CN116768889A - Novel CDK9 kinase inhibitor and preparation method and application thereof - Google Patents
Novel CDK9 kinase inhibitor and preparation method and application thereof Download PDFInfo
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- CN116768889A CN116768889A CN202310720578.3A CN202310720578A CN116768889A CN 116768889 A CN116768889 A CN 116768889A CN 202310720578 A CN202310720578 A CN 202310720578A CN 116768889 A CN116768889 A CN 116768889A
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Abstract
A novel CDK9 kinase inhibitor, a preparation method and application thereof. The invention discloses a compound with a general formula (I) or a stereoisomer, a solvate, a deuterated compound, a prodrug, a metabolite and an intermediate thereof, and pharmaceutically acceptable salts or eutectic crystals thereof, and application of a pharmaceutical composition containing the compound as a CDK9 inhibitor for preventing or treating CDK9 related diseases, in particular application of the CDK9 inhibitor for preparing medicines for treating diseases such as tumors and the like.
Description
Technical Field
The invention relates to the technical field of chemical medicines, in particular to a novel CDK9 kinase inhibitor and a preparation method and application thereof.
Background
CDK9 plays an important role in transcriptional regulation, such as the apoptosis regulator myeloid leukemia 1 (Mcl-1) and transcription of the downstream proto-oncogene MYC, controlling proliferation and survival of tumor cells. Thus, the deregulation of CDK9 signaling is a feature that is significant in a variety of cancer cells. Mechanistically, CDK9 inhibition blocks RNAPII CTD phosphorylation and induces down-regulation of MYC and Mcl-1 protein levels, which is demonstrated in various hematological malignancies. Research shows that miR-613 acts as an oncogene to inhibit migration and invasion of gastric cancer through targeting CDK 9; inhibition of CDK9 can interfere with esophageal cancer cell proliferation, inhibiting tumor formation in animal models; CDK9 inhibitors have also been shown to inhibit the growth of breast cancer cells and tumors. Targeting CDK9 can also provide a concept for treating triple negative breast cancer; intervention of CDK9 affects the biological function of glioma cells, which also demonstrates from the side that CDK9 may be a potential therapeutic target for brain gliomas. All the above indicate that CDK9 is an important target for the development of cancer therapeutic drugs.
Disclosure of Invention
The invention aims to solve the problems in the prior art and provides a novel CDK9 kinase inhibitor, and a preparation method and application thereof.
A novel CDK9 kinase inhibitor which is a 3H-imidazo [4,5-b ] pyridine derivative represented by the general formula (I) or a tautomer, stereoisomer, N-oxide, solvate, hydrate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by the general formula (I), the planar structure of the general formula (I) being as follows:
wherein X is selected from hydrogen or halogen, preferably H, cl; l is selected from-CH 2 -、-C 2 H 4 -or L is a bond, preferably-CH 2 -；R 1 Selected from the group consisting ofN-isopropylpiperazine, 1-tert-butoxycarbonyl-piperazine, morpholine, trans-1, 4-cyclohexanediamine, 1-tert-butoxycarbonyl-1, 4-cyclohexanediamine, 4-methylpiperidine, 4-aminopiperidine, 4-hydroxypiperidine, 3-aminopiperidine, 4- (methylamino) cyclohexane-1-ol, R 1 Preferably trans-1, 4-cyclohexanediamine; r is R 2 Selected from mono-or polysubstituted aryl or 3-methylphenyl, R 2 3, 5-difluorophenyl is preferred.
The 3H-imidazo [4,5-b ] pyridine compound has good CDK9 inhibition activity and selectivity.
A pharmaceutical combination comprising the above compound or a tautomer thereof, stereoisomer thereof, N-oxide thereof, hydrate thereof, solvate thereof, deuterate thereof, prodrug thereof, metabolite thereof, intermediate thereof, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.
The preparation method of the compound comprises the steps of condensing a bromine-substituted o-phenylenediamine aromatic ring with substituted phenylacetic acid, phenylpropionic acid and the like at high temperature to obtain an intermediate (2), and then carrying out Suzuki coupling reaction or acidolysis or condensation on the intermediate (2) and a synthesized borate intermediate (1) to obtain the compound related to the formula (I), wherein the synthetic route is as follows:
the use of a compound of the invention in the manufacture of a medicament for the treatment of a disease associated with the activity or expression of the cell cycle dependent kinase CDK 9. Further, in the manufacture of a medicament for use in the treatment of a disorder associated with CDK9 activity or expression level. The diseases include breast cancer, liver cancer, cervical cancer, glioma and the like.
Compared with the prior art, the technical scheme of the invention has the beneficial effects that:
the CDK9 inhibitor disclosed by the invention can block phosphorylation of RNA polymerase II CTD by selectively inhibiting CDK9 kinase activity, further regulate and control related signal channels, and inhibit proliferation of tumor cells in vitro and in vivo. Thus, the CDK9 inhibitors disclosed herein may be useful in the treatment of cancer or related disorders.
Drawings
FIG. 1 is a graph showing the results of crystal violet staining of U87 and U251 cells with Compound A32 of example 7.
FIG. 2 is a graph showing the inhibition of CDK family kinase activity by Compound A32 of example 8.
FIG. 3 is a graph showing the results of experiments in which the A32-series partial compounds of example 9 inhibit CDK9 function.
FIG. 4 is a graph showing the results of the pharmacodynamic experiments of the compound A32 of example 10 on the U87 cell mice subcutaneous transplantation tumor model.
FIG. 5 is a graph showing the results of a pharmacodynamic experiment of compound A32 of example 11 on a U87-Luc cell mouse orthotopic tumor model.
Detailed Description
Table 1 shows the structure of the compounds of the present invention and the mass spectrum and nuclear magnetic characterization data of the structures of the compounds.
TABLE 1 Structure of 3H-imidazole [4,5-b ] pyridines of the invention and high resolution Mass Spectrometry and Nuclear magnetic characterization
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Example 1: synthesis of (1 r,4 r) -N1- (5-chloro-4- (2- (3, 5-difluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) cyclohexane-1, 4-diamine (A32)
(1) Synthesis of intermediate 6-bromo-2- (3, 5-difluorobenzyl) -3H-imidazo [4,5-b ] pyridine:
a mixture of 3, 5-difluorophenylacetic acid (4.30 g,25.0 mmol) and 2, 3-diamino-5-bromopyridine (1.87 g,10.0 mmol) was melted under nitrogen and stirred for 3h at 150 ℃. The reaction mixture was treated with a 3N aqueous hydrochloric acid solution and then rendered basic by addition of aqueous ammonia. Suction filtration, filter cake washing, drying, purification by silica gel column chromatography, gradient elution method, eluting with a mixture of ethyl acetate and methanol in a volume ratio of 1:0 to 10:1, and crystallizing the product with ethyl acetate to obtain 6-bromo-2- (3, 5-difluorobenzyl) -3H-imidazo [4, 5-b)]Pyridine 2.75g, yield 90%. 1 H NMR(600MHz,DMSO-d 6 )δ11.54-14.04(m,1H),7.88(br d,J＝8.25Hz,1H),7.45(ddd,J＝2.02,7.98,11.65Hz,1H),7.38-7.42(m,1H),7.37(d,J＝8.25Hz,1H),7.19(ddd,J＝2.11,4.08,6.28Hz,1H),4.24(s,2H)，LRMS(ESI)m/z:324.0[M+H] + 。
(2) Synthesis of intermediate tert-butyl ((1 r,4 r) -4- ((5-chloro-4- (4, 5-tetramethyl-1, 3, 2-dioxin-2-yl) pyridin-2-yl) amino) cyclohexyl) carbamate:
2-fluoro-4-iodo-5-bromopyridine (2.57 g,10 mmol) and N-Boc-1, 4-cyclohexanediamine (2.14 g,10 mmol) were dissolved in 25mL of N, N-dimethylformamide, N-diisopropylethylamine (3.87 g,30 mmol) was added thereto, the reaction system was replaced with nitrogen, and the temperature was raised to 120℃for 4 hours. After TLC detection of the completion of the reaction of the raw materials, heating was stopped, the reaction solution was poured into 100mL of ice water with stirring, solid precipitation was observed, the filtration was carried out by suction, a cake was obtained, and 4.29g of white solid tert-butyl ((1 r,4 r) -4- ((5-chloro-4-iodopyridin-2-yl) amino) cyclohexyl) carbamate was obtained after drying, and the yield was 95%.
Tert-butyl ((1 r,4 r) -4- ((5-chloro-4-iodopyridin-2-yl) amino) cyclohexyl) carbamate (4.29 g,9.5 mmol), pinacol borate (3.05 g,12 mmol), 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.1 mmol) and dry anhydrous potassium acetate (0.93 g,30 mmol) obtained in the previous step were added to 25mL dry N, N-dimethylformamide, nitrogen was replaced, the reaction was carried out under nitrogen protection at a temperature of 90 ℃ for 3h, tlc detected tert-butyl ((1 r,4 r) -4- ((5-chloro-4-iodopyridin-2-yl) amino) cyclohexyl) carbamate, after complete reaction, the reaction solution was poured into 100mL ice water with stirring, extracted with (3 x 25 mL) ethyl acetate, the organic phase was combined, the saturated sodium chloride back-extracted organic phase was added to anhydrous sodium sulfate, dried, filtered off, the desiccant was concentrated, the organic phase was added to silica gel column chromatography was used, and the ether was developed for purification by chromatography. Ethyl acetate=5:1 to give 3.43g of the white powder intermediate tert-butyl ((1 r,4 r) -4- ((5-chloro-4- (4, 5-tetramethyl-1, 3, 2-dioxin-2-yl) pyridin-2-yl) amino) cyclohexyl) carbamate in 80% yield.
(3) Synthesis of (1 r,4 r) -N1- (5-chloro-4- (2- (3, 5-difluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) cyclohexane-1, 4-diamine (A32):
weighing thick-wall pressure-resistant bottle and intermediate 6-bromo-2- (3, 5-difluorobenzyl) -3H-imidazo [4,5-b]Pyridine (324 mg,1 mmol) and intermediate tert-butyl ((1 r,4 r) -4- ((5-chloro-4- (4, 5-tetramethyl-1, 3, 2-dioxin-2-yl) pyridin-2-yl) amino) cyclohexyl) carbamate (497 mg,1.1 mmol), potassium carbonate (414 mg,3 mmol) and 1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (30 mg) is dissolved in 5mL of solvent (ethylene glycol dimethyl ether: water=4:1), nitrogen is replaced for 3 times, the temperature is raised to 90 ℃ for reaction overnight, after TLC detection reaction is finished, the reaction solution is cooled to room temperature and filtered, and a filter cake is washed by a small amount of ethylene glycol dimethyl ether and dried to obtain a crude product; dissolving the crude product in a methylene dichloride-methanol 10:1 system, adding silica gel for sample mixing, separating and purifying by using column chromatography, separating a developing solvent petroleum ether and ethyl acetate=1:1 to obtain a compound tert-butyl ((1 r,4 r) -4- ((5-chloro-4- (2- (3, 5-difluorobenzyl) -3H-imidazo [4, 5-b)]Pyridin-6-yl) pyridin-2-yl) amino groups) Cyclohexyl) carbamate (A26), white powder, yield 50%, 1 H NMR(600MHz,CHLOROFORM-d)δ13.04-13.31(m,1H),8.17-8.28(m,1H),8.12(br d,J＝6.97Hz,2H),6.90(br d,J＝6.05Hz,2H),6.68(br d,J＝6.24Hz,1H),6.30-6.37(m,1H),4.64(br s,1H),4.44-4.52(m,1H),4.36(s,1H),4.34(s,1H),3.54-3.63(m,1H),3.42-3.51(m,1H),2.11-2.19(m,2H),2.03-2.09(m,2H),1.45(br s,9H),1.26-1.35(m,4H)； 13 C NMR(151MHz,CHLOROFORM-d)δ163.3(br dd,J＝12.7,248.1Hz,2C),156.9,148.8(br s,1C),148.0(br s,1C),146.0,143.0(br s,1C),142.6(d,J＝4.4Hz,1C),139.7(br d,J＝8.8Hz,1C),135.4(br s,1C),128.5(br s,1C),127.8(br s,1C),118.6-117.7(m,1C),112.2-111.8(m,1C),109.0(br s,1C),103.3-102.8(m,1C),79.4(br s,1C),69.7,49.9(br s,1C),49.2(br s,1C),36.1(br s,1C),32.1(2C),31.9(2C),28.5(3C)。
dissolving the obtained A26 in a system with volume ratio of dichloromethane to trifluoroacetic acid=2:1, stirring at room temperature for reaction for 2 hours, evaporating dichloromethane and trifluoroacetic acid under reduced pressure, continuously dispersing residual solid with dichloromethane, treating triethylamine until the residual solid is alkaline (pH=8) under stirring, concentrating an organic phase, adding silica gel for sample mixing, separating and purifying by column chromatography silica gel chromatography, and separating and purifying by using a developing solvent of dichloromethane to ammonia=10:1:0 to dichloromethane to ammonia=10:1:0.1 to obtain (1 r,4 r) -N1- (5-chloro-4- (2- (3, 5-difluorobenzyl) -3H-imidazo [4, 5-b)]Pyridin-6-yl) pyridin-2-yl) cyclohexane-1, 4-diamine (A32), yellow solid, 1 H NMR(600MHz,METHANOL-d 4 )δ8.40(d,J＝1.8Hz,1H),8.05(s,1H),8.03(d,J＝1.8Hz,1H),6.95(br d,J＝6.2Hz,2H),6.75(br t,J＝9.0Hz,1H),6.48(d,J＝2.0Hz,1H),4.34-4.27(m,2H),3.60(br t,J＝9.9Hz,1H),2.87-2.76(m,1H),2.14(br d,J＝12.1Hz,2H),2.02-1.94(m,2H),1.42-1.26(m,5H)； 13 C NMR(151MHz,METHANOL-d 4 )δ163.2(dd,J＝12.7,249.2Hz,2C),157.0,156.0(br s,1C),147.0,146.1,143.7,140.2-139.2(m,1C),131.7(br d,J＝8.8Hz,1C),128.3,124.6(br s,1C),117.5,112.3-111.4(m,1C),110.0(br s,1C),102.7-102.3(t,2C),49.6,49.4,35.1,33.2(2C),31.2(2C)。
example 2: synthesis of 4- (5-chloro-4- (2- (4-fluorophenylethyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) morpholine (A22)
(1) Synthesis of intermediate 6-bromo-2- (4-fluorophenylethyl) -3H-imidazo [4,5-b ] pyridine:
a mixture of 4-fluorobenzoic acid (4.20 g,25.0 mmol) and 2, 3-diamino-66-bromopyridine (1.87 g,10.0 mmol) was melted under nitrogen and stirred for 2h at 150 ℃. The reaction mixture was treated with a 3N aqueous hydrochloric acid solution and then rendered basic by addition of aqueous ammonia. Suction filtration, filter cake washing, drying, purification by silica gel column chromatography, gradient elution method, eluting with a mixture of ethyl acetate and methanol in a volume ratio of 1:0 to 10:1, and crystallizing the product with ethyl acetate to obtain 6-bromo-2- (4-fluorophenylethyl) -3H-imidazo [4,5-b ]]Pyridine 2.72g, yield 85%. 1 H NMR(600MHz,DMSO-d 6 )δ8.35(d,J＝2.02Hz,1H),8.16(d,J＝1.83Hz,1H),7.28-7.31(m,2H),7.08-7.12(m,2H),3.16-3.20(m,2H),3.12-3.16(m,2H)； 13 C NMR(151MHz,DMSO-d 6 )δ174.1,161.2(d,J＝241.0Hz,1C),158.6(br s,1C),143.4,137.2(d,J＝3.3Hz,1C),130.9-129.9(m,1C),115.5(d,J＝22.0Hz,1C),112.7,32.4,31.2；LRMS(ESI)m/z:320.0[M+H] + 。
(2) Synthesis of 4- (5-chloro-4- (2- (4-fluorophenylethyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) morpholine (A22):
2-fluoro-4-iodo-5-bromopyridine (2.57 g,10 mmol) and morpholine (0.87 g,10 mmol) were dissolved in 25mL of N, N-dimethylformamide, N-diisopropylethylamine (3.87 g,30 mmol) was added thereto, the reaction system was replaced with nitrogen, and then the temperature was raised to 120℃to react for 4 hours. After TLC detects that the raw materials are completely reacted, stopping heating, pouring the reaction liquid into 100mL of ice water under stirring, precipitating solid, carrying out suction filtration, taking a filter cake, and drying to obtain 2.92g of white solid 4- (5-chloro-4-iodopyridin-2-yl) morpholine, wherein the yield is 90%.
4- (5-chloro-4-iodopyridin-2-yl) morpholine (2.92 g,9.0 mmol), pinacol borate (3.05 g,12 mmol), 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.1 mmol) and dry anhydrous potassium acetate (0.93 g,30 mmol) obtained in the previous step are added to 25mL dry N, N-dimethylformamide, nitrogen is replaced, the reaction is carried out for 3h under the protection of nitrogen and the temperature is raised to 90 ℃, after TLC detection of complete reaction of 4- (5-chloro-4-iodopyridin-2-yl) morpholine, the reaction solution is poured into 100mL of ice water with stirring, extracted with (3X 25 mL) ethyl acetate, the organic phase is combined, the saturated sodium chloride is back extracted, the organic phase is added to anhydrous sodium sulfate for drying, the drying agent is removed after the concentration of the organic phase, silica gel is added for chromatographic separation and purification, and the developing solvent petroleum ether ethyl acetate=5:1 is separated to obtain a white powder intermediate 4- (5-chloro-4, 5-tetramethyl-2-yl) morpholine, the yield of which is 5, 5-4-iodopyridin-2-yl).
Weighing thick-wall pressure-resistant bottle and intermediate 6-bromo-2- (4-fluorophenethyl) -3H-imidazole [4,5-b ]]Pyridine (320 mg,1 mmol) and the intermediate 4- (5-chloro-4- (4, 5-tetramethyl-1, 3, 2-dioxin-2-yl) pyridin-2-yl) morpholine (356 mg,1.1 mmol) and potassium carbonate (414 mg,3 mmol) and 1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (30 mg) is dissolved in 5mL of solvent (ethylene glycol dimethyl ether: water=4:1), nitrogen is replaced for 3 times, the temperature is raised to 90 ℃ for reaction overnight, after TLC detection reaction is finished, the reaction solution is cooled to room temperature and filtered, and a filter cake is washed by a small amount of ethylene glycol dimethyl ether and dried to obtain a crude product; the crude product was dissolved in dichloromethane: methanol 10:1 system, adding silica gel for sample mixing, separating and purifying by column chromatography, separating with developing solvent petroleum ether and ethyl acetate=1:1 to obtain compound 4- (5-chloro-4- (2- (4-fluorophenylethyl) -3H-imidazo [4, 5-b)]Pyridin-6-yl) pyridin-2-yl) morpholine (A22), white powder, 1 H NMR(600MHz,DMSO-d 6 )δ8.42(d,J＝2.02Hz,1H),8.28(s,1H),8.08(d,J＝2.02Hz,1H),7.38(dd,J＝5.69,8.44Hz,2H),7.18(t,J＝8.89Hz,2H),7.00(s,1H),4.31(br d,J＝13.02Hz,2H),3.21-3.28(m,4H),2.98-3.05(m,2H),2.87-2.95(m,1H),1.83(br d,J＝10.09Hz,2H),1.26-1.34(m,2H)； 13 C NMR(151MHz,DMSO-d 6 )δ161.2(d,J＝242.1Hz,1C),158.2,156.2,153.4,147.5,146.5,143.4,137.3(d,J＝3.3Hz,1C),130.5(d,J＝7.7Hz,2C),130.3,127.3,117.4,115.5(d,J＝20.9Hz,2C),109.5,48.8(2C),44.2(2C),34.6,32.5,31.2。
example 3: synthesis of 1- (5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) piperidin-4-ol (Compound A18)
(1) Synthesis of intermediate 6-bromo-2- (3, 5-difluorobenzyl) -3H-imidazo [4,5-b ] pyridine:
the procedure and the work-up are described in example 1. Spectral data: 1 H NMR(600MHz,DMSO-d 6 )δ8.35(d,J＝1.83Hz,1H),8.17(d,J＝1.83Hz,1H),7.32-7.39(m,1H),7.20(br d,J＝10.09Hz,1H),7.18(d,J＝7.70Hz,1H),7.07(dt,J＝2.57,8.62Hz,1H),4.25(s,2H)； 13 C NMR(151MHz,DMSO-d 6 )δ162.61(d,J＝243.2Hz,1C),157.22,143.83,139.87(d,J＝7.7Hz,1C),130.87(d,J＝8.8Hz,1C),125.53(d,J＝3.3Hz,1C),116.24(d,J＝22.0Hz,1C),114.05(d,J＝20.9Hz,1C),112.94,35.18；LRMS(ESI)m/z:307.1[M+H] + 。
(2) Synthesis of 1- (5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) piperidin-4-ol (A18):
2-fluoro-4-iodo-5-bromopyridine (2.57 g,10 mmol) and 4-hydroxypiperidine (1.01 g,10 mmol) were dissolved in 25mL of N, N-dimethylformamide, N-diisopropylethylamine (3.87 g,30 mmol) was added thereto, the reaction system was purged with nitrogen, and then the temperature was raised to 120℃for reaction for 4 hours. After TLC detects that the raw materials are completely reacted, stopping heating, pouring the reaction liquid into 100mL of ice water under stirring, precipitating solid, carrying out suction filtration, taking a filter cake, and drying to obtain 3.05g of white solid 1- (5-chloro-4-iodopyridin-2-yl) piperidin-4-ol, wherein the yield is 90%.
1- (5-chloro-4-iodopyridin-2-yl) piperidin-4-ol (3.05 g,9.0 mmol), pinacol-borate (3.05 g,12 mmol), 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.1 mmol) and dry anhydrous potassium acetate (0.93 g,30 mmol) obtained in the previous step were added to 25mL dry N, N-dimethylformamide, nitrogen was replaced, the reaction was allowed to proceed to 90℃under nitrogen protection for 3h, after TLC detection of 1- (5-chloro-4-iodopyridin-2-yl) piperidin-4-ol was completed, the reaction solution was stirred and poured into 100mL ice water, extracted with (3X 25 mL) ethyl acetate, the organic phase was combined, the saturated sodium chloride was back extracted, the organic phase was added to anhydrous sodium sulfate for drying, the drying agent was removed by filtration, the organic phase was concentrated and then added to silica gel column chromatography for separation and purification, and the spreader petroleum ether was used: ethyl acetate = 5:1 to obtain white powder intermediate 1- (5-chloro-4- (4, 5-tetramethyl-1, 3, 2-dioxin-2-yl) pyridine-2-yl) piperidine-4-alcohol 2.19g with a yield of 72 percent.
Weighing thick-wall pressure-resistant bottle and intermediate 6-bromo-2- (3, 5-difluorobenzyl) -3H-imidazo [4,5-b]Pyridine (306 mg,1 mmol) and the intermediate 1- (5-chloro-4- (4, 5-tetramethyl-1, 3, 2-dioxin-2-yl) pyridin-2-yl) piperidin-4-ol (372 mg,1.1 mmol) potassium carbonate (414 mg,3 mmol) and 1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (30 mg) is dissolved in 5mL of solvent (ethylene glycol dimethyl ether: water=4:1), nitrogen is replaced for 3 times, the temperature is raised to 90 ℃ for reaction overnight, after TLC detection reaction is finished, the reaction solution is cooled to room temperature and filtered, and a filter cake is washed by a small amount of ethylene glycol dimethyl ether and dried to obtain a crude product; the crude product was dissolved in dichloromethane: methanol 10:1 system, adding silica gel for sample mixing, separating and purifying by column chromatography, separating with developing solvent petroleum ether and ethyl acetate=1:1 to obtain compound 1- (5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4, 5-b)]Pyridin-6-yl) pyridin-2-yl) piperidin-4-ol (A18), white powder, 1 H NMR(600MHz,METHANOL-d 4 )δ8.39(br s,1H),8.18(s,1H),7.93-8.12(m,1H),7.32(dt,J＝6.05,7.98Hz,1H),7.13-7.20(m,1H),7.10(br d,J＝9.54Hz,1H),6.97(dt,J＝2.29,8.39Hz,1H),6.71(s,1H),4.31(s,2H),4.09-4.18(m,1H),4.06(td,J＝4.31,13.39Hz,2H),3.84-3.92(m,1H),3.18(ddd,J＝3.03,10.13,13.25Hz,2H),1.93-2.01(m,2H),1.59(dtd,J＝3.85,9.45,13.02Hz,2H)； 13 C NMR(151MHz,METHANOL-d 4 )δ163.0(d,J＝246.5Hz,1C),158.0,147.3(2C),146.2,143.5(br s,1C),138.3(d,J＝7.7Hz,2C),130.3(d,J＝7.7Hz,1C),128.5(br s,1C),124.5(d,J＝3.3Hz,1C),118.3,115.7(d,J＝22.0Hz,1C),114.0(d,J＝20.9Hz,1C),109.3(2C),67.2,43.3(2C),35.3,33.3(2C)。
wherein, the invention is listed as the compound: (1 r,4 r) -N1- (5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-5-yl) pyridin-2-yl) cyclohexane-1, 4-diamine (A1), (1 r,4 r) -N1- (5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) cyclohexane-1, 4-diamine (A2), 5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-5-yl) -N- (piperidin-3-yl) pyridin-2-amine (A5), 5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) -N- (piperidin-3-yl) pyridin-2-amine (A6), (1 r,4 r) -N1- (4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-2-yl) pyridin-2-amine (A5), 5-chloro-4- (2- (3-fluorobenzyl) -pyridin-6-yl) pyridin-2-amine (A6), (1 r,4 r) -N1- (5- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) cyclohexane-1, 4-diamine (A8), (1 r,4 r) -N1- (6- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) cyclohexane-1, 4-diamine (A9), (1 r,4 r) -N1- (3- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) cyclohexane-1, 4-diamine (A10), (1 r,4 r) -N1- (5-chloro-4- (2- (3-fluorophenyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) cyclohexane-1, 4-diamine (A11), (r, 4 r) -N1- (3-chloro-4-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) cyclohexane-1, 4-diamine (A11), (1 r,4 r) -N1- (3-chloro-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) cyclohexane-1, 4-diamine (A12), (1 r, 4-1-r) -N1- (3-imidazo [ 4-b ] pyridin-6-yl) pyridin-6-yl 1- (5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) piperidin-3-amine (A13), 1- (5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) piperidin-4-amine (A14), 6- (5-chloro-2- (piperazin-1-yl) pyridin-4-yl) -2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin (A15), 5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) -N- (piperidin-4-yl) pyridin-2-amine (A16), (1 r,4 r) -N1- (5-chloro-4- (2- (3- (trifluoromethyl) benzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-amine (A16), 5-chloro-4-b ] pyridin-6-yl) pyridin-2-diamine (A23) cyclohexane, 4- ((6- (2- (((1 r,4 r) -4-aminocyclohexyl) amino) -5-chloropyridin-4-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) methyl) -2-fluorophenol (a 24), (1 r,4 r) -N1- (5-chloro-4- (2- (3-chlorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) cyclohexane-1, 4-diamine (a 27), (1 r,4 r) -N1- (5-chloro-4- (2- (3-methylbenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) cyclohexane-1, 4-diamine (a 28), (1 r,4 r) -N1- (5-chloro-4- (2- (2-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) cyclohexane-1, 4-diamine (a 29), the synthesis of (1 r,4 r) -N1- (5-chloro-4- (2- (4-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) cyclohexane-1, 4-diamine (A30), (1 r,4 r) -N1- (5-chloro-4- (2, 3-difluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) cyclohexane-1, 4-diamine (A31), (1 r,4 r) -N1- (5-chloro-4- (2- (3, 4-difluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) cyclohexane-1, 4-diamine (A33), 5-chloro-N- (piperidin-3-yl) -4- (2- (3- (trifluoromethyl) benzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) amine (A32) is similar to that of FIG. 1, FIG. 1.
Wherein, the invention is listed as the compound: tert-butyl ((1 r,4 r) -4- ((3- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) amino) cyclohexyl) carbamate (A10-1), tert-butyl ((1 r,4 r) -4- ((5-chloro-4- (2- (3-fluorophenyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) amino) cyclohexyl) carbamate (A11-1), tert-butyl ((1 r,4 r) -4- ((5-chloro-4- (2- (3-fluorophenylethyl) -3H-imidazo [4,5-b ] pyridin-6-yl) amino) pyridin-2-yl) cyclohexyl) carbamate (A12-1), tert-butyl (1- (5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-5-yl) pyridin-2-yl) piperidin-3-yl) carbamate (A13-1), tert-butyl (1- (5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) piperidin-4-yl) carbamate (a 14-1), tert-butyl 4- (5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-5-yl) pyridin-2-yl) piperazine-1-carboxylate (a 15-1), tert-butyl 4- ((5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-5-yl) pyridin-2-yl) amino) piperidine-1-carboxylate (a 16-1), tert-butyl ((1 r,4 r) -4- ((5-chloro-4- (2- (3-fluoro-4-hydroxybenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) amino) cyclohexyl) carbamate (a 24-1), tert-butyl ((1 r,4 r) -4- ((5-chloro-4- (2- (3-methylbenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) amino) cyclohexyl) carbamate (A28-1), tert-butyl ((1 r,4 r) -4- ((5-chloro-4- (2- (2-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) amino) cyclohexyl) carbamate (A29-1), tert-butyl ((1 r,4 r) -4- ((5-chloro-4- (2- (2, 3-difluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) amino) cyclohexyl) carbamate (A31-1), tert-butyl ((1 r,4 r) -4- ((5-chloro-4- (2- (3, 4-difluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) amino) cyclohexyl) carbamate (A29-1), mass spectrometry, and (33-mass spectrometry The nuclear magnetic spectrum is shown in Table 1.
Wherein, the invention is listed as the compound: synthesis of mass spectrometry compounds similar to those of mass spectrometry compounds (A) 6- (5-chloro-2- (4-methylpiperidin-1-yl) pyridin-4-yl) -2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridine (A17), (1 r,4 r) -4- ((5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) amino) cyclohexane-1-ol (A19), 6- (5-chloro-2- (4-isopropylpiperazin-1-yl) pyridin-4-yl) -2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridine (A20), 6- (5-chloro-2-fluoropyridin-4-yl) -2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridine (A21), 4- ((6- (5-chloro-2- (((1 r,4 r) -4-hydroxycyclohexyl) amino) pyridin-4-yl) -3H-imidazo [ 4-b ] pyridin-4-yl) -2-yl) 2-imidazo [4,5-b ] pyridine (A20), and (A25), the nuclear magnetic spectrum is shown in Table 1.
Wherein, the invention is listed as the compound: 4- (5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-5-yl) pyridin-2-yl) morpholine (A3), 4- (5-chloro-4- (2- (3-fluorobenzyl) -3H-imidazo [4,5-b ] pyridin-6-yl) pyridin-2-yl) morpholine (A4) and compound A22 are synthesized in a similar manner, and mass spectra and nuclear magnetic spectra are shown in Table 1.
Example 4: cytotoxicity test results of partial 3H-imidazole [4,5-b ] pyridines of the present invention
Seven tumor cells, B16F10, eahy-926, OCM-1a, ovcar-3, SW480, A498 and U87, were tested for anti-proliferation at a concentration of 1. Mu.M/10. Mu.M/20. Mu.M for the compounds of the present invention, and the cell viability results are shown in Table 2.
TABLE 2 cytotoxicity test results of partial 3H-imidazo [4,5-b ] pyridines of the present invention
Example 5: partial 3H-imidazo [4,5-b ] pyridines of the present invention inhibit CDK9 kinase Activity results
An experiment for inhibiting CDK9 kinase activity at a concentration of 1. Mu.M/50 nM was performed on a portion of the compounds of the present invention and the results are shown in Table 3.
TABLE 3 inhibition of CDK9 kinase Activity by partial 3H-imidazo [4,5-b ] pyridines of the invention
Example 6: anti-cell proliferation experiment of 3H-imidazole [4,5-b ] pyridine compound A32
MTT assay measures cell proliferation. Different tumor cells or normal cells were plated in 96-well plates, 3000 cells per well. After 12h, the target compound was added for treatment, the compound was diluted to a certain concentration gradient in the culture solution, the culture solution was discarded after 72h, fresh culture solution and MTT were mixed in a ratio of 20:1, 100. Mu.L of the mixed solution was added to each well, incubated at 37℃for 2h, and then detected at a wavelength of 490nm, and the results are shown in Table 4.
TABLE 4 IC of A32 for different cells 50 Value of
Example 7: the 3H-imidazole [4,5-b ] pyridine compound A32 of the invention inhibits the proliferation experiment of brain glioma cells
The result of crystal violet staining of two brain glioma cells treated with a concentration gradient of a32 small molecules is shown in fig. 1, and compared with the control group, a32 with different concentrations has a certain inhibition effect on proliferation of the two cells and shows a certain concentration dependence. In particular, after high concentration (2.5. Mu.M and 5. Mu.M) of small molecule treatment, glioma cell clone formation was inhibited and growth was almost arrested.
Example 8: kinase Activity inhibition assay of 3H-imidazo [4,5-b ] pyridine compound A32 of the present invention
This example tests the IC of Compound A32 of example 1 for CDK9 50 And the activity inhibiting ability of A32 to other kinases of the same family at a concentration of 1. Mu.M. The results show that at 1IC of A32 to CDK9 at 0. Mu.M ATP concentration 50 38nM; IC of A32 on CDK9 at 45. Mu.M ATP concentration 50 27nM; IC of A32 for CDK7 at 90. Mu.M ATP concentration 50 326nM, indicating about 10-fold selectivity in inhibition of CDK7 and CDK9 by A32. Meanwhile, the kinase selectivity experimental result shows that A32 has obvious difference in enzyme activity inhibition of each member of CDKs family. After 1 μm treatment with a32, kinase activity of CDK9 was almost completely inhibited, whereas the activities of the other members were all above 50%, which also suggests to some extent that a32 has CDKs family selectivity, as shown in fig. 2.
Example 9: the 3H-imidazole [4,5-b ] pyridine compound A32 inhibits CDK9 function research
CDK9/cyclin T is involved in the composition of the transcription elongation factor P-TEFb complex, and CDK9 inhibitors block the phosphorylation of CDK9/cyclin T1 on serine number 2 of the carboxy-terminal domain of RNA polymerase II. Therefore, in this example, the effect of a 32-series compounds on the phosphorylation level of serine at position 2 of the carboxy terminal domain of RNA polymerase II was used as an index to evaluate the inhibitory effect of the series compounds on CDK9 (fig. 3). This example tests the phosphorylation level of serine number 2 of the carboxy terminal domain of RNA polymerase II in U87 cells treated with the A32 series of compounds, and shows that compounds A2, A12, A23, A27, A28, A29, A30, A31, A32, A33, etc. all inhibit the phosphorylation level of serine number 2 of the carboxy terminal domain of RNA polymerase II.
Example 10: the inhibition experiment of the 3H-imidazole [4,5-b ] pyridine compound A32 on the U87 cell mouse subcutaneous transplantation tumor model
After constructing a common U87 cell mouse tumor model, the initial tumor volume reaches 100mm 3 After the start of the administration, the results of the pharmacodynamic experiments are shown in FIG. 4, and it can be seen that the tumor-bearing volume of the mice increases slowly compared with the control group after 14 days of the intraperitoneal injection of 25mg/kg, and the tumor weights finally peeled off also have statistical differences. During the experiment, the body weight of the mice in the administration group did not change significantly, and the organs of the mice in the administration group showed no obvious damage after HE staining, indicating that compound a32 was relatively safe to the mice at this dose.
Example 11: the inhibition experiment of the 3H-imidazole [4,5-b ] pyridine compound A32 on the U87-Luc cell mouse in-situ transplantation tumor model
A U87-Luc cell in-situ transplantation tumor model is constructed, and the related experimental results are shown in FIG. 5. On day 3 after tumor inoculation, mice were randomly divided into two groups and given the corresponding vehicle or A32 drug solution (25 mg/kg), and then, on days 7, 14, 21, mice were subjected to in vivo imaging, respectively, to detect fluorescence intensity. It can be seen that the intracranial fluorescence intensity of the mice in the administration group increased slowly and had a significant difference compared to the control group. After day 21, dosing was stopped, mice in the control group died in a short period, and the survival of the dosed mice was significantly prolonged. Protein extraction and apoptosis-related protein detection are carried out on the intracranial tumor tissue of the mouse, and the expression quantity of MCL-1 and BCL-2 is reduced, which also shows that A32 promotes apoptosis of tumor cells.
Claims (8)
1. A novel CDK9 kinase inhibitor comprising a structural compound of formula (I):
wherein X is selected from hydrogen or halogen; l is selected from lower alkyl chains; r is R 1 Selected from piperazinyl, morpholinyl, piperidinyl, 1, 4-cyclohexanediamino, and halogen atoms; r is R 2 Selected from a single or multiple substituted aryl or 3-methylphenyl.
2. A novel CDK9 kinase inhibitor according to claim 1, wherein: x is selected from H, cl; l is selected from-CH 2 -、-C 2 H 4 -；R 1 Selected from N-isopropylpiperazine, 1-t-butoxycarbonyl-piperazine, morpholine, trans-1, 4-cyclohexanediamine, 1-t-butoxycarbonyl-1, 4-cyclohexanediamine, 4-methylpiperidine, 4-aminopiperidine, 4-hydroxypiperidine, 3-aminopiperidine, 4- (methylamino) cyclohexane-1-ol.
3. A novel CDK9 kinase inhibitor according to claim 1, wherein: l is-CH 2 -，R 1 Is trans-1, 4-cyclohexanediamine, R 2 Is 3, 5-difluorophenyl.
4. A process for the preparation of a novel CDK9 kinase inhibitor according to any one of claims 1 to 3, which is characterized by the synthetic route:
5. a pharmaceutical combination, characterized in that: a pharmaceutical composition comprising a structural compound of formula (I) as defined in any one of claims 1 to 3 or a stereoisomer thereof, a hydrate thereof, a solvate thereof, a deuterate thereof, a prodrug thereof, a metabolite thereof, an intermediate thereof, a pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.
6. Use of a CDK9 kinase inhibitor according to any one of claims 1 to 3 in combination with a medicament according to claim 5, wherein: use in the manufacture of a medicament for the treatment of a disease associated with the activity or expression of the cell cycle dependent kinase CDK 9.
7. Use of a CDK9 kinase inhibitor according to any one of claims 1 to 3 in combination with a medicament according to claim 5, wherein: use in the manufacture of a medicament for the treatment of a disorder associated with CDK9 activity or expression level.
8. Use according to claim 6 or 7, characterized in that: the diseases include breast cancer, gastric cancer, liver cancer, cervical cancer and brain glioma.
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