CN112321568A - 4-methylpyrrole substituted indolone derivative, preparation method and medical application thereof - Google Patents

4-methylpyrrole substituted indolone derivative, preparation method and medical application thereof Download PDF

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CN112321568A
CN112321568A CN202011006491.2A CN202011006491A CN112321568A CN 112321568 A CN112321568 A CN 112321568A CN 202011006491 A CN202011006491 A CN 202011006491A CN 112321568 A CN112321568 A CN 112321568A
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oxoindol
ylidene
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胡立宏
王均伟
康迪
潘祥
宋祎
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Nanjing University of Chinese Medicine
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Abstract

The invention discloses a 4-methylpyrrole substituted indolone derivative, a preparation method and medical application thereof. Relates to the field of pharmaceutical chemistry; compared with the compound 10d discovered in the early stage, the 4-methylpyrrole substituted indolone derivative has better chemical stability, higher selectivity on FLT3-ITD, more ideal pharmacokinetic characteristic and stronger in-vivo anti-tumor activity, particularly has lower onset dosage for treating acute myeloid leukemia, has a tumor inhibition rate obviously superior to that of the compound 10d and sunitinib under the same dosage, and is difficult to generate drug resistance.

Description

4-methylpyrrole substituted indolone derivative, preparation method and medical application thereof
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a 4-methylpyrrole substituted indolone derivative or pharmaceutically acceptable salt thereof, a medicinal composition containing the compounds, a preparation method thereof and application thereof in the aspect of tumor resistance.
Background
Malignant tumors (cancers) are serious chronic diseases that threaten human health seriously, and have become one of the most serious public health problems in China in the 21 st century and even in the world. The anticancer drugs used in clinic at present mainly comprise cytotoxic drugs, but the traditional chemotherapy drugs have the defects of easy drug resistance, strong toxic and side effects, more adverse reactions, poor curative effect and the like. With the development of molecular biology and tumor pharmacology, the mechanism of tumorigenesis is further elucidated, and the research on antitumor drugs is progressing from traditional cytotoxic drugs to novel molecular-targeted antitumor drugs.
Tyrosine kinases exist in most pathogenic genes in tumor diseases, so that research and development of medicaments taking tyrosine kinases as targets (such as EGFR, FGFR, PDGFR, VEGFR, IGFR, CSF1R, c-Kit, FLT3, RET and the like) are widely concerned, and Tyrosine Kinase Inhibitors (TKI) become hot spots in the field of research of antitumor medicaments. Moreover, the tyrosine kinase inhibitor has the advantages of high selectivity, low toxicity, less side effect and the like, so that the tyrosine kinase inhibitor is superior to the traditional antitumor drugs. According to statistics, more than 80% of currently marketed kinase drugs are tyrosine kinase inhibitors, and even part of the currently marketed kinase drugs become the first choice drugs for treating tumors.
FMS-like receptor tyrosine kinase 3 (FLT 3), an important receptor tyrosine kinase in cell signaling, has abnormal activation closely related to the development of various tumors, especially Acute Myeloid Leukemia (AML). Studies have shown that FLT3 is highly expressed in more than 70% of AML patients and Acute Lymphoblastic Leukemia (ALL) patients, with more than 1/3 of AML patients being accompanied by FLT3 gene mutations. Thus, targeted therapy against FLT3 has become one of the important tools for treating AML, and large amounts of FLT3 inhibitors have entered clinical studies or are undergoing preclinical studies.
Sunitinib (Sunitinib) is a multi-target tyrosine kinase inhibitor developed by the company pfeiri, is approved by the FDA to be on the market in 2006, is mainly used for the treatment of gastrointestinal stromal tumors and renal cell carcinoma, and is the first anticancer drug approved for two types of indications at the same time. It can effectively inhibit receptor tyrosine kinases such as VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-beta, c-Kit, FLT3 and the like. By inhibiting the expression of various angiogenesis promoting factors in the cancerated cells, the aim of inhibiting the angiogenesis and 'starving' the cancer cells is achieved. Although the Sunitinib has obvious antitumor effect, the Sunitinib still shows the side effects of hypodynamia, bone marrow suppression, fever and the like in clinic, has strong tissue accumulation and can not be taken continuously, and the scheme of stopping taking for 2 weeks after continuously taking for 4 weeks is adopted in clinic. It is worth noting that Sunitinib has a direct inhibitory effect on tumor cells with FLT3 mutation, but shows strong toxic and side effects in clinical trials for treating AML, and has no therapeutic window. In earlier research, the structure of Sunitinib is modified by adopting a biological electronic isostere strategy, and a derivative 10d [ Eur.J.Med.chem.2017,127,72-86 ] with a larger treatment window than Sunitinib is found; CN104829596B ]. However, in the subsequent studies, it was found that compound 10d has low chemical stability and generates impurities after a long time at room temperature, resulting in a decrease in purity; the purity of compound 10d was maintained at low temperature (-20 ℃) and vacuum drying, while the purity decreased to 80.8% after 150 days at room temperature. In addition, the in vivo efficacy of compound 10d in a nude mouse transplantation tumor model with acute myelogenous leukemia (MV4-11) is still a certain gap compared with Sunitinib. Therefore, we need to further elucidate the reason why the compound 10d is chemically unstable, modify the structure of the unstable part, improve the chemical stability, and find out a candidate compound with better drug property and stronger activity.
Figure BDA0002693745970000021
The detection of LC-MS shows that the new impurities are mainly derivatives with the molecular weight being reduced by 2 (12.42%) and the molecular weight being reduced by 4 (6.00%). Through the separation and identification of impurities and the guess of reaction mechanism, we guess the mechanism of impurity generation and generally guess1H-NMR、 13And performing structural analysis on C-NMR, HMQC, HMBC and ROSEY to determine that the two main impurities are 10d-X and 10d-Y respectively. The above results provide the basis for further improvement of chemical stability of the compounds. Since the methyl group at the 2-position of the pyrrole ring in the structure of the compound 10d is easily oxidized, the 2-position of the pyrrole ring must be subjected to structural modification, and the methyl group is removed or replaced by a functional group which is not easily oxidized, such as Cl, Br, H and the like, and finally, the removal of the methyl group is found to improve chemical stability and maintain activity. Through a series of structural optimization and activity screening, the invention discovers the 4-methylpyrrole substituted indolone anti-tumor candidate compound with high chemical stability and stronger activity.
Disclosure of Invention
In order to solve the problems, the invention provides a 4-methylpyrrole substituted indolone derivative shown in a general formula (I), and a tautomer, an enantiomer, a diastereomer, a racemate or pharmaceutically acceptable salt thereof.
The technical scheme of the invention is as follows: a4-methylpyrrole substituted indolone derivative or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, wherein the chemical structural formula of the derivative is shown as formula (I):
Figure BDA0002693745970000031
wherein:
R1selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, amino and NHCOR3Or NHSO2R3One ofOr a plurality of the components;
R2selected from alkyl, heterocycloalkyl, alkyl-substituted heterocycloalkyl, alkenyl, aryl, heteroaryl, CH2R4、(CH2)nNR5R6And NHR7R8One or more of the above;
R3selected from alkyl or alkenyl;
R4selected from heterocycloalkyl or alkyl-substituted heterocycloalkyl;
R5and R6Are respectively selected from one or more of hydrogen, alkyl, cycloalkyl and heterocycloalkyl;
at the same time, R5And R6Forming a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycle contains one or more atoms N, O, S and the 4-7 membered heterocycle is substituted with one or more alkyl groups;
R7and R8Are respectively selected from one or more of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
at the same time, R7And R8Forming a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycle contains one or more atoms N, O, S and the 4-7 membered heterocycle is substituted with one or more alkyl groups;
n is 1 to 6.
Typical preferred compounds of the invention are, but not limited to:
Figure BDA0002693745970000032
Figure BDA0002693745970000041
Figure BDA0002693745970000051
Figure BDA0002693745970000061
another object of the present invention is to provide a method for preparing a 4-methylpyrrole-substituted indolone derivative, comprising the steps of:
the first step is as follows: compound II in POCl3And DMF, performing Vilsmeier reaction to generate a compound III; in particular, under the condition of low temperature (0 ℃), POCl3Dropwise adding the mixture into anhydrous DMF, stirring at room temperature for 0.5 hour, adding compound II dissolved in the anhydrous DMF, and heating to 80 ℃ for reaction for 0.5 hour; after the reaction is finished, quenching the reaction by using an ice-water bath, adjusting the pH value to about 7, extracting by using dichloromethane, washing by using brine, and drying to obtain a compound III;
Figure BDA0002693745970000062
the second step is that: carrying out aldol condensation reaction on the compounds III and IV under the action of alkali to generate a compound IV; specifically, dissolving the compounds III and IV in ethanol, adding pyrrolidine, and heating to 50 ℃ for reaction for 2 hours; after the reaction is finished, performing suction filtration, washing a filter cake by using ethanol, and drying to obtain a compound V;
Figure BDA0002693745970000063
the third step: carrying out nitro reduction reaction on the compound V under the action of zinc powder to obtain a compound VI; specifically, dissolving a compound in a mixed solvent of tetrahydrofuran and methanol, adding a saturated solution of ammonium chloride, heating to 50 ℃, and then adding zinc powder to react for 0.5 hour; after the reaction is finished, distilling under reduced pressure to remove the solvent, dissolving the residue with ethyl acetate, washing with saturated sodium carbonate solution and saline solution in sequence, and drying; distilling under reduced pressure to remove the solvent, pulping with methanol to obtain purified compound VI;
Figure BDA0002693745970000071
the fourth step: reacting the compound IV with a corresponding carboxylic acid compound under the action of a condensing agent; or firstly reacting with acyl chloride and then reacting with the corresponding amine compound to obtain a target compound I; specifically, dissolving the compound V and a corresponding carboxylic acid compound in DMF, adding condensing agents PyBOP and DIPEA, and reacting at room temperature for 12 hours; after the reaction is finished, adding the reaction solution into water, extracting by ethyl acetate, washing by using salt water, drying, and purifying by column chromatography; finally, removing the Boc protecting group through HCl ethyl acetate solution treatment to obtain a target compound I;
or dissolving the compound IV in tetrahydrofuran, adding DIPEA, cooling to 0 ℃, adding corresponding acyl chloride, reacting at room temperature for 0.5 hour, then distilling under reduced pressure to remove the solvent, dissolving the residue with a mixed solvent of ethyl acetate and methanol, pulping and purifying to obtain an acylation product; further dissolving the product in anhydrous DMF, adding corresponding amine compounds, heating to 50 ℃ and reacting for 12 hours; after the reaction is finished, pouring the reaction liquid into water, extracting by ethyl acetate, washing by using brine, drying, distilling under reduced pressure to remove the solvent, and pulping and purifying the residue by using ethyl acetate to obtain the target compound I.
Figure BDA0002693745970000072
Further, the isomers are selected from one or more of enantiomers, diastereomers, geometric isomers or stereoisomers.
Further, the 4-methyl pyrrole substituted indolone derivative is selected from the following group:
(S, Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) pyrrolidine-2-carboxamide hydrochloride;
(R, Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) pyrrolidine-2-carboxamide hydrochloride;
(R, Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) pyrrolidine-3-carboxamide hydrochloride;
(Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) piperidine-4-carboxamide hydrochloride;
(Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) piperidine-2-carboxamide hydrochloride;
(Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -2- (pyrrolidin-1-yl) acetamide;
(Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -2- (pyrrolidin-2-yl) acetamide hydrochloride;
(Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -2- (piperidin-1-yl) acetamide;
(Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -2- (4-methylpiperazin-1-yl) acetamide;
(Z) -2- (diethylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) acetamide;
(Z) -2- (cyclopentylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) acetamide;
(Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (pyrrolidin-1-yl) propionamide;
(Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (piperidin-1-yl) propionamide;
(Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propanamide;
(Z) -3- (diethylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) propionamide;
(Z) -3- (dimethylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) propionamide;
(Z) -3- (ethylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) propionamide;
(Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (propylamino) propionamide;
(Z) -3- (tert-butylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) propionamide;
(Z) -3- (cyclopentylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) propionamide;
(Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3-morpholinepropionamide;
(Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -6- (trifluoromethyl) nicotinamide;
(Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -4-methylpiperazine-1-carboxamide;
(Z) -N- (5- ((5-chloro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (pyrrolidin-1-yl) propanamide
(Z) -N- (5- ((5-bromo-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (pyrrolidin-1-yl) propionamide;
(Z) -N- (5- ((5-methoxy-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (pyrrolidin-1-yl) propanamide.
The invention aims to provide a pharmaceutical composition, which comprises the 4-methylpyrrole substituted indolone derivative, pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, and at least one pharmaceutically acceptable carrier, additive, auxiliary agent or excipient.
The invention also aims to provide the 4-methylpyrrole substituted indolone derivative or the pharmaceutically acceptable salt and the application of the pharmaceutical composition thereof in preparing tyrosine kinase inhibitors. The compound or the pharmaceutically acceptable salt thereof and the pharmaceutical composition thereof have obvious inhibitory activity on receptor tyrosine kinases such as VEGFR-1, VEGFR-2, PDGFR alpha, PDGFR-beta, FLT3, CSF-1R and the like, and particularly have strong inhibitory activity on FLT3, so that the compound or the pharmaceutically acceptable salt thereof can be used for preparing medicines for treating related tumor diseases caused by abnormal expression of tyrosine kinases.
The invention also aims to provide the 4-methylpyrrole substituted indolone derivative or pharmaceutically acceptable salt and application of the pharmaceutical composition thereof in preparing antitumor drugs. In vivo and in vitro antitumor tests show that the compound can obviously inhibit the growth of malignant tumors such as liver cancer, breast cancer, colon cancer and the like. Therefore, the compound or the pharmaceutically acceptable salt thereof and the pharmaceutical composition thereof can be used as a single therapeutic agent or used in combination with other antitumor drugs for treating various malignant tumors caused by abnormal expression of tyrosine kinase.
The invention also aims to provide the application of the 4-methylpyrrole substituted indolone derivative or the pharmaceutically acceptable salt and the pharmaceutical composition thereof in preparing the medicines for treating acute myelogenous leukemia. In vitro anti-tumor activity experiments show that the compound can obviously inhibit the proliferation of acute myelogenous leukemia cells. The whole animal experiment shows that the compound has good curative effect on acute myelogenous leukemia, and the effective dose is lower than that of Sunitinib and the compound 10 d. Therefore, the compound or the pharmaceutically acceptable salt thereof and the pharmaceutical composition thereof can be used as a single therapeutic agent or combined with other anti-tumor medicaments for treating acute myelogenous leukemia.
The invention has the beneficial effects that: compared with the compound 10d discovered in the early stage, the 4-methylpyrrole substituted indolone derivative has better chemical stability, higher selectivity on FLT3-ITD, more ideal pharmacokinetic characteristic and stronger in-vivo anti-tumor activity, particularly has lower onset dosage for treating acute myelogenous leukemia, has a tumor inhibition rate obviously superior to that of the compound 10d and sunitinib under the same dosage, is not easy to generate drug resistance, and has good industrial prospect.
Detailed Description
In order to more clearly illustrate the technical solution of the present invention, the following further detailed description is made on the technical solution of the present invention:
example 1
Synthesis of (S, Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) pyrrolidine-2-carboxamide hydrochloride (A01)
Figure BDA0002693745970000091
Synthesis of intermediate III: at 0 deg.C, adding POCl3(1mL) was slowly added dropwise to anhydrous DMF (1.1mL) and after stirring at room temperature for 0.5h, a solution of Compound II (0.80g,6.35mmol) in DMF (2mL) was added to the reaction mixture, which was then heated to 80 ℃ for 0.5 h. After the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, cooled in an ice bath, and saturated Na was added2CO3The reaction solution was adjusted to pH7, extracted with methylene chloride (20 mL. times.2), and the combined layers were washed successively with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate: 20:1 to 4:1) to obtain 0.79g of a white solid with a yield of 81%.1H NMR(500MHz,DMSO-d6)δ(ppm): 13.03(1H,brs),9.79(1H,s),8.17(1H,s),2.59(3H,s).
Figure BDA0002693745970000092
Synthesis of intermediate V-1: compound III (1.2g,7.79mmol) and IV-1(1.3g,8.56mmol) were dissolved in ethanol (10mL), and pyrrolidine (0.83mL,10.13mmol) was added and heated to 50 ℃ for 2 hours. After the LC-MS monitoring reaction is finished, stopping heating, cooling to room temperature, performing suction filtration, washing a filter cake with a small amount of ethanol, and performing vacuum drying to obtain orange yellow solid 2.09g with the yield of 85%.1H NMR(500MHz,DMSO-d6)δ(ppm):14.26(1H,brs),11.17(1H,s),8.29 (1H,d,J＝3.6Hz),7.90(1H,dd,J1＝9.2Hz,J2＝2.5Hz),7.85(1H,s),7.03(1H,td,J1＝9.5Hz, J2＝2.5Hz),6.88(1H,dd,J1＝8.5Hz,J2＝4.4Hz),2.61(3H,s).
Figure BDA0002693745970000101
Synthesis of intermediate VI-1: compound V-1(0.40g,1.39mmol) was dissolved in a mixed solvent of tetrahydrofuran and methanol (27mL/15 mL, V/V), a saturated solution (1mL) of ammonium chloride (0.73g,13.9mmol) was added, the mixture was heated to 50 ℃ and zinc powder (0.45g,6.96mmol) was added in portions, and the reaction was continued for 0.5 hour. After the completion of the reaction, LC-MS monitored the reaction, heating was stopped, cooling to room temperature, concentration under reduced pressure was carried out, the residue was dissolved in ethyl acetate (100mL) and a saturated sodium carbonate solution (100mL), the organic layer was separated, washed with water and a saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. And (4) carrying out suction filtration, concentrating the filtrate, pulping and purifying methanol to obtain a crude product VI-1, and directly using the crude product VI-1 for the next reaction.
Figure BDA0002693745970000102
Synthesis of intermediate VII-1: compound VI-1(0.40g,1.55mmol) and Boc-L-proline (0.37g,1.71 mmol) were dissolved in DMF (50mL), and the condensing agents PyBOP (1.05g,2.02mmol) and DIPEA (0.77mL,4.66mmol) were added and reacted at room temperature for 12 hours. After completion of the reaction was monitored by TLC, the reaction mixture was added to water (50mL), extracted with ethyl acetate (30 mL. times.2), and the organic layers were combined, washed once with water and sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was filtered with suction, concentrated, and purified by column chromatography (dichloromethane: methanol: 50:1 to 20:1) to obtain 0.54g of a yellow solid in a yield of 77%.1H NMR(500 MHz,DMSO-d6)δ(ppm):13.28(1H,s),9.47(1H,s),8.03(1H,s),7.80(1H,s),7.35(1H,s),7.19 (1H,dd,J1＝8.7Hz,J2＝2.0Hz),6.86(1H,td,J1＝8.7Hz,J2＝2.1Hz),6.81(1H,dd,J1＝8.4Hz, J2＝4.3Hz),4.51-4.58(1H,m),3.37-3.57(2H,m),2.59-2.65(1H,m),2.28(3H,s),1.90-2.07(3H, m).
Figure BDA0002693745970000103
Synthesis of compound a 01: compound VII-1(100mg,0.22mmol) was dissolved in ethanol (5mL), and saturatedThe reaction was stirred at room temperature with HCl in ethanol (5 mL). After the completion of the TLC monitoring reaction, the filtrate was concentrated under reduced pressure, and the residue was slurried with ethyl acetate (5mL) and purified, filtered under suction, and dried under vacuum to give 72mg of a yellow solid in 84% yield. mp is 239-241 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.50(1H,s),10.96(1H,s),10.26(1H,s),10.11(1H,brs), 8.68(1H,brs),7.77(1H,dd,J1＝9.3Hz,J2＝2.0Hz),7.74(1H,s),7.68(1H,d,J＝2.8Hz),6.94 (1H,td,J1＝9.6Hz,J2＝2.3Hz),6.84-6.87(1H,m),4.46-4.55(1H,m),3.26-3.28(2H,m), 2.39-2.46(1H,m),2.34(3H,s),1.92-1.99(3H,m).13C NMR(126MHz,DMSO-d6)δ(ppm): 169.9,166.8,159.6,157.7,135.3,127.4(d,J＝9.5Hz),125.7(d,J＝9.2Hz),123.8,121.2,119.5, 116.1(d,J＝2.9Hz),113.0(d,J＝24.0Hz),110.5(d,J＝8.8Hz),106.5(d,J＝25.4Hz),59.5, 46.1,30.5,24.1,9.4.HRMS(ESI):m/z[M+H]+calcd for C19H20FN4O2 +,355.1565；found, 355.1572.
Example 2
Synthesis of (R, Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) pyrrolidine-2-carboxamide hydrochloride (A02)
Figure BDA0002693745970000111
Synthesis of intermediate VII-2: compound VI-1(0.40g,1.55mmol) and Boc-D-proline (0.37g,1.71 mmol) were dissolved in DMF (50mL), and the condensing agents PyBOP (1.05g,2.02mmol) and DIPEA (0.77mL,4.66mmol) were added and reacted at room temperature for 12 hours. After completion of the reaction was monitored by TLC, the reaction mixture was added to water (50mL), extracted with ethyl acetate (30 mL. times.2), and the organic layers were combined, washed once with water and sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated, and purified by column chromatography (dichloromethane: methanol: 50:1 to 20:1) to obtain 0.53g of a yellow solid in 75% yield, which was used directly in the next reaction.
Figure BDA0002693745970000112
Synthesis of compound a 02: compound VII-2(100mg,0.22mmol) was dissolved in ethanol (5mL), and a saturated HCl solution in ethanol (5mL) was added to stir the reaction at room temperature. After the completion of the TLC monitoring reaction, the filtrate was concentrated under reduced pressure, and the residue was slurried with ethyl acetate (5mL) and purified, filtered under suction, and dried under vacuum to give 75mg of a yellow solid in 87% yield. mp is 247-249 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.50(1H,s),10.97(1H,s),10.25(1H,s),10.03(1H,brs), 8.68(1H,brs),7.77(1H,dd,J1＝9.3Hz,J2＝2.0Hz),7.74(1H,s),7.68(1H,d,J＝2.9Hz),6.94 (1H,td,J1＝9.6Hz,J2＝2.3Hz),6.84-6.87(1H,m),4.45-4.53(1H,m),3.25-3.29(2H,m), 2.39-2.42(1H,m),2.34(3H,s),1.91-1.99(3H,m).13C NMR(126MHz,DMSO-d6)δ(ppm): 169.9,166.8,159.6,157.7,135.3,127.4(d,J＝9.4Hz),125.7(d,J＝8.8Hz),123.8,121.2,119.5, 116.1(d,J＝3.0Hz),113.0(d,J＝23.9Hz),110.5(d,J＝8.5Hz),106.5(d,J＝25.4Hz),59.5, 46.1,30.5,24.1,9.4.HRMS(ESI):m/z[M+H]+calcd for C19H20FN4O2 +,355.1565；found, 355.1556.
Example 3
Synthesis of (R, Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) pyrrolidine-3-carboxamide hydrochloride (A03)
Figure BDA0002693745970000121
Synthesis of intermediate VII-3: compound VI-1(0.40g,1.55mmol) and (R) -1-Boc-3-carboxypyrrolidine (0.37g,1.71 mmol) were dissolved in DMF (50mL) and reacted at room temperature for 12 hours with the addition of the condensing agent PyBOP (1.05g,2.02mmol) and DIPEA (0.77mL,4.66 mmol). After completion of the reaction was monitored by TLC, the reaction mixture was added to water (50mL), extracted with ethyl acetate (30 mL. times.2), and the organic layers were combined, washed successively with water and sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated, and purified by column chromatography (dichloromethane: methanol: 50:1 to 20:1) to obtain 0.54g of a yellow solid in 77% yield, which was used in the next reaction.
Figure BDA0002693745970000122
Synthesis of compound a 03: compound VII-3(100mg,0.22mmol) was dissolved in ethanol (5mL), and a saturated HCl solution in ethanol (5mL) was added to stir the reaction at room temperature. After the completion of the TLC monitoring reaction, the filtrate was concentrated under reduced pressure, and the residue was slurried with ethyl acetate (5mL) and purified, filtered under suction, and dried under vacuum to give 70mg of a yellow solid in 82% yield. mp 259-261 deg.C.1H NMR(500MHz,DMSO-d6)δ(ppm):13.45(1H,s),10.92(1H,s),9.77(1H,s),9.40(1H,brs), 9.13(1H,brs),7.76(1H,dd,J1＝9.3Hz,J2＝1.7Hz),7.72(1H,s),7.67(1H,d,J＝2.4Hz),6.94 (1H,td,J1＝9.1Hz,J2＝2.1Hz),6.83-6.86(1H,m),3.28-3.34(2H,m),3.12-3.26(3H,m),2.31 (3H,s),2.23-2.27(1H,m),2.01-2.06(1H,m).13C NMR(126MHz,DMSO-d6)δ(ppm):170.1, 169.9,159.6,157.7,135.2,127.6(d,J＝9.5Hz),125.6(d,J＝9.1Hz),124.5,121.1,119.6,115.7 (d,J＝3.1Hz),113.9(d,J＝24.3Hz),110.5(d,J＝8.7Hz),106.3(d,J＝25.8Hz),47.4,45.2, 42.5,29.6,9.3.HRMS(ESI):m/z[M+H]+calcd for C19H20FN4O2 +,355.1565；found,355.1563.
Example 4
Synthesis of (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) piperidine-4-carboxamide hydrochloride (A04)
Figure BDA0002693745970000131
Synthesis of intermediate VII-4: compound VI-1(0.40g,1.55mmol) and Boc-4-piperidinecarboxylic acid (0.39g,1.71mmol) were dissolved in DMF (50mL), and the condensing agents PyBOP (1.05g,2.02mmol) and DIPEA (0.77mL,4.66mmol) were added and reacted at room temperature for 12 hours. After completion of the reaction was monitored by TLC, the reaction mixture was added to water (50mL), extracted with ethyl acetate (30 mL. times.2), and the organic layers were combined, washed successively with water and sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated, and purified by column chromatography (dichloromethane: methanol: 50:1 to 20:1) to obtain 0.60g of a yellow solid in 83% yield, which was used directly in the next reaction.
Figure BDA0002693745970000132
Synthesis of compound a 04: compound VII-4(100mg,0.22mmol) was dissolved in ethanol (5mL), and a saturated HCl solution in ethanol (5mL) was added to stir the reaction at room temperature. After the completion of the TLC monitoring reaction, the filtrate was concentrated under reduced pressure, and the residue was slurried with ethyl acetate (5mL) and purified, filtered under suction, and dried under vacuum to give 68mg of a yellow solid in 77% yield. mp is 244-246 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):12.60(1H,s),9.67(1H,s),9.18(1H,s),9.02(1H,brs), 8.90(1H,brs),8.09-8.10(1H,m),7.92(1H,d,J＝7.3Hz),7.84(1H,s),7.75-7.79(1H,m), 7.00-7.08(1H,m),3.95-4.03(1H,m),2.98-3.05(2H,m),2.77-2.90(2H,m),2.34(3H,s), 2.06-2.17(2H,m),1.78-1.88(2H,m).13C NMR(126MHz,DMSO-d6)δ(ppm):169.9,167.9, 159.6,157.7,135.2,127.5(d,J＝9.4Hz),125.6(d,J＝11.6Hz),124.6,120.8,119.4,115.7(d,J ＝3.1Hz),112.9(d,J＝23.7Hz),110.4(d,J＝8.3Hz),106.3(d,J＝25.3Hz),56.5,45.0,37.5, 30.3,23.4,9.4.HRMS(ESI):m/z[M+H]+calcd for C20H22FN4O2 +,369.1721；found,369.1741.
Example 5
Synthesis of (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) piperidine-2-carboxamide hydrochloride (A05)
Figure BDA0002693745970000141
Synthesis of intermediate VII-5: compound VI-1(0.40g,1.55mmol) and N-Boc-2-piperidinecarboxylic acid (0.39g,1.71mmol) were dissolved in DMF (50mL), and the condensing agents PyBOP (1.05g,2.02mmol) and DIPEA (0.77mL,4.66mmol) were added and reacted at room temperature for 12 hours. After completion of the reaction was monitored by TLC, the reaction mixture was added to water (50mL), extracted with ethyl acetate (30 mL. times.2), and the organic layers were combined, washed successively with water and sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated, and purified by column chromatography (dichloromethane: methanol: 50:1 to 20:1) to obtain 0.57g of a yellow solid in 78% yield, which was used directly in the next reaction.
Figure BDA0002693745970000142
Synthesis of compound a 05: compound VII-5(100mg,0.22mmol) was dissolved in ethanol (5mL), and a saturated HCl solution in ethanol (5mL) was added to stir the reaction at room temperature. After the completion of the TLC monitoring reaction, the filtrate was concentrated under reduced pressure, and the residue was slurried with ethyl acetate (5mL) and purified, filtered under suction, and dried under vacuum to give 72mg of a yellow solid in 81% yield. mp is 263-265 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.50(1H,s),10.95(1H,s),10.13(1H,s),9.26-9.28(1H, m),8.76-8.82(1H,m),7.77(1H,dd,J1＝9.3Hz,J2＝2.1Hz),7.74(1H,s),7.68(1H,d,J＝2.7 Hz),6.94(1H,td,J1＝9.6Hz,J2＝2.3Hz),6.84-6.87(1H,m),4.00-4.06(1H,m),3.25-3.28(1H, m),2.92-2.99(1H,m),2.32(3H,s),2.22-2.25(1H,m),1.82-1.85(1H,m),1.52-1.76(4H,m).13C NMR(126MHz,DMSO-d6)δ(ppm):169.9,167.2,159.6,157.7,135.3,127.4(d,J＝9.5Hz), 125.7(d,J＝10.4Hz),123.7,121.3,119.5,116.1(d,J＝2.9Hz),113.0(d,J＝24.1Hz),110.5(d, J＝8.6Hz),106.4(d,J＝25.4Hz),57.6,43.8,27.9,22.1,21.7,9.4.HRMS(ESI):m/z[M+H]+ calcd for C20H22FN4O2 +,369.1721；found,369.1716.
Example 6
Synthesis of (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -2- (pyrrolidin-1-yl) acetamide (A06)
Figure BDA0002693745970000151
Intermediate VIII-1 Synthesis: compound VI-1(0.30g,1.15mmol) was dissolved in THF (20mL), DIPEA (0.57mL,3.45mmol) was added, the temperature was lowered to 0 deg.C, chloroacetyl chloride (0.46mL,5.75mmol) was added dropwise, and after the addition was completed, the reaction was carried out at room temperature for 0.5 h. After the completion of the TLC monitoring reaction, concentration was performed under reduced pressure, and the residue was slurried with ethyl acetate (10mL) and methanol (0.5 mL). Suction filtration, the filter cake washed with ethyl acetate (1mL) and dried in vacuo to give 0.30g of a yellow solid in 76% yield.1H NMR(500 MHz,DMSO-d6)δ(ppm):13.46(1H,s),10.90(1H,s),9.75(1H,s),7.77(1H,dd,J1＝9.3Hz,J2＝2.2Hz),7.73(1H,s),7.68(1H,d,J＝2.9Hz),6.94(1H,td,J1＝8.4Hz,J2＝2.4Hz),6.83-6.85 (1H,m),4.29(2H,s),2.30(3H,s).
Figure BDA0002693745970000152
Synthesis of compound a 06: compound VIII-1(100mg,0.3mmol) was dissolved in DMF (5mL), and pyrrolidine (123. mu.L, 1.50mmol) was added and reacted at 50 ℃ for 12 hours. After completion of the TLC monitoring reaction, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed with water and saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Suction filtration, filtrate concentration, residue adding ethyl acetate (5mL), pulping and purification, suction filtration, vacuum drying to obtain yellow solid 88mg, yield 80%. mp is 250-252 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.44(1H,s), 10.89(1H,s),9.17(1H,s),7.76(1H,dd,J1＝9.3Hz,J2＝1.9Hz),7.73(1H,s),7.62(1H,d,J＝ 2.5Hz),6.94(1H,td,J1＝10.0Hz,J2＝2.0Hz),6.83-6.85(1H,m),3.26(2H,s),2.57-2.66(4H, m),2.27(3H,s),1.71-1.81(4H,m).13C NMR(126MHz,DMSO-d6)δ(ppm):169.9,168.2,159.6, 157.7,135.2,127.5(d,J＝9.3Hz),125.7(d,J＝6.3Hz),124.3,121.4,119.6,115.6(d,J＝3.0Hz), 112.8(d,J＝23.8Hz),110.4(d,J＝8.6Hz),106.3(d,J＝25.4Hz),59.0,54.3(2C),31.1,23.9, 9.1.HRMS(ESI):m/z[M+H]+calcd for C20H22FN4O2 +,369.1721；found,369.1718.
Example 7
Synthesis of (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -2- (pyrrolidin-2-yl) acetamide hydrochloride (A07)
Figure BDA0002693745970000153
Synthesis of intermediate VII-7: compound VI-1(0.40g,1.55mmol) and 2- (1- (tert-butoxycarbonyl) pyrrolidin-2-yl) acetic acid (0.39g,1.71mmol) were dissolved in DMF (50mL), and the condensing agents PyBOP (1.05g,2.02mmol) and DIPEA (0.77mL,4.66mmol) were added and reacted at room temperature for 12 hours. After completion of the TLC monitoring reaction, the reaction mixture was added to water (50mL), extracted with ethyl acetate (30 mL. times.2), and the organic layers were combined, washed successively with water and sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated, and purified by column chromatography (dichloromethane: methanol: 50:1 to 20:1) to obtain 0.58g of a yellow solid in 78% yield, which was used directly in the next reaction.
Figure BDA0002693745970000161
Synthesis of compound a 07: compound VII-7(100mg,0.22mmol) was dissolved in ethanol (5mL), and a saturated HCl solution in ethanol (5mL) was added to stir the reaction at room temperature. After the completion of the TLC monitoring reaction, the filtrate was concentrated under reduced pressure, and the residue was slurried with ethyl acetate (5mL) and purified, filtered under suction, and dried under vacuum to give 70mg of a yellow solid in 81% yield. mp is 234-236 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.45(1H,s),10.93(1H,s),9.76(1H,s),9.25(1H,brs), 9.05(1H,brs),7.76(1H,dd,J1＝9.3Hz,J2＝2.4Hz),7.72(1H,s),7.69(1H,d,J＝2.9Hz),6.93 (1H,td,J1＝9.4Hz,J2＝2.5Hz),6.83-6.86(1H,m),3.73-3.79(1H,m),3.13-3.18(2H,m),2.91 (2H,d,J＝6.9Hz),2.32(3H,s),2.10-2.18(1H,m),1.93-1.96(2H,m),1.81-1.91(1H,m).13C NMR(126MHz,DMSO-d6)δ(ppm):169.8,168.0,159.6,157.7,135.2,127.5(d,J＝9.4Hz), 125.7(d,J＝12.1Hz),124.6,120.8,119.4,115.7(d,J＝2.9Hz),112.9(d,J＝24.2Hz),110.4(d, J＝8.5Hz),106.3(d,J＝25.5Hz),56.5,44.9,37.5,30.3,23.4,9.4.HRMS(ESI):m/z[M+H]+ calcd for C20H22FN4O2 +,369.1721；found,369.1717.
Example 8
Synthesis of (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -2- (piperidin-1-yl) acetamide (A08)
Figure BDA0002693745970000162
Synthesis of compound a 08: compound VIII-1(100mg,0.3mmol) was dissolved in DMF (5mL), to which was added piperidine (149. mu.L, 1.5mmol), and the reaction was stirred at 50 ℃. After completion of the TLC monitoring reaction, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed with water and saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5mL) to the residue, pulping for purification, suction filtration, vacuum drying to give 89mg of a yellow solid in 78% yield. mp 275-277 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.44(1H,s), 10.89(1H,s),9.17(1H,s),7.77(1H,dd,J1＝9.1Hz,J2＝1.4Hz),7.74(1H,s),7.65(1H,d,J＝ 2.2Hz),6.94(1H,td,J1＝10.0Hz,J2＝2.0Hz),6.83-6.85(1H,m),3.08(2H,s),2.42-2.50(4H, m),2.28(3H,s),1.57-1.60(4H,m),1.37-1.47(2H,m).13C NMR(126MHz,DMSO-d6)δ(ppm): 169.9,167.9,159.6,157.7,135.2,127.5(d,J＝9.5Hz),125.6(d,J＝7.2Hz),124.3,120.5,119.0, 115.7(d,J＝2.8Hz),112.9(d,J＝24.1Hz),110.4(d,J＝8.5Hz),106.4(d,J＝25.4Hz),62.3, 54.6(2C),26.2(2C),23.9,8.9.HRMS(ESI):m/z[M+H]+calcd for C21H24FN4O2 +,383.1878； found,383.1872.
Example 9
Synthesis of (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -2- (4-methylpiperazin-1-yl) acetamide (A09)
Figure BDA0002693745970000171
Synthesis of compound a 09: compound VIII-1(100mg,0.3mmol) was dissolved in DMF (5mL), to which was added N-methylpiperazine (166. mu.L, 1.5mmol), and the reaction was stirred at 50 ℃. After completion of the reaction monitored by TLC, the reaction mixture was poured into water, extracted with an ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed successively with water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Suction filtration, filtrate concentration, residue adding ethyl acetate (5mL), pulping and purification, suction filtration, vacuum drying to obtain yellow solid 101mg, yield 85%. mp is 265-267 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm): 13.44(1H,s),10.89(1H,s),9.18(1H,s),7.76(1H,dd,J1＝9.4Hz,J2＝2.4Hz),7.73(1H,s), 7.65(1H,d,J＝2.9Hz),6.94(1H,td,J1＝9.5Hz,J2＝2.5Hz),6.83-6.85(1H,m),3.12(2H,s), 2.55-2.64(4H,m),2.33-2.45(4H,m),2.28(3H,s),2.19(3H,s).13C NMR(126MHz,DMSO-d6) δ(ppm):169.9,167.7,159.6,157.7,135.2,127.5(d,J＝9.5Hz),125.6(d,J＝7.0Hz),124.3, 120.7,119.2,115.7(d,J＝3.0Hz),112.9(d,J＝24.1Hz),110.4(d,J＝8.6Hz),106.4(d,J＝25.2 Hz),61.4,55.2(2C),53.2(2C),46.2,9.0.HRMS(ESI):m/z[M+H]+calcd for C21H25FN5O2 +, 398.1987；found,398.1984.
Example 10
Synthesis of (Z) -2- (diethylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) acetamide (A10)
Figure BDA0002693745970000181
Synthesis of compound a 10: compound VIII-1(100mg,0.3mmol) was dissolved in DMF (5mL), to which was added diethylamine (155. mu.L, 1.5mmol), and the reaction was stirred at 50 ℃. After TLC monitoring of the reaction completion, the reaction mixture was poured into water, extracted with ethyl acetate solution (30 mL. times.2), and combinedThe organic layer was washed with water and saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5mL) to the residue, pulping for purification, suction filtration, vacuum drying to give 80mg of a yellow solid in 72% yield. mp is 265-267 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.44(1H, s),10.89(1H,s),9.21(1H,s),7.77(1H,d,J＝9.2Hz),7.74(1H,s),7.65-7.70(1H,m),6.94(1H, td,J1＝9.0Hz,J2＝1.8Hz),6.83-6.85(1H,m),3.15(2H,s),2.60(4H,q,J＝6.8Hz),2.28(3H,s), 1.05(6H,t,J＝7.0Hz).13C NMR(126MHz,DMSO-d6)δ(ppm):169.9,169.1,159.6,157.7, 135.2,127.5(d,J＝9.4Hz),125.6(d,J＝10.3Hz),124.3,120.3,118.9,115.8(d,J＝2.9Hz), 112.9(d,J＝21.4Hz),110.4(d,J＝8.6Hz),106.4(d,J＝13.9Hz),57.5,48.4(2C),12.7(2C), 8.9.HRMS(ESI):m/z[M+H]+calcd for C20H24FN4O2 +,371.1878；found,371.1876.
Example 11
Synthesis of (Z) -2- (dimethylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) acetamide (A11)
Figure BDA0002693745970000182
Synthesis of compound a 11: compound VIII-1(100mg,0.3mmol) was dissolved in DMF (5mL), to which dimethylamine (76. mu.L, 1.5mmol) was added, and the reaction was stirred at 50 ℃. After completion of the TLC monitoring reaction, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed with water and saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5mL) to the residue, pulping for purification, suction filtration, vacuum drying to give 76mg of a yellow solid in 74% yield. mp is 271-273 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.44(1H, s),10.89(1H,s),9.16(1H,s),7.76(1H,dd,J1＝9.3Hz,J2＝2.0Hz),7.73(1H,s),7.61(1H,d,J ＝2.7Hz),6.93(1H,td,J1＝9.8Hz,J2＝2.2Hz),6.83-6.85(1H,m),3.09(2H,s),2.31(6H,s), 2.27(3H,s).13C NMR(126MHz,DMSO-d6)δ(ppm):169.9,168.2,159.6,157.7,135.2,127.5(d, J＝9.5Hz),125.7(d,J＝8.2Hz),124.3,121.4,119.7,115.6(d,J＝2.9Hz),112.9(d,J＝24.0 Hz),110.4(d,J＝8.5Hz),106.4(d,J＝25.6Hz),63.0,45.9(2C),9.1.HRMS(ESI):m/z[M+H]+ calcd for C18H20FN4O2 +,343.1565；found,343.1560.
Example 12
Synthesis of (Z) -2- (cyclopentylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) acetamide (A12)
Figure BDA0002693745970000191
Synthesis of compound a 12: compound VIII-1(100mg,0.3mmol) was dissolved in DMF (5mL), and cyclopentylamine (148. mu.L, 1.5mmol) was added thereto, followed by stirring the reaction at 50 ℃. After completion of the TLC monitoring reaction, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed with water and saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5mL) to the residue, pulping for purification, suction filtration, vacuum drying to give 95mg of yellow solid, 83% yield. mp:283-285 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.43(1H, s),10.88(1H,s),9.37(1H,s),7.76(1H,dd,J1＝9.4Hz,J2＝1.7Hz),7.73(1H,s),7.70(1H,d,J ＝2.5Hz),6.93(1H,td,J1＝9.7Hz,J2＝1.8Hz),6.83-6.85(1H,m),3.27(2H,s),3.02-3.07(1H, m),2.28(3H,s),1.62-1.75(4H,m),1.47-1.54(2H,m),1.34-1.39(2H,m).13C NMR(126MHz, DMSO-d6)δ(ppm):169.9,169.8,159.6,157.7,135.2,127.5(d,J＝9.4Hz),125.6(d,J＝10.7 Hz),124.5,120.1,118.8,115.7(d,J＝3.0Hz),112.9(d,J＝24.1Hz),110.4(d,J＝8.4Hz),106.4 (d,J＝25.6Hz),59.7,51.3,32.8(2C),23.9(2C),9.0.HRMS(ESI):m/z[M+H]+calcd for C21H24FN4O2 +,383.1878；found,383.1873.
Example 13
Synthesis of (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (pyrrolidin-1-yl) propionamide (A13)
Figure BDA0002693745970000192
Synthesis of intermediate IX-1: compound VI-1(0.30g,1.15mmol) was dissolved in THF (20mL), DIPEA (0.57mL,3.45mmol) was added, the temperature was lowered to 0 deg.C, 3-chloropropionyl chloride (0.55mL,5.75mmol) was added dropwise, and after the addition was completed, the reaction was carried out at room temperature for 0.5 h. After the completion of the TLC monitoring reaction, concentration was performed under reduced pressure, and the residue was slurried with ethyl acetate (10mL) and methanol (0.5 mL). Suction filtration, filter cake washing with ethyl acetate (1mL), vacuum drying to give yellow solid 0.32g, yield 80%.1H NMR(500 MHz,DMSO-d6)δ(ppm):13.44(1H,s),10.88(1H,s),9.50(1H,s),7.75(1H,dd,J1＝9.4Hz,J2＝2.5Hz),7.72(1H,s),7.68(1H,d,J＝3.1Hz),6.93(1H,td,J1＝9.6Hz,J2＝2.5Hz),6.83-6.85 (1H,m),3.88(2H,t,J＝6.4Hz),2.85(2H,t,J＝6.3Hz),2.30(3H,s).
Figure BDA0002693745970000201
Synthesis of compound a 13: compound IX-1(104mg,0.3mmol) was dissolved in DMF (5mL), and pyrrolidine (123. mu.L, 1.5mmol) was added thereto, followed by stirring the reaction at 50 ℃. After completion of the TLC monitoring reaction, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed with water and saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5mL) to the residue, pulping for purification, suction filtration, vacuum drying to give 90mg of a yellow solid, yield 79%. mp at 274-276 deg.C.1H NMR(500MHz,DMSO-d6)δ(ppm):13.40(1H, s),10.88(1H,s),9.99(1H,s),7.74(1H,dd,J1＝9.2Hz,J2＝1.0Hz),7.72(1H,s),7.71(1H,d,J ＝3.2Hz),6.93(1H,td,J1＝8.9Hz,J2＝2.4Hz),6.82-6.85(1H,m),2.72(2H,t,J＝6.9Hz), 2.51-2.56(4H,m),2.47-2.49(2H,m),2.27(3H,s),1.68-1.76(4H,m).13C NMR(126MHz, DMSO-d6)δ(ppm):169.8,169.7,159.6,157.7,135.2,127.6(d,J＝9.3Hz),125.6(d,J＝23.3 Hz),125.3,119.8,118.9,115.5(d,J＝2.8Hz),112.8(d,J＝23.8Hz),110.3(d,J＝8.5Hz),106.4 (d,J＝25.4Hz),53.7(2C),52.0,35.1,23.6(2C),9.0.HRMS(ESI):m/z[M+H]+calcd for C21H24FN4O2 +,383.1878；found,383.1866.
Example 14
Synthesis of (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (piperidin-1-yl) propanamide (A14)
Figure BDA0002693745970000202
Synthesis of compound a 14: compound IX-1(104mg,0.3mmol) was dissolved in DMF (5mL), and piperidine (149. mu.L, 1.5mmol) was added thereto, followed by stirring the reaction at 50 ℃. After completion of the TLC monitoring reaction, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed with water and saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5mL) to the residue, pulping for purification, suction filtration, vacuum drying to give 87mg of a yellow solid in 73% yield. mp is 270-272 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.40(1H,s), 10.88(1H,s),9.83(1H,s),7.74(1H,dd,J1＝9.3Hz,J2＝2.4Hz),7.72(1H,s),7.70(1H,d,J＝ 3.0Hz),6.93(1H,td,J1＝9.4Hz,J2＝2.5Hz),6.82-6.85(1H,m),2.58(2H,t,J＝6.6Hz), 2.37-2.48(6H,m),2.31(3H,s),1.52-1.56(4H,m),1.38-1.45(2H,m).13C NMR(126MHz, DMSO-d6)δ(ppm):169.9,169.8,159.6,157.8,135.1,127.6(d,J＝9.2Hz),125.5(d,J＝25.1 Hz),125.2,120.0,119.1,115.5(d,J＝3.0Hz),112.8(d,J＝24.6Hz),110.4(d,J＝8.6Hz),106.3 (d,J＝25.7Hz),55.1,54.1(2C),33.2,26.0(2C),24.5,9.3.HRMS(ESI):m/z[M+H]+calcd for C22H26FN4O2 +,397.2034；found,397.2022.
Example 15
Synthesis of (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide (A15)
Figure BDA0002693745970000211
Synthesis of compound a 15: compound IX-1(104mg,0.3mmol) was dissolved in DMF (5mL), and N-methylpiperazine (166. mu.L, 1.5mmol) was added thereto, followed by stirring the reaction at 50 ℃. After completion of the reaction monitored by TLC, the reaction mixture was poured into water, extracted with an ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed successively with water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5mL) to the residue, pulping for purification, suction filtration, vacuum drying to give 103mg of a yellow solid in 84% yield. mp is 285-287 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm): 13.40(1H,s),10.88(1H,s),9.74(1H,s),7.74(1H,d,J＝9.3Hz),7.72(1H,s),7.66-7.69(1H,m), 6.93(1H,t,J1＝7.8Hz),6.82-6.85(1H,m),2.61(2H,t,J＝6.0Hz),2.35-2.48(10H,m),2.31 (3H,s),2.16(3H,s).13C NMR(126MHz,DMSO-d6)δ(ppm):169.8,169.7,159.6,157.7,135.1, 127.6(d,J＝9.4Hz),125.5(d,J＝25.0Hz),125.2,120.1,119.2,115.5(d,J＝3.0Hz),112.8(d,J ＝23.9Hz),110.4(d,J＝8.4Hz),106.3(d,J＝25.5Hz),55.2(2C),54.4,52.8(2C),46.2,33.2, 9.6.HRMS(ESI):m/z[M+H]+calcd for C22H27FN5O2 +,412.2143；found,412.2137.
Example 16
Synthesis of (Z) -3- (diethylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) propanamide (A16)
Figure BDA0002693745970000212
Synthesis of compound a 16: compound IX-1(104mg,0.3mmol) was dissolved in DMF (5mL), diethylamine (155. mu.L, 1.5mmol) was added thereto, and then the reaction was stirred at 50 ℃. After completion of the TLC monitoring reaction, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed with water and saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5mL) to the residue, pulping for purification, suction filtration, vacuum drying to give 84mg of a yellow solid in 73% yield. mp:251-253 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.41(1H, s),10.87(1H,s),9.86(1H,s),7.74(1H,dd,J1＝9.3Hz,J2＝1.6Hz),7.71(1H,s),7.69(1H,d,J ＝2.5Hz),6.93(1H,td,J1＝9.4Hz,J2＝2.3Hz),6.83-6.85(1H,m),2.72(2H,t,J＝6.8Hz), 2.53-2.56(4H,m),2.44(2H,t,J＝6.7Hz),2.29(3H,s),1.00(6H,t,J＝7.1Hz).13C NMR(126 MHz,DMSO-d6)δ(ppm):170.0,169.8,159.6,157.7,135.1,127.5(d,J＝9.4Hz),125.5(d,J＝ 21.5Hz),125.3,120.0,119.1,115.4(d,J＝3.0Hz),112.8(d,J＝24.0Hz),110.4(d,J＝8.6Hz), 106.4(d,J＝25.6Hz),49.0,46.2(2C),33.4,12.0(2C),9.2.HRMS(ESI):m/z[M+H]+calcd for C21H26FN4O2 +,385.2034；found,385.2030.
Example 17
Synthesis of (Z) -3- (dimethylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) propanamide (A17)
Figure BDA0002693745970000221
Synthesis of compound a 17: compound IX-1(104mg,0.3mmol) was dissolved in DMF (5mL), to which dimethylamine (76. mu.L, 1.5mmol) was added, and the reaction was stirred at 50 ℃. After completion of the TLC monitoring reaction, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed with water and saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Suction filtration, filtrate concentration, residue in ethyl acetate (5mL) pulping purification, suction filtration, vacuum drying to yellow solid 69mg, yield 65%. mp is 270-272 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.41 (1H,s),10.88(1H,s),9.84(1H,s),7.75(1H,dd,J1＝9.3Hz,J2＝2.2Hz),7.72(1H,s),7.69(1H, d,J＝2.9Hz),6.93(1H,td,J1＝9.4Hz,J2＝2.3Hz),6.83-6.85(1H,m),2.57(2H,t,J＝6.9Hz), 2.46(2H,t,J＝6.7Hz),2.28(3H,s),2.22(6H,s).13C NMR(126MHz,DMSO-d6)δ(ppm): 169.8,169.7,159.6,157.7,135.1,127.6(d,J＝9.4Hz),125.5(d,J＝23.4Hz),125.2,120.1, 119.1,115.5(d,J＝3.0Hz),112.8(d,J＝23.9Hz),110.4(d,J＝8.6Hz),106.4(d,J＝25.5Hz), 55.6,45.2(2C),33.9,9.1.HRMS(ESI):m/z[M+H]+calcd for C19H22FN4O2 +,357.1721；found, 357.1707.
Example 18
Synthesis of (Z) -3- (ethylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) propanamide (A18)
Figure BDA0002693745970000231
Synthesis of compound a 18: compound IX-1(104mg,0.3mmol) was dissolved in DMF (5mL), to which was added ethylamine (83. mu.L, 1.5mmol), and the reaction was stirred at 50 ℃. After completion of the TLC monitoring reaction, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed with water and saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5mL) to the residue, pulping for purification, suction filtration, vacuum drying to give 76mg of a yellow solid, yield 71%. mp is 252-254 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.41(1H,s), 10.88(1H,s),9.84(1H,s),7.75(1H,dd,J1＝9.3Hz,J2＝2.2Hz),7.72(1H,s),7.70(1H,d,J＝ 2.9Hz),6.93(1H,td,J1＝9.4Hz,J2＝2.3Hz),6.83-6.85(1H,m),2.81(2H,t,J＝6.3Hz), 2.58-2.63(2H,m),2.45(2H,t,J＝6.2Hz),2.29(3H,s),1.06(3H,t,J＝7.1Hz).13C NMR(126 MHz,DMSO-d6)δ(ppm):170.0,169.8,159.6,157.7,135.1,127.6(d,J＝9.2Hz),125.5(d,J＝ 24.1Hz),125.3,120.0,119.1,115.4(d,J＝2.9Hz),112.8(d,J＝23.9Hz),110.3(d,J＝8.2Hz), 106.4(d,J＝25.3Hz),45.7,43.6,35.8,15.4,9.2.HRMS(ESI):m/z[M+H]+calcd for C19H22FN4O2 +,357.1721；found,357.1715.
Example 19
Synthesis of (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (propylamino) propionamide (A19)
Figure BDA0002693745970000232
Synthesis of compound a 19: compound IX-1(104mg,0.3mmol) was dissolved in DMF (5mL), to which was added n-propylamine (123. mu.L, 1.5mmol), and the reaction was stirred at 50 ℃. After completion of the TLC monitoring reaction, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed with water and saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5mL) to the residue, pulping for purification, suction filtration, vacuum drying to give 83mg of a yellow solid in 75% yield. mp at 243-245 deg.C.1H NMR(500MHz,DMSO-d6)δ(ppm):13.40(1H, s),10.88(1H,s),10.00(1H,s),7.74(1H,dd,J1＝9.3Hz,J2＝1.5Hz),7.71(1H,s),7.69(1H,d,J ＝2.0Hz),6.93(1H,td,J1＝9.4Hz,J2＝2.3Hz),6.83-6.85(1H,m),2.79(2H,t,J＝6.3Hz), 2.53-2.58(2H,m),2.44(2H,t,J＝6.4Hz),2.29(3H,s),1.43-1.48(2H,m),0.89(3H,t,J＝7.3 Hz).13C NMR(126MHz,DMSO-d6)δ(ppm):170.0,169.8,159.6,157.7,135.1,127.6(d,J＝9.5 Hz),125.5(d,J＝20.9Hz),125.3,120.1,119.1,115.4(d,J＝2.9Hz),112.8(d,J＝24.1Hz), 110.3(d,J＝8.6Hz),106.4(d,J＝25.4Hz),51.3,45.9,35.9,23.0,12.3,9.2.HRMS(ESI):m/z [M+H]+calcd for C20H24FN4O2 +,371.1878；found,371.1873.
Example 20
Synthesis of (Z) -3- (tert-butylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) propanamide (A20)
Figure BDA0002693745970000241
Synthesis of compound a 20: compound IX-1(104mg,0.3mmol) was dissolved in DMF (5mL), to which was added tert-butylamine (158. mu.L, 1.5mmol), and the reaction was stirred at 50 ℃. After completion of the TLC monitoring reaction, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed with water and saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5mL) to the residue, pulping for purification, suction filtration, vacuum drying to give 94mg of a yellow solid in 82% yield. mp is 237-239 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.40(1H, s),10.87(1H,s),10.11(1H,s),7.74(1H,dd,J1＝9.3Hz,J2＝1.5Hz),7.71(1H,s),7.69-7.70 (1H,m),6.93(1H,td,J1＝9.4Hz,J2＝2.3Hz),6.82-6.85(1H,m),2.78(2H,t,J＝6.1Hz),2.42 (2H,t,J＝6.1Hz),2.30(3H,s),1.09(9H,s).13C NMR(126MHz,DMSO-d6)δ(ppm):170.0, 169.8,159.6,157.7,135.1,127.6(d,J＝9.6Hz),125.5(d,J＝21.4Hz),125.3,119.8,119.0, 115.4(d,J＝2.9Hz),112.8(d,J＝23.9Hz),110.4(d,J＝8.5Hz),106.2(d,J＝25.4Hz),50.6, 38.8,36.8,29.0(3C),9.4.HRMS(ESI):m/z[M+H]+calcd for C21H26FN4O2 +,385.2034；found, 385.2029.
Example 21
Synthesis of (Z) -3- (cyclopentylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) propanamide (A21)
Figure BDA0002693745970000242
Synthesis of compound a 21: compound IX-1(104mg,0.3mmol) was dissolved in DMF (5mL), and cyclopentylamine (148. mu.L, 1.5mmol) was added thereto, followed by stirring the reaction at 50 ℃. After completion of the TLC monitoring reaction, the reaction mixture was poured into water, ethyl acetate solution: (30 mL. times.2), the organic layers were combined, washed successively with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5mL) to the residue, pulping for purification, suction filtration, vacuum drying to give 90mg of a yellow solid in 76% yield. mp is 258-260 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.40(1H, s),10.88(1H,s),10.06(1H,s),7.74(1H,dd,J1＝9.3Hz,J2＝1.5Hz),7.71(1H,s),7.69(1H,d,J ＝2.5Hz),6.93(1H,td,J1＝9.4Hz,J2＝2.3Hz),6.82-6.85(1H,m),3.02-3.07(1H,m),2.78(2H, t,J＝6.3Hz),2.43(2H,t,J＝6.2Hz),2.29(3H,s),1.74-1.81(2H,m),1.59-1.66(2H,m), 1.46-1.53(2H,m),1.29-1.36(2H,m).13C NMR(126MHz,DMSO-d6)δ(ppm):170.2,169.8, 159.6,157.7,135.1,127.6(d,J＝9.4Hz),125.5(d,J＝20.5Hz),125.3,120.0,119.1,115.4(d,J ＝2.9Hz),112.8(d,J＝23.9Hz),110.4(d,J＝8.5Hz),106.2(d,J＝25.5Hz),59.5,44.6,36.2, 32.9(2C),24.1(2C),9.2.HRMS(ESI):m/z[M+H]+calcd for C22H26FN4O2 +,397.2034；found, 397.2030.
Example 22
Synthesis of (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3-morpholinepropionamide (A22)
Figure BDA0002693745970000251
Synthesis of compound a 22: compound IX-1(104mg,0.3mmol) was dissolved in DMF (5mL), and morpholine (131. mu.L, 1.5mmol) was added thereto, followed by stirring the reaction at 50 ℃. After completion of the TLC monitoring reaction, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed with water and saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5mL) to the residue, pulping for purification, suction filtration, vacuum drying to give 92mg of a yellow solid in 77% yield. mp is 257-259 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.40(1H,s), 10.88(1H,s),9.61(1H,s),7.74(1H,dd,J1＝9.3Hz,J2＝1.5Hz),7.71(1H,s),7.68(1H,d,J＝ 2.8Hz),6.93(1H,td,J1＝9.4Hz,J2＝2.3Hz),6.82-6.85(1H,m),3.57-3.64(4H,m),2.62(2H,t, J＝6.9Hz),2.37-2.50(6H,m),2.30(3H,s).13C NMR(126MHz,DMSO-d6)δ(ppm):169.9, 169.7,159.6,157.7,135.1,127.6(d,J＝9.5Hz),125.5(d,J＝19.6Hz),125.1,120.4,119.3, 115.4(d,J＝3.1Hz),112.8(d,J＝24.0Hz),110.4(d,J＝8.5Hz),106.3(d,J＝25.5Hz),66.6 (2C),54.8,53.5(2C),33.1,9.3.HRMS(ESI):m/z[M+H]+calcd for C21H24FN4O3 +,399.1827； found,399.1826.
Example 23
Synthesis of (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -6- (trifluoromethyl) nicotinamide (A23)
Figure BDA0002693745970000261
Synthesis of compound a 23: compound VI-1(0.40g,1.55mmol) and 4-trifluoromethylbenzoic acid (0.59g,3.10 mmol) were dissolved in DMF (50mL), and the condensing agents PyBOP (1.05g,2.02mmol) and DIPEA (0.77mL,4.66mmol) were added and reacted at room temperature for 12 hours. After completion of the reaction was monitored by TLC, the reaction mixture was added to water (50mL), extracted with ethyl acetate (30 mL. times.2), and the organic layers were combined, washed successively with water and sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was filtered with suction, concentrated, and purified by column chromatography (dichloromethane: methanol: 50:1 to 20:1) to obtain 0.51g of a yellow solid in a yield of 77%. mp:>300℃. 1H NMR(500MHz,DMSO-d6)δ(ppm):13.57(1H,s),10.94(1H,s),10.21(1H,s),9.26(1H,s), 8.57(1H,d,J＝6.8Hz),8.11(1H,d,J＝8.2Hz),7.79(1H,d,J＝2.4Hz),7.78(1H,s),7.74(1H, d,J＝3.0Hz),6.95(1H,td,J1＝9.5Hz,J2＝2.5Hz),6.84-6.87(1H,m),2.37(3H,s).13C NMR (126MHz,DMSO-d6)δ(ppm):169.9,162.9,157.7,149.8,138.3,135.2,133.8,127.5(d,J＝9.4 Hz),125.8(d,J＝23.0Hz),125.1,124.0,123.0,121.1,121.0,120.8,120.7,116.0(d,J＝3.0Hz), 113.0(d,J＝24.5Hz),110.5(d,J＝8.7Hz),106.4(d,J＝24.9Hz),9.5.HRMS(ESI):m/z [M+H]+calcd for C21H15F4N4O2 +,431.1131；found,431.1114.
example 24
Synthesis of (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -4-methylpiperazine-1-carboxamide (A24)
Figure BDA0002693745970000262
Synthesis of compound a 24: compound VI-1(0.40g,1.55mmol) was dissolved in THF (20mL) and DIPEA (0.51mL,3.1mmol) and p-nitrophenyl chloroformate (469mg, 2.32mmol) were added. After 20min at room temperature, N-methylpiperazine (687. mu.L, 6.2mmol) was added to the reaction mixture, and the reaction was continued for 0.5 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure by LC-MS detection, and purified by column chromatography (dichloromethane: methanol: 100:1 to 20:1) to obtain 0.41g of a yellow solid with a yield of 70%. mp is 257-259 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.43(1H,s),10.84(1H,s),7.91(1H,s), 7.73(1H,dd,J1＝9.4Hz,J2＝2.2Hz),7.70(1H,s),7.37(1H,d,J＝2.8Hz),6.91(1H,td,J1＝ 9.0Hz,J2＝2.4Hz),6.82-6.85(1H,m),3.39-3.51(4H,m),2.35-2.50(4H,m),2.28(3H,s),2.23 (3H,s).13C NMR(126MHz,DMSO-d6)δ(ppm):169.9,159.5,157.7,156.1,135.0,127.6(d,J＝9.4Hz),125.9(d,J＝19.8Hz),124.4,121.6 118.1,114.7(d,J＝2.9Hz),112.8(d,J＝24.4Hz), 110.3(d,J＝8.7Hz),106.2(d,J＝25.2Hz),66.6(2C),54.9(2C),46.1,44.1(2C),9.3.HRMS (ESI):m/z[M+H]+calcd for C20H23FN5O2 +,384.1836；found,384.1826.
Example 25
Synthesis of (Z) -N- (5- ((5-chloro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (pyrrolidin-1-yl) propionamide (A25)
Figure BDA0002693745970000271
Synthesis of intermediate V-2: compound III (1.2g,7.79mmol) and IV-2(1.4g,8.56mmol) were dissolved in ethanol (10mL), and pyrrolidine (0.83mL,10.13mmol) was added and heated to 50 ℃ for 2 hours. After the LC-MS monitoring reaction is finished, stopping heating, cooling to room temperature, performing suction filtration, washing a filter cake with a small amount of ethanol, and performing vacuum drying to obtain orange yellow solid 2.3g with the yield of 85%.1H NMR(500MHz,DMSO-d6)δ(ppm):14.19(1H,brs),11.25(1H,s),8.28 (1H,dd,J1＝3.6Hz,J2＝1.4Hz),8.11(1H,s),7.88(1H,s),7.22(1H,dd,J1＝8.3Hz,J2＝1.9 Hz),6.88(1H,dd,J1＝8.3Hz,J2＝1.4Hz),2.60(3H,s).
Figure BDA0002693745970000272
Synthesis of intermediate VI-1: compound V-2(0.42g,1.39mmol) was dissolved in a mixed solvent of tetrahydrofuran and methanol (27mL/15 mL, V/V), a saturated solution (1mL) of ammonium chloride (0.73g,13.9mmol) was added, the mixture was heated to 50 ℃ and zinc powder (0.45g,6.96mmol) was added in portions, and the reaction was continued for 0.5 hour. After the completion of the reaction, LC-MS monitored the reaction, heating was stopped, cooling to room temperature, concentration under reduced pressure was carried out, the residue was dissolved in ethyl acetate (100mL) and a saturated sodium carbonate solution (100mL), the organic layer was separated, washed with water and a saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. And (4) carrying out suction filtration, concentrating the filtrate, pulping and purifying methanol to obtain a crude product VI-1, and directly using the crude product VI-1 for the next reaction.
Figure BDA0002693745970000273
Synthesis of intermediate IX-2: compound VI-2(0.31g,1.15mmol) was dissolved in THF (20mL), DIPEA (0.57mL,3.45mmol) was added, the temperature was lowered to 0 deg.C, 3-chloropropionyl chloride (0.55mL,5.75mmol) was added dropwise, and after the addition was completed, the reaction was carried out at room temperature for 0.5 h. After the completion of the TLC monitoring reaction, concentration was performed under reduced pressure, and the residue was slurried with ethyl acetate (10mL) and methanol (0.5 mL). Suction filtration, filter cake washing with ethyl acetate (1mL), vacuum drying to give yellow solid 0.31g, yield 75%.1H NMR(500 MHz,DMSO-d6)δ(ppm):13.40(1H,s),11.00(1H,s),9.52(1H,s),7.98((1H,d,J＝1.7Hz), 7.78(1H,s),7.69(1H,d,J＝3.0Hz),7.13(1H,dd,J1＝8.3Hz,J2＝2.0Hz),6.86(1H,d,J＝8.2 Hz),3.88(2H,t,J＝6.3Hz),2.85(2H,t,J＝6.3Hz),2.30(3H,s).
Figure BDA0002693745970000281
Synthesis of compound a 25: compound IX-2(109mg,0.3mmol) was dissolved in DMF (5mL), and pyrrolidine (123. mu.L, 1.5mmol) was added thereto, followed by stirring the reaction at 50 ℃. After completion of the TLC monitoring reaction, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed with water and saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Suction filtration, filtrate concentration, residue adding ethyl acetate (5mL), pulping and purification, suction filtration, vacuum drying to obtain yellow solid 96mg, yield 80%. mp:251-253 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.35(1H, s),10.99(1H,s),9.99(1H,s),7.97(1H,d,J1＝1.9Hz),7.77(1H,s),7.71(1H,d,J＝3.0Hz), 7.13(1H,dd,J1＝8.2Hz,J2＝2.0Hz),6.86(1H,d,J＝8.2Hz),2.72-2.74(2H,m),2.51-2.57(4H, m),2.46-2.50(2H,m),2.28(3H,s),1.71-1.76(4H,m).13C NMR(126MHz,DMSO-d6)δ(ppm): 169.6,137.5,128.0,126.0,125.9,125.8,125.6,125.3,123.1,120.1,119.2,118.9,114.7,111.1, 53.7(2C),51.8,35.1,23.6(2C),9.0.HRMS(ESI):m/z[M+H]+calcd for C21H24ClN4O2 +, 399.1582；found,399.1579.
Example 26
Synthesis of (Z) -N- (5- ((5-bromo-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (pyrrolidin-1-yl) propionamide (A26)
Figure BDA0002693745970000282
Synthesis of intermediate V-3The composition is as follows: compound III (1.2g,7.79mmol) and IV-3(1.8g,8.56mmol) were dissolved in ethanol (10mL), and pyrrolidine (0.83mL,10.13mmol) was added and heated to 50 ℃ for 2 hours. After the LC-MS monitoring reaction is finished, stopping heating, cooling to room temperature, performing suction filtration, washing a filter cake with a small amount of ethanol, and performing vacuum drying to obtain 1.84g of orange solid with the yield of 80%.1H NMR(500MHz,DMSO-d6)δ(ppm):14.19(1H,brs),11.26(1H,s),8.28 (1H,d,J＝3.5Hz),8.24(1H,s),7.90(1H,s),7.36(1H,d,J＝8.3Hz),6.85(1H,d,J＝8.3Hz), 2.61(3H,s).
Figure BDA0002693745970000291
Synthesis of intermediate VI-3: compound V-3(0.48g,1.39mmol) was dissolved in a mixed solvent of tetrahydrofuran and methanol (27mL/15 mL, V/V), a saturated solution (1mL) of ammonium chloride (0.73g,13.9mmol) was added, the mixture was heated to 50 ℃ and zinc powder (0.45g,6.96mmol) was added in portions, and the reaction was continued for 0.5 hour. After the completion of the reaction, LC-MS monitored the reaction, heating was stopped, cooling to room temperature, concentration under reduced pressure was carried out, the residue was dissolved in ethyl acetate (100mL) and a saturated sodium carbonate solution (100mL), the organic layer was separated, washed with water and a saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. And (4) carrying out suction filtration, concentrating the filtrate, pulping and purifying methanol to obtain a crude product VI-3, and directly using the crude product VI-3 for the next reaction.
Figure BDA0002693745970000292
Synthesis of intermediate IX-3: compound VI-3(0.36g,1.15mmol) was dissolved in THF (20mL), DIPEA (0.57mL,3.45mmol) was added, the temperature was lowered to 0 deg.C, 3-chloropropionyl chloride (0.55mL,5.75mmol) was added dropwise, and after the addition was completed, the reaction was carried out at room temperature for 0.5 h. After the completion of the TLC monitoring reaction, concentration was performed under reduced pressure, and the residue was slurried with ethyl acetate (10mL) and methanol (0.5 mL). Suction filtration, filter cake washing with ethyl acetate (1mL), vacuum drying to obtain yellow solid 0.30g, yield 65%.1H NMR(500 MHz,DMSO-d6)δ(ppm):13.40(1H,s),11.01(1H,s),9.52(1H,s),8.10(1H,s),7.78(1H,s), 7.69(1H,d,J＝2.9Hz),7.27(1H,dd,J1＝8.2Hz,J2＝0.7Hz),6.82(1H,d,J＝8.2Hz),3.88(2H, t,J＝6.3Hz),2.85(2H,t,J＝6.3Hz),2.31(3H,s).
Figure BDA0002693745970000293
Synthesis of compound a 26: compound IX-3(122mg,0.3mmol) was dissolved in DMF (5mL), and pyrrolidine (123. mu.L, 1.5mmol) was added thereto, followed by stirring the reaction at 50 ℃. After completion of the TLC monitoring reaction, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed with water and saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5mL) to the residue, pulping for purification, suction filtration, vacuum drying to give 97mg of yellow solid, yield 73%. mp:251-253 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.35(1H, s),10.99(1H,s),10.00(1H,s),8.10(1H,d,J1＝1.8Hz),7.78(1H,s),7.71(1H,d,J＝2.9Hz), 7.26(1H,dd,J1＝8.2Hz,J2＝1.8Hz),6.82(1H,d,J＝2.9Hz),2.72(2H,t,J＝6.6Hz), 2.52-2.57(4H,m),2.46-2.50(2H,m),2.28(3H,s),1.70-1.76(4H,m).13C NMR(126MHz, DMSO-d6)δ(ppm):169.6,169.4,137.8,128.8,128.4,125.9,125.6,125.4,121.7,120.2,119.2, 114.5,113.7,111.6,53.7(2C),51.8,35.1,23.6(2C),9.0.HRMS(ESI):m/z[M+H]+calcd for C21H24BrN4O2 +,443.1077；found,443.1075.
Example 27
Synthesis of (Z) -N- (5- ((5-methoxy-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (pyrrolidin-1-yl) propionamide (A27)
Figure BDA0002693745970000301
Synthesis of intermediate V-4: compound III (1.2g,7.79mmol) and IV-4(1.4g,8.56mmol) were dissolved in ethanol (10mL), and pyrrolidine (0.83mL,10.13mmol) was added and heated to 50 ℃ for 2 hours. L isAfter the C-MS monitoring reaction is finished, stopping heating, cooling to room temperature, carrying out suction filtration, washing a filter cake with a small amount of ethanol, and carrying out vacuum drying to obtain 1.91g of orange solid with the yield of 82%.1H NMR(500MHz,DMSO-d6)δ(ppm):14.38(1H,brs),10.97(1H,s),8.26 (1H,d,J＝3.7Hz),7.79(1H,s),7.61(1H,s),6.78-6.82(2H,m),3.79(3H,s),2.62(3H,s).
Figure BDA0002693745970000302
Synthesis of intermediate VI-4: compound V-4(0.42g,1.39mmol) was dissolved in a mixed solvent of tetrahydrofuran and methanol (27mL/15 mL, V/V), a saturated solution (1mL) of ammonium chloride (0.73g,13.9mmol) was added, the mixture was heated to 50 ℃ and zinc powder (0.45g,6.96mmol) was added in portions, and the reaction was continued for 0.5 hour. After the completion of the reaction, LC-MS monitored the reaction, heating was stopped, cooling to room temperature, concentration under reduced pressure was carried out, the residue was dissolved in ethyl acetate (100mL) and a saturated sodium carbonate solution (100mL), the organic layer was separated, washed with water and a saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. And (4) carrying out suction filtration, concentrating the filtrate, pulping and purifying methanol to obtain a crude product VI-4, and directly using the crude product VI-4 for the next reaction.
Figure BDA0002693745970000303
Synthesis of intermediate IX-4: compound VI-4(0.31g,1.15mmol) was dissolved in THF (20mL), DIPEA (0.57mL,3.45mmol) was added, the temperature was lowered to 0 deg.C, 3-chloropropionyl chloride (0.55mL,5.75mmol) was added dropwise, and after the addition was completed, the reaction was carried out at room temperature for 0.5 h. After the completion of the TLC monitoring reaction, concentration was performed under reduced pressure, and the residue was slurried with ethyl acetate (10mL) and methanol (0.5 mL). Suction filtration was performed, and the filter cake was washed with ethyl acetate (1mL) and dried in vacuo to give 0.29g of a yellow solid in 70% yield.1H NMR(500 MHz,DMSO-d6)δ(ppm):13.39(1H,s),10.70(1H,s),9.49(1H,s),7.66(1H,s),7.62(1H,d,J＝2.8Hz),7.46(1H,d,J＝2.0Hz),6.76(1H,d,J＝8.4Hz),6.71(1H,dd,J1＝8.4Hz,J2＝1.9Hz), 3.88(2H,t,J＝6.3Hz),3.78(3H,s),2.85(2H,t,J＝6.3Hz),2.30(3H,s).
Figure BDA0002693745970000311
Synthesis of compound a 27: compound IX-4(107mg,0.3mmol) was dissolved in DMF (5mL), and pyrrolidine (123. mu.L, 1.5mmol) was added thereto, followed by stirring the reaction at 50 ℃. After completion of the TLC monitoring reaction, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL. times.2), and the organic layers were combined, washed with water and saturated sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5mL) to the residue, pulping for purification, suction filtration, vacuum drying to give 102mg of a yellow solid in 86% yield. mp is 254-256 ℃.1H NMR(500MHz,DMSO-d6)δ(ppm):13.43 (1H,s),10.68(1H,s),9.98(1H,s),7.63-7.68(2H,m),7.47(1H,s),6.74-6.80(1H,m),6.70(1H, dd,J1＝8.4Hz,J2＝1.8Hz),3.78(3H,s),2.72(2H,t,J＝6.7Hz),2.52-2.56(4H,m),2.45-2.49 (2H,m),2.28(3H,s),1.69-1.78(4H,m).13C NMR(126MHz,DMSO-d6)δ(ppm):169.8,169.6, 155.3,132.9,126.9,125.4,125.1,124.5,119.0,118.0,116.6,113.0,110.3,104.5,56.1,53.7(2C), 52.0,35.1,23.6(2C),9.0.HRMS(ESI):m/z[M+H]+calcd for C22H27N4O3 +,395.2078；found, 395.2073.
Example 28
Long term stability test of Compounds
The experimental method comprises the following steps: the compounds were left open at room temperature for more than 90 days and the purity of the compounds was determined by HPLC normalization (table 1).
TABLE 1 Long-term stability test results for the example compounds
Figure BDA0002693745970000312
Figure BDA0002693745970000321
Results display: the series of compounds have good chemical stability, and can be placed in an open air at room temperature for 90 days and subjected to HPLC-UV1And through H-NMR spectrum analysis, the purity of each compound is not obviously reduced, and the chemical stability of each compound is obviously superior to that of the compound 10 d.
Example 29
Stability test of Compound A13 in pure Water and acidic aqueous solution
The experimental method comprises the following steps: compound a13 was dissolved in pure water at pH7 and an acidic aqueous solution at pH2, samples were taken at different time points and the purity of the compound was determined by HPLC normalization (table 2).
TABLE 2 stability test results of Compound A13 in pure Water and acidic aqueous solution
Figure BDA0002693745970000322
The results show that: the purity of compound a13 did not change significantly in aqueous solutions at pH7 and pH2 over one week, indicating that compound a13 has good stability in aqueous and strongly acidic solutions.
Example 30
Proliferation inhibitory Activity of Compound on human AML cell line
The experimental method comprises the following steps: human acute myeloid leukemia MV-4-11 and MOLM-13 are FLT3 mutant cell lines. The CCK-8 method was used to determine the in vitro antiproliferative activity of the compounds on MV-4-11: test compounds were diluted to two-fold final concentration with a 2-fold gradient of medium and 200 μ L to 2mL EP tubes were taken for use. An appropriate amount of cells in the logarithmic growth phase is taken and resuspended in the culture medium, the cells are added into the culture medium containing the tested compound in equal volume, the cells are evenly mixed by being inverted for 10 times, and the cells are sequentially added into a 96-well plate, wherein each well is 100 mu L. At 37 ℃ with 5% CO2After incubation for 70h, 10ul CCK-8 was added to each well and incubation continued for 2 h. The microplate reader reads the OD450 absorbance value, and the experiment is repeated for three times. The data were analyzed and processed using Graphpad Prism 5 software to determine IC50。
The results show that: most of the compounds have good proliferation inhibition activity on human MV-4-11 and MOLM-13 cells, and maintain strong FLT3 inhibition activity (Table 3). Wherein, the proliferation inhibition activities of the compounds A13, A18, A25 and A27 on the AML cells MV-4-11 and MOLM-13 are all superior to sunitinib.
TABLE 3 proliferation inhibitory Activity of the example Compounds on human AML cells and in vitro inhibitory Activity of FLT3
Figure BDA0002693745970000331
Figure BDA0002693745970000341
Example 31
In vitro proliferation inhibitory Activity of Compound A13 on solid tumor cells
The experimental method comprises the following steps: HCT-116 is a colon cancer cell line; MDA-MB-231 is a breast cancer cell line; HT-29 is a colon cancer cell line; hela is a cervical cancer cell line; HepG2 is a liver cancer cell line. The in vitro antiproliferative activity of compounds on solid tumor cells was determined using the MTT method: trypsinizing the cells in logarithmic growth phase, counting, resuspending the appropriate amount of cells in culture medium, 100. mu.L per well in 96-well plate, overnight culturing, adding 100. mu.L per well of 2-fold gradient diluted test compound or control medium, 5% CO at 37 deg.C2After culturing in an incubator for 44h, 20 μ L of MTT is added into each well, incubation is continued for 4h at 37 ℃, an enzyme-linked immunosorbent assay (OD 490) absorbance value is read by an enzyme-linked immunosorbent assay (ELISA) instrument, and the experiment is repeated for three times. Analyzing the processed data by adopting Graphpad Prism 5 software to obtain IC50The value is obtained.
TABLE 4 in vitro proliferation inhibitory Activity of Compound A13 on solid tumor cells
Figure BDA0002693745970000342
The results show that: the compound A13 has better proliferation inhibition activity on tumor cells HCT-116, MDA-MB-231, HT-29, Hela and HepG2 (table 4), and the proliferation inhibition activity is better than that of Sunitinib.
Example 32
In vitro inhibitory activity of compound A13 on partial tyrosine kinase
The experimental method comprises the following steps: the in vitro inhibitory activity of compound a13 on partial tyrosine kinases was determined using the method of Mobility Shift Assay: compounds were diluted 3-fold from 1 μ M starting concentration to 9 concentrations and then transferred 250nL to 384 well plates using Echo550, and 250nL of 100% DMSO was added to negative and positive control wells, respectively. 10 μ L of 2.5 fold final concentration kinase solution was added to each of the compound wells and the positive control wells; mu.L of kinase buffer was added to the negative control wells. After centrifugation at 1000rpm for 30 seconds, shaking and mixing, incubation at room temperature for 10 minutes, 15. mu.L of a mixed solution of ATP and kinase substrate at 25/15 fold final concentration was added. And (3) centrifuging the 384-well plate at 1000rpm for 30 seconds, shaking and mixing uniformly, incubating at room temperature for 30 minutes, adding 30 mu L of termination detection solution, stopping the kinase reaction, centrifuging at 1000rpm for 30 seconds, shaking and mixing uniformly, and reading the conversion rate by using a Caliper EZ Reader II. The data were analyzed and processed using Graphpad Prism 5 software to determine IC50The value is obtained.
The results show that: the compound A13 shows certain inhibitory activity on various tyrosine kinases such as FLT3, CSF-1R, PDGFR alpha, PDGFR beta, VEGFR1, VEGFR2 and the like, and especially shows strong inhibitory activity on FLT3, FLT3-ITD and FLT3-D835Y mutants (Table 5). The compound A13 has strong and selective inhibitory activity on FLT3-ITD, has over 50 times of selectivity on other receptor tyrosine kinases and over 1000 times of selectivity on c-Kit, and can reduce myelosuppressive toxicity of other FLT3 inhibitors such as Midostaurin, AC220 and the like caused by synchronous inhibition of FLT3 and c-Kit.
TABLE 5 in vitro inhibitory Activity of Compound A13 on partial tyrosine kinases
Figure BDA0002693745970000351
Example 33
Effect of compound A13 in vivo on inhibiting growth of MV-4-11 nude mouse transplanted tumor
The experimental method comprises the following steps: MV-4-11 cell in vitro culture and amplificationTaking a proper amount of cells in logarithmic growth phase, re-suspending the cells in serum-free IMDM medium and Matrigel (1:1) suspension, and preparing the suspension into 5X 10 cells under the aseptic condition6mu.L of the cell suspension, 100. mu.L of the cell suspension was inoculated subcutaneously into the anterior left axillary fossa of male Balb/c nude mice by means of a syringe. When the tumor volume grows to 100-200mm3In time, animals with moderate tumor size were randomly grouped into 5 animals per group. Separately administering blank Medium (ddH)2O), sunitinib (5mg/kg/d), A13 low dose (2.5mg/kg/d), A13 medium dose (5mg/kg/d), A13 high dose (10mg/kg/d), gavage once a day for 3 weeks. During the administration period, body weight and tumor size of nude mice were measured daily. After the experiment, the cervical vertebra is dislocated and killed, and the tumor is taken and weighed.
The formula for Tumor Volume (TV) is: TV 1/2 × a × b2And a represents the tumor major axis; b represents the tumor minor axis.
The results show that: compound A13 was able to dose-dependently inhibit tumor growth with no effect on mouse body weight following continuous gavage for 3 weeks in the MV-4-11 nude mouse graft tumor model. Wherein the tumor inhibition rate under the dosage of 2.5mg/kg/d reaches 55.68 percent, is obviously superior to the tumor inhibition rate of sunitinib under the dosage of 5mg/kg/d (29.92 percent), and is superior to the tumor inhibition rate of 10d under the dosage of 10mg/kg/d (52.43 percent). The in vivo pharmacodynamic data of 10d are derived from different batches of experiments, which are quoted from Eur.J.Med.Chem.2017,127 and 72-86.The compound A13 can lead the tumor to be nearly completely regressed under the dosage of 10mg/kg/d, and the tumor inhibition rate reaches 93.44 percent (Table 6).
TABLE 6 antitumor Effect of Compounds A13 and 10d on MV4-11 acute myeloid leukemia model
Figure BDA0002693745970000361
P < 0.05; p < 0.01; p <0.001 (compared to solvent control).
Example 34
Effect of compound A24 in vivo on inhibiting growth of MV-4-11 nude mouse transplanted tumor
The experimental method comprises the steps of in vitro culture of MV-4-11 cells and transplantation of tumor graftSimilar to example 33, nude mice with moderate tumor size were selected and randomly divided into 5 groups of 5 mice each. Separately administering blank Medium (ddH)2O), sunitinib (5mg/kg/d), A24 low dose (2.5mg/kg/d), A24 medium dose (5mg/kg/d), and A24 high dose (10mg/kg/d), administered by intragastric administration once a day for 2 weeks. During the administration period, body weight and tumor size of nude mice were measured. After the experiment, the cervical vertebrae were dislocated and sacrificed, and the tumor was weighed.
TABLE 7 antitumor Effect of Compound A24 on MV4-11 acute myeloid leukemia model
Figure BDA0002693745970000362
P < 0.05; p < 0.01; p <0.001 (compared to solvent control).
The results show that: compound A24 was able to dose-dependently inhibit tumor growth with no effect on mouse body weight following 2 weeks of continuous gavage in the MV-4-11 nude mouse graft tumor model. Wherein the tumor inhibition rate under the dosage of 5mg/kg/d reaches 58.42 percent, the dosage of 10mg/kg/d can completely eliminate the transplanted tumor, and the tumor inhibition rate reaches 92.16 percent (Table 7).
Example 35
Compound A13 in vivo inhibiting MOLM-13 nude mouse transplanted tumor growth effect
The experimental method comprises the following steps of MOLM-13 cell in-vitro culture and amplification, taking a proper amount of cells in logarithmic growth phase, suspending the cells in a serum-free 1640 culture medium and Matrigel (1:1) suspension, and preparing the cells into 5 multiplied by 10 under the aseptic condition6mu.L of the cell suspension, 100. mu.L of the cell suspension was inoculated subcutaneously into the anterior left axillary fossa of male Balb/c nude mice by means of a syringe. When the tumor volume grows to 100-200mm3Animals with moderate tumor size were selected and randomly divided into 6 groups. Blank medium (ddH2O), positive drug sunitinib (20mg/kg/d), sunitinib (40mg/kg/d), A13 low dose (10mg/kg/d), A13 medium dose (20mg/kg/d) and A13 high dose (40mg/kg/d) are respectively given, and the administration period is 16 days after intragastric administration once a day. During the administration period, body weight and tumor size of nude mice were measured daily. After the experiment, the cervical vertebrae were dislocated and sacrificed, and the tumor was weighed.
TABLE 8 antitumor Effect of Compound A13 on MOLM-13 acute myeloid leukemia model
Figure BDA0002693745970000371
P < 0.05; p < 0.01; p <0.001 (compared to solvent control).
The results show that: compound A13 was able to dose-dependently inhibit tumor growth on MOLM-13 nude mouse graft tumor model by continuous gavage for 16 days, and had no effect on mouse body weight. Wherein the tumor inhibition rate under the dosage of 10mg/kg/d reaches 76.24 percent, the dosage of 20mg/kg/d can ensure that the transplanted tumor is nearly completely regressed, and the tumor inhibition rate reaches 97.95 percent, which is obviously superior to 80.27 percent of the tumor inhibition rate of sunitinib under the dosage of 20mg/kg/d (Table 8).
Example 36
Effect of compound A13 in vivo inhibiting growth of HepG2 nude mouse transplanted tumor
The experimental method comprises the following steps: culturing and expanding HepG2 cells in vitro, taking the cells in the logarithmic phase of growth, counting, taking a proper amount of cells, suspending the cells in serum-free DMEM medium and Matrigel (1:1) suspension, and preparing the suspension into 1 × 10 cells under aseptic conditions6mu.L of the cell suspension, 100. mu.L of the cell suspension was inoculated subcutaneously into the anterior left axillary fossa of male Balb/c nude mice by means of a syringe. When the tumor volume grows to 100-200mm3Animals with moderate tumor size were selected and randomly divided into 5 groups. Separately administering blank Medium (ddH)2O), sunitinib 40mg/kg, A13 low dose (20mg/kg/d), A13 medium dose (40mg/kg/d) and A13 high dose (80mg/kg/d), wherein the administration period is 2 weeks after the administration of the composition by intragastric administration once a day. During the administration period, the body weight and tumor size of nude mice were measured daily. After the experiment, the cervical vertebrae were dislocated and sacrificed, and the tumor was weighed.
The results show that: compound a13 was able to dose-dependently inhibit tumor growth with no effect on mouse body weight by continuous gavage for 2 weeks on HepG2 nude mouse graft tumor model. Wherein the tumor inhibition rate under the dosage of 20mg/kg/d reaches 54.94 percent, which is equivalent to the tumor inhibition rate (55.11 percent) of sunitinib under the dosage of 40mg/kg/d, and the tumor inhibition rate under the dosage of 80mg/kg/d reaches 87.70 percent.
TABLE 9 tumor-inhibiting effect of Compound A13 on HepG2 liver cancer model
Figure BDA0002693745970000381
P < 0.05; p < 0.01; p <0.001 (compared to solvent control).
Example 37
In vivo efficacy of Compound A13 on HT-29 Colon cancer nude mouse transplantable tumors
The experimental method comprises the following steps: HT-29 cell in vitro culture and amplification, collecting cells in logarithmic phase of growth, counting, re-suspending appropriate amount of cells in serum-free 1640 medium and Matrigel (1:1) suspension, and preparing into 1 × 10 under aseptic condition6mu.L of the cell suspension, 100. mu.L of the cell suspension was inoculated subcutaneously into the axilla of the anterior left limb of male Balb/c nude mice by using a syringe, respectively. Periodically observing the growth of the animals and the transplanted tumors; regularly observing the growth of animals and transplanted tumors; when the tumor volume grows to 100-200mm3At this time, animals with moderately large tumors were selected and randomized into 5 groups. The animals were dissected as in example 36 for groups, dose, mode of administration and end of experiment.
TABLE 10 antitumor Effect of Compound A13 on HT-29 Colon cancer model
Figure BDA0002693745970000382
P < 0.05; p < 0.01; p <0.001 (compared to solvent control).
The results show that: compound A13 was able to dose-dependently inhibit tumor growth with no effect on mouse body weight following continuous gavage for 2 weeks in the HT-29 nude mouse graft tumor model. Wherein the tumor inhibition rate under the dosage of 80mg/kg/d reaches 78.22 percent.

Claims (9)

  1. A 4-methylpyrrole substituted indolone derivative or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, wherein the chemical structural formula of the compound is shown as formula (I):
    Figure FDA0002693745960000011
    wherein:
    R1selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, amino and NHCOR3Or NHSO2R3One or more of the above;
    R2selected from alkyl, heterocycloalkyl, alkyl-substituted heterocycloalkyl, alkenyl, aryl, heteroaryl, CH2R4、(CH2)nNR5R6And NHR7R8One or more of the above;
    R3selected from alkyl or alkenyl;
    R4selected from heterocycloalkyl or alkyl-substituted heterocycloalkyl;
    R5and R6Are respectively selected from one or more of hydrogen, alkyl, cycloalkyl and heterocycloalkyl;
    at the same time, R5And R6Forming a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycle contains one or more atoms N, O, S and the 4-7 membered heterocycle is substituted with one or more alkyl groups;
    R7and R8Are respectively selected from one or more of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
    at the same time, R7And R8Forming a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycle contains one or more atoms N, O, S and the 4-7 membered heterocycle is substituted with one or more alkyl groups;
    n is 1 to 6.
  2. 2. A process for the preparation of a 4-methylpyrrole substituted indolone derivative, or pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, according to claim 1:
    Figure FDA0002693745960000012
    the first step is as follows: compound II in POCl3And DMF, performing Vilsmeier reaction to generate a compound III; in particular, under low temperature conditions, POCl3Dropwise adding the mixture into anhydrous DMF, stirring at room temperature for 0.5h, adding a compound II dissolved in the anhydrous DMF, and heating to 80 ℃ for reaction for 0.5 h; after the reaction is finished, quenching the reaction by using an ice-water bath, adjusting the pH value to about 7, extracting by using dichloromethane, washing by using brine, and drying to obtain a compound III;
    the second step is that: carrying out aldol condensation reaction on the compounds III and IV under the action of alkali to generate a compound IV; specifically, dissolving the compounds III and IV in ethanol, adding pyrrolidine, heating to 50 ℃ and reacting for 2 h; after the reaction is finished, carrying out suction filtration, washing a filter cake by using ethanol, and drying to obtain a compound V;
    the third step: carrying out nitro reduction reaction on the compound V under the action of zinc powder to obtain a compound VI; specifically, dissolving the compound in a mixed solvent of tetrahydrofuran and methanol, adding a saturated solution of ammonium chloride, heating to 50 ℃, and then adding zinc powder to react for 0.5 h; after the reaction is finished, distilling under reduced pressure to remove the solvent, dissolving the residue with ethyl acetate, washing with saturated sodium carbonate solution and saline solution in sequence, and drying; distilling under reduced pressure to remove the solvent, pulping with methanol to obtain purified compound VI;
    the fourth step: reacting the compound IV with a carboxylic acid compound under the action of a condensing agent; or firstly reacting with acyl chloride and then reacting with an amine compound to obtain a target compound I; specifically, dissolving a compound V and a carboxylic acid compound in DMF, adding condensing agents PyBOP and DIPEA, and reacting at room temperature for 12 h; after the reaction is finished, adding the reaction solution into water, extracting by ethyl acetate, washing by using salt water, drying, and purifying by column chromatography; finally, removing the Boc protecting group by HCl ethyl acetate solution treatment to obtain a target compound I;
    or dissolving the compound IV in tetrahydrofuran, adding DIPEA, cooling to 0 ℃, adding acyl chloride, reacting at room temperature for 0.5 hour, distilling under reduced pressure to remove the solvent, dissolving the residue with a mixed solvent of ethyl acetate and methanol, pulping and purifying to obtain an acylation product; dissolving the product in anhydrous DMF, adding an amine compound, heating to 50 ℃ and reacting for 12 h; after the reaction is finished, pouring the reaction liquid into water, extracting by ethyl acetate, washing by using brine, drying, distilling under reduced pressure to remove the solvent, and pulping and purifying the residue by using ethyl acetate to obtain the target compound I.
  3. 3. The 4-methylpyrrole substituted indolone derivative or pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof according to claim 1, wherein the isomer is selected from one or more of enantiomer, diastereoisomer, geometric isomer or stereoisomer.
  4. 4. The 4-methylpyrrole-substituted indolone derivative or pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof according to claim 1, wherein said 4-methylpyrrole-substituted indolone is selected from the group consisting of:
    (S, Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) pyrrolidine-2-carboxamide hydrochloride;
    (R, Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) pyrrolidine-2-carboxamide hydrochloride;
    (R, Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) pyrrolidine-3-carboxamide hydrochloride;
    (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) piperidine-4-carboxamide hydrochloride;
    (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) piperidine-2-carboxamide hydrochloride;
    (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -2- (pyrrolidin-1-yl) acetamide;
    (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -2- (pyrrolidin-2-yl) acetamide hydrochloride;
    (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -2- (piperidin-1-yl) acetamide;
    (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -2- (4-methylpiperazin-1-yl) acetamide;
    (Z) -2- (diethylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) acetamide;
    (Z) -2- (cyclopentylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) acetamide;
    (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (pyrrolidin-1-yl) propionamide;
    (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (piperidin-1-yl) propionamide;
    (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide;
    (Z) -3- (diethylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) propionamide;
    (Z) -3- (dimethylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) propionamide;
    (Z) -3- (ethylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) propionamide;
    (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (propylamino) propionamide;
    (Z) -3- (tert-butylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) propionamide;
    (Z) -3- (cyclopentylamino) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) propionamide;
    (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3-morpholinepropionamide;
    (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -6- (trifluoromethyl) nicotinamide;
    (Z) -N- (5- ((5-fluoro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -4-methylpiperazine-1-carboxamide;
    (Z) -N- (5- ((5-chloro-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (pyrrolidin-1-yl) propanamide
    (Z) -N- (5- ((5-bromo-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (pyrrolidin-1-yl) propionamide;
    (Z) -N- (5- ((5-methoxy-2-oxoindol-3-ylidene) methyl) -4-methyl-1H-pyrrol-3-yl) -3- (pyrrolidin-1-yl) propionamide.
  5. 5. A pharmaceutical composition comprising a 4-methylpyrrole-substituted indolone derivative of any one of claims 1 to 3 or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof.
  6. 6. Use of a 4-methylpyrrole-substituted indolone derivative of any one of claims 1 to 4, or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, for the preparation of a tyrosine kinase inhibitor.
  7. 7. Use of the 4-methylpyrrole-substituted indolone derivative of any one of claims 1 to 6 or pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, or the pharmaceutical composition of claim 5 for the preparation of a medicament for the treatment and/or prevention of diseases associated with abnormal expression of tyrosine kinases.
  8. 8. Use of the 4-methylpyrrole-substituted indolone derivative of any one of claims 1 to 7 or pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, or the pharmaceutical composition according to claim 5 for the preparation of a medicament for the treatment and/or prevention of tumors caused by abnormal expression of tyrosine kinases or tumor cell proliferation and migration driven by tyrosine kinases.
  9. 9. Use of a 4-methylpyrrole-substituted indolone derivative according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, or a pharmaceutical composition according to claim 5 for the manufacture of a medicament for the treatment of acute myeloid leukemia.
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