tricyclic spiro-bicyclic class of compounds

Abstract

Disclosed are tricyclic spiro-bicyclic compounds having the following structure, which are useful for treating cancer.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to tricyclic spirochetal bicyclic compounds. Background Technology

[0002] Methionine adenosyltransferase (MAT), also known as S-adenosylmethionine synthetase, has the main biological function of catalyzing the reaction of methionine and ATP to produce the biological methyl donor S-adenosylmethionine (SAM, AdoMet, or SAMe). The reaction catalyzed by MAT is considered an important rate-limiting step in the methionine metabolic cycle.

[0003] The MAT family comprises three members: MAT1A, MAT2A, and MAT2B. MAT1A is specifically expressed in the human liver, while MAT2A and MAT2B are widely distributed in various human tissues. In normal liver cells, MAT1A and MAT2A maintain a dynamic balance, jointly preserving intracellular SAM homeostasis. However, in hepatocellular carcinoma (HCC), MAT1A expression is abnormally downregulated, while MAT2A expression is abnormally upregulated. This gene expression shift from MAT1A to MAT2A promotes cancer invasion and metastasis, and is closely associated with increased metastasis and poor recurrence-free survival (RFS) in HCC patients. Besides HCC, abnormally elevated MAT2A expression levels are also found in various tumors such as gastric cancer, colorectal cancer, and pancreatic cancer, and are closely related to tumor development and progression. Because MAT2A plays a crucial role in the pathogenesis of various tumors, and because gene silencing of MAT2A can inhibit the proliferation of cancer cells such as liver cancer cells or gastric cancer cells and induce apoptosis, MAT2A has become a drug target for anti-tumor therapy.

[0004] Currently, there are no MAT2A inhibitors on the market, so there is an urgent need to develop new MAT2A inhibitors. Summary of the Invention

[0005] In one aspect of the invention, the invention discloses compounds of Formula I or pharmaceutically acceptable salts thereof;

[0006] Formula I,

[0007] n is 0 or 1;

[0008] R 1 C 1-6 alkyl;

[0009] R 2 Halogen or C 1-6 Halogenated alkyl groups.

[0010] In some embodiments of the present invention, R 1 C 1-3 Alkyl groups, and other variables as defined in this invention.

[0011] In some embodiments of the present invention, R 1 The methyl group is methyl, and the other variables are as defined in this invention.

[0012] In some embodiments of the present invention, R 2 Halogen or C 1-3 Halogenated alkyl groups, and other variables as defined in this invention.

[0013] In some embodiments of the present invention, R 2 It is either -Cl or -CF3, and the other variables are as defined in this invention.

[0014] In some embodiments of the present invention, n is 1, and the remaining variables are as defined in the present invention.

[0015] In some embodiments of the present invention, the compound is:

[0016] .

[0017] In some embodiments of the present invention, the compound is:

[0018] .

[0019] In another aspect, the present invention also provides a pharmaceutical composition. According to embodiments of the invention, the pharmaceutical composition comprises the foregoing compounds or pharmaceutically acceptable salts thereof.

[0020] In another aspect of the invention, the invention also proposes the use of the foregoing compounds or pharmaceutically acceptable salts thereof, or the foregoing pharmaceutical compositions, in the preparation of treatments for cancer. According to embodiments of the invention, the cancer comprises a deletion and / or incomplete function of the gene encoding methionine phosphorylase (MTAP).

[0021] According to embodiments of the present invention, the cancer is selected from lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, diffuse large B-cell lymphoma, non-Hodgkin lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colorectal cancer, colorectal cancer, or bile duct cancer; the lung cancer is selected from non-small cell lung cancer, squamous cell carcinoma of the lung, or adenocarcinoma of the lung; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

[0022] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the pharmacological activity of the parent compound. Such salts include: salts formed by addition to an inorganic acid or an organic acid, such as nitric acid, phosphoric acid, carbonic acid, etc.; organic acids such as propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, gluconic acid, stearic acid, mucoacinic acid, etc.; or salts formed when an acidic proton present on the parent compound is replaced by a metal ion, such as an alkali metal ion or an alkaline earth metal ion; or coordination compounds formed with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing an acid radical or a base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of this invention. Furthermore, the prodrugs can be converted into the compounds of this invention in the in vivo environment via chemical or biochemical methods.

[0023] As used in this article, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0024] The compounds represented by Formula I of this invention can be prepared using synthetic methods known in the art or in combination with methods known in the art. The solvents, temperatures, and other reaction conditions given in this invention are exemplary and can be varied according to methods well known in the art. The compounds of the embodiments described in this invention can be synthesized according to the methods described in the embodiments, based on their specific structures, using appropriate starting materials, or can be synthesized using methods similar to those described in the embodiments. The starting materials used to synthesize the compounds of the embodiments of this invention can be prepared by known synthetic methods or similar methods described in the literature, or obtained from commercial sources. The compounds can be further resolved to obtain their stereoisomers by methods well known in the art, such as crystallization, chromatography, etc., with resolution conditions readily obtained by those skilled in the art through conventional means or limited experimentation. As a further explanation, the compounds of Formula I of this invention can be synthesized using the following methods, wherein the solvents, temperatures, and other reaction conditions in each step can be the same as or similar to those described in the following embodiments, or reaction conditions known in the art can be used. Detailed Implementation

[0025] The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0026] The present invention will be described in detail below through embodiments, but this does not imply any adverse limitations on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0027] Example 1

[0028]

[0029] Step 1: Dissolve starting material 1-1 (5 g, 24.68 mmol) in 100 mL of carbon tetrachloride, add NBS (5.71 g, 32.1 mmol) and AIBN (1.499 g, 9.13 mmol), stir and heat to 85°C overnight. After the reaction is complete, cool to room temperature, filter, and concentrate the filtrate under reduced pressure to obtain target compound 1-2. 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.12 (dd, J = 9.3, 1.9 Hz, 1H), 4.61 (s, 2H), 3.98 (s, 3H).

[0030] Step 2: Compounds 1-2 (6.91 g, 24.55 mmol) were dissolved in 45 mL of anhydrous methanol. Sodium methoxide / methanol solution (15 mL, 5 M, 75 mmol) was slowly added in an ice-water bath, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, 100 mL of ethyl acetate was added, and the reaction was quenched in an ice-water bath. The reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was separated by column chromatography to obtain the target compounds 1-3. LCMS: 233.0 [M+H] + .

[0031] Step 3: Compounds 1-3 (3 g, 12.9 mmol) were dissolved in 30 mL of methanol and 8 mL of water. Sodium hydroxide (2.063 g, 51.6 mmol) was added in portions over an ice-water bath, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, 10 mL of water and 30 mL of ethyl acetate were added, and the mixture was extracted. The aqueous phase was collected, and the pH was adjusted to ~1 with concentrated hydrochloric acid. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the target compounds 1-4. LCMS: 219.0 [M+H] + .

[0032] Step 4: Compounds 1-4 (172 mg, 0.787 mmol) and ammonium chloride (54.7 mg, 1.023 mmol) were added to 3 mL of DMF, followed by the sequential addition of N,N-diisopropylethylamine (0.275 mL, 1.574 mmol) and HATU (449 mg, 1.180 mmol). The mixture was stirred at room temperature for 5 hours. After the reaction was complete, 20 mL of water was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain compounds 1-5. LCMS: 218.0 [M+H] + . 1 HNMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 7.10 (dd, J = 9.8, 1.6 Hz, 1H), 6.23 (d, J = 48.8 Hz, 2H), 4.59 (s, 2H), 3.44 (s, 3H).

[0033] Step 5: Compounds 1-5 (41 mg, 0.188 mmol) were dissolved in 2 mL of dichloroethane, and phosphorus oxychloride (0.035 mL, 0.377 mmol) was added. The mixture was heated to 90°C and stirred overnight. After the reaction was complete, the solution was concentrated under reduced pressure and separated by column chromatography to obtain compounds 1-6. LCMS: 200.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 0.8 Hz, 1H), 7.17 (dd, J = 8.4, 1.6 Hz, 1H), 4.61 (s, 2H), 3.50 (s, 3H).

[0034] Step Six: Dissolve 6,7-dihydro-5H-cyclopentano[b]pyridin-5-one (318 mg, 2.206 mmol) in 5 mL of tetrahydrofuran. Slowly add sodium hydride (132 mg, 3.31 mmol) in an ice-water bath and stir for 1 hour. Then add compounds 1-6 (484 mg, 2.426 mmol) and continue stirring at room temperature for 3 hours. After the reaction is complete, slowly add the reaction solution dropwise to 100 mL of ice water. Extract three times with ethyl acetate. Dry the combined organic phases over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography to obtain the target compounds 1-7. LCMS: 324.0 [M+H] + .

[0035] Step 7: Compounds 1-7 (180 mg, 0.556 mmol) were added to 3 mL of concentrated hydrochloric acid and heated to 100°C with stirring overnight. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain the target compounds 1-8. LCMS: 347.0 [M+H] + .

[0036] Step 8: Compounds 1-8 (130 mg, 0.374 mmol) were added to a methylamine / tetrahydrofuran solution (3 mL, 0.374 mmol), and the mixture was heated to 50°C and stirred for 3 hours. After the reaction was complete, the solution was concentrated under reduced pressure, and the target compounds 1-9 were separated by column chromatography. LCMS: 342.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.49 (d, J = 4.2 Hz, 1H), 8.47 – 8.40 (m, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.20 (s, 1H), 6.98 (d, J = 1.6 Hz, 1H), 6.78 (t, J = 5.2 Hz, 1H), 4.74 – 4.64 (m, 2H), 3.08 (d, J = 4.4 Hz, 3H).

[0037] Step 9: Compounds 1-9 (80 mg, 0.234 mmol) and triethylamine (0.065 mL, 0.468 mmol) were dissolved in 2 mL of dichloromethane. Methanesulfonyl chloride (0.036 mL, 0.468 mmol) was slowly added under nitrogen protection, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solution was concentrated under reduced pressure and purified by preparative liquid chromatography to obtain target compound 1. LCMS: 324.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ 8.39 (t, J = 3.2 Hz, 1H), 7.60 (s, 1H), 7.19 (s, 1H), 7.16 (d, J = 3.2 Hz, 2H), 4.92 (s, 2H), 3.57 - 3.49 (m, 1H), 3.41 (s, 3H), 3.36 – 3.32 (m, 1H), 2.89 – 2.83 (m, 1H), 2.56 – 2.43 (m, 1H).

[0038] Example 2

[0039]

[0040] Step 1: Using 2-1 as the starting material, the target compound 2 was synthesized following the same synthetic steps as in Example 1. LCMS: 372.3 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.43 (dd, J = 4.9, 1.6 Hz, 1H), 7.63 (s, 1H), 7.31 – 7.22 (m, 2H), 7.12 (s, 1H), 3.99 – 3.83 (m, 2H), 3.46 (d, J = 9.4 Hz, 3H), 3.43 – 3.33 (m, 1H), 3.29 – 3.14 (m, 3H), 2.87 – 2.80 (m, 1H), 2.47 – 2.30 (m, 1H).

[0041] Example 3: Cell viability test

[0042] The CellTiter-Glo luminescence assay was used to evaluate the antiproliferative activity of compounds against the non-small cell lung cancer cell line NCI-H838 after 10 days in vitro. On day 0, cells were seeded at a density of 1500 cells per well in 96-well plates and cultured in RPMI-1640 medium containing 10% fetal bovine serum. On day 1, the test compound was added at an initial concentration of 10 µM, serially diluted 3-fold to a total of 10 concentrations. The positive control STS was added at an initial concentration of 2 µM, serially diluted 3-fold to a total of 9 concentrations. All cells were cultured at 37°C and 5% CO2 for 5 days after drug addition. On day 6, the number of cells in the DMSO control group was counted, and the cells were seeded again at a density of 1500 cells per well in 96-well plates. Cells in other groups were treated at the same proportion as the DMSO control group. All cells were treated with the corresponding concentration of compound as on day 1 and cultured for another 5 days. On day 10, cell viability was detected using the CellTiter-Glo reagent. The inhibitory effect of the compound on cell proliferation was evaluated using the luminescence signal, and the IC50 was calculated after fitting. 50 The values ​​are shown in Table 1 below.

[0043] Table 1

[0044]

[0045] Although specific embodiments of the present invention have been described in detail, those skilled in the art can make various modifications and substitutions to the details of the technical solutions of the present invention based on all the teachings disclosed, and all such modifications and substitutions are within the scope of protection of the present invention. The full scope of the present invention is given by the appended claims and any equivalents thereof.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is: 。 2. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof.

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