A compound and its use in the preparation of ATM kinase inhibitors

Abstract

The application provides a kind of compound and its purposes in preparation ATM kinase inhibitor, belong to the field of chemical medicine.The structure of the compound is as shown in formula I.The compound provided by the application can effectively inhibit the activity of ATM kinase, can be used to prepare ATM kinase inhibitor, and prepare the medicine for preventing and / or treating the disease related to ATM kinase activity.It is known to those skilled in the art that ATM kinase inhibitor can be used as radiotherapy or chemotherapy sensitizer for treating various tumors.The application also proves that compound 37 has significant radiosensitization effect in inhibiting the proliferation of colorectal cancer cells, and its radiosensitization effect is better than that of positive control compound AZD0156.The compound provided by the application can be used to prepare radiotherapy or chemotherapy sensitizer, and has wide application prospect in tumor radiotherapy or chemotherapy synergistic sensitization treatment.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceuticals, specifically relating to an 8-heteroaryl-1H-[1,2,3]triazolo[4,5-c]quinoline derivative and its use in the preparation of ATM kinase inhibitors. Background Technology

[0002] Malignant tumors have become a serious public health problem threatening the health of the Chinese population. Data from the National Cancer Center shows that malignant tumors account for 24% of all deaths in China, and this number has been rising steadily in recent years. Furthermore, the annual medical expenses incurred due to malignant tumors in my country have exceeded 200 billion yuan.

[0003] Typically, the treatment of malignant tumors involves multidisciplinary comprehensive therapy. Clinically, the main treatment methods are surgical resection, radiotherapy, and chemotherapy. Statistics show that approximately 70% of malignant tumor patients require radiotherapy during their multidisciplinary comprehensive treatment, and many cancers can only be treated with radiotherapy and chemotherapy. However, tumor resistance and drug resistance to radiotherapy and chemotherapy often lead to treatment failure. Furthermore, tumor tissue does not absorb X-rays well during radiotherapy, so currently, large doses are usually required to completely kill the tumor, while high-dose X-rays can damage surrounding normal tissues and organs. Multidrug resistance (MDR) and toxic side effects of chemotherapy drugs also place a significant burden and harm on the patient's body. Therefore, seeking ways to improve the effectiveness of tumor treatment is urgent, and radiotherapy and chemotherapy sensitizers have attracted considerable attention as potential adjuvant drugs.

[0004] DNA damage is the primary mechanism by which radiotherapy and some chemotherapy methods (such as those using DNA topoisomerase inhibitors) kill tumor cells. Therefore, the combined use of drugs that can inhibit DNA damage repair can sensitize radiotherapy and chemotherapy, improve the efficiency of radiotherapy and chemotherapy in killing tumor cells, and bring benefits to patients.

[0005] When DNA is damaged, intracellular receptors detect the damaged DNA immediately and activate the damage repair system, coordinating downstream cellular responses. One such kinase, a serine / threonine kinase called ATM kinase (ataxiate langiectasia mutated kinase), plays a crucial role in DNA damage responses (DDR). When a double-strand break occurs in DNA, ATM kinase is activated, regulating the cell cycle and inhibiting normal cell division. This prevents damaged or erroneous DNA from entering daughter cells and provides sufficient time for repair, thus maintaining the normal cellular genome. However, in tumor cells, abnormally active ATM kinase-regulated repair can lead to increased resistance to radiotherapy and chemotherapy, weakening the therapeutic effects. Therefore, inhibiting ATM kinase activity can suppress DNA damage repair in tumor cells after radiotherapy and chemotherapy, thus enhancing the sensitization effect of these treatments.

[0006]

[0007] ATM kinase inhibitors, as sensitizers of radiotherapy and chemotherapy, have good drug properties and can be used in combination for the treatment of various tumors to improve therapeutic effects, attracting great attention from major pharmaceutical companies both domestically and internationally. Several small-molecule inhibitors targeting ATM kinase have been reported. KU-55933 is the first selective small-molecule inhibitor of ATM kinase; however, its poor solubility and permeability limit its in vivo application. KU60019, developed with the same scaffold, represents a new ATM kinase inhibitor with further improvements in activity and selectivity, but its physicochemical properties remain unsatisfactory. AstraZeneca has developed another highly active, selective small-molecule ATM kinase inhibitor, AZD0156, which possesses potential sensitizing and antitumor activities against radiotherapy and chemotherapy. It can prevent DNA damage checkpoint activation, disrupt DNA damage repair, induce tumor cell apoptosis, and lead to the death of tumor cells overexpressing ATM. However, the sensitizing effect of AZD0156 against radiotherapy and chemotherapy is limited, and its effect on inhibiting tumor cell proliferation needs further improvement. Summary of the Invention

[0008] The purpose of this invention is to provide an 8-heteroaryl-1H-[1,2,3]triazolo[4,5-c]quinoline derivative and its use in the preparation of ATM kinase inhibitors.

[0009] This invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof.

[0010]

[0011] Where X is selected from CH or N;

[0012] a is selected from 1, 2, or 3;

[0013] R 1 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, halogenated or unhalogenated C. 1～6 Alkyl, halogenated or unhalogenated C 1～6 Alkoxy, OLR 3 NR 4 R 5 NCOR 6 COOR 6 ;

[0014] L is selected from C 1～5 Alkylene;

[0015] R 3 Selected from NR 7 R 8 Not replaced or R 9 Substituted 3- to 8-membered saturated heterocyclic groups, unsubstituted or R 9 Substituted 3- to 8-membered saturated cycloalkyl groups; R 7 R 8 Each is independently selected from hydrogen and C. 1～6 Alkyl, or R 7 R 8 Connected into a loop; R 9 Selected from C 1～6 alkyl;

[0016] R 4 R 5 Each is independently selected from hydrogen and C. 1～6 Alkyl, or R 4 R 5 Connect them into a ring;

[0017] R 6 Selected from hydrogen, C 1～6 alkyl;

[0018] R 2 Selected from hydrogen, unsubstituted or R 10 Replacement C 1～6 Alkyl, unsubstituted or R 10 Replacement C 1～6 Alkoxy, unsubstituted or R 11 Substituted 3-8 aryl groups, unsubstituted or R 11 Substituted 3- to 8-membered heteroaryl, halogen, hydroxyl, carboxyl, amino, nitro, cyano groups;

[0019] R 10 Selected from those that have not been replaced or have been R 11 Substituted 3-8 aryl groups, unsubstituted or R 11 Substituted 3- to 8-membered heteroaryl groups; R 11 Selected from hydrogen, halogens, C 1～6 Alkyl, C 1～6 Alkoxy, hydroxy, carboxyl, amino, nitro, cyano.

[0020] Furthermore, the structure of the compound is shown in Formula II:

[0021]

[0022] Among them, R 1a R 1b Each is independently selected from hydrogen, halogen, cyano, hydroxyl, halogenated or unhalogenated C. 1～4 Alkyl, halogenated or unhalogenated C 1～4 Alkoxy, OLR 3 NR 4 R 5 , NHCOR 6 COOR 6 ;

[0023] L is selected from C 1～4 Alkylene;

[0024] R 3 Selected from NR 7 R 8 Not replaced or R 9 Substituted 3- to 6-membered saturated heterocyclic groups, unsubstituted or R 9 Substituted 3- to 6-membered saturated cycloalkyl groups; R 7 R 8 Each is independently selected from hydrogen and C. 1～4 Alkyl, or R 7 R 8 Connected into a ring, wherein the ring is either not replaced or R c Substituted 5-6 member nitrogen-containing heterocycles, R c Selected from C 1～4 Alkyl; R 9 Selected from C 1～4 alkyl;

[0025] R 4 R 5 Each is independently selected from hydrogen and C. 1～4 Alkyl, or R 4 R 5 Connected into a ring, wherein the ring is either not replaced or R d Substituted 5-6 member nitrogen-containing heterocycles, R d Selected from amino protecting groups, C1～4 alkyl;

[0026] R 6 Selected from hydrogen, C 1～4 alkyl;

[0027] R 2 Selected from hydrogen, unsubstituted or R 10 Replacement C 1～4 Alkyl, unsubstituted or R 11 Substituted 5-6 aryl groups, unsubstituted or R 11 Substituted 5- to 6-membered heteroaryl groups;

[0028] R 10 Selected from those that have not been replaced or have been R 11 Substituted 5-6 aryl groups, unsubstituted or R 11 Substituted 5-6 aryl groups; R 11 Selected from hydrogen, halogens, C 1～4 Alkyl, C 1～4 Alkoxy, hydroxy, carboxyl, amino, nitro, cyano.

[0029] Furthermore, R 1a Selected from hydrogen, halogen, cyano, hydroxyl, halogenated or non-halogenated C 1～3 Alkyl, halogenated or unhalogenated 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 unhalogenated C 1～3 Alkoxy;

[0030] L is selected from C 1～3 Alkylene;

[0031] R 3 Selected from NR 7 R 8 Not replaced or R 9 The substituted 5- to 6-membered saturated heterocyclic group, preferably the 5- to 6-membered saturated heterocyclic group. R 7 R 8 Each is independently selected from hydrogen and C. 1～3 Alkyl, or R 7 R 8 Connected into a ring, wherein the ring is either not replaced or R c Substituted 5-6 member nitrogen-containing heterocycles, R c Selected from C 1～3 Alkyl groups, wherein the 5- to 6-membered nitrogen-containing heterocycles are preferably alkyl groups. R 9 Selected from C 1～3 alkyl;

[0032] R 4 R 5 Each is independently selected from hydrogen and C. 1～3 Alkyl, or R 4 R 5 The rings are connected to form an unsubstituted 5- or 6-membered nitrogen-containing heterocycle, preferably a nitrogen-containing heterocycle.

[0033] R 6 Selected from C 1～3 alkyl;

[0034] R 2 Selected from hydrogen, unsubstituted or R 10 Replacement C 1～3 Alkyl, unsubstituted or R 11 Substituted phenyl;

[0035] R 10 Selected from those that have not been replaced or have been R 11 Substituted phenyl; R 11 Selected from hydrogen, halogens, C 1～3 Alkyl, C 1～3 Alkoxy, hydroxy, carboxyl, amino, nitro, cyano.

[0036] Furthermore, the structure of the compound is shown in Formula III:

[0037]

[0038] Among them, R 4 R 5 Each is independently selected from hydrogen and C. 1～3 Alkyl, or R 4 R 5 The rings are connected to form an unsubstituted 5- or 6-membered nitrogen-containing heterocycle, preferably a nitrogen-containing heterocycle.

[0039] b is selected from 1, 2, or 3;

[0040] R e Selected from hydrogen, methyl, and ethyl;

[0041] R f Selected from hydrogen, halogens, C 1～3 Alkyl, C 1～3 Alkoxy, hydroxy, carboxyl, amino, nitro, cyano.

[0042] Furthermore, the structure of the compound is shown in Formula IV:

[0043]

[0044] Among them, R 1a Selected from hydrogen, halogen, cyano, hydroxyl, halogenated or non-halogenated C 1～3 Alkyl, halogenated or unhalogenated 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 unhalogenated C 1～3 Alkoxy;

[0045] L is selected from C 1～3 Alkylene, R 3 Selected from NR 7 R 8 Not replaced or R 9 The substituted 5- to 6-membered saturated heterocyclic group, preferably the 5- to 6-membered saturated heterocyclic group. R 7 R 8 Each is independently selected from hydrogen and C. 1～3 Alkyl, or R 7 R 8 Connected into a ring, wherein the ring is either not replaced or R c Substituted 5-6 member nitrogen-containing heterocycles, R c Selected from C 1～3 Alkyl groups, wherein the 5- to 6-membered nitrogen-containing heterocycles are preferably alkyl groups. R 9 Selected from C 1～3 alkyl;

[0046] R 4 R 5 Each is independently selected from hydrogen and C. 1～3 Alkyl, or R 4 R 5 The rings are connected to form an unsubstituted 5- or 6-membered nitrogen-containing heterocycle, preferably a nitrogen-containing heterocycle.

[0047] R 6 Selected from C 1～3 alkyl;

[0048] R 2 Selected from hydrogen, unsubstituted or R 10 Replacement C 1～3 Alkyl, unsubstituted or R 11Substituted phenyl;

[0049] R 10 Selected from those that have not been replaced or have been R 11 Substituted phenyl; R 11 Selected from hydrogen, halogens, C 1～3 Alkyl, C 1～3 Alkoxy, hydroxy, carboxyl, amino, nitro, cyano.

[0050] Furthermore, the structure of the compound is shown below:

[0051]

[0052]

[0053]

[0054]

[0055] The present invention also provides a drug preparation which is a formulation made of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof as the active ingredient, plus pharmaceutically acceptable excipients.

[0056] The present invention also provides the use of the above-mentioned compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or optical isomers thereof, or deuterated compounds thereof, in the preparation of ATM kinase inhibitors; wherein the ATM kinase inhibitors are preferably drugs for the prevention and / or treatment of diseases related to ATM kinase activity.

[0057] The present invention also provides the use of the above-mentioned compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or optical isomers thereof, or deuterated compounds thereof, in the preparation of radiosensitizers or chemosensitizers.

[0058] Furthermore, the radiosensitizer or chemotherapy sensitizer is a sensitizer for treating tumors, including colorectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid 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, etc.

[0059] The compounds provided by this invention can effectively inhibit the activity of ATM kinase, among which compound 37 has the best inhibitory effect on ATM kinase, IC50. 50 As low as 0.99 nM. The compounds provided by this invention can be used to prepare ATM kinase inhibitors, as well as drugs for the prevention and / or treatment of diseases related to ATM kinase activity.

[0060] As is well known to those skilled in the art, ATM kinase inhibitors can be used as radiosensitizers or chemosensitizers for treating various tumors, including colorectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid 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. This invention also demonstrates that compound 37 of this invention has a significant radiosensitizing effect in inhibiting the proliferation of colorectal cancer cells, and its radiosensitizing effect is superior to that of the positive control compound AZD0156. The compounds provided by this invention can be used to prepare radiosensitizers or chemosensitizers, and have broad application prospects in the synergistic radiosensitization therapy of tumors.

[0061] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0062] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0063] Figure 1 The radiosensitizing effects of compound 37 and the positive control compound AZD0156 are shown. Detailed Implementation

[0064] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0065] Example 1 Preparation of Compound 8

[0066]

[0067] Step a: Preparation of intermediate 1 (5-bromo-2-((2-nitrovinyl)amino)benzoic acid)

[0068]

[0069] Add 25 g (115 mmol) of 2-amino-5-bromobenzoic acid 2a to a mixture of concentrated hydrochloric acid (37%) and water (10:1). Stir at room temperature for 8 hours, then filter and collect the filtrate. In another reaction flask, mix crushed ice (35 g) and sodium hydroxide (15 g, 375 mmol) under ice bath stirring. Slowly add nitromethane (8.2 g, 134 mmol) to the mixture. After the addition is complete, react under ice bath for 1 hour, then move to room temperature and continue stirring for 1 hour. Pour the mixture into an acidic aqueous solution (28 g ice and 42 mL concentrated hydrochloric acid) under ice bath to obtain a solution containing nitroxyacetaldehyde oxime. Mix the solutions obtained from the two steps and stir at room temperature for 18 hours. A large amount of yellow precipitate precipitates in the reaction solution. Filter, wash the filter cake with water, and dry under vacuum to obtain crude intermediate 1. No further purification is required; it can be used directly in the next reaction.

[0070] Step b: Preparation of intermediate 2 (6-bromo-3-nitroquinoline-4-phenol)

[0071]

[0072] Add the crude intermediate 1 (5 g, 17 mmol) and potassium acetate (2 g, 21 mmol) obtained in the previous step to a round-bottom flask containing acetic anhydride, and react at 120 °C for 2 hours. After the reaction is complete, filter and collect the filter cake, wash with acetic acid, then wash with water, and further vacuum dry the filter cake to obtain 2.4 g 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] +

[0073] Step c: Preparation of intermediate 3 (6-bromo-4-chloro-3-nitroquinoline)

[0074]

[0075] Intermediate 2 (7.5 g, 28 mmol) was added to a round-bottom flask and refluxed at 100 °C for 3 hours using phosphorus oxychloride (40 mL) as solvent. After the reaction was complete, excess phosphorus oxychloride was removed by vacuum distillation. The remaining mixture was slowly poured into crushed ice for quenching, neutralized with saturated sodium bicarbonate, and then extracted with ethyl acetate. The extraction was repeated twice, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 15.2 g of brown crude intermediate 3, which was used directly in the next reaction without further purification.

[0076] Step d: Preparation of intermediate 4 (6-bromo-N-isopropyl-3-nitroquinoline-4-amine)

[0077]

[0078] 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 the mixture was stirred for 2 min. Then, triethylamine (1.66 mL, 12 mmol) was added dropwise. After the addition was complete, the mixture was moved to 60 °C and reacted overnight. After the reaction was complete, the solvent was evaporated under reduced pressure, and the mixture was washed with a large amount of water and ultrasonically. After the solid was ultrasonicated until it formed a uniform fine flocculent structure, it was filtered. The filter cake was washed again with a large amount of water until the filtrate was colorless, yielding 2.31 g of yellow solid, which is intermediate 4. No further purification is required before it can be used for the next step. 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,1 H),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] + .

[0079] Step e: Intermediate 5(6-bromo-N) 4 Preparation of (-isopropylquinoline-3,4-diamine)

[0080]

[0081] Intermediate 4 (0.93 g, 3 mmol) was added to a round-bottom flask and dissolved in acetic acid (30 mL). Reduced iron powder (850 mg, 15 mmol) was added in portions to this mixture while stirring at 60 °C. After the addition was complete, stirring was continued at 60 °C for approximately 4 hours. After the reaction was complete, the mixture was cooled to room temperature to obtain intermediate 5, which was soluble in acetic acid and could be used directly in the next step without further purification.

[0082] Step f: Preparation of intermediate 6 (8-bromo-1-isopropyl-1H-[1,2,3]triazolo[4,5-c]quinoline)

[0083]

[0084] The acetic acid solution (3 mmol) of intermediate 5 from the previous step was placed in an ice bath and stirred. It was then diluted with water and adjusted to acidity with concentrated hydrochloric acid. Sodium nitrite (230 mg, 3.3 mmol) was slowly added to the mixture. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 30 minutes. After the reaction was complete as monitored by TLC, the reaction solution was poured into a large volume of water. The acetic acid was neutralized with sodium carbonate, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, filtered, evaporated under reduced pressure, and purified by column chromatography to obtain intermediate 6 (690 mg, overall yield of 79%) as a white solid.

[0085] Step g: Preparation of compound 8 (5-(1-isopropyl-1H-[1,2,3]triazolo[4,5-c]quinolin-8-yl)pyridine-2-amine)

[0086]

[0087] Intermediate 6 (93 mg, 0.3 mmol) and pinacol ester of 2-amino-5-pyridineboronic acid (66.2 mg, 0.3 mmol) were placed in a double-necked flask. K₂CO₃ (82.8 mg, 0.6 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (12.2 mg, 0.015 mmol) were added. A mixed solution of dioxane and water (dioxane:water = 4:1) was used as the solvent. Under argon protection, the mixture was reacted overnight at 100 °C. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was collected, concentrated under reduced pressure, and separated by column chromatography to obtain 61 mg of compound 8 (yellow solid, 67% yield). 1 H NMR (400MHz, DMSO-d6) 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] + .

[0088] Example 2 Preparation of Compound 5 and Compound 37

[0089]

[0090] Step a: Same as step a in Example 1;

[0091] Step b: Same as step b in Example 1;

[0092] Step c: Same as step c in Example 1;

[0093] Step d: Preparation of intermediate 4'((R)-6-bromo-3-nitro-N-(1-phenylethyl)quinoline-4-amine)

[0094]

[0095] In a round-bottom flask, intermediate 3 (1.42 g, 5 mmol) and triethylamine (1.01 g, 10 mmol) prepared in the previous step were added and dissolved in ethanol (20 mL). R(+)-alpha-methylbenzylamine was slowly added with stirring at room temperature. After the addition was complete, the mixture was transferred to 60 °C and reacted overnight. After the reaction was complete, the solvent was evaporated under reduced pressure, and a large amount of water was added to the residue, precipitating a yellow solid. The solid was filtered, washed with water, and the filter cake was dried under vacuum to obtain 1.5 g 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] +

[0096] Step e: Intermediate 5'((R)-6-bromo-N 4 Preparation of (1-phenylethyl)quinoline-3,4-diamine

[0097]

[0098] Intermediate 4' (1.12 g, 3 mmol) was added to a round-bottom flask and dissolved in acetic acid (30 mL). Reduced iron powder (850 mg, 15 mmol) was added in portions to the mixture while stirring at 60 °C. After the addition was complete, stirring was continued at 60 °C for approximately 4 hours. After the reaction was complete, the mixture was cooled to room temperature to obtain intermediate 5', which was soluble in acetic acid and could be used directly in the next step without further purification.

[0099] Step f: Preparation of intermediate 6'((R)-8-bromo-1-(1-phenylethyl)-1H-[1,2,3]triazolo[4,5-c]quinoline)

[0100]

[0101] The acetic acid solution (3 mmol) of intermediate 5' from the previous step was placed in an ice bath and stirred. Water was added to dilute the solution, and the solution was adjusted to acidity with concentrated hydrochloric acid. Sodium nitrite (230 mg, 3.3 mmol) was slowly added to the mixture. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 30 minutes. After the reaction was monitored by TLC, the reaction solution was poured into a large amount of water, the acetic acid was neutralized with sodium carbonate, and then extracted with ethyl acetate. The organic phases were combined, dried, filtered, evaporated under reduced pressure, and purified by column chromatography to obtain intermediate 6' (470 mg, overall yield of 44% from both steps) as a white solid. 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,1 H),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] + .

[0102] Step g: Preparation of compound 5 ((R)-8-(6-fluoropyridin-3-yl)-1-(1-phenylethyl)-1H-[1,2,3]triazolo[4,5-c]quinoline)

[0103]

[0104] Intermediate 6' (106 mg, 0.3 mmol) and pinacol ester of 2-fluoro-5-pyridineboronic acid (67 mg, 0.3 mmol) were placed in a double-necked flask. K2CO3 (82.8 mg, 0.6 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (12.2 mg, 0.015 mmol) were added. A mixed solution of dioxane and water (dioxane:water = 4:1) was used as a solvent. Under argon protection, the mixture was reacted overnight at 100 °C. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was collected, concentrated under reduced pressure, and separated by column chromatography to obtain 68 mg of compound 5 (white solid, 61% yield). 1H NMR(400MHz, DMSO-d6)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),7.4 1(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] + .

[0105] 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)propyl-1-amine)

[0106]

[0107] 3-Dimethylamino-1-propanol (35 μL, 0.3 mmol) was dissolved in N,N-dimethylacetamide (2 mL), and NaH (14 mg, 0.6 mmol) was added under nitrogen protection. After stirring for a period of time, compound 5 (111 mg, 0.3 mmol) was slowly added. After the addition was complete, the mixture was moved to 50 °C and reacted overnight. After the reaction was complete, water and dichloromethane were added for extraction. The lower organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The residue was concentrated and purified by column chromatography to give 71 mg of compound 37 (white solid, 52% yield). 1 H NMR (400MHz, DMSO-d6) 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=6.6H z,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] + .

[0108] Other target compounds listed in Table 1 of this invention were prepared by referring to the methods of Example 1 or Example 2. The structural and characterization data of the obtained target compounds are shown in Table 1.

[0109] Table 1. Structural and characterization data of target compounds 1-50

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121] The following experimental examples demonstrate the beneficial effects of the present invention.

[0122] Experiment Example 1: Inhibitory Activity Test of Compounds Against ATM Kinase

[0123] 1. Experimental Methods

[0124] The purpose of this experiment was to detect the inhibitory activity of the compounds of this invention against ATM kinase in vitro, using an isotope labeling method (labeling the γ-phosphate group on ATP). The kinase inhibitory activity of the test compounds was measured using IC50. 50 The IC50 is expressed as the half-maximal inhibitory concentration (IC50) or the inhibition rate of the test compound against ATM kinase activity at a concentration of 10 μM. 50 The value can be calculated by measuring the inhibition rate of the test compound on ATM kinase activity at a series of different concentrations. The experimental method is as follows: In a reaction tube, buffer (8 mM MOPS, pH 7.0, 0.2 mM EDTA, 10 mM MnCl2), ATM kinase (5-10 mU), ATM kinase substrate, 10 mM magnesium acetate, and γ-ray dihydrogen phosphate were added sequentially. 33P-ATP solution and different concentrations of the test compound were prepared. Mg ATP was then added to the reaction to initiate the enzyme reaction, and the mixture was incubated at room temperature for 40 minutes. The reaction was terminated with 5 μL of 3% phosphate buffer, and 10 μL of the reaction solution was titrated onto a Filtermat A membrane. The membrane was washed three times with 75 mM phosphate solution for 5 minutes each time, followed by one wash with methanol. The Filtermat A membrane was then dried and subjected to scintillation counting. The scintillation count value reflected the degree of substrate phosphorylation, thus characterizing the inhibition of kinase activity. The IC50 of the test compound against ATM kinase was determined. 50 As shown in Table 2.

[0125] 2. Experimental Results

[0126] Table 2. Inhibitory effects of the tested compounds on ATM kinase

[0127]

[0128] It can be seen that the compounds of the present invention can effectively inhibit the activity of ATM kinase, among which compound 37 has the best inhibitory effect on ATM kinase, IC50. 50 As low as 0.99nM.

[0129] Experiment Example 2: Test of the radiosensitizing effect of the compound

[0130] 1. Experimental Methods

[0131] This experiment, based on clonogenic assays, involved seeding SW620 colorectal cancer cells in logarithmic growth phase at 100-500 cells per well in 12-well plates and culturing overnight at 37°C and 5% CO2. Cells were treated with different concentrations of compounds or DMSO for 1 hour, followed by X-ray irradiation (2.5 Gy or 5 Gy) to induce DNA double-strand damage, with or without irradiation. After irradiation, cells were cultured in a cell culture incubator for 16 hours. The cell supernatant was discarded, and complete culture medium (without the compound) was added, with the medium being replaced every 3 days. After 10-14 days of culture, the cell supernatant was discarded, and the cells were washed once with PBS. Cells were fixed with 4% paraformaldehyde at room temperature for 20 minutes. The supernatant was discarded, and the cells were gently washed twice with PBS. 0.3 mL of crystal violet staining solution was added to each well, and staining was performed at room temperature for 10-15 minutes. The staining solution was removed, and the cells were washed twice with water. Excess liquid in the wells was aspirated, and the cells were air-dried before photographing and analysis. The results are as follows: Figure 1 As shown.

[0132] 2. Experimental Results

[0133] from Figure 1It can be seen that, compared with the DMSO group, compound 37 at a concentration of 0.5 μM can significantly inhibit the proliferation of colorectal cancer cells SW620 under a radiation intensity of 2.5 Gy, and its radiosensitizing effect is better than that of the positive control compound AZD0156.

[0134] In summary, this invention provides an 8-heteroaryl-1H-[1,2,3]triazolo[4,5-c]quinoline derivative of Formula I and its use in the preparation of ATM kinase inhibitors. The compounds provided by this invention can effectively inhibit the activity of ATM kinase and can be used to prepare ATM kinase inhibitors, as well as drugs for the prevention and / or treatment of diseases related to ATM kinase activity. As is known to those skilled in the art, ATM kinase inhibitors can be used as radiosensitizers or chemosensitizers for the treatment of various tumors. This invention also demonstrates that compound 37 has a significant radiosensitizing effect in inhibiting the proliferation of colorectal cancer cells, and its radiosensitizing effect is superior to that of the positive control compound AZD0156. The compounds provided by this invention can be used to prepare radiosensitizers or chemosensitizers, and have broad application prospects in the synergistic radiosensitization therapy of tumors.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, characterized in that, The structure of the compound is shown in Formula II: Formula II Among them, R 1a C selected from hydroxyl, halogenated or non-halogenated 1~3 Alkyl, OLR 3 NR 4 R 5 , NHCOR 6 ;R 1b Selected from hydrogen, halogens, C 1~3 Alkoxy; L is selected from C 1~3 Alkylene; R 3 Selected from NR 7 R 8 Not replaced or R 9 The substituted 6-membered saturated heterocyclic group, wherein the 6-membered saturated heterocyclic group is ;R 7 R 8 Each is independently selected from hydrogen and C. 1~3 Alkyl, or R 7 R 8 Connected into a ring, wherein the ring is either not replaced or R c Substituted 5-6 member nitrogen-containing heterocycles, R c Selected from C 1~3 Alkyl group, wherein the 5-6 member nitrogen-containing heterocycle is , , , ;R 9 Selected from C 1~3 alkyl; R 4 R 5 Connected into a ring, wherein the ring is an unsubstituted 6-membered nitrogen-containing heterocycle, and the 6-membered nitrogen-containing heterocycle is or ; R 6 Selected from C 1~3 alkyl; R 2 Selected from those that have not been replaced or have been R 10 Replacement C 1~3 Alkyl, unsubstituted or R 11 Substituted phenyl; R 10 Selected from those that have not been replaced or have been R 11 Substituted phenyl; R 11 Selected from hydrogen, halogens, C 1~3 Alkyl, C 1~3 Alkyl group.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, characterized in that, The structure of the compound is shown in Formula III: Formula III Among them, R 4 R 5 Each is independently selected from hydrogen and C. 1~3 Alkyl, or R 4 R 5 The rings are connected to form unsubstituted 5-6 member nitrogen-containing heterocycles. , , or ; b is selected from 1, 2, or 3; R e Selected from hydrogen, methyl, and ethyl; R f Selected from hydrogen, halogens, C 1~3 Alkyl, C 1~3 Alkyl group.

3. A compound, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, characterized in that, The structure of the compound is shown in Formula IV: Formula IV Among them, R 1a For NR 4 R 5 ;R 1b It is hydrogen; R 4 R 5 Each is independently selected from hydrogen and C. 1~3 alkyl; R 2 Selected from those that have not been replaced or have been R 10 Replacement C 1~3 alkyl; R 10 It is an unsubstituted phenyl group.

4. A compound, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, characterized in that, The structure of the compound is shown below: 。 5. A drug, characterized in that, It is a formulation prepared by adding pharmaceutically acceptable excipients to a compound as described in any one of claims 1-2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, as an active ingredient, or a compound as described in any one of claims 3-4, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.

6. Use of the compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, or the compound of any one of claims 3-4, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, in the preparation of an ATM kinase inhibitor.

7. The use according to claim 6, characterized in that, The ATM kinase inhibitor is a drug for the prevention and / or treatment of diseases related to ATM kinase activity.

8. Use of the compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, or the compound of any one of claims 3-4, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, in the preparation of a radiosensitizer or a chemosensitizer, wherein the radiosensitizer or chemosensitizer is a sensitizer for treating tumors, and the tumor is colorectal cancer.

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