CN115197130A - Aryl urea derivative and preparation method and application thereof - Google Patents
Aryl urea derivative and preparation method and application thereof Download PDFInfo
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- CN115197130A CN115197130A CN202210891463.6A CN202210891463A CN115197130A CN 115197130 A CN115197130 A CN 115197130A CN 202210891463 A CN202210891463 A CN 202210891463A CN 115197130 A CN115197130 A CN 115197130A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses an aryl urea derivative and a preparation method and application thereof, relating to the technical field of medicinal chemistry, wherein the structure of the aryl urea derivative is shown as the following formula I and II:
the aryl urea compound is subjected to CDK8 kinase activity screening in vitro, and the result shows that the aryl urea compound has stronger inhibitory activity on CDK 8; and the results of in vitro anti-tumor activity screening show that the compound shows stronger inhibition activity on tumor cells; the aryl urea compound has the advantages of novel structure, simple synthesis process, high product purity and good application prospect.
Description
The technical field is as follows:
the invention relates to the technical field of medicinal chemistry, in particular to an aryl urea derivative and a preparation method and application thereof.
Background art:
current treatments for cancer are mainly chemotherapy, CAR-T cell immunotherapy and the use of targeted inhibitors. Chemotherapy causes the immunity of patients to be reduced, and the patients are easy to be infected and have great side effects. CAR-T treatment has many adverse reactions such as cytokine release syndrome CRS, off-target effects, neurotoxicity, anaphylaxis, graft versus host disease, tumor lysis syndrome, and the like. The most serious of these is CRS, which is a fatal uncontrolled systemic inflammatory response. The increased risk of TRM often renders these patients unable to receive optimal chemotherapy or stem cell transplantation. Thus, new targeted therapies offer the promise of effective antitumor activity, reducing the toxicity of off-target effects.
The cell cycle-dependent protease 8 (cyclin-dependent kinase 8, CDK8), originally designated protein K35, was found as a putative kinase partner for cyclin C. The CDK8 gene is located on human chromosome 13q12.13, transcribed into a 53kDa protein containing 464 amino acids, whose kinase activity is regulated by association with Cyc-C, and the 13q12.13 chromosomal region is amplified in most colon cancers. Of the many cellular functions of CDK8, the most notable is the involvement in transcription. CDK8 and MED12, MED13, cys-C constitute an intermediary complex, a large multi-subunit protein complex, central to the regulation of transcription in eukaryotes. In 2008, hahn and his collaborators at dana-farber cancer institute in the united states for the first time suggested that CDK8 could act as an oncogene in colorectal cancer by regulating β -catenin, and later studies showed that CDK8 is overexpressed in cancers such as melanoma, breast cancer, acute myeloid leukemia, pancreatic cancer, prostate cancer, and the like. Studies have shown that CDK8 kinase activity impairs natural killer cell defense against malignant cells and inhibits tumor surveillance on pro-cells. CDK8 was shown to have an important role in the survival of these cancers by gene knockout. These lines of evidence suggest that carcinogenesis of CDK8 in these cancers as well as inhibition of CDK8 protein activity can inhibit tumorigenesis. Therefore, the discovery of a potent and selective small molecule CDK8 inhibitor for the treatment of cancer could be a novel strategy for the treatment of cancer.
The invention content is as follows:
the invention aims to solve the technical problem of providing aryl urea derivatives and a preparation method thereof, wherein the compounds belong to a potential CDK8 Type II inhibitor, and the compound 29 is superior to the positive drug sorafenib in protein level and cell level significance and can be applied to research on preparation of antitumor drugs.
One of the objects of the present invention is to provide an aryl urea derivative represented by formulas I and II:
wherein R is 1 ，R 2 ，R 3 ，R 4 Is selected from CH 3 、OCH 3 、CF 3 Any one of CN, H, F, cl and Br;
R 5 selected from 2-aminopyridine, 7-nitrogenAny one group of heteroindoles and derivatives thereof;
x is selected from CH 2 NH, O, S.
The structural formula of the aryl urea compound is shown as follows (compounds 1-54):
the invention also provides a preparation method of the aryl urea derivative, which comprises the following steps:
(1) Carrying out nucleophilic substitution reaction on 2-nitro-5-bromopyridine and (3-hydroxyphenyl) tert-butyl carbamate to obtain an intermediate M1;
(2) Removing deprotection of the intermediate M1 to obtain an intermediate M2;
(3) Reacting the intermediate M2 with an arylamine derivative to obtain an intermediate M3;
(4) And carrying out reduction reaction on the intermediate M3 to obtain the compounds 1-19.
The reaction equation is as follows:
(5) Synthesis route conditions for Compounds 20-42 were identical to those for Compounds 1-19 except that the starting material, t-butyl (3-hydroxyphenyl) carbamate, was replaced with t-butyl (4-hydroxyphenyl) carbamate; wherein compound 29 is brominated to provide compound 53.
The reaction equation is as follows:
(6) Carrying out nucleophilic substitution reaction on the 5-hydroxy-7-azaindole and the 3-fluoronitrobenzene to obtain an intermediate M7;
(7) Carrying out reduction reaction on the intermediate M7 to obtain an intermediate M8;
(8) The intermediate M8 reacts with an arylamine derivative to obtain compounds 43-46.
The reaction equation is as follows:
(10) The synthetic route of the compound 47-50 is identical to that of the compound 43-46, and the raw material 3-fluoronitrobenzene is changed into 4-fluoronitrobenzene.
The reaction equation is as follows:
(11) Reducing the intermediate M4 to obtain an intermediate M11;
(12) Intermediate M11 is acetylated to give intermediate M12;
(13) Removing Boc from the intermediate M12 under the condition of trifluoroacetic acid to obtain an intermediate M13;
(14) The intermediate M13 reacts with an arylamine derivative to give compounds 51-52.
The reaction equation is as follows:
(15) Compound 54 the synthesis route was identical to that of Compound 1 except that the starting tert-butyl (3-hydroxyphenyl) carbamate was replaced with tert-butyl (4-mercaptophenyl) carbamate.
The reaction equation is as follows:
the invention also aims to provide a pharmaceutical composition containing the aryl urea derivative or the pharmaceutically acceptable salt thereof.
The fourth purpose of the invention is to provide a pharmaceutical preparation, which comprises an effective component and pharmaceutically acceptable auxiliary materials and/or carriers, wherein the effective component contains the aryl urea derivative or the pharmaceutically acceptable salt thereof.
The fifth purpose of the invention is to provide the application of the aryl urea derivative or the pharmaceutically acceptable salt thereof in preparing CDK8 inhibitors.
The sixth purpose of the invention is to provide the application of the aryl urea derivative or the pharmaceutically acceptable salt thereof in preparing antitumor drugs. The tumor is selected from melanoma, breast cancer, acute myeloid leukemia, pancreatic cancer, prostate cancer, colorectal cancer, etc.
The beneficial effects of the invention are:
(1) The arylurea compounds of the invention can be used for biological or pharmacological phenomena, studies on the signaling pathway conduction in which CDK8 participates, and evaluation of novel CDK8 inhibitors;
(2) The aryl urea compound is subjected to CDK8 kinase activity screening in vitro, and the result shows that the aryl urea compound has strong inhibitory activity on CDK8 and low toxicity;
(3) The aryl urea compound is screened for anti-tumor activity in vitro, and the result shows that the aryl urea compound has stronger inhibitory activity on tumor cells and lower toxicity;
(4) The aryl urea compound provided by the invention has the advantages of novel structure, simple synthesis process, high product purity and good application prospect.
Description of the drawings:
FIG. 1 shows the results of the in vivo antitumor activity test of Compound 29 of the present invention.
The specific implementation mode is as follows:
in order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described in the following combined with the specific embodiments.
Example 1
Synthesis of tert-butyl (3- ((6-nitropyridin-3-yl) oxy) phenyl) carbamate (intermediate M1):
the compound, 2-nitro-5-bromopyridine (10g, 49.27mmol), (3-hydroxyphenyl) carbamic acid tert-butyl ester (10.3g, 49.27mmol), cesium carbonate (20.9g, 64.05mmol), N, N-dimethylformamide (100 mL) was reacted at 40 ℃ for 20 hours. After the reaction is finished, adding water and ethyl acetate, stirring, assisting filtration by using diatomite, and washing a filter cake by using ethyl acetate; standing, separating, extracting the water phase with ethyl acetate, mixing the organic phases, washing with saturated salt solution, drying with anhydrous sodium sulfate, and performing column chromatography to obtain yellow solid 8.35g with yield of 51.2%.
Synthesis of (3- ((6-nitropyridin-3-yl) oxy) aniline (intermediate M2)
Adding compound M1 (3- ((6-nitropyridin-3-yl) oxy) phenyl) carbamic acid tert-butyl ester (8.3g, 25.07mmol) into dichloromethane (50 mL), stirring in an ice bath, dropwise adding trifluoroacetic acid (8.6 g, 75.21mmol), and reacting at 25 ℃ for 2h after dropwise addition; directly concentrating to obtain yellow solid, adding ethyl acetate and sodium bicarbonate aqueous solution, stirring, separating liquid, drying and concentrating to obtain brownish red solid 5g, and the yield is 85.6%.
Synthesis of 1- (3- ((6-nitropyridin-3-yl) oxy) phenyl) -3-phenylurea (intermediate M3)
Triphosgene (100mg, 1.07mmol) was first dissolved in tetrahydrofuran (10 mL), and the solution (compound aniline (100mg, 1.07mmol) and N, N-diisopropylethylamine (276mg, 2.14mmol) were dissolved in tetrahydrofuran (2 mL)) was added dropwise under ice. Stirring for 40 minutes in ice bath, adding a compound M2 (3- ((6-nitropyridin-3-yl) oxy) aniline (230mg, 1.00mmol) and reacting for 5 hours at 30 ℃, adding water and ethyl acetate to stir after the reaction is finished, standing, separating liquid, extracting a water phase with ethyl acetate, combining organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, and performing column chromatography to obtain a product, wherein 263mg of a yellow solid is obtained, and the yield is 75%.
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3-phenylurea (Compound 1):
intermediate M3 (263mg, 0.75mmol), methylene chloride (10 mL), methanol (10 mL)), and a saturated aqueous ammonium chloride solution (10 mL) were added zinc powder 150mg under ice-cooling, and reacted at 30 ℃ for 1 hour. After the reaction is finished, water and dichloromethane are added for stirring, the mixture is subjected to suction filtration, standing and liquid separation, the water phase is sequentially extracted by the dichloromethane, the organic phases are combined, the mixture is washed by saturated salt solution and dried by anhydrous sodium sulfate, and the product is obtained by column chromatography, so that 135mg of white solid is obtained, and the yield is 56.3%. 1 H NMR(400MHz,DMSO-d 6 )δ8.75(s,1H),8.59(s,1H),7.77(d,J＝2.8Hz,1H),7.42(d,J＝7.6Hz,2H),7.27(t,J＝7.9Hz,2H),7.23(dd,J＝5.1,3.8Hz,1H),7.20(d,J＝8.3Hz,1H),7.11(t,J＝2.1Hz,1H),7.05(dd,J＝8.1,1.0Hz,1H),6.97(t,J＝7.3Hz,1H),6.55–6.47(m,2H),5.90(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 16 N 4 O 2 :321.1346；found:321.1349.
Example 2
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (o-tolyl) urea (Compound 2):
the procedure is as in example 1, substituting aniline with 2-methylaniline. 1 H NMR(400MHz,DMSO-d 6 )δ9.07(s,1H),7.85(s,1H),7.81(d,J＝7.9Hz,1H),7.77(d,J＝2.8Hz,1H),7.33–7.19(m,2H),7.15(dd,J＝14.4,7.6Hz,2H),7.09(d,J＝8.1Hz,1H),7.06(t,J＝2.1Hz,1H),6.94(t,J＝7.0Hz,1H),6.54(d,J＝3.5Hz,1H),6.52–6.46(m,1H),5.89(s,2H),2.22(s,3H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 18 N 4 O 2 :335.1503；found:335.1502.
Example 3
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (2-fluorophenyl) urea (compound 3):
the procedure is as in example 1, substituting aniline with 2-fluoroaniline. 1 H NMR(400MHz,DMSO)δ9.14(s,1H),8.48(d,J＝2.4Hz,1H),8.12(td,J＝8.3,1.6Hz,1H),7.77(d,J＝2.6Hz,1H),7.28–7.16(m,3H),7.16–7.08(m,2H),7.08–6.97(m,2H),6.53(ddd,J＝9.3,5.6,0.6Hz,2H),5.92(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 15 N 4 O 2 F:339.1252；found:339.1297.
Example 4
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (2-chlorophenyl) urea (Compound 4):
the procedure is as in example 1, substituting aniline with 2-chloroaniline. 1 H NMR(400MHz,DMSO)δ9.47(s,1H),8.26(s,1H),8.14(dd,J＝8.3,1.5Hz,1H),7.78(d,J＝2.8Hz,1H),7.45(dd,J＝8.0,1.4Hz,1H),7.33–7.26(m,1H),7.26–7.19(m,2H),7.11–6.99(m,3H),6.60–6.46(m,2H),5.92(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 15 N 4 O 2 Cl:355.0956；found:355.0998.
Example 5
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-fluorophenyl) urea (compound 5):
the procedure is as in example 1, substituting aniline with 3-fluoroaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.82(d,J＝2.1Hz,2H),7.77(d,J＝2.9Hz,1H),7.45(dt,J＝12.0,2.2Hz,1H),7.29(dd,J＝15.2,8.1Hz,1H),7.25–7.18(m,2H),7.15–7.02(m,3H),6.78(td,J＝8.4,2.4Hz,1H),6.63–6.39(m,2H),5.89(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 15 N 4 O 2 F:339.1252；found:339.1255.
Example 6
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-chlorophenyl) urea (Compound 6):
the procedure is as in example 1, replacing aniline by 3-chloroaniline. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(d,J＝6.6Hz,2H),7.76(d,J＝2.7Hz,1H),7.66(t,J＝1.9Hz,1H),7.32–7.24(m,2H),7.24–7.19(m,2H),7.12(t,J＝2.2Hz,1H),7.06(dd,J＝8.1,1.1Hz,1H),7.03–6.98(m,1H),6.53(s,1H),6.51(s,1H),5.90(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 15 N 4 O 2 Cl:355.0956；found:355.0954.
Example 7
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-bromophenyl) urea (Compound 7):
the procedure is as in example 1, substituting aniline with 3-bromoaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.83(s,1H),8.80(s,1H),7.81(s,1H),7.76(d,J＝2.7Hz,1H),7.29(d,J＝8.2Hz,1H),7.22(dt,J＝7.7,5.1Hz,3H),7.15(d,J＝7.8Hz,1H),7.08(dd,J＝8.7,5.0Hz,2H),6.61–6.45(m,2H),5.90(s,2H).HRMS(ESI):m/z[M+H]+calcd for C 18 H 15 N 4 O 2 Br:399.0451；found:399.0453.
Example 8
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-methylphenyl) urea (Compound 8):
the procedure is as in example 1, replacing aniline by 3-methylaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.72(s,1H),8.50(s,1H),7.77(d,J＝2.8Hz,1H),7.26(s,1H),7.22(dd,J＝8.9,3.0Hz,2H),7.19(d,J＝1.6Hz,1H),7.15(t,J＝7.7Hz,1H),7.10(t,J＝2.2Hz,1H),7.05(d,J＝8.0Hz,1H),6.79(d,J＝7.2Hz,1H),6.58–6.34(m,2H),5.90(s,2H),2.27(s,3H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 18 N 4 O 2 :335.1503；found:335.1503.
Example 9
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-methoxyphenyl) urea (Compound 9):
the procedure is as in example 1, replacing aniline by 3-methoxyaniline. 1 H NMR(400MHz,DMSO)δ8.87(s,1H),8.74(s,1H),7.76(d,J＝2.7Hz,1H),7.22(dd,J＝8.9,3.0Hz,2H),7.19–7.16(m,1H),7.15–7.13(m,1H),7.10(t,J＝2.2Hz,1H),7.06(dd,J＝8.1,1.0Hz,1H),6.92(dd,J＝8.1,1.2Hz,1H),6.58–6.53(m,1H),6.50(ddd,J＝5.5,3.7,3.1Hz,2H),5.89(s,2H),3.73(s,3H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 18 N 4 O 3 :351.1452；found:351.1453.
Example 10
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-cyanophenyl) urea (Compound 10):
the procedure is as in example 1, replacing the aniline by 3-cyanoaniline. 1 H NMR(400MHz,DMSO-d 6 )δ9.51(s,1H),9.35(s,1H),7.94(s,1H),7.76(d,J＝2.8Hz,1H),7.65(d,J＝8.2Hz,1H),7.48(t,J＝7.9Hz,1H),7.40(d,J＝7.6Hz,1H),7.28–7.18(m,2H),7.16(s,1H),7.05(d,J＝8.0Hz,1H),6.52(d,J＝8.8Hz,2H),5.89(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 15 N 5 O 2 :346.1299；found:346.1295.
Example 11
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-trifluoromethylphenyl) urea (Compound 11):
the procedure is as in example 1, replacing the aniline by 3-trifluoromethylaniline. 1 H NMR(500MHz,DMSO-d 6 )δ8.97(s,1H),8.88(s,1H),7.95(s,1H),7.77(d,J＝1.1Hz,1H),7.58(d,J＝8.2Hz,1H),7.52(t,J＝7.9Hz,1H),7.33(d,J＝7.6Hz,1H),7.30–7.21(m,2H),7.17–7.04(m,2H),6.61–6.49(m,2H),5.88(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 15 N 4 O 2 F 3 :389.1220；found:389.1221.
Example 12
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (4-fluorophenyl) urea (Compound 12):
the procedure is as in example 1, substituting aniline with 4-fluoroaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.74(s,1H),8.62(s,1H),7.76(d,J＝2.8Hz,1H),7.48–7.39(m,2H),7.24–7.17(m,2H),7.16–7.08(m,3H),7.04(dd,J＝8.1,1.1Hz,1H),6.51(d,J＝8.7Hz,2H),5.89(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 15 N 4 O 2 F:339.1252；found:339.1254.
Example 13
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (4-fluorophenyl) urea (Compound 13):
the procedure is as in example 1, substituting aniline with 4-chloroaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.83(s,1H),8.78(s,1H),7.76(d,J＝2.8Hz,1H),7.50–7.40(m,2H),7.35–7.28(m,2H),7.25–7.17(m,2H),7.11(t,J＝2.1Hz,1H),7.04(dd,J＝8.1,1.1Hz,1H),6.56–6.48(m,2H),5.89(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 15 N 4 O 2 Cl355.0956；found:355.0955.
Example 14
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (4-methylphenyl) urea (Compound 14):
the procedure is as in example 1, replacing aniline by 4-methylaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.69(s,1H),8.47(s,1H),7.76(d,J＝2.9Hz,1H),7.31(s,1H),7.29(d,J＝2.4Hz,1H),7.25–7.20(m,1H),7.19(d,J＝8.2Hz,1H),7.10–7.07(m,2H),7.06(s,1H),7.03(dd,J＝8.1,1.1Hz,1H),6.50(ddd,J＝4.8,4.0,2.8Hz,2H),5.88(s,2H),2.24(s,3H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 18 N 4 O 2 :335.1503；found:335.1507.
Example 15
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (4-fluoro-3-trifluoromethylphenyl) urea (Compound 15):
the procedure is as in example 1, substituting aniline with 4-fluoro-3-trifluoromethylaniline. 1 H NMR(500MHz,DMSO-d 6 )δ9.53(s,1H),9.38(s,1H),8.02–7.94(m,1H),7.90–7.83(m,2H),7.70–7.62(m,1H),7.44(t,J＝9.7Hz,1H),7.32(dd,J＝15.2,7.0Hz,2H),7.16(dd,J＝8.2,0.8Hz,1H),7.10(d,J＝9.4Hz,1H),6.67(dd,J＝8.1,2.2Hz,1H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 15 N 4 O 2 F 3 :407.1126；found:407.1122.
Example 16
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (4-chloro-3-trifluoromethylphenyl) urea (Compound 16):
the procedure is as in example 1, substituting aniline with 4-chloro-3-trifluoromethylaniline. 1 H NMR(500MHz,DMSO-d 6 )δ9.96(s,1H),9.65(s,1H),8.05(d,J＝2.3Hz,1H),7.93(d,J＝2.7Hz,1H),7.86(dd,J＝9.6,2.7Hz,1H),7.66–7.62(m,1H),7.61(d,J＝8.8Hz,1H),7.33(t,J＝2.1Hz,1H),7.29(t,J＝8.2Hz,1H),7.13(dd,J＝8.1,1.1Hz,1H),7.08(d,J＝9.6Hz,1H),6.65(dd,J＝8.1,2.0Hz,1H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 14 N 4 O 2 F 3 Cl:423.0830；found:423.0831.
Example 17
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-chloro-4-methylphenyl) urea (compound 17):
the procedure is as in example 1, replacing aniline by 3-chloro-4-methylaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.78(s,1H),8.68(s,1H),7.76(d,J＝2.8Hz,1H),7.64(d,J＝2.1Hz,1H),7.27–7.13(m,4H),7.07(dt,J＝9.2,1.6Hz,2H),6.57–6.45(m,2H),5.89(s,2H),2.26(s,3H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 17 N 4 O 2 Cl:369.1113；found:369.1111.
Example 18
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-chloro-4-fluorophenyl) urea (Compound 18):
the procedure is as in example 1, substituting aniline with 3-chloro-4-fluoroaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.86(s,1H),8.82(s,1H),7.75(dd,J＝6.7,2.3Hz,2H),7.35–7.27(m,2H),7.24–7.18(m,2H),7.08(dt,J＝9.1,1.6Hz,2H),6.56–6.47(m,2H),5.89(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 14 N 4 O 2 FCl:373.0862；found:373.0861.
Example 19
Synthesis of 1- (3- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3, 4-dichlorophenyl) urea (Compound 19):
the procedure is as in example 1, substituting 3, 4-dichloroaniline for aniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.91(d,J＝10.8Hz,2H),7.83(d,J＝2.5Hz,1H),7.76(d,J＝2.7Hz,1H),7.51(d,J＝8.8Hz,1H),7.32(dd,J＝8.8,2.5Hz,1H),7.26–7.15(m,2H),7.08(dt,J＝9.1,1.6Hz,2H),6.60–6.38(m,2H),5.89(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 14 N 4 O 2 Cl 2 :389.0567；found:389.0565.
Example 20
Synthesis of tert-butyl (4- ((6-nitropyridin-3-yl) oxy) phenyl) carbamate (intermediate M4):
the compound, 2-nitro-5-bromopyridine (10g, 49.27mmol), (4-hydroxyphenyl) carbamic acid tert-butyl ester (10.3g, 49.27mmol), cesium carbonate (20.9g, 64.05mmol), N, N-dimethylformamide (100 mL) was reacted at 40 ℃ for 20 hours. After the reaction is finished, adding water and ethyl acetate, stirring, assisting filtration by using diatomite, and washing a filter cake by using ethyl acetate; standing, separating, extracting the water phase with ethyl acetate, mixing the organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, and performing column chromatography to obtain yellow solid 10.19g with yield of 62.5%.
Synthesis of (4- ((6-nitropyridin-3-yl) oxy) aniline (intermediate M5)
Adding compound M4 (4- ((6-nitropyridin-3-yl) oxy) phenyl) carbamic acid tert-butyl ester (10.19g, 30.78mmol) into dichloromethane (100 mL), stirring in an ice bath, dropwise adding trifluoroacetic acid (11.43g, 100mmol), and reacting for 2h at 25 ℃; directly concentrating to obtain yellow solid, adding ethyl acetate and sodium bicarbonate aqueous solution, stirring, separating liquid, drying and concentrating to obtain red brown solid 7.5g, and the yield is 81.5%.
Synthesis of 1- (4- ((6-nitropyridin-3-yl) oxy) phenyl) -3-phenylurea (intermediate M6)
Triphosgene (100mg, 1.07mmol) was first dissolved in tetrahydrofuran (10 mL), and the solution (compound aniline (100mg, 1.07mmol) and N, N-diisopropylethylamine (276mg, 2.14mmol) were dissolved in tetrahydrofuran (2 mL)) was added dropwise under ice. Stirring for 40 minutes in ice bath, adding a compound M5 (4- ((6-nitropyridine-3-yl) oxy) aniline (230mg, 1.00mmol) and reacting for 5 hours at 30 ℃, adding water and ethyl acetate after the reaction is finished, stirring, standing, separating liquid, extracting a water phase with ethyl acetate sequentially, combining organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, and performing column chromatography to obtain a product, wherein 245mg of a yellow solid is obtained, and the yield is 70%.
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3-phenylurea (Compound 20):
intermediate M6 (245350 mg, 0.70mmol), dichloromethane (10 mL), methanol (10 mL), saturated ammonium chlorideTo an aqueous solution (10 mL), zinc powder (150mg) was added under ice-cooling, and the mixture was reacted at 30 ℃ for 1 hour. After the reaction is finished, adding water and dichloromethane, stirring, carrying out suction filtration, standing, separating liquid, extracting the water phase with dichloromethane, combining organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, and carrying out column chromatography to obtain a product, wherein the white solid is 100mg. 1 H NMR(400MHz,DMSO-d 6 )δ8.59(d,J＝5.0Hz,2H),7.73(d,J＝2.4Hz,1H),7.42(dd,J＝17.9,8.4Hz,4H),7.27(t,J＝7.7Hz,2H),7.20(dd,J＝8.8,2.7Hz,1H),6.97(d,J＝7.2Hz,1H),6.87(d,J＝8.8Hz,2H),6.51(d,J＝8.9Hz,1H),5.89(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 16 N 4 O 2 :321.1346；found:321.1345.
Example 21
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (2-fluorophenyl) urea (Compound 21):
the procedure is as in example 20, substituting aniline with 2-fluoroaniline. 1 H NMR(400MHz,DMSO)δ9.00(s,1H),8.49(d,J＝2.4Hz,1H),8.15(td,J＝8.3,1.5Hz,1H),7.73(d,J＝2.8Hz,1H),7.45–7.35(m,2H),7.23(ddd,J＝11.7,8.2,1.3Hz,1H),7.20–7.16(m,1H),7.13(t,J＝7.7Hz,1H),7.03–6.96(m,1H),6.92–6.82(m,2H),6.49(d,J＝8.9Hz,1H),5.85(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 15 N 4 O 2 F:339.1252；found:339.1190.
Example 22
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (2-chlorophenyl) urea (Compound 22):
the procedure is as in example 20, replacing aniline by 2-chloroaniline. 1 H NMR(400MHz,DMSO)δ9.36(s,1H),8.25(s,1H),8.17(dd,J＝8.3,1.5Hz,1H),7.74(d,J＝2.6Hz,1H),7.43(ddd,J＝14.7,7.4,1.8Hz,3H),7.29(s,1H),7.19(dd,J＝8.9,3.0Hz,1H),7.03(dd,J＝7.7,1.3Hz,1H),6.91–6.84(m,2H),6.49(dd,J＝8.9,0.4Hz,1H),5.86(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 15 N 4 O 2 Cl:355.0956；found:355.0999.
Example 23
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-fluorophenyl) urea (Compound 23):
the procedure is as in example 20, substituting aniline with 3-fluoroaniline. 1 H NMR(400MHz,DMSO-d 6 )δ9.91(s,1H),9.59(s,1H),7.72(d,J＝2.7Hz,1H),7.50(d,J＝12.0Hz,1H),7.40(d,J＝8.9Hz,2H),7.28(dd,J＝15.3,8.0Hz,1H),7.17(dd,J＝8.8,2.8Hz,1H),7.10(d,J＝8.1Hz,1H),6.86(d,J＝8.9Hz,2H),6.74(td,J＝8.4,2.0Hz,1H),6.50(d,J＝8.9Hz,1H),5.86(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 15 N 4 O 2 F:339.1252；found:339.1257.
Example 24
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-chlorophenyl) urea (Compound 24):
the procedure is as in example 20, replacing the aniline by 3-chloroaniline. 1 H NMR(400MHz,DMSO-d 6 )δ10.06(s,1H),9.71(s,1H),7.79–7.63(m,2H),7.40(d,J＝8.9Hz,2H),7.28(d,J＝6.1Hz,2H),7.17(dd,J＝8.9,2.8Hz,1H),7.03–6.92(m,1H),6.85(d,J＝8.9Hz,2H),6.50(d,J＝8.9Hz,1H),5.85(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 15 N 4 O 2 Cl:355.0956；found:355.0959.
Example 25
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-bromophenyl) urea (Compound 25):
the procedure is as in example 20, replacing the aniline by 3-bromoaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.82(s,1H),8.67(s,1H),7.85(t,J＝1.9Hz,1H),7.73(d,J＝2.9Hz,1H),7.40(d,J＝2.1Hz,1H),7.39(d,J＝2.2Hz,1H),7.34–7.27(m,1H),7.23(t,J＝8.0Hz,1H),7.18(dd,J＝8.9,3.0Hz,1H),7.15–7.11(m,1H),6.87(d,J＝2.1Hz,1H),6.86(d,J＝2.1Hz,1H),6.49(d,J＝8.9Hz,1H),5.84(s,2H).HRMS(ESI):m/z[M+H]+calcd for C 18 H 15 N 4 O 2 Br:399.0451；found:399.0451.
Example 26
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-methylphenyl) urea (Compound 26):
the procedure is as in example 20, replacing the aniline by 3-methylaniline. 1 H NMR(400MHz,DMSO-d 6 )δ9.71(s,1H),9.63(s,1H),7.72(d,J＝2.8Hz,1H),7.42(d,J＝2.1Hz,1H),7.40(d,J＝2.1Hz,1H),7.27(d,J＝7.3Hz,2H),7.17(dd,J＝8.9,3.0Hz,1H),7.13(d,J＝7.5Hz,1H),6.85(d,J＝2.0Hz,1H),6.83(d,J＝2.1Hz,1H),6.74(d,J＝7.2Hz,1H),6.52–6.47(m,1H),5.85(s,2H),2.26(s,3H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 18 N 4 O 2 :335.1503；found:335.1506.
Example 27
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-methoxyphenyl) urea (Compound 27):
the procedure is as in example 20, replacing the aniline by 3-methoxyaniline. 1 H NMR(400MHz,DMSO-d 6 )δ9.09(d,J＝15.3Hz,2H),7.73(d,J＝2.0Hz,1H),7.41(d,J＝8.6Hz,2H),7.21(s,1H),7.16(dd,J＝15.5,5.6Hz,2H),6.95(s,1H),6.85(d,J＝8.6Hz,2H),6.51(dd,J＝13.4,8.6Hz,2H),5.84(s,2H),3.72(s,3H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 18 N 4 O 3 :351.1452；found:351.1457.
Example 28
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-cyanophenyl) urea (Compound 28):
the procedure is as in example 20, replacing the aniline by 3-cyanoaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.96(s,1H),8.76(s,1H),8.01–7.90(m,1H),7.74(d,J＝2.9Hz,1H),7.70–7.63(m,1H),7.48(t,J＝7.9Hz,1H),7.41(d,J＝9.0Hz,3H),7.18(dd,J＝8.9,2.9Hz,1H),6.93–6.78(m,2H),6.49(d,J＝8.9Hz,1H),5.84(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 15 N 5 O 2 :346.1299；found:346.1298.
Example 29
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-trifluoromethylphenyl) urea (Compound 29):
the procedure is as in example 20, replacing the aniline by 3-trifluoromethylaniline. 1 H NMR(500MHz,DMSO-d 6 )δ9.56(s,1H),9.30(s,1H),8.00(s,1H),7.83(d,J＝9.6Hz,1H),7.78(d,J＝2.6Hz,1H),7.61(d,J＝8.2Hz,1H),7.56–7.47(m,3H),7.31(d,J＝7.7Hz,1H),7.12–7.01(m,3H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 15 N 4 O 2 F 3 :389.1220；found:389.1220.
Example 30
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (4-fluorophenyl) urea (Compound 30):
the procedure is as in example 20, substituting aniline with 4-fluoroaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.68(s,1H),8.62(s,1H),7.72(d,J＝2.9Hz,1H),7.48–7.42(m,2H),7.39(d,J＝2.2Hz,1H),7.39–7.36(m,1H),7.17(dd,J＝8.9,3.0Hz,1H),7.14–7.07(m,2H),6.86(d,J＝2.1Hz,1H),6.85(d,J＝2.1Hz,1H),6.49(d,J＝8.9Hz,1H),5.82(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 15 N 4 O 2 F:339.1252；found:339.1252.
Example 31
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (4-chlorophenyl) urea (Compound 31):
the procedure is as in example 20, replacing aniline by 4-chloroaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.81(s,1H),8.68(s,1H),7.80(dd,J＝6.8,2.0Hz,1H),7.73(d,J＝2.8Hz,1H),7.43–7.39(m,1H),7.39–7.36(m,1H),7.30(td,J＝6.7,4.2Hz,2H),7.18(dd,J＝8.9,3.0Hz,1H),6.92–6.73(m,2H),6.49(d,J＝8.9Hz,1H),5.84(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 15 N 4 O 2 Cl355.0956；found:355.0958.
Example 32
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (4-methylphenyl) urea (Compound 32):
the procedure is as in example 20, replacing the aniline by 4-methylaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.54(s,1H),8.49(s,1H),7.73(d,J＝2.8Hz,1H),7.40(d,J＝2.2Hz,1H),7.38(d,J＝2.2Hz,1H),7.33(s,1H),7.31(s,1H),7.20(dd,J＝8.9,3.0Hz,1H),7.08(s,1H),7.06(s,1H),6.87(d,J＝2.1Hz,1H),6.85(d,J＝2.2Hz,1H),6.51(d,J＝8.9Hz,1H),5.90(s,2H),2.24(s,3H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 18 N 4 O 2 :335.1503；found:335.1504.
Example 33
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (4-methoxyphenyl) urea (Compound 33):
the procedure is as in example 20, replacing the aniline by 4-methoxyaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.50(s,1H),8.40(s,1H),7.72(d,J＝2.8Hz,1H),7.36(dd,J＝16.5,9.0Hz,4H),7.20(dd,J＝8.9,2.9Hz,1H),6.86(dd,J＝8.9,1.1Hz,4H),6.52(d,J＝8.9Hz,1H),5.91(s,2H),3.71(s,3H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 18 N 4 O 3 :351.1452；found:351.1451.
Example 34
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (4-trifluoromethylphenyl) urea (Compound 34):
the procedure is as in example 20, substituting aniline with 4-trifluoromethylaniline. 1 H NMR(400MHz,DMSO-d 6 )δ9.08(s,1H),8.75(s,1H),7.73(d,J＝2.9Hz,1H),7.64(q,J＝9.0Hz,4H),7.48–7.41(m,1H),7.41–7.38(m,1H),7.18(dd,J＝8.9,3.0Hz,1H),6.99–6.87(m,1H),6.87–6.83(m,1H),6.49(d,J＝8.9Hz,1H),5.84(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 15 N 4 O 2 F 3 :389.1220；found:389.1223.
Example 35
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (4-fluoro-3- (trifluoromethyl) phenyl) urea (compound 35):
the procedure is as in example 20, substituting aniline for 4-fluoro-3-trifluoromethylaniline. 1 H NMR(500MHz,DMSO-d 6 )δ9.56(s,1H),9.28(s,1H),8.06–7.96(m,1H),7.83(dd,J＝9.6,1.8Hz,1H),7.81–7.74(m,1H),7.70–7.62(m,1H),7.50(d,J＝8.9Hz,2H),7.43(t,J＝9.8Hz,1H),7.08(d,J＝9.6Hz,1H),7.06–7.02(m,2H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 15 N 4 O 2 F 3 :407.1126；found:407.1126.
Example 36
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (4-chloro-3- (trifluoromethyl) phenyl) urea (compound 36):
the procedure is as in example 20, substituting aniline with 4-chloro-3-trifluoromethylaniline. 1 H NMR(500MHz,DMSO-d 6 )δ9.94(s,1H),9.50(s,1H),8.10(d,J＝2.4Hz,1H),7.86–7.80(m,2H),7.64(dd,J＝8.8,2.4Hz,1H),7.60(d,J＝8.8Hz,1H),7.49(d,J＝9.0Hz,2H),7.10–7.01(m,3H),3.44(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 14 N 4 O 2 F 3 Cl:423.0830；found:423.0831.
Example 37
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-chloro-4-fluorophenyl) urea (Compound 37):
the procedure is as in example 20, substituting aniline with 3-chloro-4-fluoroaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.82(s,1H),8.68(s,1H),7.73(d,J＝2.7Hz,1H),7.49(d,J＝2.1Hz,1H),7.47(d,J＝2.1Hz,1H),7.40(d,J＝2.2Hz,1H),7.38(d,J＝2.2Hz,1H),7.32(d,J＝2.1Hz,1H),7.30(d,J＝2.0Hz,1H),7.18(dd,J＝8.9,3.0Hz,1H),6.87(d,J＝2.2Hz,1H),6.85(d,J＝2.2Hz,1H),6.54–6.29(m,1H),5.83(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 14 N 4 O 2 FCl:373.0862；found:373.0861.
Example 38
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3, 4-dichlorophenyl) urea (Compound 38):
the procedure is as in example 20, substituting 3, 4-dichloroaniline for aniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.94(s,1H),8.73(s,1H),7.88(d,J＝2.5Hz,1H),7.73(d,J＝2.8Hz,1H),7.50(d,J＝8.8Hz,1H),7.40(d,J＝2.1Hz,1H),7.38(d,J＝2.1Hz,1H),7.32(dd,J＝8.8,2.5Hz,1H),7.18(dd,J＝8.9,3.0Hz,1H),6.91–6.83(m,2H),6.49(d,J＝8.9Hz,1H),5.85(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 14 N 4 O 2 Cl 2 :389.0567；；found:389.0566.
Example 39
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3-chloro-4-methylphenyl) urea (Compound 39):
the procedure is as in example 20, replacing the aniline by 3-chloro-4-methylaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.99(s,1H),8.88(s,1H),7.73(d,J＝2.8Hz,1H),7.68(d,J＝2.0Hz,1H),7.42–7.39(m,1H),7.39–7.36(m,1H),7.22(d,J＝8.4Hz,1H),7.20–7.14(m,2H),6.88–6.85(m,1H),6.85–6.82(m,1H),6.49(d,J＝8.9Hz,1H),5.84(s,2H),2.25(s,3H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 17 N 4 O 2 Cl:369.1113；found:369.1115.
Example 40
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (2, 3-dichlorophenyl) urea (Compound 40):
the procedure is as in example 20, replacing aniline by 2, 3-dichloroaniline. 1 H NMR(400MHz,DMSO-d 6 )δ9.42(s,1H),8.41(s,1H),8.17(dd,J＝8.1,1.7Hz,1H),7.74(d,J＝2.9Hz,1H),7.42(d,J＝2.1Hz,1H),7.40(d,J＝2.1Hz,1H),7.32(t,J＝8.1Hz,1H),7.27(dd,J＝8.0,1.7Hz,1H),7.18(dd,J＝8.9,2.9Hz,1H),6.95–6.78(m,2H),6.49(d,J＝8.9Hz,1H),5.84(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 14 N 4 O 2 Cl 2 :389.0567；found:389.0568.
Example 41
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (3, 5-dichlorophenyl) urea (Compound 41):
the procedure is as in example 20, replacing aniline by 3, 5-dichloroaniline. 1 H NMR(400MHz,DMSO-d 6 )δ8.99(s,1H),8.79(s,1H),7.73(d,J＝2.8Hz,1H),7.53(d,J＝1.8Hz,2H),7.41(d,J＝2.1Hz,1H),7.40–7.37(m,1H),7.18(dd,J＝8.9,3.0Hz,1H),7.14(t,J＝1.8Hz,1H),6.94–6.87(m,1H),6.87–6.84(m,1H),6.49(d,J＝8.9Hz,1H),5.84(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 14 N 4 O 2 Cl 2 :389.0567；found:389.0568.
Example 42
Synthesis of 1- (4- ((6-aminopyridin-3-yl) oxy) phenyl) -3- (6- (trifluoromethyl) pyridin-2-yl) urea (Compound 42):
the procedure is as in example 20, substituting 6- (trifluoromethyl) -2-aminopyridine for aniline. 1 H NMR(500MHz,DMSO-d 6 )δ10.08(d,J＝9.4Hz,1H),9.84(d,J＝3.1Hz,1H),8.09–8.00(m,2H),7.91–7.72(m,2H),7.51(t,J＝8.2Hz,3H),7.17–7.03(m,3H).HRMS(ESI):m/z[M+H] + calcd for C 18 H 14 N 5 O 2 F 3 :390.1172；found:390.1177
Example 43
Synthesis of 5- (3-nitrophenoxy) -1H-pyrrolo [2,3-b ] pyridine (intermediate M7):
5-hydroxy-7-azaindole (2.5g, 17.73mmol) and the compound 3-fluoronitrobenzene (2.62g, 19.50mmol) were dissolved in N, N-dimethylformamide (50 mL), and then the reaction solution was stirred at 80 ℃ for 14 hours with the addition of potassium carbonate (4.9g, 35.46mmol). After the reaction, ethyl acetate (300 mL) was added, the mixture was filtered, the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and then subjected to column chromatography to obtain intermediate M7.
Synthesis of 5- (3-aminophenoxy) -1H-pyrrolo [2,3-b ] pyridine (intermediate M8)
Intermediate M7 (2g, 7.84mmol) and CH 3 OH (40 mL) was added to the reaction flask, followed by Raney nickel (300 mg) reaction solution and stirred at 25 ℃ under a hydrogen balloon pressure for 6h. After the reaction is finished, suction filtration is carried out, and the intermediate M8 is obtained by the column chromatography of the filtrate.
Synthesis of 1- (3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) phenyl) -3- (3- (trifluoromethyl) phenyl) urea (Compound 43)
Triphosgene (147mg, 0.50mmol) was dissolved in tetrahydrofuran (15 mL), and then a solution of 3-trifluoromethylaniline (217mg, 1.35mmol) and DIPEA (387mg, 3mmol) in tetrahydrofuran (5 mL) was added under ice-bath. The reaction was stirred at 0 ℃ for one h, intermediate M8 (281mg, 1.25mmol) was added to the reaction, and then stirred at 25 ℃ for 5h. After the reaction, ethyl acetate and saturated salt were addedWashing with water, drying over anhydrous sodium sulfate, and performing column chromatography to obtain compound 43. 1 H NMR(500MHz,DMSO-d 6 )δ11.75(s,1H),8.91(d,J＝37.6Hz,2H),8.09(s,1H),7.94(s,1H),7.72(s,1H),7.60–7.52(m,2H),7.49(t,J＝7.7Hz,1H),7.30(d,J＝7.2Hz,1H),7.26(t,J＝8.0Hz,1H),7.15(d,J＝13.8Hz,2H),6.61(d,J＝7.5Hz,1H),6.45(s,1H).HRMS(ESI):m/z[M+H] + calcd for C 21 H 15 N 4 O 2 F 3 :413.1220found:413.1223.
Example 44
Synthesis of 1- (3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) phenyl) -3- (3-chlorophenyl) urea (Compound 44):
the procedure is as in example 43, 3-chloroaniline is used instead of 3-trifluoromethylaniline. 1 H NMR(400MHz,DMSO-d 6 )δ11.76(s,1H),8.84(s,1H),8.80(s,1H),8.09(d,J＝2.6Hz,1H),7.72(d,J＝2.5Hz,1H),7.65(t,J＝1.9Hz,1H),7.57–7.51(m,1H),7.26(ddd,J＝12.8,9.9,7.2Hz,3H),7.16–7.09(m,2H),7.04–6.97(m,1H),6.63–6.56(m,1H),6.45(dd,J＝3.4,1.9Hz,1H).HRMS(ESI):m/z[M+H] + calcd for C 20 H 15 N 4 O 2 Cl:379.0956；found:379.0961.
Example 45
Synthesis of 1- (3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) phenyl) -3- (4-methyl-3-trifluoromethylphenyl) urea (Compound 45):
the procedure is as in example 43, replacing 3-trifluoromethylaniline with 4-methyl-3-trifluoromethylaniline. 1 H NMR(500MHz,DMSO-d 6 )δ11.74(s,1H),8.81(d,J＝2.4Hz,2H),8.09(d,J＝2.4Hz,1H),7.85(d,J＝1.3Hz,1H),7.71(d,J＝2.3Hz,1H),7.54(t,J＝2.8Hz,1H),7.48(d,J＝8.2Hz,1H),7.31(d,J＝8.3Hz,1H),7.25(t,J＝8.0Hz,1H),7.14(d,J＝8.5Hz,2H),6.64–6.55(m,1H),6.45(dt,J＝7.0,3.5Hz,1H),2.36(s,3H).HRMS(ESI):m/z[M+H] + calcd for C 22 H 17 N 4 O 2 F 3 :427.1376；found:427.1377.
Example 46
Synthesis of 1- (3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) phenyl) -3- (4-chloro-3-trifluoromethylphenyl) urea (Compound 46):
the procedure is as in example 43, replacing 3-trifluoromethylaniline with 4-chloro-3-trifluoromethylaniline. 1 H NMR(500MHz,DMSO-d 6 )δ11.73(s,1H),9.05(s,1H),8.91(s,1H),8.07(d,J＝2.6Hz,1H),8.01(d,J＝2.2Hz,1H),7.70(d,J＝2.5Hz,1H),7.60(dt,J＝16.1,5.5Hz,2H),7.53(t,J＝2.9Hz,1H),7.29–7.21(m,1H),7.12(dd,J＝8.5,5.2Hz,2H),6.60(dd,J＝8.1,1.8Hz,1H),6.44(dd,J＝3.3,1.9Hz,1H).HRMS(ESI):m/z[M+H] + calcd for C 21 H 14 N 4 O 2 F 3 Cl:447.0830；found:447.0833.
Example 47
Synthesis of 5- (4-nitrophenoxy) -1H-pyrrolo [2,3-b ] pyridine (intermediate M9):
5-hydroxy-7-azaindole (2.5g, 17.73mmol) and the compound 4-fluoronitrobenzene (2.62g, 19.50mmol) were dissolved in N, N-dimethylformamide (50 mL), and then the reaction solution was stirred at 80 ℃ for 14 hours with the addition of potassium carbonate (4.9g, 35.46mmol). After the reaction, ethyl acetate (300 mL) was added, followed by suction filtration, washing of the filtrate with saturated brine, drying over anhydrous sodium sulfate, and column chromatography to give intermediate M9.
Synthesis of 5- (4-aminophenoxy) -1H-pyrrolo [2,3-b ] pyridine (intermediate M10)
Intermediate M9 (2g, 7.84mmol) and CH 3 OH (40 mL) was added to the reaction flask, followed by Raney nickel (300 mg) and the reaction stirred at 25 ℃ under hydrogen balloon pressure for 10h. After the reaction is finished, suction filtration is carried out, and the intermediate M10 is obtained by the column chromatography of the filtrate.
Synthesis of 1- (4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) phenyl) -3- (3- (trifluoromethyl) phenyl) urea (Compound 47):
triphosgene (147mg, 0.50mmol) was dissolved in tetrahydrofuran (15 mL), and then a solution of 3-trifluoromethylaniline (217mg, 1.35mmol) and DIPEA (387mg, 3mmol) in tetrahydrofuran (5 mL) was added under ice-bath. The reaction was stirred at 0 ℃ for one hour, and intermediate M10 (281mg, 1.25mmol) was added to the reaction, followed by stirring at 25 ℃ for 5 hours. After the reaction solution is finished, ethyl acetate is added, the mixture is washed by saturated saline solution, dried by anhydrous sodium sulfate and subjected to column chromatography to obtain a compound 47. 1 H NMR(500MHz,DMSO-d 6 )δ11.70(s,1H),9.00(s,1H),8.75(s,1H),8.07(d,J＝2.6Hz,1H),8.02(s,1H),7.63(d,J＝2.5Hz,1H),7.59(d,J＝8.4Hz,1H),7.53–7.49(m,2H),7.47–7.43(m,2H),7.30(d,J＝7.7Hz,1H),6.99–6.91(m,2H),6.42(dd,J＝3.3,1.9Hz,1H).HRMS(ESI):m/z[M+H] + calcd for C 21 H 15 N 4 O 2 F 3 :413.1220found:413.1220.
Example 48
Synthesis of 1- (4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) phenyl) -3- (3-chlorophenyl) urea (Compound 48):
the procedure is as in example 47, 3-chloroaniline is used instead of 3-trifluoromethylaniline. 1 H NMR(400MHz,DMSO-d 6 )δ11.70(s,1H),8.89(s,1H),8.76(s,1H),8.06(d,J＝2.6Hz,1H),7.67(dd,J＝37.9,2.1Hz,2H),7.57–7.47(m,1H),7.45–7.37(m,2H),7.28(d,J＝2.7Hz,2H),7.00(dt,J＝6.6,2.2Hz,1H),6.96–6.88(m,2H),6.42(dd,J＝3.4,1.9Hz,1H).HRMS(ESI):m/z[M+H] + calcd for C 20 H 15 N 4 O 2 Cl:379.0956；found:379.0958.
Example 49
Synthesis of 1- (4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) phenyl) -3- (4-chloro-3-trifluoromethylphenyl) urea (Compound 49):
the procedure is as in example 47, replacing 3-trifluoromethylaniline with 4-chloro-3-trifluoromethylaniline. 1 H NMR(400MHz,DMSO)δ11.72(s,1H),9.30(s,1H),8.94(s,1H),8.11(d,J＝2.3Hz,1H),8.06(d,J＝2.6Hz,1H),7.68–7.58(m,3H),7.56–7.48(m,1H),7.48–7.40(m,2H),6.99–6.88(m,2H),6.42(dd,J＝3.3,1.9Hz,1H).HRMS(ESI):m/z[M+H] + calcd for C 21 H 14 N 4 O 2 F 3 Cl:447.0830；found:447.0829.
Example 50
Synthesis of 1- (4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) phenyl) -3- (4-methyl-3-trifluoromethylphenyl) urea (Compound 50):
the procedure is as in example 47, replacing 3-trifluoromethylaniline with 4-methyl-3-trifluoromethylaniline. 1 H NMR(500MHz,DMSO-d 6 )δ11.69(s,1H),8.85(s,1H),8.67(s,1H),8.06(d,J＝2.5Hz,1H),7.93(d,J＝1.6Hz,1H),7.62(d,J＝2.4Hz,1H),7.51(dd,J＝7.6,5.1Hz,2H),7.44(d,J＝8.9Hz,2H),7.32(d,J＝8.3Hz,1H),6.94(d,J＝8.9Hz,2H),6.42(dd,J＝3.1,1.9Hz,1H),2.37(s,3H).HRMS(ESI):m/z[M+H] + calcd for C 22 H 17 N 4 O 2 F 3 :427.1376；found:427.1380.
Example 51
Synthesis of tert-butyl (4- ((6-aminopyridin-3-yl) oxy) phenyl) carbamate (intermediate M11):
intermediate M4 (2g, 7.84mmol) and methanol (40 mL) were added to a reaction flask, followed by Raney nickel (350 mg), under hydrogen balloon pressure, and the reaction was stirred at 25 ℃ for 12h. After the reaction is finished, filtering, and carrying out column chromatography on the filtrate to obtain an intermediate M11.
Synthesis of tert-butyl (4- ((6-acetamidopyridin-3-yl) oxy) phenyl) carbamate (intermediate M12):
intermediate M11 (301mg, 1mmol), 4-dimethylaminopyridine (5 mg) and triethylamine (120mg, 1.2mmol) were dissolved in dichloromethane (20 mL), and then the reaction mixture was added dropwise with acetyl chloride (87mg, 1.1mmol), stirred at 30 ℃ for 2 hours, after completion of the reaction, dichloromethane was added, followed by washing with water and column chromatography to give intermediate M12.
Synthesis of N- (5- (4-aminophenoxy) pyridin-2-yl) acetamide (intermediate M13):
intermediate M12 (200mg, 0.58mmol) was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (200mg, 1.74mmol) was added under ice bath. And (3) stirring the reaction solution at 30 ℃ for 1h, directly concentrating after the reaction is finished, adding ethyl acetate and a saturated sodium bicarbonate solution, fully stirring, separating, drying filtrate by anhydrous sodium sulfate, and performing column chromatography to obtain an intermediate M13.
Synthesis of N- (5- (4- (3- (3- (trifluoromethyl) phenyl) ureido) phenoxy) pyridin-2-yl) acetamide (Compound 51):
triphosgene (53mg, 0.18mmol) was dissolved in tetrahydrofuran (15 mL), a solution of 3-trifluoromethylaniline (74mg, 0.45mmol) and DIPEA (135mg, 1.04mmol) in tetrahydrofuran (5 mL) was added at 0 ℃, the reaction mixture was stirred at 0 ℃ for 1h, and the mixture was addedIntermediate M13 (106mg, 0.45mmol) w. The mixture was stirred at 35 ℃ for 5h. After the reaction, water and ethyl acetate were added to separate the solution, which was washed with saturated brine, dried and subjected to column chromatography to obtain compound 51. 1 H NMR(400MHz,DMSO)δ10.53(s,1H),9.04(s,1H),8.82(s,1H),8.07(dd,J＝17.9,14.7Hz,3H),7.58(d,J＝8.5Hz,1H),7.54–7.44(m,4H),7.30(d,J＝7.6Hz,1H),7.05–6.93(m,2H),2.09(s,3H).HRMS(ESI):m/z[M+H] + calcd for C 21 H 17 N 4 O 3 F 3 :431.1326；found:431.1299.
Example 52
Synthesis of N- (5- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) phenoxy) pyridin-2-yl) (compound 52):
the procedure is as in example 51, replacing 3-trifluoromethylaniline with 4-chloro-3-trifluoromethylaniline. 1 H NMR(500MHz,DMSO-d 6 )δ10.48(s,1H),9.25(s,1H),8.94(s,1H),8.09(dd,J＝14.3,2.6Hz,3H),7.64(dd,J＝8.8,2.1Hz,1H),7.60(d,J＝8.8Hz,1H),7.50–7.43(m,3H),7.00(d,J＝8.9Hz,2H),2.08(s,3H).HRMS(ESI):m/z[M+H] + calcd for C 21 H 16 N 4 O 3 F 3 Cl:465.0936；found:465.0940.
Example 53
Synthesis of 1- (4- ((6-amino-5-bromopyridin-3-yl) oxy) phenyl) -3- (3- (trifluoromethyl) phenyl) urea (Compound 53):
compound 29 (200mg, 0.52mmol) was dissolved in N, N-dimethylformamide (15 mL), followed by addition of NBS (116mg, 0.65mmol). And stirring the reaction solution at 25 ℃ for 1h, adding ethyl acetate and sodium thiosulfate aqueous solution after the reaction is finished, fully stirring, separating, washing with water, drying and carrying out column chromatography to obtain the compound 53.
1 H NMR(400MHz,DMSO-d 6 )δ9.01(s,1H),8.77(s,1H),8.01(s,1H),7.83(d,J＝2.5Hz,1H),7.63–7.54(m,2H),7.51(d,J＝7.8Hz,1H),7.43(d,J＝8.9Hz,2H),7.30(d,J＝7.5Hz,1H),6.92(d,J＝8.9Hz,2H),6.14(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 14 N 4 O 2 F 3 Br:467.0325；found:467.0324.
Example 54
Synthesis of tert-butyl (4- ((6-nitropyridin-3-yl) thio) phenyl) carbamate (intermediate M14):
the compound, tert-butyl 2-nitro-5-bromopyridine (10g, 49.27mmol) (4-mercaptophenyl) carbamate (10.3g, 49.27mmol), cesium carbonate (20.9g, 64.05mmol) and N, N-dimethylformamide (100 mL) were reacted at 40 ℃ for 20 hours. After the reaction is finished, adding water and ethyl acetate, stirring, assisting filtration by using diatomite, and washing a filter cake by using ethyl acetate; standing, separating, extracting water phase with ethyl acetate, mixing organic phases, washing with saturated salt solution, drying with anhydrous sodium sulfate, and performing column chromatography to obtain yellow solid 10.19g with yield of 62.5%.
Synthesis of (4- ((6-nitropyridin-3-yl) thio) aniline (intermediate M15)
Adding compound M4 (4- ((6-nitropyridin-3-yl) thio) phenyl) carbamic acid tert-butyl ester (10.19g, 30.78mmol) into dichloromethane (100 mL), stirring in an ice bath, dropwise adding trifluoroacetic acid (11.43g, 100mmol), and reacting for 2h at 25 ℃; directly concentrating to obtain yellow solid, adding ethyl acetate and sodium bicarbonate aqueous solution, stirring, separating liquid, drying and concentrating to obtain red brown solid 7.5g, and the yield is 81.5%.
Synthesis of 1- (4- ((6-nitropyridin-3-yl) thio) phenyl) -3-phenylurea (intermediate M16)
Triphosgene (100mg, 1.07mmol) was first dissolved in tetrahydrofuran (10 mL), and the solution (compound aniline (100mg, 1.07mmol) and N, N-diisopropylethylamine (276mg, 2.14mmol) were dissolved in tetrahydrofuran (2 mL)) was added dropwise under ice. Stirring for 40min in ice bath, adding compound M15 (4- ((6-nitropyridin-3-yl) thio) aniline (230mg, 1.00mmol), reacting for 5h at 30 ℃, adding water and ethyl acetate, stirring, standing, separating, extracting the water phase with ethyl acetate, combining the organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, and performing column chromatography to obtain a product, wherein the yellow solid is 245mg, and the yield is 70%.
Synthesis of 1- (4- ((6-aminopyridin-3-yl) thio) phenyl) -3- (3- (trifluoromethyl) phenyl) urea (Compound 54):
intermediate M16 (24mgs, 0.70mmol), methylene chloride (10 mL), methanol (10 mL)), and a saturated aqueous ammonium chloride solutionTo the solution (10 mL) was added zinc powder 150mg under ice-cooling, and the mixture was reacted at 30 ℃ for 1 hour. After the reaction is finished, adding water and dichloromethane, stirring, carrying out suction filtration, standing, separating liquid, extracting the water phase with dichloromethane, combining organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, and carrying out column chromatography to obtain a product, wherein the white solid is 100mg. 1 H NMR(400MHz,DMSO)δ9.03(s,1H),8.84(s,1H),8.07–7.97(m,2H),7.50(ddd,J＝14.4,11.1,5.5Hz,3H),7.44–7.36(m,2H),7.30(d,J＝7.5Hz,1H),7.13–7.03(m,2H),6.49(d,J＝8.6Hz,1H),6.36(s,2H).HRMS(ESI):m/z[M+H] + calcd for C 19 H 15 N 4 OSF 3 :405.1169；found:405.1110.
Example 55
In vitro CDK8 kinase inhibitory activity and in vitro antitumor activity evaluation:
compounds 1-54 were tested for CDK8 Kinase inhibitory activity by ADP-Glo Kinase Assay (Promega) using black 384 well plates. Active CDK8 kinase was diluted in the mixture (5 ng CDK8 kinase, 0.5. Mu.g substrate, 50. Mu.M DTT, 1. Mu.L buffer, dd H added per well 2 O to 3 μ L), then 1uL of compound solution at a concentration of 1uM (equivalent to 5-fold dilution in the system, final compound concentration of 200 nM) was added per well, followed by 1uL ATP (adenosine triphosphate) at a final concentration of 50 μ M. After incubation for 1h at room temperature, ADP-Glo solution and kinase detection reagent were added and data was collected by a microplate reader.
The compounds 1 to 54 according to the invention all show a certain CDK8 kinase inhibitory activity at a concentration of 200nM, preferably the compounds of which the inhibition rate is higher are subjected to the MTT assay and tested for their activity on normal and colorectal cancer cells. Sorafenib was selected as a positive control and the results are shown in table 1.
MTT test: HCT-116, HT-29, SW-480, CT-26, GES-1 cells were seeded at 6000 cells/well in 96-well plates, and the CO was 5% at 37 ℃% 2 The incubator is used for 24 hours; discarding the culture medium, adding 100 μ L compound solution (concentration of 100, 20, 4, 0.8, 0.016 μ M) at each concentration, and culturing for 48 hr; then adding MTT (5 mg/mL,20 mu L) and incubating for 4h at 37 ℃; remove the medium and add 150 μ L DMSO to dissolve; by means of a microplate reader (Perk)inElmer Envision) at 492nm, and calculating GI 50 The value is obtained.
TABLE 1
As can be seen from table 1, the kinase activity and cellular activity of compound 29 were significantly superior to sorafenib.
Example 56
Evaluation of in vivo antitumor activity:
to evaluate the in vivo anti-tumor activity of compound 29, different doses (10 mg/kg and 40 mg/kg) of compound 29 were orally administered once a day to Balb/c mice that had been subcutaneously transplanted with CT-26 tumor cells. Tumor volume and body weight were recorded every two days. As shown in FIGS. 1A-B, the increase in tumor volume was most pronounced in the control group, and significantly slower in the treated group compared to the control group. Tumor growth inhibition value (TGI) was used to evaluate the inhibition of tumor growth by compound 29 in vivo, the TGI value increasing with increasing dose of compound 29 (fig. 1C). The results show that compound 29 effectively reduced the tumor volume in CT-26 tumor-bearing mice. H & E staining of tumor tissue showed significant changes after treatment, indicating the efficiency and specificity of compound 29 in vivo (FIG. 1D). To investigate the effect of compound 29 on CDK8 in vivo, the expression level of β -catenin in tumor samples was examined. IHC analysis showed β -catenin downregulation after treatment with compound 29 (fig. 1E-F). To investigate the effect of compound 29 on molecular targets in vivo, the expression levels of β -catenin, E2F1, c-Myc associated with CDK8 were examined in tumor samples. Western blot analysis shows that after the compound 29 is treated, the beta-catenin and the c-Myc are down-regulated, the E2F1 is up-regulated, and CDK8 has no obvious change, which indicates that WNT/beta-catenin signal channels related to the CDK8 participate in the in vivo anti-tumor effect exertion of the compound 29.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (7)
1. An aryl urea derivative is characterized in that the structure of the aryl urea derivative is shown as formulas I and II:
wherein R is 1 ，R 2 ，R 3 ，R 4 Is selected from CH 3 、OCH 3 、CF 3 Any one group of CN, H, F, cl and Br;
R 5 any one group selected from 2-aminopyridine, 7-azaindole and derivatives thereof;
x is selected from CH 2 Any one of NH, O and S.
2. A process for the preparation of arylurea derivatives according to claim 1, characterized in that: the method comprises the following steps:
(1) Nucleophilic substitution reaction is carried out on 2-nitro-5-bromopyridine and (3-hydroxyphenyl) carbamic acid tert-butyl ester to obtain an intermediate M1;
(2) Removing deprotection of the intermediate M1 to obtain an intermediate M2;
(3) Reacting the intermediate M2 with an arylamine derivative to obtain an intermediate M3;
(4) Carrying out reduction reaction on the intermediate M3 to obtain compounds 1-19;
the reaction equation is as follows:
(5) Synthesis route conditions for Compounds 20-42 were identical to those for Compounds 1-19 except that the starting material, t-butyl (3-hydroxyphenyl) carbamate, was replaced with t-butyl (4-hydroxyphenyl) carbamate; wherein compound 29 is brominated to provide compound 53;
the reaction equation is as follows:
(6) Carrying out nucleophilic substitution reaction on the 5-hydroxy-7-azaindole and the 3-fluoronitrobenzene to obtain an intermediate M7;
(7) Carrying out reduction reaction on the intermediate M7 to obtain an intermediate M8;
(8) Reacting the intermediate M8 with an arylamine derivative to obtain a compound 43-46;
the reaction equation is as follows:
(10) The synthetic route of the compound 47-50 is identical to that of the compound 43-46, and the raw material 3-fluoronitrobenzene is changed into 4-fluoronitrobenzene;
the reaction equation is as follows:
(11) Reducing the intermediate M4 to obtain an intermediate M11;
(12) Intermediate M11 is acetylated to give intermediate M12;
(13) Removing Boc from the intermediate M12 under the trifluoroacetic acid condition to obtain an intermediate M13;
(14) Reacting the intermediate M13 with an arylamine derivative to obtain compounds 51-52;
the reaction equation is as follows:
(15) Compound 54 synthetic route is the same as compound 1 except that the starting material tert-butyl (3-hydroxyphenyl) carbamate is replaced with tert-butyl (4-mercaptophenyl) carbamate;
the reaction equation is as follows:
3. a pharmaceutical composition comprising an arylurea derivative according to claim 1 or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical preparation comprising an active ingredient and a pharmaceutically acceptable adjuvant and/or carrier, wherein the active ingredient comprises the arylurea derivative or a pharmaceutically acceptable salt thereof according to claim 1.
5. Use of an arylurea derivative according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a CDK8 inhibitor.
6. Use of the arylurea derivative or the pharmaceutically acceptable salt thereof according to claim 1 for the preparation of an antitumor medicament.
7. Use according to claim 6, characterized in that: the tumor is selected from melanoma, breast cancer, acute myeloid leukemia, pancreatic cancer, prostate cancer, and colorectal cancer.
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Citations (4)
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| US20100168430A1 (en) * | 2005-08-05 | 2010-07-01 | Chugai Seiyaku Kabushiki Kaisha | Multikinase inhibitor |
| CN111601790A (en) * | 2018-03-15 | 2020-08-28 | 福建海西新药创制有限公司 | Heteroaryl compounds as protein kinase inhibitors |
| CN115141197A (en) * | 2022-07-27 | 2022-10-04 | 安徽医科大学 | 3-aromatic heterocyclic substituted phenyl derivative and preparation method and application thereof |
| CN115991705A (en) * | 2022-12-26 | 2023-04-21 | 安徽医科大学 | 3- (1H pyrrolo [2,3-b ] pyridin-5-yl) benzoyl derivatives, preparation and application thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100168430A1 (en) * | 2005-08-05 | 2010-07-01 | Chugai Seiyaku Kabushiki Kaisha | Multikinase inhibitor |
| CN111601790A (en) * | 2018-03-15 | 2020-08-28 | 福建海西新药创制有限公司 | Heteroaryl compounds as protein kinase inhibitors |
| CN115141197A (en) * | 2022-07-27 | 2022-10-04 | 安徽医科大学 | 3-aromatic heterocyclic substituted phenyl derivative and preparation method and application thereof |
| CN115991705A (en) * | 2022-12-26 | 2023-04-21 | 安徽医科大学 | 3- (1H pyrrolo [2,3-b ] pyridin-5-yl) benzoyl derivatives, preparation and application thereof |
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| CA化学文摘收录: ""STN检索报告1"", 《STN检索平台REGISTRY数据库（在线）》, no. 2022, pages 2767425 - 89 * |
| PHILIPPE BERGERON ET AL.: ""Design and Development of a Series of Potent and Selective Type II Inhibitors of CDK8"", 《ACS MED. CHEM. LETT.》, vol. 7, pages 595 - 600 * |
| YAO YAO YAN ET AL.: ""Design and Synthesis of a 2‑Amino-pyridine Derivative as a Potent CDK8 Inhibitor for Anti-colorectal Cancer Therapy"", 《J. MED. CHEM.》, vol. 65, pages 13216 - 13239 * |
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