Benzo-aza compound as well as preparation method and application thereof

Abstract

The invention discloses a benzo-aza compound as well as a preparation method and application thereof. The benzazepine compound and the pharmaceutically acceptable salt of the benzazepine compound prepared by the invention have relatively high sensitivity and very strong cytotoxic activity to human colon cancer cells HCT116 tumor cells. The triethylene diamine catalyst is adopted in the process of preparing the benzo-aza compound, the reaction conditions are relatively conventional, the reaction process is mild, simple and convenient, the operation is easy, the cost is low, and the method is suitable for industrial large-scale production; according to the method, various substrates are used as reactants, products with various and complex structures are obtained, the yield is high, and the application range of the method is widened. The compound prepared by the preparation method disclosed by the invention has relatively high cytotoxic activity on human colon cancer cells HCT116. Therefore, the preparation method provided by the invention can provide a basis for screening the benzazepine compound with good activity on tumor cells, and is beneficial to further screening out compounds with more excellent biological activity.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a benzo[a]azapyridine. Compounds, their preparation methods, and applications. Background Technology

[0002] Benzaza Derivative compounds are widely found in pharmaceutical active molecules and natural products, and have broad application prospects in the life sciences field, being considered an important framework. This basic framework is widely present in various natural products and pharmaceutical active molecules. For example, Tienopramine (I) and Amezepine (II) are two marketed antidepressants; Mozavaptan (III) is an angiotensin V2 receptor antagonist; Benazepril (IV) is an angiotensin-converting enzyme inhibitor; and compound V is a γ-secretase inhibitor. The structural formulas of these compounds are as follows:

[0003]

[0004] These compounds exhibit Notch signaling inhibitory activity in tumor cells.

[0005] Currently, benzo[a]aza The methods for synthesizing derivatives are very limited. Most methods require expensive transition metal catalysis, and the synthesis of raw materials involves many steps and harsh reaction conditions. Summary of the Invention

[0006] Purpose of the invention: The purpose of this invention is to address the shortcomings of existing technologies by providing a benzo[a]azapyridine... Compounds, their preparation methods, and uses. This invention expands the scope of benzo[a]aza compounds. The range of derivatives is extensive, and these compounds can enhance the sensitivity to human colon cancer cells HCT116, exhibiting high cytotoxic activity against HCT116.

[0007] Technical solution: The objective of this invention is achieved through the following technical solution:

[0008] This invention provides a benzo[a]azapyridine of Formula 1 Compounds or their pharmaceutically acceptable salts:

[0009]

[0010] in,

[0011] R 1 The substituent is selected from substituted or unsubstituted C1-3 alkyl groups, substituted or unsubstituted phenyl groups, wherein the substituent is selected from halogens, C1-3 alkyl groups, alkoxy groups, phenyl groups, or hydroxyl groups;

[0012] R 2 Selected from hydrogen, C1-3 alkyl, halogen, alkoxy, substituted alkoxy, or hydroxyl;

[0013] R 3 It is selected from C1-3 alkyl, halogen, alkoxy, substituted alkoxy, hydroxy or nitro groups.

[0014] In some preferred embodiments,

[0015] R 1 Selected from methyl, ethyl, phenyl, or phenethyl;

[0016] R 2 Selected from hydrogen, C1-3 alkyl, halogen, or alkoxy;

[0017] R 3 Selected from methyl, halogen or nitro.

[0018] In some preferred embodiments, the pharmaceutically acceptable salt includes, but is not limited to, acid addition salts formed by the compound of Formula 1 with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, and mandelic acid; it also includes acid salts formed by the compound of Formula 1 with an inorganic base.

[0019] The compounds of Formula 1 of the present invention are preferably the following compounds:

[0020]

[0021]

[0022] The compounds of Formula 1 described above, as involved in this invention, can also exist in the form of their salts, which are converted into compounds of Formula 1 in vivo. For example, within the scope of this invention, the compounds of this invention are converted into pharmaceutically acceptable salt forms according to processes known in the art, and used in salt form.

[0023] Another object of the present invention is to provide a method for preparing a compound of formula 1, comprising the following steps:

[0024]

[0025] Compound of Formula 2 (allene derivative) and compound of Formula 3 (N-(2-((phenylimino)methyl)phenyl)benzenesulfonamide derivative) were used as reactants. The reaction was carried out in an organic solvent under the catalysis of triethylenediamine DABCO catalyst at room temperature with stirring. After the reaction was completed, the mixture was concentrated and purified to obtain compound of Formula 1.

[0026] Among them, R 1 R2 R 3 As defined in Equation 1.

[0027] All compounds of Formula 1 of this invention can be prepared by the methods described above or similarly described, with the appropriate starting materials selected according to the different substituents and their positions. Those skilled in the art should recognize that the above methods aid in understanding this invention but do not limit its scope; unless otherwise specified, variables are defined as mentioned in Formula 1.

[0028] In a preferred embodiment of the present invention, the molar ratio of the compound of formula 2, the compound of formula 3, and the DABCO catalyst is 2.3:1:0.2.

[0029] In a preferred embodiment of the present invention, the organic solvent is selected from ethyl acetate.

[0030] More preferably, the ratio of the compound of formula 3 to ethyl acetate is 0.1:2 mmol / mL.

[0031] In a preferred embodiment of the present invention, the purification is carried out by silica gel column chromatography, and the eluent is a mixture of petroleum ether and ethyl acetate with a volume ratio of 8:1.

[0032] The preparation method of this invention can achieve benzo[a]azapyridine in one step. The synthesis of compounds yields excellent results, is environmentally friendly, has a wide range of applications, and uses readily available raw materials, mild reaction conditions, safe and simple operation, convenient post-processing, short reaction time, and diverse product structures, thus possessing potential socio-economic benefits.

[0033] Another object of the present invention is to provide a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0034] The pharmaceutical compositions of the present invention can be administered in various known ways, such as orally, parenterally, by inhalation spray, or via an implanted reservoir. The pharmaceutical compositions of the present invention can be administered alone or in combination with other antitumor drugs. Oral compositions can be any orally acceptable dosage form, including, but not limited to, tablets, capsules, emulsions, suspensions, dispersions, and solutions. Commonly used pharmaceutically acceptable carriers include stabilizers, diluents, surfactants, lubricants, antioxidants, binders, colorants, fillers, emulsifiers, etc.

[0035] Sterile injectable compositions may be formulated using suitable dispersants or wetting agents and suspending agents in accordance with techniques known in the art. Pharmaceutically acceptable carriers and solvents that may be used include water, mannitol, sodium chloride solution, etc.

[0036] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be varied to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and route of administration, and is non-toxic to the patient. The selected dosage level depends on a variety of factors, including the activity of the specific compound of the present invention or its salt used, the route of administration, the time of administration, the excretion rate of the specific composition used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the specific composition used, the age, sex, weight, general health condition, and medical history of the patient being treated, and similar factors known in the medical field.

[0037] Another object of the present invention is to provide the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof in the preparation of an antitumor drug.

[0038] The tumor in question is human colon cancer.

[0039] Beneficial effects:

[0040] (1) The benzo[a]aza prepared in this invention The compounds and their pharmaceutically acceptable salts exhibit high sensitivity and strong cytotoxic activity against HCT116 tumor cells. Therefore, these compounds can be used to prepare antitumor drugs.

[0041] (2) In the preparation of benzo[a]aza The compounding process uses DABCO catalyst, the reaction conditions are relatively conventional, the reaction process is mild, simple, easy to operate, and low in cost, making it suitable for large-scale industrial production and broadening the scope of application of this method. A variety of substrates were used as reactants, resulting in products with diverse and complex structures and high yields. Detailed Implementation

[0042] The preparation method of the compound of Formula 1 of the present invention is described below with reference to specific embodiments, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art.

[0043] In the following examples, unless otherwise stated, allene derivatives, N-(2-((phenylimino)methyl)phenyl)benzenesulfonamide derivatives, DABCO catalysts, and other reagents are commercially available or obtained in accordance with known literature reports (Ke Wu, Quanxin Li, Wenbo Su, Shaofei Ni, Qingfa Zhou. Experimental and theoretical study of phosphine-catalyzed reaction modes in the reaction of α-substituted allenes with aryl imines. Angewandte Chemie International Edition, 2023, 62(51):e202314191; Miao Zhan, Xiang Pu, Bin He, Dawen Niu, Xia Zhang. Intramolecular Umpolung Allylation of Imines. Organic Letters, 2018, 20(18):5857-5860.); the experimental methods described are generally performed under conventional conditions or conditions recommended by the manufacturer.

[0044] Example 1: Synthesis of 2,4-dimethyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1a)

[0045]

[0046] 0.23 mmol of 1-methyl-3-vinylpyrrolidine-2,5-dione and 0.1 mmol of (E)-4-methyl-N-(2-(phenylimino)methyl)phenyl)benzenesulfonamide were added to 2 mL of ethyl acetate as reactants, and 0.02 mmol of triethylenediamine was added as a catalyst. The mixture was stirred at 25 °C for 20 h, and the reaction was monitored by TLC until complete. After concentration, the mixture was purified by silica gel column chromatography (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 8:1) to obtain a white solid 1a. The yield was 99%. 1 HNMR(300MHz,Chloroform-d)δ(ppm)7.71-7.61(m,1H),7.56-7.42(m,2H),7.36-7 .25(m,3H),7.17-7.08(m,2H),6.94(s,1H),3.08(s,3H),2.88(s,3H),2.41(s,3H). 13C NMR (75MHz, Chloroform-d) δ (ppm) 166.82, 166.49, 147.78, 144.94, 135.74, 134.58, 134.42, 133.30, 132.84, 131.26, 131.24, 129.56, 129.33, 127.79, 126.12, 124.73, 24.45, 22.51, 21.60 HRMS (ESI-TOF) calculated C 21 H 19 N₂O₄S(M+H) + =395.1060, measured value 395.1051.

[0047] Example 2: Synthesis of 2,4,7-trimethyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1b)

[0048]

[0049] The preparation method is as described in Example 1, using 1-methyl-3-vinylidene-2,5-dione and (E)-4-methyl-N-(5-methyl-2-((phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product 1b with a yield of 77%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.33(s,1H),7.32-7.25(m,3H),7.23-7.18(m,1H), 7.11(d,J=8.0Hz,2H),6.90(s,1H),3.07(s,3H),2.86(s,3H),2.48(s,3H),2.40(s,3H). 13 C NMR (101MHz, Chloroform-d) δ (ppm) 166.91, 166.58, 146.94, 144.86, 144.66, 135.71, 134.40, 133.27, 131.56, 131.32, 131.11, 130.43, 129.25, 127.82, 125.14, 124.93, 24.39, 22.47, 21.58, 21.47. HRMS (ESI-TOF) calculated C 22 H 21 N₂O₄S(M+H) + =409.1217, measured value 409.1224.

[0050] Example 3: Synthesis of 7-fluoro-2,4-dimethyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1c)

[0051]

[0052] The preparation method is as described in Example 1, using 1-methyl-3-vinylidene-2,5-dione and (E)-4-fluoro-N-(5-methyl-2-((phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product 1c with a yield of 80%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.35-7.29(m,3H),7.28-7.23(m,1H),7.23-7.1 7(m,1H),7.13(d,J=8.1Hz,2H),6.90(s,1H),3.08(s,3H),2.85(s,3H),2.41(s,3H). 13 CNMR (101MHz, Chloroform-d) δ (ppm): 166.91, 166.65, 166.28, 164.36, 146.81, 145.20, 136.16, 136.05, 135.51, 132.58, 132.48, 130.93, 130.89, 130.16, 129.40, 127.82, 125.63, 125.61, 124.97, 120.25, 120.03, 117.33, 117.12, 24.46, 22.42, 21.59. HRMS (ESI-TOF) calculated value C. 21 H 18 FN2O4S(M+H + = 413.0966, measured value 413.0963.

[0053] Example 4: Synthesis of 7-chloro-2,4-dimethyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1d)

[0054]

[0055] The preparation method is as described in Example 1, using 1-methyl-3-vinylpyrrolidine-2,5-dione and (E)-4-chloro-N-(5-methyl-2-((phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product 1d with a yield of 80%. 1H NMR(300MHz,Chloroform-d)δ(ppm)7.55-7.50(m,1H),7.50-7.41(m,1H),7.36-7.30(m,2H) ,7.28-7.22(m,1H),7.19-7.09(m,2H),6.89(s,1H),3.09(s,3H),2.86(s,3H),2.42(s,3H). 13 C NMR (101MHz, Chloroform-d) δ (ppm) 166.56, 166.23, 147.62, 145.23, 138.98, 135.53, 135.29, 132.99, 132.89, 131.81, 130.05, 129.90, 129.43, 127.83, 126.38, 124.93, 24.49, 22.45, 21.59. HRMS (ESI-TOF) calculated C 21 H 18 ClN2O4S(M+H + =429.0670, measured value 429.0674.

[0056] Example 5: Synthesis of 7-bromo-2,4-dimethyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1e)

[0057]

[0058] The preparation method is as described in Example 1, using 1-methyl-3-vinylpyrrolidine-2,5-dione and (E)-4-bromo-N-(5-methyl-2-((phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product 1e with a yield of 67%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.67(s,1H),7.64-7.57(m,1H),7.37-7.30 (m,2H),7.22-7.10(m,3H),6.88(s,1H),3.09(s,3H),2.86(s,3H),2.42(s,3H). 13CNMR (101MHz, Chloroform-d) δ (ppm): 166.56, 166.21, 147.79, 145.23, 135.74, 135.54, 135.24, 133.41, 132.82, 131.93, 130.15, 129.44, 127.84, 126.93, 126.53, 124.94, 24.50, 22.46, 21.60. HRMS (ESI-TOF) calculated value C. 21 H 18 BrN2O4S(M+H + =473.0165, measured value 473.0158.

[0059] Example 6: Synthesis of 7-methoxy-2,4-dimethyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1f)

[0060]

[0061] The preparation method is as described in Example 1, using 1-methyl-3-vinylpyrrolidine-2,5-dione and (E)-4-methoxy-N-(5-methyl-2-((phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product 1f with a yield of 79%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.35-7.30(m,2H),7.24(d,J=8.5Hz,1H),7.12(d,J=8.0 Hz,2H),7.07-6.99(m,2H),6.89(s,1H),3.93(s,3H),3.07(s,3H),2.85(s,3H),2.41(s,3H). 13 C NMR (101MHz, Chloroform-d) δ (ppm) 167.06, 166.67, 164.23, 145.46, 144.91, 135.93, 135.61, 132.48, 131.20, 129.23, 127.88, 127.11, 125.28, 123.71, 117.27, 116.33, 55.92, 24.36, 22.47, 21.58. HRMS (ESI-TOF) calculated C 22 H 21 N₂O₅S(M+H) + =425.1166, measured value 425.1169.

[0062] Example 7: Synthesis of 6-methyl-2,4-dimethyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (compound 1g)

[0063]

[0064] The preparation method is as described in Example 1, using 1-methyl-3-vinylidene-2,5-dione and (E)-5-methyl-N-(5-methyl-2-((phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain 1 g of white solid product with a yield of 87%. 1 H NMR(300MHz,Chloroform-d)δ(ppm)7.50-7.42(m,1H),7.42-7.34(m,1H),7.34-7.28(m, 2H),7.17-7.07(m,3H),6.89(s,1H),3.08(s,3H),2.86(s,3H),2.42(s,3H),2.41(s,3H). 13 C NMR (101MHz, Chloroform-d) δ (ppm) 166.84, 166.56, 147.72, 144.83, 139.81, 135.79, 134.17, 134.04, 132.52, 132.21, 131.63, 131.42, 129.28, 127.80, 125.96, 124.70, 24.40, 22.43, 21.57, 21.00. HRMS (ESI-TOF) calculated C 22 H 21 N₂O₄S(M+H) + =409.1217, measured value 409.1220.

[0065] Example 8: Synthesis of 6-fluoro-2,4-dimethyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1h)

[0066]

[0067] The preparation method is as described in Example 1, using 1-methyl-3-vinylidene-2,5-dione and (E)-5-fluoro-N-(5-methyl-2-((phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product in 1 hour, with a yield of 56%. 1H NMR(300MHz,Chloroform-d)δ(ppm)7.54-7.45(m,1H),7.39-7.29(m,3H),7.19-7. 10(m,2H),7.04-6.96(m,1H),6.83(s,1H),3.10(s,3H),2.88(s,3H),2.42(s,3H). 13 C NMR (101MHz, Chloroform-d) δ (ppm) 166.44, 166.23, 163.70, 161.20, 148.60, 145.17, 136.23, 136.14, 135.59, 134.83, 134.74, 130.63, 130.60, 129.76, 129.74, 129.44, 127.78, 127.26, 124.61, 120.14, 119.92, 117.17, 116.94, 24.51, 22.49, 21.59. HRMS (ESI-TOF) calculated C 21 H 18 FN2O4S(M+H + =413.0966, measured value 413.0967.

[0068] Example 9: Synthesis of 6-chloro-2,4-dimethyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1i)

[0069]

[0070] The preparation method is as described in Example 1, using 1-methyl-3-vinylpyrrolidine-2,5-dione and (E)-5-chloro-N-(5-methyl-2-((phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product 1i with a yield of 72%. 1 H NMR(300MHz,Chloroform-d)δ(ppm)7.64-7.55(m,1H),7.47-7.39(m,1H),7.36-7. 25(m,3H),7.19-7.10(m,2H),6.81(s,1H),3.09(s,3H),2.86(s,3H),2.42(s,3H). 13C NMR (101MHz, Chloroform-d) δ (ppm) 166.36, 166.19, 148.44, 145.23, 135.73, 135.54, 135.52, 134.14, 133.07, 132.96, 130.55, 129.62, 129.48, 127.77, 127.29, 124.65, 24.53, 22.49, 21.60. HRMS (ESI-TOF) calculated C 21 H 18 ClN2O4S(M+H + = 429.0670, measured value 429.0665. Example 10: Synthesis of 6-bromo-2,4-dimethyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (compound 1j)

[0071]

[0072] The preparation method is as described in Example 1, using 1-methyl-3-vinylpyrrolidine-2,5-dione and (E)-5-bromo-N-(5-methyl-2-((phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product 1j with a yield of 62%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 7.79-7.71 (m, 1H), 7.45 (d, J = 2.3Hz, 1H), 7.39- 7.29(m,3H),7.18-7.11(m,2H),6.81(s,1H),3.09(s,3H),2.86(s,3H),2.42(s,3H). 13 C NMR (101MHz, Chloroform-d) δ (ppm) 166.33, 166.18, 148.41, 145.24, 136.05, 135.95, 135.53, 134.34, 133.59, 133.55, 129.53, 129.48, 127.77, 127.29, 124.66, 123.50, 24.52, 22.48, 21.60. HRMS (ESI-TOF) calculated C 21 H 18 BrN2O4S(M+H + =473.0165, measured value 473.0170.

[0073] Example 11: Synthesis of 5-((4-fluorophenyl)sulfonyl)-2,4-dimethylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1k)

[0074]

[0075] The preparation method is as described in Example 1, using 1-methyl-3-vinylidene-2,5-dione and (E)-4-fluoro-N-(2-(phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product 1k with a yield of 86%.

[0076] 1 H NMR(300MHz,Chloroform-d)δ(ppm)7.75-7.63(m,1H),7.57-7.48(m,2H),7.47 -7.40(m,2H),7.39-7.31(m,1H),7.08-6.97(m,3H),3.10(s,3H),2.89(s,3H). 13 C NMR (101MHz, Chloroform-d) δ (ppm) 167.09, 166.70, 166.35, 164.53, 147.68, 135.01, 134.98, 134.45, 134.22, 133.49, 132.74, 131.38, 131.23, 130.47, 130.37, 129.77, 126.53, 124.70, 116.19, 115.97, 24.54, 22.54. HRMS (ESI-TOF) calculated C 20 H 16 FN2O4S(M+H + =399.0809, measured value 399.0807.

[0077] Example 12: Synthesis of 5-((4-chlorophenyl)sulfonyl)-2,4-dimethylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 11)

[0078]

[0079] The preparation method is as described in Example 1, using 1-methyl-3-vinylidene-2,5-dione and (E)-4-chloro-N-(2-(phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain 1 liter of white solid product with a yield of 78%. 1 H NMR (300MHz, Chloroform-d) δ (ppm) 7.75-7.63 (m, 1H), 7.57-7.45 (m, 2H), 7.40-7.29 (m, 5H), 7.04 (s, 1H), 3.11 (s, 3H), 2.88 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ (ppm) 166.63, 166.33, 147.46, 140.50, 137.40, 134.44, 134.11, 133.50, 132.65, 131.41, 131.32, 129.80, 129.07, 129.04, 126.54, 124.80, 24.56, 22.49. HRMS (ESI-TOF) calculated C 20 H 16 ClN2O4S(M+H + =415.0514, measured value 415.0521.

[0080] Example 13: Synthesis of 5-((4-bromophenyl)sulfonyl)-2,4-dimethylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1m)

[0081]

[0082] The preparation method is as described in Example 1, using 1-methyl-3-vinylpyrrolidine-2,5-dione and (E)-4-bromo-N-(2-(phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product 1m with a yield of 74%. 1 HNMR(300MHz,Chloroform-d)δ(ppm)7.74-7.63(m,1H),7.55-7.45(m,4H),7.41-7.32(m,1H),7.32-7.23(m,2H),7.04(s,1H),3.11(s,3H),2.88(s,3H). 13 C NMR (101MHz, Chloroform-d) δ (ppm) 166.60, 166.33, 147.41, 137.91, 134.44, 134.09, 133.49, 132.63, 132.04, 131.42, 131.33, 129.81, 129.12, 129.03, 126.54, 124.82, 24.56, 22.47. HRMS (ESI-TOF) calculated C 20 H 16 BrN2O4S(M+H + =459.0009, measured value 459.0014.

[0083] Example 14: Synthesis of 5-((3-nitrophenyl)sulfonyl)-2,4-dimethylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1n)

[0084]

[0085] The preparation method is as described in Example 1, using 1-methyl-3-vinylpyrrolidine-2,5-dione and (E)-3-nitro-N-(2-(phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product 1n with a yield of 91%. 1 HNMR(400MHz,Chloroform-d)δ(ppm)8.44-8.35(m,1H),8.25-8.19(m,1H),7.80-7.70(m 2H),7.63-7.50(m,3H),7.39-7.31(m,1H),6.90(s,1H),3.08(s,3H),2.92(s,3H). 13 CNMR (101MHz, Chloroform-d) δ 166.41, 166.00, 148.03, 146.87, 141.00, 133.95, 133.91, 133.60, 132.71, 131.55, 130.84, 130.21, 130.13, 127.99, 126.66, 125.18, 122.90, 24.55, 22.52. HRMS (ESI-TOF) calculated value C 20 H 16 N3O6S(M+H + =426.0754, measured value 426.0754.

[0086] Example 15: Synthesis of 2-ethyl-4-methyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1o)

[0087]

[0088] The preparation method is as described in Example 1, using 1-ethyl-3-vinylidene-2,5-dione and (E)-4-methyl-N-(2-(phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product 10, with a yield of 61%. 1 HNMR(400MHz,Chloroform-d)δ(ppm)7.71-7.62(m,1H),7.55-7.44(m,2H),7.37-7.28(m,3H),7.16 -7.09(m,2H),6.94(s,1H),3.64(q,J=7.2Hz,2H),2.88(s,3H),2.41(s,3H),1.22(t,J=7.2Hz,3H). 13C NMR (101MHz, Chloroform-d) δ (ppm) 166.47, 166.12, 147.45, 144.94, 135.66, 134.62, 134.31, 133.26, 132.89, 131.23, 129.53, 129.30, 127.84, 126.08, 125.02, 33.28, 22.38, 21.57, 13.43. HRMS (ESI-TOF) calculated C 22 H 21 N₂O₄S(M+H) + =409.1217, measured value 409.1224.

[0089] Example 16: Synthesis of 2-phenyl-4-methyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1p)

[0090]

[0091] The preparation method is as described in Example 1, using 1-phenyl-3-vinylidene-2,5-dione and (E)-4-methyl-N-(2-(phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product 1p with a yield of 90%. 1 HNMR(300MHz,Chloroform-d)δ(ppm)7.75-7.66(m,1H),7.58-7.45(m,4H),7.45-7.32(m,6H),7.22-7.15(m,2H),7.09(s,1H),2.93(s,3H),2.43(s,3H). 13 C NMR (101MHz, Chloroform-d) δ (ppm) 165.70, 165.40, 148.80, 145.11, 135.74, 134.74, 134.42, 133.56, 132.88, 132.34, 131.48, 131.35, 129.63, 129.37, 129.15, 128.58, 127.92, 126.43, 125.74, 124.62, 22.65, 21.63. HRMS (ESI-TOF) calculated C 26 H 21 N₂O₄S(M+H) + =457.1217, measured value 457.1213.

[0092] Example 17: Synthesis of 2-phenylethyl-4-methyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1q)

[0093]

[0094] The preparation method is as described in Example 1, using 1-phenylethyl-3-vinylidene-2,5-dione and (E)-4-methyl-N-(2-(phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product 1q with a yield of 79%. 1 HNMR(400MHz,Chloroform-d)δ(ppm)7.71-7.63(m,1H),7.56-7.45(m,2H),7.39-7.32(m,3H),7.32-7.28(m,3H),7 .27-7.24(m,2H),7.07-7.00(m,2H),6.89(s,1H),3.93-3.76(m,2H),2.99-2.91(m,2H),2.87(s,3H),2.39(s,3H). 13 C NMR (101MHz, Chloroform-d) δ (ppm) 166.40, 166.21, 147.74, 144.91, 137.80, 135.66, 134.62, 134.37, 133.29, 132.90, 131.23, 131.15, 129.54, 129.32, 128.85, 128.64, 127.76, 126.80, 126.02, 124.71, 39.53, 33.98, 22.49, 21.57. HRMS (ESI-TOF) calculated C 28 H 25 N₂O₄S(M+H) + =485.1530, measured value 485.1521.

[0095] Example 18: Synthesis of 7-fluoro-4-methyl-2-phenylethyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1r)

[0096]

[0097] The preparation method is as described in Example 1, using 1-phenylethyl-3-vinylidene-2,5-dione and (E)-4-fluoro-N-(5-methyl-2-((phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product 1r with a yield of 77%. 1H NMR(400MHz,Chloroform-d)δ(ppm)7.39-7.32(m,2H),7.32-7.24(m,7H),7.24-7.17(m,1H),7 .07-7.01(m,2H),6.85(s,1H),3.93-3.76(m,2H),3.03-2.89(m,2H),2.85(s,3H),2.39(s,3H). 13 C NMR(101MHz,Chloroform-d)δ(ppm)166.93,166.27,166.03,164.38,146.76,145.18,137.75,136.19,136.08,135.41,132.56,132.46,130.87, 130.84,130.09,129.40,128.84,128.65,127.79,126.82,125.50,125.4 8,124.95,120.31,120.09,117.34,117.12,39.56,33.95,22.41,21.57. HRMS (ESI-TOF) calculated value C 28 H 24 FN2O4S(M+H + =503.1435, measured value 503.1432.

[0098] Example 19: Synthesis of 7-chloro-4-methyl-2-phenylethyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1s)

[0099]

[0100] The preparation method is as described in Example 1, using 1-phenylethyl-3-vinylidene-2,5-dione and (E)-4-chloro-N-(5-methyl-2-((phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product 1s with a yield of 79%. 1 H NMR(300MHz,Chloroform-d)δ(ppm)7.56-7.49(m,1H),7.49-7.43(m,1H),7.39-7.32(m,2H),7.31-7.22 (m,6H),7.08-7.00(m,2H),6.83(s,1H),3.95-3.73(m,2H),3.05-2.87(m,2H),2.85(s,3H),2.39(s,3H). 13C NMR (101MHz, Chloroform-d) δ (ppm) 166.16, 165.96, 147.56, 145.20, 138.99, 137.72, 135.43, 135.31, 132.95, 132.92, 131.79, 129.96, 129.90, 129.43, 128.83, 128.65, 127.79, 126.83, 126.25, 124.90, 39.58, 33.93, 22.44, 21.57. HRMS (ESI-TOF) calculated C 28 H 24 ClN2O4S(M+H + =519.1140, measured value 519.1133.

[0101] Example 20: Synthesis of 7-bromo-4-methyl-2-phenylethyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1t)

[0102]

[0103] The preparation method is as described in Example 1, using 1-phenylethyl-3-vinylidene-2,5-dione and (E)-4-bromo-N-(5-methyl-2-((phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain 1 t of white solid product with a yield of 80%. 1 H NMR(300MHz,Chloroform-d)δ(ppm)7.70-7.65(m,1H),7.64-7.56(m,1H),7.41-7.31(m,2H),7.31-7.24(m,5H),7.1 8(d,J=8.3Hz,1H),7.08-7.00(m,2H),6.82(s,1H),3.95-3.73(m,2H),3.00-2.89(m,2H),2.85(s,3H),2.39(s,3H). 13 C NMR (101MHz, Chloroform-d) δ (ppm) 166.17, 165.93, 147.73, 145.20, 137.72, 135.79, 135.43, 135.26, 133.34, 132.82, 131.92, 130.06, 129.44, 128.83, 128.65, 127.79, 126.93, 126.83, 126.39, 124.91, 39.59, 33.93, 22.44, 21.58. HRMS (ESI-TOF) calculated C 28 H 24BrN2O4S(M+H + =563.0635, measured value 563.0644.

[0104] Example 21: Synthesis of 4,6-dimethyl-2-phenylethyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1u)

[0105]

[0106] The preparation method is as described in Example 1, using 1-phenylethyl-3-vinylidene-2,5-dione and (E)-5-methyl-N-(5-methyl-2-((phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain 1u of white solid product with a yield of 63%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 7.50-7.43 (m, 1H), 7.42-7.31 (m, 3H), 7.32-7.23 (m, 5H), 7.11 (d, J = 2.0Hz, 1 H),7.06-7.00(m,2H),6.84(s,1H),3.92-3.75(m,2H),3.03-2.90(m,2H),2.86(s,3H),2.43(s,3H),2.39(s,3H). 13 C NMR (101MHz, Chloroform-d) δ (ppm) 166.44, 166.29, 147.68, 144.81, 139.80, 137.83, 135.69, 134.18, 133.99, 132.59, 132.24, 131.62, 131.35, 129.28, 128.84, 128.63, 127.77, 126.78, 125.83, 124.68, 39.50, 33.98, 22.42, 21.56, 21.00. HRMS (ESI-TOF) calculated C 29 H 27 N₂O₄S(M+H) + =499.1686, measured value 499.1690.

[0107] Example 22: Synthesis of 8-bromo-4-methyl-2-phenylethyl-5-toluenesulfonylbenzo[b]pyrrolo[3,4-e]aza-1,3(2H,5H)-dione (Compound 1v)

[0108]

[0109] The preparation method is as described in Example 1, using 1-phenylethyl-3-vinylidene-2,5-dione and (E)-5-bromo-N-(5-methyl-2-((phenylimino)methyl)phenyl)benzenesulfonamide as reactants to obtain a white solid product 1v with a yield of 65%. 1 H NMR (300MHz, Chloroform-d) δ (ppm) 7.80-7.70 (m, 1H), 7.44 (d, J = 2.3Hz, 1H), 7.40-7.32 (m, 3H), 7.32-7.2 3(m,5H),7.09-7.00(m,2H),6.76(s,1H),3.96-3.74(m,2H),3.06-2.87(m,2H),2.86(s,3H),2.40(s,3H). 13 C NMR (101MHz, Chloroform-d) δ (ppm) 165.95, 165.92, 148.37, 145.21, 137.69, 135.98, 135.96, 135.42, 134.41, 133.62, 133.54, 129.48, 129.43, 128.83, 128.66, 127.73, 127.16, 126.85, 124.62, 123.51, 39.60, 33.91, 22.47, 21.58. HRMS (ESI-TOF) calculated C 28 H 24 BrN2O4S(M+H + =563.0635, measured value 563.0627.

[0110] Example 23 Bioactivity Test

[0111] The cytotoxic activity of the compounds synthesized in this invention against human colon cancer cells HCT116 was tested using the MTT assay (Qihe Jiang, Yujiang Tang, Qinglan Hu, Bichuan Wang, Xiuqin Ruan, Qingfa Zhou, Discovery of novel itaconimide-based derivatives aspotent HDAC inhibitors for the efficient treatment of prostate cancer, European Journal of Medicinal Chemistry, Volume 269, 2024, 116315). The results are shown in Table 1.

[0112] The positive control drug chidamide showed an IC50 value of 50% for HCT116 cells.50 It is 0.92 μM.

[0113] Table 1. Cytotoxic activity of compound 1 in this invention against human colon cancer cells HCT116.

[0114]

[0115] "++++" indicates 0.1-1μM; "+++" indicates 1-10μM; "++" indicates 10-100μM; "+" indicates 100-1000μM.

[0116] As can be seen from Examples 1-22 of this invention, the preparation method of this invention achieves benzo[a]azapyridine in one step. The synthesis of compounds yields excellent results, is environmentally friendly, and has a wide range of applications. Furthermore, the raw materials are readily available, the reaction conditions are mild, the operation is safe and simple, the post-processing is convenient, the reaction time is short, and the product structures are diverse, thus broadening the scope of application of this method.

[0117] The embodiments of this invention used a variety of substrates as reactants, resulting in structurally diverse and complex products. The synthesized compounds exhibited high cytotoxic activity against human colon cancer cells HCT116. Therefore, the preparation method of benzo[a]aza compounds provided by this invention can provide a foundation for screening compounds with good activity against tumor cells, and help to further screen for compounds with even better biological activity.

[0118] As described above, although the invention has been shown and described with reference to specific preferred embodiments, it should not be construed as limiting the invention itself. Various changes in form and detail may be made without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

1. A benzo[a]azapyridine of Formula 1 Compounds or their pharmaceutically acceptable salts: in, R 1 The substituent is selected from substituted or unsubstituted C1-3 alkyl groups, substituted or unsubstituted phenyl groups, wherein the substituent is selected from halogens, C1-3 alkyl groups, alkoxy groups, phenyl groups, or hydroxyl groups; R 2 Selected from hydrogen, C1-3 alkyl, halogen, alkoxy, substituted alkoxy, or hydroxyl; R 3 It is selected from C1-3 alkyl, halogen, alkoxy, substituted alkoxy, hydroxy or nitro groups.

2. The compound according to claim 1, characterized in that: R 1 Selected from methyl, ethyl, phenyl, or phenethyl; R 2 Selected from hydrogen, C1-3 alkyl, halogen, or alkoxy; R 3 Selected from methyl, halogen or nitro.

3. The compound according to claim 1, characterized in that... Selected from:

4. A method for preparing the compound of formula 1 according to claim 1, characterized in that, Includes the following steps: Compound of Formula 2 (allene derivative) and compound of Formula 3 (N-(2-((phenylimino)methyl)phenyl)benzenesulfonamide derivative) were used as reactants. The reaction was carried out in an organic solvent under the catalysis of triethylenediamine DABCO catalyst at room temperature with stirring. After the reaction was completed, the mixture was concentrated and purified to obtain compound of Formula 1. Among them, R 1 R 2 R 3 As defined in Equation 1.

5. The preparation method according to claim 4, characterized in that, The molar ratio of the compound of formula 2, the compound of formula 3, and the DABCO catalyst is 2.3:1:0.

2.

6. The preparation method according to claim 4, characterized in that, The organic solvent is selected from ethyl acetate.

7. The preparation method according to claim 6, characterized in that, The ratio of the compound of Formula 3 to ethyl acetate is 0.1:2 mmol / mL.

8. The preparation method according to claim 4, characterized in that, The purification was performed by silica gel column chromatography, using a mixture of petroleum ether and ethyl acetate at a volume ratio of 8:1 as the eluent.

9. A pharmaceutical composition, characterized in that: This includes the compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1-3 in the preparation of an antitumor drug.

Images