Deuterated heterocyclic ketone compounds and their uses

Abstract

The present invention relates to a compound represented by formula (I) or an optical isomer, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof. 1 ~R 17 are each independently selected from hydrogen and deuterium; R 18 , R 19 is hydrogen, but R 1 ~R 19 The deuterated compounds and their salts, hydrates or solvates have excellent metabolic stability and pharmacokinetic properties, and are highly expected to be used in the preparation of tubulin inhibitors, anticancer drugs, antiviral drugs, and novel coronavirus pneumonia treatment drugs. TIFF2025510438000033.tif47170

Description

[Technical field]

[0001] The present invention relates to deuterated heterocyclic ketone compounds and uses thereof. [Background technology]

[0002] Sabyabizabulin (VERU-111, ABI-231) is an orally effective α- and β-tubulin inhibitor with the structural formula: TIFF2025510438000002.tif23170, which has significant antiproliferative activity against tumor cell lines such as prostate cancer, and is clinically used to treat advanced breast and prostate cancer. Recent studies have shown that sabizablin has anti-inflammatory effects and can prevent the cytokine storm caused by COVID-19, and in a Phase III clinical trial, it reduced the relative risk of death in patients by 55%.

[0003] Deuterated drugs refer to replacing some of the hydrogen atoms in a drug molecule with deuterium. The shape and volume of deuterium in a drug molecule are close to hydrogen, so deuterated drugs generally retain the biological activity and selectivity of the original drug. Because C-D bonds are more stable than C-H bonds, deuterated drugs are less likely to break C-D bonds during chemical reactions, and have a longer half-life.

[0004] Because the metabolic process of the living system is complicated, the pharmacokinetic properties of drugs in vivo are influenced by various factors and show corresponding complexity. Compared with the corresponding non-deuterated drugs, the changes in the pharmacokinetic properties of deuterated drugs show a great deal of randomness and unpredictability. Deuteration of a specific site can not only not increase the half-life, but may even shorten the half-life (Scott L. Harbeson, Roger D. Tung. Deuterium in Drug Discovery and Development, p405-406.), and may deteriorate the pharmacokinetic properties. On the other hand, hydrogen at a specific position on the drug molecule is difficult to be deuterated due to steric hindrance and other reasons, so deuteration of drugs is not arbitrary, and the site to be deuterated is unpredictable.

[0005] If sabizablin can be deuterized to further improve its pharmacokinetic properties and reduce its toxic side effects, it will be of great advantage and significance for the further development of drugs for the treatment of malignant tumors and COVID-19. Summary of the Invention

[0006] It is an object of the present invention to provide deuterated sabizabrin compounds.

[0007] The present invention provides a compound represented by formula (I) or an optical isomer, a pharma- ceutically acceptable salt, hydrate or solvate thereof, TIFF2025510438000003.tif47170 Here, R 1 ~R 17 are each independently selected from hydrogen and deuterium; R 18 , R 19 is hydrogen, but R 1 ~R 19 and hydrogen at the same time.

[0008] Furthermore, the above compound has a structure represented by formula (II). TIFF2025510438000004.tif47170

[0009] Furthermore, the above compound has a structure represented by formula (III). TIFF2025510438000005.tif47170

[0010] Furthermore, the above compound has a structure represented by formula (IV). TIFF2025510438000006.tif47170

[0011] Furthermore, the above compound has a structure represented by formula (V). TIFF2025510438000007.tif47170

[0012] Furthermore, the above compound has a structure represented by formula (VI). TIFF2025510438000008.tif47170

[0013] Furthermore, the above compound has a structure represented by formula (VII). TIFF2025510438000009.tif47170

[0014] Furthermore, the above compound has a structure represented by formula (VIII). TIFF2025510438000010.tif47170

[0015] Furthermore, R 1 , R 2 , R 3 is simultaneously hydrogen and simultaneously deuterium, and R 4 , R 5 , R 6 is simultaneously hydrogen and simultaneously deuterium, and R 7 , R 8 , R 9 is simultaneously hydrogen and simultaneously deuterium.

[0016] Furthermore, the above compound is The compound is one of the following: TIFF2025510438000011.tif81170TIFF2025510438000012.tif79170

[0017] Further, the pharma- ceutically acceptable salts mentioned above are the phosphate, dextro-camphorsulfonate, hydrochloride, hydrobromide, hydrofluoride, sulfate, nitrate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, methanesulfonate, benzenemethanesulfonate, benzenesulfonate, aspartate or glutamate salts of the indicated compounds.

[0018] The present invention further provides the use of the above compound or an optical isomer, pharma- ceutically acceptable salt, hydrate or solvate thereof in the preparation of a medicament for treating cancer and / or COVID-19 infection, influenza virus infection, syncytial virus infection and / or acute respiratory distress syndrome.

[0019] Additionally, such cancers include, but are not limited to, melanoma, prostate cancer, and breast cancer.

[0020] The present invention further provides the use of the above compound or an optical isomer, pharma- ceutically acceptable salt, hydrate or solvate thereof in the preparation of a tubulin inhibitor.

[0021] The present invention further provides a drug which is a formulation prepared and formed by adding the above-mentioned compound or an optical isomer, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof as an active ingredient and a pharma- ceutically acceptable additive. Effect of the Invention

[0022] Beneficial effects of the present invention: In the present invention, the deuterated compound produced by deuterizing sabizabrin has anticancer activity, and is superior in metabolic stability and pharmacokinetics to sabizabrin, and is highly expected to be applied.

[0023] Obviously, based on the above content of the present invention, various other improvements, substitutions or modifications can be made according to ordinary technical knowledge and conventional means in this field, without departing from the above basic technical idea of ​​the present invention.

[0024] The above contents of the present invention will be described in more detail below in the form of specific implementations in the form of examples. However, the scope of the above subject matter of the present invention should not be construed as being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] All the raw materials and equipment used in the present invention are known products and can be obtained by purchasing commercially available products.

[0026] Example 1: Synthesis of (2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-tris(methoxy-d3)phenyl)methanone JPEG2025510438000013.jpg55170

[0027] First step: Synthesis of 3-(1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole Compound 1-(phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-1H-indole (2 g, 5.22 mmol) and compound 2-bromo-1H-imidazole (1 eq, 0.77 g, 5.22 mmol) were weighed into a 100 mL eggplant flask, anhydrous dioxane / water (30 / 10 mL) was added, sodium carbonate (2 eq, 1.45 g, 10.44 mmol), tetrakis(triphenylphosphine)palladium (0.1 eq, 0.6 g, 0.52 mmol) were added, and the mixture was purged with argon three times, followed by reaction at 100 ° C. overnight. The reaction was stopped by adding a saturated ammonium chloride solution, extracted with EA (5 × 50 mL), rotary dried, and purified by column chromatography (EA / PE = 1 / 1). The compound 3-(1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (1.8 g, 5.52 mmol, >100%) was obtained. LC / MS (ESI+), C 17 H 13 N 3 O 2 S([M+H] + ) m / e calculated value 324.07, measured value 324.2.

[0028] Second and third steps: Synthesis of 3-(4,5-dibromo-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole In a 100 mL eggplant flask, add the compound 3-(1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (1.8 g, 5.52 mmol), add 30 mL of anhydrous THF, slowly add NBS (2.5 eq, 2.3 g, 13.8 mmol) at room temperature, stir for 2 hours, add saturated sodium thiosulfate solution to quench the reaction, extract three times with EA, swirl dry, and dilute with DCM. Add 30 mL of DIPEA (1.7 mL, 11.04 mmol), slowly add SEMCI (1.2 eq, 1.2 mL, 6.8 mmol) in an ice-water bath, stir for 2 hours, then add saturated sodium bicarbonate solution to quench the reaction, extract with DCM (4 x 30 mL), and purify by column chromatography (EA / PE=1 / 5) to obtain compound 3-(4,5-dibromo-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (0.975 g, 1.60 mmol, 30%). LC / MS (ESI+), C 23 H 25 Br 2 N 3 O 3 SSi([M+H] + ) m / e calculated values ​​611.97, 609.98, measured values ​​612.1, 614.1.

[0029] Fourth step: Synthesis of 3,4,5-tris(methoxy-d3)benzaldehyde In a 50 mL sealed tube, 3,4,5-trihydroxybenzaldehyde (2.0 g, 12.98 mmol) was weighed, 15 mL of anhydrous DMF was added, potassium carbonate (4.0 eq, 7.2 g, 51.94 mmol) was added, and CD3I (4.0 eq, 3.5 mL, 51.94 mmol) was carefully added. The mixture was stirred at 80 °C overnight. After cooling to room temperature, the reaction was quenched by adding saturated ammonium chloride solution. The mixture was extracted with EA (5 × 50 mL), spun dry, and purified by column chromatography (EA / PE = 1 / 3) to obtain the compound 3,4,5-tris(methoxy-d3)benzaldehyde (2.15 g, 10.48 mmol, 81%).

[0030] Fifth step: Synthesis of (5-bromo-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)(3,4,5-tris(methoxy-d3)phenyl)methanol In a 100mL eggplant-shaped flask, the compound 3-(4,5-dibromo-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (0.66g, 1.08mmol) was added, 30mL of anhydrous THF was added, and argon replacement was performed three times. Then, isopropylmagnesium chloride-lithium chloride (2eq, 1.3M, 2mL, 2.16mmol) was added dropwise at room temperature, and the mixture was stirred at room temperature for 30 minutes. The compound 3,4,5-tris(methoxy-d3)benzaldehyde (2eq, 0.5g, 2.16mmol) was dissolved in 10mL of anhydrous THF, and added dropwise to the above reaction solution, and stirred for 3 hours. The reaction was quenched by adding saturated sodium chloride solution, extracted with EA, rotovapped, and subjected to column chromatography (EA / PE=1 / 3) to obtain the compound (5-bromo-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)(3,4,5-tris(methoxy-d3)phenyl)methanol (0.571 g, 0.77 mmol, 72%). LC / MS (ESI+), C 33 H 29 D 9 Br 2 N 3 O 7 SSi([M+H] + ) m / e calculated values ​​737.19, 739.19, measured values ​​737.2, 739.2.

[0031] Sixth step: Synthesis of (5-bromo-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)(3,4,5-tris(methoxy-d3)phenyl)methanone In a 100 mL eggplant flask, add the compound (5-bromo-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)(3,4,5-tris(methoxy-d3)phenyl)methanol (0.571 g, 0.77 mmol), add 30 mL of DCM, add sodium bicarbonate (4 eq, 0.31 g, 3.08 mmol) in an ice-water bath, slowly add DMP (2 eq, 0.66 g, 1.56 mmol), react for 1.5 hours, then slowly add saturated sodium bicarbonate solution to stop the reaction. Extraction with DCM, rotary evaporation, and column chromatography (EA / PE=1 / 4) were performed to obtain the compound (5-bromo-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)(3,4,5-tris(methoxy-d3)phenyl)methanone (0.498 g, 0.68 mmol, 87%). LC / MS (ESI+), C 33 H 27 D 9 Br 2 N 3 O 7 SSi([M+H] + ) m / e calculated values ​​735.18, 737.18, measured values ​​735.2, 737.2.

[0032] Seventh and eighth steps: Synthesis of (2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-tris(methoxy-d3)phenyl)methanone In a 100 mL eggplant flask, the compound (5-bromo-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)(3,4,5-tris(methoxy-d3)phenyl)methanone (0.498 g, 0.68 mmol) was added, and 5 mL of n-butanol, potassium carbonate (4 eq, 0.376 g, 2.72 mmol), triphenylphosphine (0.4 eq, 0.071 g, 0.27 mmol), and palladium acetate (0.1 eq, 0.015 g, 0.07 mmol) were added, and the reaction was carried out at 120 ° C. for 5 hours, and the reaction was stopped by adding a saturated sodium chloride solution, and the mixture was extracted with EA. After the n-butanol was spun down at high temperature, DCM / TFA (10 mL / 5 mL) was added directly, stirred for 1.5 h, quenched by slowly adding saturated sodium bicarbonate solution, extracted with DCM, spun down, and subjected to column chromatography to obtain compound HC-8174-01, (2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-tris(methoxy-d3)phenyl)methanone (0.25 g, 0.64 mmol, 95% for two steps). LC / MS (ESI+), C 21 H 10 D 9 N 3 O 4 (〔M+H〕 + ) m / e calculated 387.19, found 387.20. The desired compound is a mixture of tautomers (3:2). 1 H NMR (400 MHz, DMSO-d 6 ): δ 13.07(s, 1H), 11.61(s, 1H), 8.45(dd, J=18.4, 7.8Hz, 1H), 8.38~7.75(m, 3H), 7.55~7.35(m, 1H), 7.33~6.97(m, 3H).

[0033] Example 2: Synthesis of (2-(1H-indol-3-yl)-1H-imidazol-4-yl-5-d)(3,4,5-trimethoxyphenyl)methanone JPEG2025510438000014.jpg56170

[0034] First and second steps: synthesis of 3-(4,5-diiodo-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole Compound 3-(1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (2.65 g, 8.21 mmol) was added to a 100 mL eggplant flask, 50 mL of NaOH solution (2 M, 20 mL) was added, 10 mL of THF was added to aid dissolution, iodine (2.5 eq, 5.2 g, 20.53 mmol) was slowly added at room temperature, and the mixture was stirred for 2 hours, after which a saturated sodium thiosulfate solution was added to quench the reaction, and the mixture was extracted three times with EA, then rotary dried, and subjected to column chromatography. Then, 30 mL of DCM and DIPEA (1.1 mL) were added, and SEMCI (0.7 mL) was slowly added in an ice-water bath. After stirring for 2 hours, the reaction was quenched by adding saturated sodium bicarbonate solution, extracted with DCM (4 x 30 mL), and purified by column chromatography (EA / PE = 1 / 5) to obtain the compound 3-(4,5-diiodo-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (2.19 g, 3.12 mmol, 51%). LC / MS (ESI+), C 23 H 25 I 2 N 3 O 3 SSi([M+H] + ) m / e calculated value 705.95, measured value 706.1.

[0035] Third step: Synthesis of (5-iodo-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanol In a 100mL eggplant flask, the compound (4,5-diiodo-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (2.19g, 3.12mmol) was added, 30mL of anhydrous THF was added, and argon replacement was performed three times. Then, isopropylmagnesium chloride-lithium chloride (2eq, 1.3M, 2.0mL, 2.16mmol) was added dropwise at room temperature, and the mixture was stirred at room temperature for 30 minutes. The compound 3,4,5-trimethoxybenzaldehyde (2eq, 1.2g, 6.2mmol) was dissolved in 10mL of anhydrous THF, and added dropwise to the above reaction solution, and stirred for 3 hours. The reaction was quenched by adding saturated sodium chloride solution, extracted with EA, rotovapped, and subjected to column chromatography (EA / PE=1 / 3) to obtain the compound (5-iodo-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanol (1.55 g, 1.98 mmol, 64%). LC / MS (ESI+), C 33 H 38 IN 3 O 7 SSi(〔M+H〕 + ) m / e calculated value 776.12, measured value 776.2.

[0036] Fourth step: Synthesis of (2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl-5-d)(3,4,5-trimethoxyphenyl)methanol In a 100 mL eggplant flask, the compound (5-iodo-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanol (0.2 g, 0.26 mmol) was added and dissolved in 5 mL of deuterated methanol. 1 mL of anhydrous THF was added to aid dissolution. 0.2 g of palladium hydroxide was added and the D 2 Substitution is performed three times, D 2The mixture was reacted under atmospheric pressure for 5 hours, directly filtered, rotovapped, and subjected to column chromatography to obtain the compound (2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl-5-d)(3,4,5-trimethoxyphenyl)methanol (0.128 g, 0.194 mmol, 75%). LC / MS (ESI+), C 33 H 38 DN 3 O 7 SSi([M+H] + ) m / e calculated value 651.23, measured value 651.20.

[0037] Fifth, sixth and seventh steps: synthesis of (2-(1H-indol-3-yl)-1H-imidazol-4-yl-5-d)(3,4,5-trimethoxyphenyl)methanone In a 100 mL eggplant flask, add the compound (1-(phenylsulfonyl)-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl-5-d)(3,4,5-trimethoxyphenyl)methanol (0.128 g, 0.197 mmol), add 30 mL of DCM, add sodium bicarbonate (4 eq, 0.068 g, 0.7 8 mmol) in an ice-water bath, slowly add DMP (2 eq, 0.25 g, 0.3 9 mmol), react for 1.5 hours, then slowly add saturated sodium bicarbonate solution to quench the reaction. Extract with DCM and proceed directly to the next step. The crude product of (2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl-5-d)(3,4,5-trimethoxyphenyl)methanone was obtained.

[0038] The crude product of (2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl-5-d)(3,4,5-trimethoxyphenyl)methanone was added to a 100 mL eggplant flask, DCM / TFA (10 mL / 5 mL) was added at room temperature, stirred for 1.5 hours, quenched by slowly adding saturated sodium bicarbonate solution, extracted with DCM, spun dry, sodium hydroxide (20 eq, 0.16 g, 3.88 mmol), methanol / water = 5 mL / 20 mL, and stirred at 100 °C overnight. Extraction with EA, rotary evaporation, and column chromatography gave compound HC-8550-01, (2-(1H-indol-3-yl)-1H-imidazol-4-yl-5-d)(3,4,5-trimethoxyphenyl)methanone (0.054 g, 0.140 mmol, 72% for three steps). LC / MS (ESI+), C 21 H 18 DN 3 O 4 (〔M+H〕 + ) m / e calculated 379.14, found 379.20. The desired compound is a mixture of tautomers (3:2). 1 H NMR (400 MHz, DMSO-d 6 ): δ 13.07(s, 1H), 11.61(s, 1H), 8.58~7.83(m, 3H), 7.56~7.37(m, 1H), 7.26~7.06(m, 3H), 3.91(s, 6H), 3.78(s, 3H).

[0039] Example 3: Synthesis of (2-(1H-indol-3-yl)-1H-imidazol-4-yl-5-d)(3,4,5-tris(methoxy-d3)phenyl)methanone The target compound was obtained by preparing the compound in the same manner as in Examples 1 and 2 of TIFF2025510438000015.tif24170. LC / MS (ESI+), C 21 H 9 D 10 N 3 O 4 ([M+H] +) m / e calculated 379.14, found 379.20. The desired compound is a mixture of tautomers (3:2). 1 H NMR (400 MHz, DMSO): δ 13.1(s, 1H), 11.6(s, 1H), 8.43(d, J=7.7Hz, 1H), 7.53~7.03(m, 5H).

[0040] Example 4: Synthesis of (2-(1H-indol-3-yl)-1H-imidazol-4-yl-5-d)(3,5-dimethoxy-4-(methoxy-d3)phenyl)methanone TIFF2025510438000016.tif24170 The target compound was obtained by the same method as in Examples 1 and 2. LC / MS (ESI+), C 21 H 15 D 4 N 3 O 4 ([M+H] + ) m / e calculated 379.14, found 379.20. The desired compound is a mixture of tautomers (3:2). 1 H NMR(400 MHz, DMSO): δ 13.0(d, J=53.5Hz, 1H), 11.6(d, J=53.6Hz, 1H), 8.44(dd, J=18.6, 7.7Hz, 1H), 8.37~7.91(m, 2H), 7.53~7.39(m, 1H), 7.24~7.07(m, 3H), 3.91(s, 6H).

[0041] Example 5: Synthesis of (2-(1H-indol-3-yl)-1H-imidazol-4-yl-5-d)(3,4-dimethoxy-5-(methoxy-d3)phenyl)methanone TIFF2025510438000017.tif24170 The target compound was obtained by the same method as in Examples 1 and 2. LC / MS (ESI+), C 21 H 15 D 4 N 3 O 4 ([M+H] + ) m / e calculated 379.14, found 379.20. The desired compound is a mixture of tautomers (3:2).1 H NMR (400 MHz, DMSO): δ 13.0(s, 1H), 11.54(s, 1H), 8.45(dd, J=18.0, 7.9Hz, 1H), 8.39~7.89(m, 2H), 7.56~7.37(m, 1H), 7.26~7.07(m, 3H), 3.91(s, 3H), 3.78(s, 3H).

[0042] Example 6: Synthesis of (2-(1H-indol-3-yl)-1H-imidazol-4-yl-5-d)(3-methoxy-4,5-bis(methoxy-d3)phenyl)methanone TIFF2025510438000018.tif24170 The target compound was obtained by the same method as in Examples 1 and 2. LC / MS (ESI+), C 21 H 12 D 7 N 3 O 4 ([M+H] + ) m / e calculated value 385.18, measured value 385.20. 1 H NMR (400 MHz, DMSO): δ 13.1(s, 1H), 11.6(s, 1H), 8.43(d, J=7.7Hz, 1H), 8.46~7.61(m, 2H), 7.47(d, J=8.0Hz, 1H), 7.23~7.10(m, 3H), 3.90(s, 3H).

[0043] Example 7: Synthesis of (2-(1H-indol-3-yl)-1H-imidazol-4-yl-5-d)(4-methoxy-3,5-bis(methoxy-d3)phenyl)methanone TIFF2025510438000019.tif24170 The target compound was obtained by the same method as in Examples 1 and 2. LC / MS (ESI+), C 21 H 12 D 7 N 3 O 4 ([M+H] + ) m / e calculated 385.18, found 385.20. The desired compound is a tautomeric mixture (3:2). 1H NMR (400 MHz, DMSO-d 6 ): δ 13.07(s, 1H), 11.61(s, 1H), 8.43(dt, J=26.9, 13.6Hz, 1H), 8.38~7.94(m, 1H), 7.93(s, 1H), 7.53~7.38(m, 1H), 7.30~7.03(m, 3H), 3.78(s, 3H).

[0044] The beneficial effects of the present invention will now be described through the following test examples.

[0045] Test Example 1: Experiment on metabolic stability of the compound of the present invention in human hepatocyte microsomes First step: Phosphate buffer (200 mM), high purity water, MgCl 2 The mother liquor was prepared using a solution (50 mM), where the concentrations of phosphate were 100 mM, MgCl 2 The concentration was 5 mM.

[0046] Second step: Two experiments were carried out as follows. A) Reduced coenzyme II (NADPH) was added: 10 μL of human liver microsomes at a concentration of 20 mg / mL and 40 μL of NADPH at a concentration of 10 mM were added to the incubation test. The final concentrations of liver microsomes and NADPH were 0.5 mg / mL and 1 mM. B) No NADPH was added: 10 μL of human liver microsomes at a concentration of 20 mg / mL and 40 μL of high purity water were added to the incubation test. The final concentration of liver microsomes was 0.5 mg / mL.

[0047] Third step: positive control or test compound was added and the reaction was started. The final concentration of the test compound was 2 μM.

[0048] Fourth step: 50 μL was removed from the reaction solution at each time point of 0, 15, 30, 45, and 60 min. Four volumes of acetonitrile and IS (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 2 μM ketoprofen) were added to the reaction solution. The samples were centrifuged for 40 min. 100 μL of the supernatant was taken, 100 μL of high-purity water was added, and analyzed by LC-MS / MS. Peak areas were determined from the extracted ion chromatograms. The slope value k was determined by linear regression of the natural logarithm of the percent parent drug remaining versus incubation time curve. The in vitro half-life (in vitro t 1 / 2 ) was sought.

[0049] The results of the experiment on the metabolic stability of the compounds of the present invention in human liver microsomes are shown in Table 1.

[0050] [Table 1]

[0051] As shown in Table 1, the compounds of the present invention showed a longer half-life than sabizablin in experiments in human liver microsomes, and the compounds of the present invention showed superior metabolic stability in the human body to sabizablin, and are expected to show superior pharmacokinetics in the human body.

[0052] Test Example 2: Pharmacokinetics of the compound of the present invention in mice 1) Experimental materials and equipment LC-20AD high performance liquid chromatography system (Shimadzu Corporation, Japan) API4000 triple quadrupole mass spectrometer (Applied Biosystems, USA) Phoenix WinNolin pharmacokinetic software (version 6.3, Certara, USA) High-speed refrigerated centrifuge (Thermo Fisher Scientific) Analytical balance (Sartorius, SECURA225D-1CN) ICR mouse (Chengdu Dashuo Experimental Animal Co., Ltd.)

[0053] 2) Experimental methods and results The appropriate amount of each drug was accurately weighed and added in proportion to the final volume of DMSO 5%, HS-15 15%, and D5W 80%, and then sonicated, vortexed, sonicated, and vortexed to give a drug concentration of 0.3 mg / ml (for intragastric administration).

[0054] Eighteen healthy adult ICR mice were divided into two groups (nine in the intravenous group and nine in the intragastric group), and after fasting overnight (water was allowed ad libitum), they were administered the drug via the tail vein or stomach, respectively. The dose for intragastric administration was 3 mg / kg. Using a satellite blood sampling method, 0.1 ml of blood was collected from three mice at different time points, anticoagulated with the anticoagulant EDTA-K2, centrifuged at 4°C for 5 minutes to separate plasma, and stored at -80°C for measurement. For intravenous administration, samples were collected at 5 minutes, 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration. For intragastric administration, samples were collected before administration (0 hours) and at 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration. Drug concentrations in plasma were measured by LC / MS / MS. The pharmacokinetic index in mice is shown in Table 2.

[0055] [Table 2]

[0056] As Table 2 shows, the compounds of the present invention showed higher exposure in mice.

[0057] Test Example 3: Pharmacokinetics of the compound of the present invention in rats 1) Experimental materials and equipment LC-20AD high performance liquid chromatography system (Shimadzu Corporation) API4000 triple quadrupole mass spectrometer (Applied Biosystems) Phoenix WinNolin pharmacokinetic software (version 6.3, Certara) High-speed refrigerated centrifuge (Thermo Fisher Scientific) SD rats (Chengdu Dashuo Laboratory Animal Co., Ltd.)

[0058] 2) Experimental methods and results The appropriate amount of drug (equivalent to 3 mg of prototype drug) was accurately weighed and added in a proportional manner according to the preparation of the final volume of DMSO 5%, HS-15 15%, D5W 80%, and then sonicated, vortex mixed, sonicated, and vortex mixed. Three healthy adult male SD rats (180-250 g) were fasted overnight (water was allowed ad libitum), and then intragastrically administered at a dose of 5 ml / kg. 0.1 ml of blood was collected from the retroorbital venous plexus before administration and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration, and the plasma was separated by centrifugation at 4°C for 5 minutes and stored at -20°C for measurement. The concentration of the test compound in the plasma was then measured by LC / MS / MS method.

[0059] [Table 3]

[0060] As Table 3 shows, compounds of the present invention showed higher exposure in rats.

[0061] In summary, the deuterated sabizablin compound provided by the present invention has superior metabolic stability in the human body and pharmacokinetics in animals to those of sabizablin, and is expected to have better pharmacokinetics in the human body, and is therefore highly expected to be applied.

Claims

1. A compound represented by formula (I) or an optical isomer, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof, R １ ~R １７ are each independently selected from hydrogen and deuterium; R １８ , R １９ is hydrogen, but R １ ~R １９ and hydrogen at the same time, The compound or an optical isomer, a pharma- ceutically acceptable salt, hydrate or solvate thereof.

2. The compound has a structure represented by formula (II):

2. The compound according to claim 1, or an optical isomer, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof.

3. The compound has a structure represented by formula (III):

2. The compound according to claim 1, or an optical isomer, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof.

4. The compound has a structure represented by formula (IV):

4. The compound according to claim 2 or 3, or an optical isomer, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof.

5. The compound has a structure represented by formula (V):

5. The compound according to claim 4, or an optical isomer, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof.

6. The compound has a structure represented by formula (VI):

2. The compound according to claim 1, or an optical isomer, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof.

7. The compound has a structure represented by formula (VII):

2. The compound according to claim 1, or an optical isomer, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof.

8. The compound has a structure represented by formula (VIII):

2. The compound according to claim 1, or an optical isomer, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof.

9. The R １ , R ２ , R ３ are simultaneously hydrogen or simultaneously deuterium, and said R ４ , R ５ , R ６ are simultaneously hydrogen or simultaneously deuterium, and said R ７ , R ８ , R ９ are simultaneously hydrogen or simultaneously deuterium, 9. The compound according to claim 8, or an optical isomer, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof.

10. The compound is The compound is any one of the following compounds:

10. The compound according to any one of claims 1 to 9, or an optical isomer, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof.

11. the pharma- ceutically acceptable salt is a phosphate, dextro-camphorsulfonate, hydrochloride, hydrobromide, hydrofluoride, sulfate, nitrate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, methanesulfonate, benzenemethanesulfonate, benzenesulfonate, aspartate or glutamate salt of the compound, 11. The compound according to any one of claims 1 to 10, or an optical isomer, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof.

12. Use of the compound according to any one of claims 1 to 11 or an optical isomer, pharma- ceutically acceptable salt, hydrate or solvate thereof in the preparation of a medicament for treating cancer, COVID-19 infection, influenza virus infection, syncytial virus infection and / or acute respiratory distress syndrome.

13. The cancer includes melanoma, prostate cancer, or breast cancer.

13. The use according to claim 12.

14. 12. Use of a compound according to any one of claims 1 to 11 or an optical isomer, a pharma- ceutically acceptable salt, hydrate or solvate thereof in the preparation of a tubulin inhibitor.

15. A drug comprising a compound according to any one of claims 1 to 11 or an optical isomer, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof as an active ingredient, and a pharma-ceutically acceptable additive, which is prepared and formed as a formulation.

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