CN117756799A - Compound and application thereof in preparation of ATM kinase inhibitor - Google Patents
Compound and application thereof in preparation of ATM kinase inhibitor Download PDFInfo
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- CN117756799A CN117756799A CN202211166989.4A CN202211166989A CN117756799A CN 117756799 A CN117756799 A CN 117756799A CN 202211166989 A CN202211166989 A CN 202211166989A CN 117756799 A CN117756799 A CN 117756799A
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a compound and application thereof in preparing an ATM kinase inhibitor, and belongs to the field of chemical medicines. The structure of the compound is shown as a formula I. The compound provided by the invention can effectively inhibit the activity of ATM kinase, and can be used for preparing an ATM kinase inhibitor and preparing a medicament for preventing and/or treating diseases related to the activity of ATM kinase. In the artATM kinase inhibitors are well known to those skilled in the art as radiosensitizers or chemosensitizers for the treatment of a variety of tumors. The invention also proves that the compound 37 has remarkable radiosensitization effect in inhibiting colorectal cancer cell proliferation, and the radiosensitization effect is better than that of a positive control compound AZD0156. The compound provided by the invention can be used for preparing a radiotherapy or chemotherapy sensitizer, and has a wide application prospect in the radiotherapy and chemotherapy synergistic sensitization treatment of tumors.
Description
Technical Field
The invention belongs to the field of chemical medicines, and particularly relates to an 8-heteroaryl-1H- [1,2,3] triazolo [4,5-c ] quinoline derivative and application thereof in preparing an ATM kinase inhibitor.
Background
Malignant tumor has become one of serious public health problems threatening the health of people in China, and data of the national cancer center show that: the number of malignant tumor deaths has reached 24% of all resident deaths, and there has been a continuing trend in recent years. In addition, medical expenses caused by malignant tumors in China are continuously increased every year, and the annual medical expenses are over 2000 hundred million yuan.
In general, the treatment of malignant tumors involves a combination of multidisciplinary treatments. The three modes of surgical excision, radiotherapy and chemotherapy are mainly adopted for clinical treatment. It is counted that about 70% of malignant tumor patients need to receive radiotherapy during the whole multidisciplinary comprehensive treatment, and various cancers can only be treated by radiotherapy and chemotherapy. However, the resistance and drug resistance of the tumor to radiotherapy and chemotherapy often cause treatment failure, and in addition, the absorption of X-rays in radiotherapy by tumor tissues is not high, so that a large dosage is usually required in clinic at present to thoroughly kill the tumor, and the high dosage of X-rays causes damage to normal tissues and organs around the tumor; the multidrug resistance (MDR) and toxic side effects of chemotherapeutic agents can also place a significant burden and hazard on the patient's body. Therefore, the approach of improving the tumor treatment effect is urgent, and the chemoradiotherapy sensitizer is highly focused as a potential treatment auxiliary drug.
DNA damage is the main principle of killing tumor cells by radiation therapy and partial chemotherapy (e.g., using DNA topoisomerase inhibitors, etc.). Therefore, the combined use of the drugs capable of preventing DNA damage repair can play a role in sensitization during radiotherapy and chemotherapy, improve the killing efficiency of radiotherapy and chemotherapy on tumor cells, and bring benefit to patients.
After DNA is damaged, intracellular receptors will detect the damaged DNA at the first time and initiate the damage repair system, coordinating downstream cellular responses. Among these are serine/threonine kinases, ATM kinase (ataxia telangiectasia mutated kinase, ataxia telangiectasia kinase), which play a vital role in the injury response of DNA (DNA damage responses, DDR). When DNA is subjected to double-strand break, ATM kinase is activated to play roles in regulating cell cycle and preventing cell division from being normally carried out. This action prevents, on the one hand, damaged or erroneous DNA from entering the daughter cells; on the other hand, the method provides sufficient time for repairing damaged DNA, thereby achieving the purpose of maintaining the normal genome of the cells. However, in tumor cells, abnormal activity of the repair action regulated by ATM kinase can lead to the enhancement of the resistance of the tumor cells to radiotherapy and chemotherapy, and the treatment effect of the radiotherapy and the chemotherapy is weakened. Therefore, the inhibition of the activity of ATM kinase can play a role in inhibiting the repair of DNA damage of tumor cells after radiotherapy and chemotherapy, and plays a role in sensitization of radiotherapy and chemotherapy.
The ATM kinase inhibitor is used as a sensitizer for radiotherapy and chemotherapy, has good drug-forming property, can be used in combination in the treatment of various tumors, improves the treatment effect, and has attracted great attention from various large medical enterprises at home and abroad. Small molecule inhibitors of ATM kinase have been reported in several cases. KU-55933 is the first selective small molecule inhibitor of ATM kinase, however, its solubility, permeability, etc. are too poor to limit its application in vivo. KU60019 developed by the same skeleton is used as a new ATM kinase inhibitor, and the activity and selectivity are further improved, but the physicochemical properties are still not ideal. The company aslicon developed another high-activity selective small molecule ATM kinase inhibitor AZD0156, which has potential chemosensitization and anti-tumor activity, can prevent the activation of DNA damage checkpoints, damage DNA damage repair, induce apoptosis of tumor cells, and cause death of tumor cells over-expressing ATM. However, the chemoradiotherapy sensitization effect of AZD0156 is limited, and the effect of inhibiting the proliferation of tumor cells needs to be further improved.
Disclosure of Invention
The invention aims to provide 8-heteroaryl-1H- [1,2,3] triazolo [4,5-c ] quinoline derivatives and application thereof in preparing ATM kinase inhibitors.
The invention provides a compound shown in a formula I, or pharmaceutically acceptable salt thereof, or stereoisomer thereof, or optical isomer thereof, or deuterated compound thereof,
wherein X is selected from CH or N;
a is selected from 1,2 or 3;
R 1 each independently selected from hydrogen, halogen, cyano, hydroxy, halogenated or unhalogenated C 1～6 Alkyl, halogenated or non-halogenated C 1～6 Alkoxy, OLR 3 、NR 4 R 5 、NCOR 6 、COOR 6 ；
L is selected from C 1～5 An alkylene group;
R 3 selected from NR 7 R 8 Unsubstituted or substituted by R 9 Substituted 3-8 membered saturated heterocyclic group, unsubstituted or R 9 Substituted 3-8 membered saturated cycloalkyl; r is R 7 、R 8 Each independently selected from hydrogen, C 1～6 Alkyl, or R 7 、R 8 Connected into a ring; r is R 9 Selected from C 1～6 An alkyl group;
R 4 、R 5 each independently selected from hydrogen, C 1～6 Alkyl, or R 4 、R 5 Connected into a ring;
R 6 selected from hydrogen, C 1～6 An alkyl group;
R 2 selected from hydrogen, unsubstituted or R 10 Substituted C 1～6 Alkyl, unsubstituted or substituted by R 10 Substituted C 1～6 Alkoxy, unsubstituted or substituted by R 11 Substituted 3-8 membered aryl, unsubstituted or R 11 Substituted 3-8 membered heteroaryl, halogen, hydroxy, carboxy, ammoniaA group, a nitro group, a cyano group;
R 10 selected from unsubstituted or R 11 Substituted 3-8 membered aryl, unsubstituted or R 11 Substituted 3-8 membered heteroaryl; r is R 11 Selected from hydrogen, halogen, C 1～6 Alkyl, C 1～6 Alkoxy, hydroxy, carboxyl, amino, nitro, cyano.
Further, the structure of the compound is shown as a formula II:
wherein R is 1a 、R 1b Each independently selected from hydrogen, halogen, cyano, hydroxy, halogenated or unhalogenated C 1～4 Alkyl, halogenated or non-halogenated C 1～4 Alkoxy, OLR 3 、NR 4 R 5 、NHCOR 6 、COOR 6 ；
L is selected from C 1～4 An alkylene group;
R 3 selected from NR 7 R 8 Unsubstituted or substituted by R 9 Substituted 3-6 membered saturated heterocyclic group, unsubstituted or R 9 Substituted 3-6 membered saturated cycloalkyl; r is R 7 、R 8 Each independently selected from hydrogen, C 1～4 Alkyl, or R 7 、R 8 Connected in a ring, the ring being unsubstituted or R c Substituted 5-6 membered nitrogen-containing heterocycle, R c Selected from C 1～4 An alkyl group; r is R 9 Selected from C 1～4 An alkyl group;
R 4 、R 5 each independently selected from hydrogen, C 1～4 Alkyl, or R 4 、R 5 Connected in a ring, the ring being unsubstituted or R d Substituted 5-6 membered nitrogen-containing heterocycle, R d Selected from amino protecting groups, C 1～4 An alkyl group;
R 6 selected from hydrogen, C 1～4 An alkyl group;
R 2 selected from hydrogen, unsubstituted or R 10 Substituted C 1～4 Alkyl, unsubstituted or substituted by R 11 Substituted 5-to 6-membered aryl, unsubstituted or R 11 Substituted 5-to 6-membered heteroaryl;
R 10 selected from unsubstituted or R 11 Substituted 5-to 6-membered aryl, unsubstituted or R 11 Substituted 5-to 6-membered heteroaryl; r is R 11 Selected from hydrogen, halogen, C 1～4 Alkyl, C 1～4 Alkoxy, hydroxy, carboxyl, amino, nitro, cyano.
Further, R 1a Selected from hydrogen, halogen, cyano, hydroxy, halogenated or unhalogenated C 1～3 Alkyl, halogenated or non-halogenated C 1～3 Alkoxy, OLR 3 、NR 4 R 5 、NHCOR 6 ；R 1b Selected from hydrogen, halogen, halogenated or non-halogenated C 1～3 Alkyl, halogenated or non-halogenated C 1～3 An alkoxy group;
l is selected from C 1～3 An alkylene group;
R 3 selected from NR 7 R 8 Unsubstituted or substituted by R 9 Substituted 5-to 6-membered saturated heterocyclic group, the 5-to 6-membered saturated heterocyclic group is preferablyR 7 、R 8 Each independently selected from hydrogen, C 1～3 Alkyl, or R 7 、R 8 Connected in a ring, the ring being unsubstituted or R c Substituted 5-6 membered nitrogen-containing heterocycle, R c Selected from C 1～3 Alkyl, the 5-to 6-membered nitrogen-containing heterocycle is preferablyR 9 Selected from C 1～3 An alkyl group;
R 4 、R 5 each independently selected from hydrogen, C 1～3 Alkyl, or R 4 、R 5 Is connected to form a ring, the ring is an unsubstituted 5-6 membered nitrogen-containing heterocyclic ring, and the 5-6 membered nitrogen-containing heterocyclic ring is preferably
R 6 Selected from C 1～3 An alkyl group;
R 2 selected from hydrogen, unsubstituted or R 10 Substituted C 1～3 Alkyl, unsubstituted or substituted by R 11 A substituted phenyl group;
R 10 selected from unsubstituted or R 11 A substituted phenyl group; r is R 11 Selected from hydrogen, halogen, C 1～3 Alkyl, C 1～3 Alkoxy, hydroxy, carboxyl, amino, nitro, cyano.
Further, the structure of the compound is shown in a formula III:
wherein R is 4 、R 5 Each independently selected from hydrogen, C 1～3 Alkyl, or R 4 、R 5 Is connected to form a ring, the ring is an unsubstituted 5-6 membered nitrogen-containing heterocyclic ring, and the 5-6 membered nitrogen-containing heterocyclic ring is preferably
b is selected from 1,2 or 3;
R e selected from hydrogen, methyl, ethyl;
R f selected from hydrogen, halogen, C 1～3 Alkyl, C 1～3 Alkoxy, hydroxy, carboxyl, amino, nitro, cyano.
Further, the structure of the compound is shown as a formula IV:
wherein R is 1a Selected from hydrogen, halogen, cyano, hydroxy, halogenated or unhalogenated C 1～3 Alkyl groupC, halogenated or not 1～3 Alkoxy, OLR 3 、NR 4 R 5 、NHCOR 6 ；R 1b Selected from hydrogen, halogen, halogenated or non-halogenated C 1～3 Alkyl, halogenated or non-halogenated C 1～3 An alkoxy group;
l is selected from C 1～3 Alkylene group, R 3 Selected from NR 7 R 8 Unsubstituted or substituted by R 9 Substituted 5-to 6-membered saturated heterocyclic group, the 5-to 6-membered saturated heterocyclic group is preferablyR 7 、R 8 Each independently selected from hydrogen, C 1～3 Alkyl, or R 7 、R 8 Connected in a ring, the ring being unsubstituted or R c Substituted 5-6 membered nitrogen-containing heterocycle, R c Selected from C 1～3 Alkyl, said 5-to 6-membered nitrogen containing heterocycle is preferably +.>R 9 Selected from C 1～3 An alkyl group;
R 4 、R 5 each independently selected from hydrogen, C 1～3 Alkyl, or R 4 、R 5 Is connected to form a ring, the ring is an unsubstituted 5-6 membered nitrogen-containing heterocyclic ring, and the 5-6 membered nitrogen-containing heterocyclic ring is preferably
R 6 Selected from C 1～3 An alkyl group;
R 2 selected from hydrogen, unsubstituted or R 10 Substituted C 1～3 Alkyl, unsubstituted or substituted by R 11 A substituted phenyl group;
R 10 selected from unsubstituted or R 11 A substituted phenyl group; r is R 11 Selected from hydrogen, halogen, C 1～3 Alkyl, C 1～3 Alkoxy, hydroxy, carboxyl, amino, nitro, cyano.
Further, the structure of the compound is as follows:
the invention also provides a medicine, which is a preparation prepared by taking the compound, or pharmaceutically acceptable salt, or stereoisomer, or optical isomer, or deuterated compound thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
The invention also provides application of the compound, or pharmaceutically acceptable salt, or stereoisomer, or optical isomer, or deuterated compound thereof in preparing ATM kinase inhibitor; the ATM kinase inhibitor is preferably a drug for preventing and/or treating diseases related to ATM kinase activity.
The present invention also provides the use of the above compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, in the preparation of a radiosensitizer or a chemosensitizer.
Further, the radiotherapy sensitizer or chemotherapy sensitizer is a sensitizer for treating tumors including colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, bladder cancer, endometrial cancer, cervical cancer, biliary tract cancer, and the like.
The compound provided by the invention can effectively inhibit the activity of ATM kinase, wherein, the compound 37 stimulates ATMOptimal enzyme inhibition effect, IC 50 As low as 0.99nM. The compounds provided by the invention can be used for preparing ATM kinase inhibitors and preparing medicines for preventing and/or treating diseases related to ATM kinase activity.
ATM kinase inhibitors are well known to those skilled in the art as chemosensitizers for the treatment of a variety of tumors, including colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small-cell lung cancer, non-small-cell lung cancer, bladder cancer, endometrial cancer, cervical cancer, biliary tract cancer, and the like. The invention also proves that the compound 37 has remarkable radiosensitization effect in inhibiting colorectal cancer cell proliferation, and the radiosensitization effect is better than that of a positive control compound AZD0156. The compound provided by the invention can be used for preparing a radiotherapy or chemotherapy sensitizer, and has a wide application prospect in the radiotherapy and chemotherapy synergistic sensitization treatment of tumors.
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.
Drawings
FIG. 1 shows the radiosensitization of Compound 37 and the positive control Compound AZD0156.
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 Compound 8
Step a: preparation of intermediate 1 (5-bromo-2- ((2-nitrovinyl) amino) benzoic acid
To a mixture of concentrated hydrochloric acid (37%) and water (10:1) was added 2-amino-5 bromobenzoic acid 2a (25 g,115 mmol), and the mixture was stirred at room temperature for 8 hours, filtered, and the filtrate was collected. Crushed ice (35 g) and sodium hydroxide (15 g,375 mmol) are stirred and mixed in another reaction bottle under ice bath, nitromethane (8.2 g,134 mmol) is slowly added into the mixture, the mixture reacts under ice bath for 1 hour after the addition, the mixture is moved to room temperature and stirred for 1 hour, and then the mixture is poured into an acidic aqueous solution under ice bath (a mixture of 28g of ice and 42mL of concentrated hydrochloric acid) to obtain a solution containing nitroaldoxime. The solutions obtained in the two steps were mixed and stirred at room temperature for 18 hours. A large amount of yellow precipitate is precipitated in the reaction liquid, the reaction liquid is filtered, a filter cake is washed by water, and a crude product intermediate 1 is obtained through vacuum drying, and the reaction liquid can be directly used for the next reaction without further purification.
Step b: preparation of intermediate 2 (6-bromo-3-nitroquinolin-4-ol)
To a round bottom flask containing acetic anhydride was added crude intermediate 1 (5 g,17 mmol) obtained in the previous step and potassium acetate (2 g,21 mmol) and reacted at 120℃for 2 hours. After the reaction, the filter cake was collected by filtration and washed with acetic acid, then with water, and further vacuum drying of the filter cake was performed to obtain 2.4g of gray intermediate 2. 1 H NMR(400MHz,DMSO-d6)δ13.21(s,1H),9.24(s,1H),8.32(d,J＝2.3Hz,1H),7.96(dd,J＝8.8,2.3Hz,1H),7.71(d,J＝8.8Hz,1H).MS(ESI)m/z:268.9[M+H] +
Step c: preparation of intermediate 3 (6-bromo-4-chloro-3-nitroquinoline)
Intermediate 2 (7.5 g,28 mmol) was added to a round bottom flask and reacted at 100℃for 3 hours under reflux with phosphorus oxychloride (40 mL) as solvent. After the reaction is finished, the redundant phosphorus oxychloride is distilled off under reduced pressure, the rest mixed solution is slowly poured into crushed ice for quenching, the mixture is neutralized by saturated sodium bicarbonate and then is extracted by ethyl acetate, back extraction is carried out for 2 times, organic phases are combined, anhydrous sodium sulfate is dried, and 15.2g of brown crude intermediate 3 is obtained after filtration and spin drying, and is directly used for the next reaction without further purification.
Step d: preparation of intermediate 4 (6-bromo-N-isopropyl-3-nitroquinolin-4-amine)
Intermediate 3 (2.3 g,8 mmol) was added to a reaction flask containing ethanol, isopropylamine (0.685 mL,8 mmol) was slowly added at room temperature and stirred for 2min, and triethylamine (1.66 mL,12 mmol) was added dropwise. After the addition, the reaction was carried out overnight at 60 ℃. After the reaction is completed, the solvent is distilled off under reduced pressure, ultrasonic cleaning is carried out after a large amount of water is added, after the solid is subjected to ultrasonic treatment until the solid is uniformly and finely flocculent, filtering is carried out, and a large amount of clear water is used for cleaning a filter cake until the filtrate is colorless, so that 2.31g of yellow solid, namely an intermediate 4, can be used for the next feeding without further purification. 1 H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.71(s,1H),8.33(d,J＝7.5Hz,1H),7.94(d,J＝8.4Hz,1H),7.78(d,J＝8.7Hz,1H),4.04-3.81(m,1H),1.32(d,J＝5.9Hz,6H).MS(ESI)m/z:310.0[M+H] + .
Step e: intermediate 5 (6-bromo-N) 4 -isopropyl quinoline-3, 4-diamine)
To a round bottom flask was added intermediate 4 (0.93 g,3 mmol) and dissolved in acetic acid (30 mL) and the mixture was added reduced iron powder (850 mg,15 mmol) in portions with stirring at 60℃and after addition stirring was continued for about 4 hours at 60 ℃. After the reaction was completed, the reaction was allowed to warm to room temperature to give intermediate 5 dissolved in acetic acid, which was used directly in the next step without further purification.
Step f: preparation of intermediate 6 (8-bromo-1-isopropyl-1H- [1,2,3] triazolo [4,5-c ] quinoline)
The acetic acid solution (3 mmol) of intermediate 5 from the previous step was stirred in an ice bath, diluted with water and brought to acidity with concentrated hydrochloric acid. To the mixture was slowly added sodium nitrite (230 mg,3.3 mmol), and after the addition, the ice bath was removed and stirred at room temperature for 30 minutes. After the completion of the TLC monitoring, the reaction solution was poured into a large amount of water, acetic acid was neutralized with sodium carbonate, followed by extraction with ethyl acetate, the organic phases were combined, dried and filtered, and after evaporation to dryness under reduced pressure, isolated and purified by column chromatography to give intermediate 6 (690 mg, 79% of total yield in both steps) as a white solid.
Step g: preparation of Compound 8 (5- (1-isopropyl-1H- [1,2,3] triazolo [4,5-c ] quinolin-8-yl) pyridin-2-amine)
Intermediate 6 (93 mg,0.3 mmol) was placed in a double-necked flask with 2-amino-5-pyridineboronic acid pinacol ester (66.2 mg,0.3 mmol) and K was added 2 CO 3 (82.8 mg,0.6 mmol) and [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex (12.2 mg,0.015 mmol), a mixed solution of dioxane and water (dioxane: water=4:1) was used as a solvent, and the mixture was allowed to react overnight under argon protection at 100 ℃. After the completion of the reaction, celite was filtered, and the filtrate was collected, concentrated under reduced pressure, and then separated by column chromatography to give 61mg of compound 8 (yellow solid, 67% yield). 1 H NMR(400MHz,DMSO-d 6 )δ9.50(s,1H),8.53(d,J＝5.5Hz,2H),8.28(d,J＝8.5Hz,1H),8.14(dd,J＝8.6,1.9Hz,1H),7.98(dd,J＝8.6,2.4Hz,1H),6.63(d,J＝8.5Hz,1H),6.25(s,2H),5.86(p,J＝6.5Hz,1H),1.79(d,J＝6.4Hz,6H).MS(ESI)m/z:305.2[M+H] + .
Example 2 preparation of Compound 5 and Compound 37
Step a: step a) was performed as in example 1;
step b: step b as in example 1;
step c: step c) is the same as in example 1;
step d: preparation of intermediate 4' ((R) -6-bromo-3-nitro-N- (1-phenylethyl) quinolin-4-amine)
To a round bottom flask was added intermediate 3 (1.42 g,5 mmol) prepared in the previous step, triethylamine (1.01 g,10 mmol) dissolved in ethanol (20 mL), R (+) -alpha-methylbenzylamine was slowly added under stirring at room temperature, and after the addition, the mixture was moved to 60℃for reaction overnight. After the reaction was completed, the solvent was distilled off under reduced pressure, a large amount of water was added to the residue to precipitate a yellow solid, which was filtered, washed with water, and the cake was dried under vacuum to obtain 1.5g of intermediate 4' (yellow solid, 81% yield). 1 H NMR(400MHz,DMSO-d6)δ8.98(s,2H),8.69(s,1H),7.93(dd,J＝8.8,1.9Hz,1H),7.80(d,J＝8.8Hz,1H),7.33(q,J＝8.2Hz,4H),7.25(t,J＝6.8Hz,1H),5.23–5.07(m,1H),1.67(d,J＝6.6Hz,3H).MS(ESI)m/z:372.0[M+H] +
Step e: intermediate 5' ((R) -6-bromo-N 4 Preparation of- (1-phenylethyl) quinoline-3, 4-diamine
To a round bottom flask was added intermediate 4' (1.12 g,3 mmol) and dissolved in acetic acid (30 mL) and the mixture was added reduced iron powder (850 mg,15 mmol) in portions with stirring at 60℃and after addition stirring was continued for about 4 hours at 60 ℃. After the reaction was completed, the reaction was allowed to warm to room temperature to give intermediate 5' dissolved in acetic acid, which was used directly in the next step without further purification.
Step f: preparation of intermediate 6' ((R) -8-bromo-1- (1-phenylethyl) -1H- [1,2,3] triazolo [4,5-c ] quinoline)
An acetic acid solution (3 mmol) of the intermediate 5' of the above step was stirred in an ice bath, diluted with water and brought to acidity with concentrated hydrochloric acid. To the mixture was slowly added sodium nitrite (230 mg,3.3 mmol), and after the addition, the ice bath was removed and stirred at room temperature for 30 minutes. After the completion of the TLC monitoring, the reaction solution was poured into a large amount of water, acetic acid was neutralized with sodium carbonate, followed by extraction with ethyl acetate, the organic phases were combined, dried and filtered, and after evaporation to dryness under reduced pressure, the intermediate 6' (470 mg, 44% of total yield in two steps) was isolated as a white solid by column chromatography. 1 H NMR(400MHz,Chloroform-d)δ9.57(s,1H),8.25(d,J＝2.1Hz,1H),8.13(d,J＝8.9Hz,1H),7.80(dd,J＝8.9,2.1Hz,1H),7.40–7.33(m,2H),7.33–7.27(m,1H),7.24–7.18(m,2H),6.38(q,J＝7.0Hz,1H),2.34(d,J＝7.0Hz,3H).ESI-MS m/z:353.0[M+H] + .
Step g: preparation of Compound 5 ((R) -8- (6-fluoropyridin-3-yl) -1- (1-phenethyl) -1H- [1,2,3] triazolo [4,5-c ] quinoline)
Intermediate 6' (106 mg,0.3 mmol) and 2-fluoro-5-pyridineboronic acid pinacol ester (67 mg,0.3 mmol) were placed in a double neck flask and K was added 2 CO 3 (82.8 mg,0.6 mmol) and [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex (12.2 mg,0.015 mmol), a mixed solution of dioxane and water (dioxane: water=4:1) was used as a solvent, and the mixture was allowed to react overnight under argon protection at 100 ℃. After the completion of the reaction, celite was filtered, and the filtrate was collected, concentrated under reduced pressure, and then separated by column chromatography to give 68mg of compound 5 (white solid, 61% yield). 1 H NMR(400MHz,DMSO-d 6 )δ9.64(s,1H),8.59(d,J＝2.6Hz,1H),8.48(d,J＝2.0Hz,1H),8.36–8.29(m,2H),8.17(dd,J＝8.6,2.0Hz,1H),7.41(dd,J＝8.6,2.9Hz,1H),7.38–7.30(m,2H),7.29–7.20(m,3H),7.03(q,J＝6.8Hz,1H),2.23(d,J＝6.8Hz,3H).MS(ESI)m/z:379.1[M+H] + .
Step h: preparation of Compound 37 ((R) -N, N-dimethyl-3- ((5- (1- (1- (phenylphenyl)) -1H- [1,2,3] triazolo [4,5-c ] quinolin-8-yl) pyridin-2-yl) oxy) propan-1-amine)
3-dimethylamino-1-propanol (35. Mu.L, 0.3 mmol) was dissolved in N, N-dimethylacetamide (2 mL), naH (14 mg,0.6 mmol) was added and then nitrogen was added for protection, and after stirring for a period of time, compound 5 (111 mg,0.3 mmol) was slowly added. After the addition, the reaction was carried out at 50℃overnight. After the completion of the reaction, water and methylene chloride were added for extraction, the lower organic phase was collected, dried over anhydrous sodium sulfate, the filtrate was collected by filtration, and the residue after concentration was separated and purified by column chromatography to give 71mg of compound 37 (white solid, 52% yield). 1 H NMR(400MHz,DMSO-d 6 )δ9.60(s,1H),8.55(d,J＝2.6Hz,1H),8.43(d,J＝2.0Hz,1H),8.27(d,J＝8.7Hz,1H),8.13(dd,J＝8.7,2.0Hz,1H),8.05(dd,J＝8.7,2.6Hz,1H),7.38–7.30(m,2H),7.29–7.20(m,3H),7.05–6.97(m,2H),4.38(t,J＝6.6Hz,2H),2.42(t,J＝7.1Hz,2H),2.26–2.15(m,9H),1.91(p,J＝6.8Hz,2H).ESI-MS m/z:453.2[M+H] + .
Other target compounds of the present invention in table 1 were prepared by referring to the procedure of example 1 or example 2. The structure and characterization data of the resulting target compounds are shown in table 1.
TABLE 1 Structure and characterization data for target Compounds 1-50
The following experiments prove the beneficial effects of the invention.
Test of inhibitory Activity of Compounds of Experimental example 1 against ATM kinase
1. Experimental method
The aim of this experiment was to detect the in vitro inhibitory activity of the compounds of the invention against ATM kinase by means of isotope labelling (labelling of gamma phosphate groups on ATP). IC for kinase inhibitory Activity of test Compounds 50 (half inhibition concentration) or inhibition of ATM kinase activity by the test compound at a concentration of 10 μm. IC (integrated circuit) 50 The values can be obtained by the test compound over a range of different compoundsThe inhibition rate of the ATM kinase activity at the concentration is calculated. The experimental method is as follows: in one reaction tube, a buffer (8mM MOPS,pH 7.0,0.2mM EDTA,10mM MnCl) 2 ) ATM kinase (5-10 mU), substrate for ATM kinase, 10mM magnesium acetate and gamma 33 P-ATP solutions, as well as test compounds at different concentrations. Mg ATP was then added to the reaction to start the enzymatic reaction process and incubated for 40 minutes at room temperature. The reaction was finally stopped with 5. Mu.L of 3% phosphate buffer and 10. Mu.L of the reaction solution was titrated onto a Filtermat A membrane, washed three times with 75mM phosphate solution for 5 minutes each and once with methanol. Finally, the Filtermat A membrane is dried and scintillation counted, the magnitude of which reflects the extent to which the substrate is phosphorylated, thus allowing characterization of the inhibition of kinase activity. IC of test compound to ATM kinase 50 As shown in table 2.
2. Experimental results
TABLE 2 inhibition of ATM kinase by test compounds
It can be seen that the compound of the present invention is effective in inhibiting the activity of ATM kinase, wherein the inhibitory effect of Compound 37 on ATM kinase is optimal, IC 50 As low as 0.99nM.
Test of radiosensitization Effect of Compounds of Experimental example 2
1. Experimental method
The experiment is based on a colony formation experiment, colorectal cancer cells SW620 in the logarithmic growth phase were seeded in 12-well plates at 100-500 cells per well and cultured overnight at 37℃under 5% CO 2. After 1h treatment of the cells with different concentrations of compound or DMSO, DNA double-strand damage was induced with or without irradiation with X-rays (2.5 Gy or 5 Gy). After irradiation, the cells were continued to be cultured in a cell incubator for 16 hours. The cell supernatant was discarded, and complete medium without compound was added, and the complete medium was refreshed every 3 days. After 10-14 days of incubation, the cell supernatant was discarded and washed 1 time with PBS. Cells were fixed with 4% paraformaldehyde at room temperature for 20min. The supernatant was discarded and the cells were gently washed 2 times with PBS. 0.3mL of crystal violet staining solution is added to each hole, and the mixture is stained for 10 to 15 minutes at room temperature. Sucking the staining solution, cleaning the cells with clear water for 2 times, sucking the redundant liquid in the holes, naturally airing, and then photographing and analyzing. The results are shown in FIG. 1.
2 experimental results
As can be seen from fig. 1, compared with the DMSO group, compound 37 at a concentration of 0.5 μm can exert a radiosensitization effect of significantly inhibiting proliferation of colorectal cancer cells SW620 at a radiation intensity of 2.5Gy, and the radiosensitization effect thereof is superior to that of the positive control compound AZD0156.
In summary, the invention provides an 8-heteroaryl-1H- [1,2,3] triazolo [4,5-c ] quinoline derivative shown in formula I and application thereof in preparing an ATM kinase inhibitor. The compound provided by the invention can effectively inhibit the activity of ATM kinase, and can be used for preparing an ATM kinase inhibitor and preparing a medicament for preventing and/or treating diseases related to the activity of ATM kinase. ATM kinase inhibitors are well known to those skilled in the art as radiosensitizers or chemosensitizers for the treatment of a variety of tumors. The invention also proves that the compound 37 has remarkable radiosensitization effect in inhibiting colorectal cancer cell proliferation, and the radiosensitization effect is better than that of a positive control compound AZD0156. The compound provided by the invention can be used for preparing a radiotherapy or chemotherapy sensitizer, and has a wide application prospect in the radiotherapy and chemotherapy synergistic sensitization treatment of tumors.
Claims (10)
1. A compound represented by the formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, characterized in that,
wherein X is selected from CH or N;
a is selected from 1,2 or 3;
R 1 each independently selected from hydrogen, halogen, cyano, hydroxy, halogenated or unhalogenated C 1～6 Alkyl, halo orNon-halogenated C 1～6 Alkoxy, OLR 3 、NR 4 R 5 、NCOR 6 、COOR 6 ；
L is selected from C 1～5 An alkylene group;
R 3 selected from NR 7 R 8 Unsubstituted or substituted by R 9 Substituted 3-8 membered saturated heterocyclic group, unsubstituted or R 9 Substituted 3-8 membered saturated cycloalkyl; r is R 7 、R 8 Each independently selected from hydrogen, C 1～6 Alkyl, or R 7 、R 8 Connected into a ring; r is R 9 Selected from C 1～6 An alkyl group;
R 4 、R 5 each independently selected from hydrogen, C 1～6 Alkyl, or R 4 、R 5 Connected into a ring;
R 6 selected from hydrogen, C 1～6 An alkyl group;
R 2 selected from hydrogen, unsubstituted or R 10 Substituted C 1～6 Alkyl, unsubstituted or substituted by R 10 Substituted C 1～6 Alkoxy, unsubstituted or substituted by R 11 Substituted 3-8 membered aryl, unsubstituted or R 11 Substituted 3-to 8-membered heteroaryl, halogen, hydroxy, carboxy, amino, nitro, cyano;
R 10 selected from unsubstituted or R 11 Substituted 3-8 membered aryl, unsubstituted or R 11 Substituted 3-8 membered heteroaryl; r is R 11 Selected from hydrogen, halogen, C 1～6 Alkyl, C 1～6 Alkoxy, hydroxy, carboxyl, amino, nitro, cyano.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, wherein the compound has the structure of formula II:
wherein R is 1a 、R 1b Each independently selected from hydrogen, halogen, cyano, hydroxy, halogenated or unhalogenated C 1～4 Alkyl, halogenated or non-halogenated C 1～4 Alkoxy, OLR 3 、NR 4 R 5 、NHCOR 6 、COOR 6 ；
L is selected from C 1～4 An alkylene group;
R 3 selected from NR 7 R 8 Unsubstituted or substituted by R 9 Substituted 3-6 membered saturated heterocyclic group, unsubstituted or R 9 Substituted 3-6 membered saturated cycloalkyl; r is R 7 、R 8 Each independently selected from hydrogen, C 1～4 Alkyl, or R 7 、R 8 Connected in a ring, the ring being unsubstituted or R c Substituted 5-6 membered nitrogen-containing heterocycle, R c Selected from C 1～4 An alkyl group; r is R 9 Selected from C 1～4 An alkyl group;
R 4 、R 5 each independently selected from hydrogen, C 1～4 Alkyl, or R 4 、R 5 Connected in a ring, the ring being unsubstituted or R d Substituted 5-6 membered nitrogen-containing heterocycle, R d Selected from amino protecting groups, C 1～4 An alkyl group;
R 6 selected from hydrogen, C 1～4 An alkyl group;
R 2 selected from hydrogen, unsubstituted or R 10 Substituted C 1～4 Alkyl, unsubstituted or substituted by R 11 Substituted 5-to 6-membered aryl, unsubstituted or R 11 Substituted 5-to 6-membered heteroaryl;
R 10 selected from unsubstituted or R 11 Substituted 5-to 6-membered aryl, unsubstituted or R 11 Substituted 5-to 6-membered heteroaryl; r is R 11 Selected from hydrogen, halogen, C 1～4 Alkyl, C 1～4 Alkoxy, hydroxy, carboxyl, amino, nitro, cyano.
3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof,characterized in that R 1a Selected from hydrogen, halogen, cyano, hydroxy, halogenated or unhalogenated C 1～3 Alkyl, halogenated or non-halogenated C 1～3 Alkoxy, OLR 3 、NR 4 R 5 、NHCOR 6 ；R 1b Selected from hydrogen, halogen, halogenated or non-halogenated C 1～3 Alkyl, halogenated or non-halogenated C 1～3 An alkoxy group;
l is selected from C 1～3 An alkylene group;
R 3 selected from NR 7 R 8 Unsubstituted or substituted by R 9 Substituted 5-to 6-membered saturated heterocyclic group, the 5-to 6-membered saturated heterocyclic group is preferablyR 7 、R 8 Each independently selected from hydrogen, C 1～3 Alkyl, or R 7 、R 8 Connected in a ring, the ring being unsubstituted or R c Substituted 5-6 membered nitrogen-containing heterocycle, R c Selected from C 1～3 Alkyl, said 5-to 6-membered nitrogen containing heterocycle is preferably +.>R 9 Selected from C 1～3 An alkyl group;
R 4 、R 5 each independently selected from hydrogen, C 1～3 Alkyl, or R 4 、R 5 Is connected to form a ring, the ring is an unsubstituted 5-6 membered nitrogen-containing heterocyclic ring, and the 5-6 membered nitrogen-containing heterocyclic ring is preferably
R 6 Selected from C 1～3 An alkyl group;
R 2 selected from hydrogen, unsubstituted or R 10 Substituted C 1～3 Alkyl, unsubstituted or substituted by R 11 Substituted phenyl；
R 10 Selected from unsubstituted or R 11 A substituted phenyl group; r is R 11 Selected from hydrogen, halogen, C 1～3 Alkyl, C 1～3 Alkoxy, hydroxy, carboxyl, amino, nitro, cyano.
4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, wherein the compound has the structure according to formula III:
wherein R is 4 、R 5 Each independently selected from hydrogen, C 1～3 Alkyl, or R 4 、R 5 Is connected to form a ring, the ring is an unsubstituted 5-6 membered nitrogen-containing heterocyclic ring, and the 5-6 membered nitrogen-containing heterocyclic ring is preferably
b is selected from 1,2 or 3;
R e selected from hydrogen, methyl, ethyl;
R f selected from hydrogen, halogen, C 1～3 Alkyl, C 1～3 Alkoxy, hydroxy, carboxyl, amino, nitro, cyano.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, wherein the compound has the structure of formula IV:
wherein R is 1a Selected from hydrogen, halogen, cyano, hydroxy, halogenated or unhalogenated C 1～3 Alkyl, halogenated or non-halogenated C 1～3 Alkoxy, OLR 3 、NR 4 R 5 、NHCOR 6 ；R 1b Selected from hydrogen, halogen, halogenated or non-halogenated C 1～3 Alkyl, halogenated or non-halogenated C 1～3 An alkoxy group;
l is selected from C 1～3 Alkylene group, R 3 Selected from NR 7 R 8 Unsubstituted or substituted by R 9 Substituted 5-to 6-membered saturated heterocyclic group, the 5-to 6-membered saturated heterocyclic group is preferablyR 7 、R 8 Each independently selected from hydrogen, C 1～3 Alkyl, or R 7 、R 8 Connected in a ring, the ring being unsubstituted or R c Substituted 5-6 membered nitrogen-containing heterocycle, R c Selected from C 1～3 Alkyl, the 5-to 6-membered nitrogen-containing heterocycle is preferablyR 9 Selected from C 1～3 An alkyl group;
R 4 、R 5 each independently selected from hydrogen, C 1～3 Alkyl, or R 4 、R 5 Is connected to form a ring, the ring is an unsubstituted 5-6 membered nitrogen-containing heterocyclic ring, and the 5-6 membered nitrogen-containing heterocyclic ring is preferably
R 6 Selected from C 1～3 An alkyl group;
R 2 selected from hydrogen, unsubstituted or R 10 Substituted C 1～3 Alkyl, unsubstituted or substituted by R 11 A substituted phenyl group;
R 10 selected from unsubstituted or R 11 A substituted phenyl group;R 11 selected from hydrogen, halogen, C 1～3 Alkyl, C 1～3 Alkoxy, hydroxy, carboxyl, amino, nitro, cyano.
6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, wherein the compound has the structure shown below:
7. a medicament, which is a preparation prepared by taking the compound according to any one of claims 1 to 6, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or optical isomers thereof, or deuterated compounds thereof as active ingredients and adding pharmaceutically acceptable auxiliary materials.
8. Use of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, in the preparation of an ATM kinase inhibitor; the ATM kinase inhibitor is preferably a drug for preventing and/or treating diseases related to ATM kinase activity.
9. Use of a compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, for the preparation of a radiosensitizer or a chemosensitizer.
10. Use according to claim 9, characterized in that: the radiotherapy sensitizer or the chemotherapy sensitizer is used for treating tumors, wherein the tumors comprise colorectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B cell lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, bladder cancer, endometrial cancer, cervical cancer and biliary tract cancer.
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| CN202211166989.4A CN117756799A (en) | 2022-09-23 | 2022-09-23 | Compound and application thereof in preparation of ATM kinase inhibitor |
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| CN202211166989.4A CN117756799A (en) | 2022-09-23 | 2022-09-23 | Compound and application thereof in preparation of ATM kinase inhibitor |
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