a chemotherapeutic drug.
  20. The composition of claim 19, wherein: the chemotherapeutic drug is cisplatin, doxorubicin, olapanib, bleomycin, doxorubicin, etoposide, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, MEDI4736, AZD1775, AZD 6758, AZD1390 or AZD0156.
  21. An antitumor drug, characterized in that: a preparation comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof as an active ingredient, and a pharmaceutically acceptable carrier.
  22. A method of treating a tumor, comprising: the method comprising using the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in combination with an antitumor agent or radiation therapy.
  23. The method as claimed in claim 22, wherein: the antitumor drug is a chemotherapeutic drug.
  24. The method according to claim 23, wherein: the chemotherapeutic drug is cisplatin, doxorubicin, olapanib, bleomycin, doxorubicin, etoposide, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, MEDI4736, AZD1775, AZD 6758, AZD1390 or AZD0156.
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