CN115232030A - Aryl urea compound and preparation method and pharmaceutical application thereof - Google Patents

Aryl urea compound and preparation method and pharmaceutical application thereof Download PDF

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CN115232030A
CN115232030A CN202110441682.XA CN202110441682A CN115232030A CN 115232030 A CN115232030 A CN 115232030A CN 202110441682 A CN202110441682 A CN 202110441682A CN 115232030 A CN115232030 A CN 115232030A
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肖志艳
张浩超
景连栋
杨亚军
刘曼
来芳芳
陈晓光
杨颖�
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Abstract

The invention belongs to the technical field of medicines, and discloses an arylurea compound shown as a formula (I), a preparation method and a pharmaceutical application thereof, a physiologically acceptable salt, a solvate and a crystal form thereof, a preparation method of the compound, a pharmaceutical preparation containing the compound, and clinical application of the compound in treating CDK8 related diseases such as tumors and the like.

Description

Aryl urea compound and preparation method and pharmaceutical application thereof
Technical Field
The invention relates to the technical field of medicines, and relates to aryl urea compounds with a general formula (I), a preparation method and a medicinal application thereof, and physiologically acceptable salts thereof. The application of the compounds in preparing CDK8 inhibitors and medicaments for treating tumors and medicinal compositions containing the compounds.
Background
Malignant tumors have become serious diseases seriously threatening human health, and the drug therapy plays an important role in the clinical treatment of tumors. The antitumor drugs include cytotoxic drugs and molecular targeted drugs. The nonspecific defect of the former causes damage to normal organs and tissues of tumor patients, and the targeted selectivity of the latter on tumor cells improves the drug effect and reduces the damage to normal organisms. At present, many pharmaceutical companies successfully develop molecular targeted antitumor drugs, and the clinical application of tumor molecular targeted therapy is greatly promoted.
Cyclin-dependent kinases (CDKs) are serine/threonine kinases that are activated upon binding to cyclins (cyclins) and catalyze phosphorylation of substrates. Meanwhile, CDKs regulate cell cycle progression under the synergy of cyclin-dependent kinase inhibitors and play a key role in gene transcription, and are considered as potential therapeutic targets for a variety of diseases including tumors. The successful marketing of these drugs, from pan-CDK inhibitors (Alvocidib) to more specific CDK inhibitors (CDK 4/6 selective inhibitors Palbociclib, ribociclib and Abemaciclib) for decades, validated CDK as a therapeutic target for cancer and demonstrated the importance of achieving subtype-selective inhibition in achieving CDK4/6 selective inhibitors.
CDK8 is a unique member of the CDK family. As one of the key components of the mediator complex, it is involved in multiple signaling pathways, regulating the transcription of the relevant genes under specific circumstances in the organism. CDK8 is highly expressed in many cancer samples and is considered as a potential target for treating malignant tumors such as colorectal cancer, breast cancer, gastric cancer, ovarian cancer, melanoma and the like, and selective inhibition of CDK8 is a feasible way for treating cancers.
To date, various structural types of CDK8 small molecule inhibitors have been reported in the literature, but no CDK8 inhibitors have been successfully marketed due to their pharmacokinetic properties and kinase selectivity. Currently, the development of CDK8 inhibitors is still in the primary stage, with only two CDK8 selective inhibitors (BCD-115 and SEL 120-34A) entering the clinical trial stage. Therefore, the inventors of the present application are intended to provide novel potent selective CDK8 small molecule inhibitors, providing a chemical template for the study of novel anti-tumor drug candidates.
Disclosure of Invention
The invention aims to provide an aryl urea compound shown as a general formula (I).
Another object of the present invention is to provide a process for preparing an arylurea compound represented by the general formula (I) or an analog thereof.
The invention also aims to provide application of the compound shown in the general formula (I) in preparing CDK8 inhibitors and in preparing medicaments for treating tumors.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
Figure BDA0003035260180000021
wherein,
R 1 selected from halogen, trifluoromethyl, single or multiple on benzene ringR 1 A substituent group;
x and Y are selected from N or C;
R 2 selected from H, CF 3 ﹑F﹑CN﹑NO 2 ﹑NH 2 ﹑N(CH 3 ) 2 C1-C3 alkyl, C1-C3 alkoxy or the following fragments:
Figure BDA0003035260180000022
in another aspect of the present invention, there is provided a compound represented by the general formula (IA):
Figure BDA0003035260180000031
wherein,
R 1 selected from halogen, trifluoromethyl, having one or more R on the phenyl ring 1 A substituent group;
R 2 is selected from R 2 Selected from H, CF 3 ﹑F﹑CN﹑NO 2 ﹑NH 2 ﹑N(CH 3 ) 2 C1-C3 alkyl, C1-C3 alkoxy or the following fragments:
Figure BDA0003035260180000032
still another embodiment of the present invention is to provide a compound represented by the general formula (IB):
Figure BDA0003035260180000033
wherein,
R 1 selected from halogen, trifluoromethyl, having one or more R on the phenyl ring 1 A substituent group;
x and Y are selected from N or C;
another embodiment of the present invention provides the compound or a physiologically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure BDA0003035260180000034
Figure BDA0003035260180000041
Figure BDA0003035260180000051
still another embodiment of the present invention provides a method for synthesizing a compound represented by the general formula (I), comprising the steps of:
reacting a compound of formula II with a compound of formula III to produce a compound of formula (I):
Figure BDA0003035260180000052
wherein R is 1 、R 2 X and Y are as defined above.
The compounds TM-1 to TM-9 were synthesized analogously, for example with compound TM-1, by the following procedure:
Figure BDA0003035260180000061
taking the compound TM-14 as an example, the compounds TM-10, TM-14 and TM-15 are synthesized similarly through the compounds TM-12 and TM-13, taking the compound TM-14 as an example, and the preparation process is as follows:
Figure BDA0003035260180000062
the synthesis of compounds TM-16 to TM-25 is similar, taking compound TM-16 as an example, and the preparation process is as follows:
Figure BDA0003035260180000063
for the preparation of medicaments, the compounds of the general formula (I) are mixed in a known manner with suitable pharmaceutical carrier substances, fragrances, flavors and colors in a known manner and are tableted or coated, or are suspended or dissolved in water or oil with other additional substances.
The invention also relates to a pharmaceutical composition containing a pharmaceutically effective dose of the compound shown in the general formula I and a pharmaceutically acceptable carrier.
The compounds of the invention may be administered orally or parenterally. The oral preparation can be tablet, capsule, and coating agent, and the parenteral preparation can be injection and suppository. These formulations are prepared according to methods well known to those skilled in the art. Adjuvants used for the manufacture of tablets, capsules, coatings are the customary auxiliaries, such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms, such as water, ethanol, propylene glycol, vegetable oils, such as corn oil, peanut oil, olive oil, etc. The formulations containing the compounds of the present invention may also contain other adjuvants such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, coloring agents, and the like.
The invention also provides application of the compound in preparing CDK8 inhibitors and medicines for treating tumors.
The beneficial technical effects are as follows:
poor specificity of action is one of the major challenges facing current kinase inhibitor research. The compound has the characteristics and advantages of specifically inhibiting CDK8, and is expected to provide a novel, safe and effective CDK8 inhibitor as a small-molecule antitumor drug.
Drawings
FIG. 1. Inhibitory Effect of Compound TM-8 on 25 kinases
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS) or High Resolution Mass Spectrometry (HRMS). The NMR shift (δ) is given in units of parts per million (ppm). m.p. is the melting point given in ° c, the temperature is uncorrected. The column chromatography generally uses 200-300 mesh silica gel as a carrier. NMR was measured using INOVA-300 and CDCl as the solvent 3 、DMSO-D 6 Internal standard is TMS and chemical shifts are given in ppm. MS was measured using an Agilent LC/MSD TOF LC/MS spectrometer.
Example 1: preparation of TM-1
Figure BDA0003035260180000081
3, 4-dichlorobenzene (188mg, 1.0 mmol) was dissolved in 10mL dichloromethane, 4-fluorophenethylamine (139mg, 1.0 mmol) was added, and the reaction was stirred at room temperature for 2h. After the reaction is finished, a large amount of white solid is generated, the solid is filtered by suction and washed by dichloromethane for several times, and the white solid product is obtained with the yield of about 85 percent. 1 H NMR(400MHz,DMSO-d 6 )δ8.80(s,1H),7.84(d,J＝2.4Hz,1H)，7.44(d，J＝8.8Hz,1H),7.28(d,J＝5.6Hz,1H),7.25(d,J＝5.6Hz,1H),7.22(dd,J＝8.8，2.4Hz,1H),7.12(d,J＝8.8Hz,2H),6.25(t,J＝5.6Hz,1H),3.32(td,J＝7.2,5.6Hz,2H),2.68(t,J＝7.2Hz,2H). 13 C NMR(125MHz,DMSO-d 6 )δF-C(163.75,161.66,159.74，157.54),154.62,140.61，135.44,135.42，130.75，130.36，130.29,121.96，118.44,117.50,2×F-C-CH(115.00,114.83),40.52,34.64.HR-ESI-MS：m/z＝327.04626[M+H] + ,calcd for C 15 H 14 ON 2 Cl 2 F：327.04617.
Example 2: preparation of TM-2
Figure BDA0003035260180000082
4-methyl phenethylamine and 3, 4-dichlorobenzene isocyanateThus, the synthesis and operation were the same as for compound 1, with a yield of about 78%. 1 H NMR(400MHz,DMSO-d 6 )δ8.80(s，1H),7.84(d,J＝2.8Hz,1H)，7.43(d,J＝8.8Hz,1H),7.22(dd,J＝8.8,2.8Hz,1H),7.11(s,4H),6.22(t,J＝5.6Hz，1H),3.31(td,J＝7.2,5.6Hz,2H),2.70(t,J＝7.2Hz,2H),2.27(s,3H)； 13 C NMR(125MHz,DMSO-d 6 )δ154.75,140.79,136.29,135.04，130.90,130.43,128.98,128.98，128.56，128.56,122.09,118.57，117.62,40.74，35.27,20.67.HR-ESI-MS：m/z＝323.07166[M+H] + ,calcd for C 16 H 17 ON 2 Cl 2 ：323.07125.
Example 3: preparation of TM-3
Figure BDA0003035260180000091
4-nitrophenylethylamine and 3, 4-dichlorobenzene isocyanate, and the synthesis method and operation are the same as those of the compound 1, and the yield is about 62%. 1 H NMR(400MHz,DMSO-d 6 )δ8.81(s,1H),8.18(dd,J＝6.8，2.0Hz,2H),7.83(d,J＝2.8Hz,1H),7.53(dd,J＝6.8,2.0Hz,2H),7.44(d,J＝8.8Hz,1H)，7.22(dd,J＝8.8,2.8Hz,1H)，6.33(t,J＝5.6Hz,1H),3.40(td,J＝7.2,5.6Hz,2H),2.91(t,J＝7.2Hz,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ154.65,147.89,145.95,140.56,130.76，130.29,129.96,129.96,123.33,123.33,122.06,118.52,117.57,39.94,35.36.HR-ESI-MS：m/z＝354.03989[M+H] + ,calcd for C 15 H 14 O 3 N 3 Cl 2 ：354.04067.
Example 4: preparation of TM-4
Figure BDA0003035260180000092
4-nitrophenylethylamine and 4-chloro-3-trifluoromethylphenyl isocyanate, and the synthesis method and operation thereof are the same as those of the compound 1, and the yield is about 61%. 1 H NMR(400MHz,DMSO-d 6 )δ9.00(s,1H),8.18(d,J＝8.4Hz,2H),8.05(s,1H),7.54(s,2H),7.53(d,J＝8.4Hz,2H),6.38(t,J＝5.6Hz,1H),3.40(td，J＝6.8,5.6Hz,2H),2.92(t,J＝6.8Hz,2H). 13 C NMR(125MHz,DMSO-d6)δ154.84,148.03,146.10,140.09,131.87,130.13，130.13,C-CF 3 (126.93,126.69,126.45,126.21)，CF 3 (126.14,123.97,121.80,119.63)，123.48,123.48,122.30，121.36，CH-C-CF 3 (116.18,116.13,116.09，116.04),40.12,35.49.HR-ESI-MS：m/z＝388.06488[M+H] + ,calcd for C 16 H 14 O 3 N 3 ClF 3 ：388.06703.
Example 5: preparation of TM-5
Figure BDA0003035260180000093
4-trifluoromethyl phenethylamine and 3, 4-dichlorobenzene isocyanate, and the synthesis method and operation are the same as those of the compound 1, and the yield is about 37 percent. 1 H NMR(400MHz,DMSO-d 6 )δ8.80(s,1H),7.84(d,J＝2.4Hz,1H),7.67(d,J＝8.0Hz,2H),7.47(d,J＝8.0Hz，2H),7.44(d,J＝8.8Hz,1H),7.22(dd,J＝8.8，2.4Hz，1H),6.29(t,J＝5.6Hz,1H),3.38(td,J＝6.8,5.6Hz，2H),2.85(t,J＝6.8Hz,2H)； 13 C NMR(125MHz,DMSO-d6)δ154.64,144.39，140.58,130.76,130.29,129.45,129.45,CF 3 (127.57,125.40,123.24,121.08),C-CF 3 (127.14,126.89，126.64,126.39),2×CH-C-CF 3 (125.09,125.07，125.03,125.00),122.02,118.49,117.54,40.10,35.28.HR-ESI-MS：m/z＝377.04297[M+H] + ,calcd for C 16 H 14 ON 2 Cl 2 F 3 ：377.04298.
Example 6: preparation of TM-6
Figure BDA0003035260180000101
4-trifluoromethyl phenethylamine and 4-chloro-3-trifluoromethyl phenylisocyanate, and the synthesis method and operation are the same as those of the compound 1, and the yield is about 93 percent. 1 H NMR(400MHz，DMSO-d 6 )δ8.99(s，1H)，8.05(d，J＝1.6Hz,1H),7.67(d,J＝8.0Hz,2H)，7.54(d，J＝2.0Hz,1H)，7.53(s,1H)，7.47(d,J＝8.0Hz,2H),6.35(t,J＝5.6Hz,1H),3.39(td,J＝7.2,5.6Hz，2H),2.86(t,J＝7.2Hz,2H). 13 C NMR(125MHz,DMSO-d 6 )δ154.68,144.37,139.95,131.71,129.47,129.47,CF 3 (127.56,125.40,123.24,121.08),C-CF 3 (126.89,126.63),C-CF 3 (126.54,126.30),CF 3 (125.96,123.82,121.65,119.48),2×CH-C-CF 3 (125.09,125.06,125.03,125.00),122.13,121.19,CH-C-CF 3 (115.99,115.95,115.91,115.87),40.13,35.28.HR-ESI-MS：m/z＝411.07083[M+H] + ,calcd for C 17 H 14 ON 2 ClF 6 ：411.06934.
Example 7: preparation of TM-7
Figure BDA0003035260180000102
4-methoxy phenethylamine and 3, 4-dichlorobenzene isocyanate, and the synthesis method and operation are the same as the compound 1, and the yield is about 84 percent. 1 H NMR(400MHz，DMSO-d 6 )δ8.81(s,1H),7.84(d，J＝2.4Hz，1H)，7.44(d,J＝8.8Hz,1H)，7.22(dd，J＝8.8，2.4Hz，1H)，7.13(dd，J＝9.6，5.2Hz,1H),7.15(d,J＝8.8Hz,1H),6.87(dd,J＝9.6,5.2Hz,1H),6.87(d,J＝8.8Hz,1H),6.22(t,J＝5.6Hz,1H),3.72(s,3H),3.29(td,J＝7.2,5.6Hz,2H)，2.68(t，J＝7.2Hz,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ157.54,154.60，140.65,131.08,130.75,130.29,129.49，129.49，121.92,118.40,117.47,113.66,113.66,54.85,40.75,34.65.HR-ESI-MS：m/z＝339.06723[M+H] + ，calcd for C 16 H 17 O 2 N 2 Cl 2 ：339.06616.
Example 8: preparation of TM-8
Figure BDA0003035260180000111
4-methoxy phenethylamine and 4-chloro-3-trifluoromethyl phenylisocyanate, and the synthesis method and operation thereof are the same as those of the compound 1, and the yield is about 89%. 1 H NMR(400MHz,DMSO-d 6 )δ8.99(s，1H),8.06(d,J＝2.4Hz,1H),7.55(d,J＝2.0Hz，1H),7.54(s，1H),7.15(dd,J＝6.8,2.0Hz，2H),6.87(dd,J＝6.8,2.0Hz，2H)，6.27(t，J＝5.6Hz，1H)，3.72(s，3H)，3.29(td，J＝7.2,5.6Hz,2H),2.69(t,J＝7.2Hz，2H). 13 C NMR(125MHz,DMSO-d 6 )δ157.56,154.66,140.03,131.72,131.08,129.51,129.51,C-CF 3 (126.79,126.55,126.31,126.07)，CF 3 (126.01，123.84,121.67,119.41),122.07,121.10，CH-C-CF 3 (115.93，115.89,115.85,115.80),113.67,113.67,54.85,40.79,34.66.HR-ESI-MS：m/z＝373.09372[M+H] + ,calcd for C 17 H 17 O 2 N 2 ClF 3 ：373.09252.
Example 9: preparation of TM-9
Figure BDA0003035260180000112
The p-3- (2-aminoethyl) pyridine is obtained by reacting 3, 4-dichlorobenzene isocyanate, and the synthesis method and operation are the same as those of the compound 1, and the yield is about 74 percent. 1 H NMR(400MHz,DMSO-d 6 )δ8.81(s,1H),8.45(d,J＝2.4Hz,1H),8.43(dd,J＝4.8,1.6Hz,1H),7.83(d,J＝2.4Hz,1H),7.66(dt,J＝8.0,1.6Hz,1H),7.44(d,J＝8.8Hz,1H),7.35-7.31(m,1H),7.22(dd,J＝8.8,2.4Hz,1H),6.31(t,J＝5.6Hz,1H),3.36(q,J＝6.8,5.6Hz,2H),2.78(t,J＝6.8Hz,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ154.63,149.79,147.33,140.59,136.11,134.79，130.75,130.29,123.37,122.01,118.48,117.54,40.08,32.58.HR-ESI-MS：m/z＝310.05148[M+H] + ,calcd for C 14 H 14 ON 3 Cl 2 ：310.05084.
Example 10: preparation of TM-10
Figure BDA0003035260180000121
1) 1- (3, 4-dichlorophenyl) -3- (4-hydroxyphenylethyl) urea
3, 4-dichlorobenzene (188mg, 1.0 mmol) was dissolved in 10mL of dichloromethane, p-hydroxyphenylethylamine (137mg, 1.0 mmol) was added, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, a large amount of white solid was produced, and the solid was filtered with suction and washed with dichloromethane several times to obtain the product as a white solid (210 mg, yield 65%).
2) 1- (3, 4-dichlorophenyl) -3- (4- (2-morpholin-2-oxyethoxy) phenethyl) urea
1- (3, 4-dichlorophenyl) -3- (4-hydroxyphenylethyl) urea (324mg, 1.0mmol), 4- (2-chloroacetyl) morpholine (163mg, 1.0mmol) and K were weighed 2 CO 3 (276 mg,2.0 mmol), KI (84mg, 0.5 mmol), dissolved in 10mL DMF and stirred at 80 deg.C in an oil bath for about 6h. After the reaction is finished, the DMF is evaporated to dryness under reduced pressure, anhydrous ether is added, and a white solid product is separated out by stirring, wherein the yield is about 82%. 1 H NMR(400MHz,DMSO-d 6 )δ8.89(s，1H),7.85(d,J＝2.0Hz,1H)，7.44(d,J＝6.8Hz,1H)，7.22(dd，J＝6.8,2.0Hz，1H)，7.14(d，J＝6.8Hz,2H)，6.86(d，J＝6.8Hz,2H)，6.31(t，J＝4.4Hz，1H)，4.79(s,2H)，3.62-3.54(m，4H),3.47-3.43(m，4H)，3.28(dd，J＝5.6，4.4Hz，2H)，2.68(t，J＝5.6Hz,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ165.99,156.32,154.64,140.68，131.56,130.75,130.28,129.38,129.38,121.90,118.40,117.47,114.38,114.38,65.95,65.90,65.65,44.62,41.44，40.72,34.64.HR-ESI-MS：m/z＝452.11447[M+H] + ，calcd for C 21 H 24 O 4 N 3 Cl 2 ：452.11384.
Example 11: preparation of TM-11
Figure BDA0003035260180000122
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4-hydroxyphenylethyl) urea and 2-chloro-1-morpholinoethan-1-one, and synthetic method, operation and combination thereofThe yield was about 65% with the same thing 10. 1 H NMR(400MHz,DMSO-d 6 )δ9.02(s,1H),8.07(d,J＝2.4Hz,1H),7.57-7.51(m,2H),7.14(d,J＝8.6Hz,2H),6.86(d,J＝8.6Hz,2H),6.31(t,J＝5.6Hz,1H),4.78(s,2H),3.63–3.53(m,4H),3.48-3.42(m,4H),3.31(td,J＝7.2,5.6Hz,2H),2.69(t,J＝7.2Hz,2H). 13 C NMR(125MHz,DMSO-d 6 )δ166.00,156.33,154.68,140.05,131.72,131.55,129.40,129.40,C-CF 3 (26.79,126.55,126.31,126.06),CF 3 (126.01,123.84,121.67,119.50),122.08,121.10,CH-C-CF 3 (115.89,115.84),114.39,114.39,65.95,65.91,65.66,44.63,41.45,40.77,34.65.HR-ESI-MS：m/z＝486.14102[M+H] + ,calcd for C 22 H 24 O 4 N 3 ClF 3 ：486.14020.
Example 12: preparation of TM-12
Figure BDA0003035260180000131
The compound is obtained by weighing 1- (3, 4-dichlorophenyl) -3- (4-hydroxyphenylethyl) urea and ethyl bromoacetate for reaction, and the synthesis method and operation thereof are the same as the compound 10, and the yield is about 68 percent. 1 H NMR(400MHz,DMSO-d 6 )δ8.80(s,1H),7.85(d，J＝2.4Hz,1H),7.43(d,J＝8.8Hz,1H),7.22(dd,J＝8.8,2.4Hz,1H),7.15(dd,J＝6.8,2.0Hz,2H),6.86(dd,J＝6.8,2.0Hz,2H),6.25(t,J＝5.6Hz,1H)，4.74(s，2H)，4.16(q，J＝7.2Hz,2H)，3.29(td,J＝7.8，5.6Hz,2H),2.68(t,J＝7.8Hz,2H),1.21(t，J＝7.2Hz,3H)； 13 C NMR(125MHz,DMSO-d 6 )δ168.72，155.92，154.6，140.64，131.89,130.75,130.29，129.51，129.51，121.93,118.41,117.48,114.27,114.27,64.48,60.47，40.67,34.61,13.94.HR-ESI-MS：m/z＝411.08682[M+H] + ,calcd for C 19 H 21 O 4 N 2 Cl 2 :411.08729.
Example 13: preparation of TM-13
Figure BDA0003035260180000132
Dissolving compound 2- (4- (2- (3- (3- (3, 4-dichlorophenyl) ureido) ethyl) phenoxy) ethyl acetate (410mg, 1.0 mmol) in 20ml of absolute ethyl alcohol, dropwise adding 4ml of 1M NaOH aqueous solution, stirring at room temperature for 2h, after the reaction is finished, evaporating the solvent under reduced pressure, adding distilled water for dissolving, washing with ethyl acetate, adjusting the pH of an aqueous layer to about 5 by using 1M HCl aqueous solution, and precipitating white solid with the yield of about 72%. 1 H NMR(400MHz,DMSO-d 6 )δ10.46(s,1H),7.88(d,J＝2.0Hz,1H),7.75(t，J＝5.2Hz,1H),7.37(d,J＝9.2Hz,1H),7.32(dd,J＝9.2,2.0Hz,1H),7.07(dd,J＝7.2,1.2Hz,2H),6.75(dd,J＝7.2,1.2Hz,2H),4.18(s,2H),3.19(td,J＝6.8,5.2Hz，2H),2.58(t,J＝6.8Hz,2H). 13 C NMR(125MHz,DMSO-d 6 )δ172.07,157.12,155.32,141.66,130.67,130.50,130.03,129.14,129.14,120.99,118.08,117.30,114.12,114.12,67.42,40.85,34.44.HR-ESI-MS：m/z＝383.05566[M+H] + ,calcd for C 17 H 17 O 4 N 2 Cl 2 ：383.05599.
Example 14: preparation of TM-14
Figure BDA0003035260180000141
2- (4- (2- (3, 4-dichlorophenyl) ureido) ethyl) phenoxy) acetic acid (191mg, 0.5 mmol), 4-aminopyridine (56.5 mg,0.6 mmol), HATU (228mg, 0.6 mmol), DIEA (129mg, 1.0 mmol) were weighed out and dissolved in 10mL of a mixed solvent of dichloromethane and DMF (1: 1), and the reaction was stirred at room temperature for about 4 hours. After the reaction is finished, the solvent is evaporated to dryness under reduced pressure, ethyl acetate is added, the mixture is washed by saturated saline solution, the organic layer is concentrated to obtain a crude product, and the crude product is subjected to silica gel column chromatography to obtain a white solid product with the yield of about 67%. 1 H NMR(400MHz,DMSO-d 6 )δ10.46(s,1H),8.85(s,1H),8.44(dd,J＝4.4,1.6Hz,2H),7.84(d,J＝2.4Hz,1H),7.62(dd,J＝4.4,1.6Hz,2H),7.43(d,J＝8.8Hz,1H)，7.22(dd，J＝8.8，2.4Hz,1H)，7.17(dd，J＝6.8，2.0Hz,2H)，6.93(dd，J＝6.8,2.0Hz,2H),6.29(t,J＝5.6Hz,1H),4.72(s,2H),3.29(td,J＝6.8,5.6Hz,2H),2.69(t,J＝6.8Hz,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ167.88,156.03,154.62,150.30，150.30，144.95,140.66，132.01,130.73，130.27,129.55,129.55,121.89,118.40，117.47,114.43，114.43,113.38，113.38，66.91,40.68,34.64；HR-ESI-MS：m/z＝459.09915[M+H] + ,calcd for C 22 H 21 O 3 N 4 Cl 2 ：459.09852.
Example 15: preparation of TM-15
Figure BDA0003035260180000151
2- (4- (2- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) ethyl) phenoxy) acetic acid and 4-aminopyridine, the synthesis and operation of which are the same as those of compound 14, with a yield of about 77%. 1 H NMR(400MHz,DMSO-d 6 )δ10.95(s,1H)，8.99(s,1H),8.59(dd,J＝5.6,1.6Hz 2H),8.06(d,J＝2.0Hz,1H),7.87(dd,J＝5.6,1.6Hz 2H),7.54(d,J＝2.0Hz,1H),7.54(s,1H),7.18(dd,J＝6.4,2.0Hz 2H)，6.94(dd,J＝6.4,2.0Hz 2H)，6.30(t,J＝5.6Hz,1H)，4.79(s,2H),3.31(td，J＝7.2,5.6Hz,2H),2.70(t,J＝7.2Hz,2H). 13 C NMR(125MHz，DMSO-d 6 )δ168.81,156.11,154.83，148.77,146.63,140.17,132.28,131.88，129.75，129.75,C-CF 3 (126.94,126.70,126.46,126.22),CF 3 (126.16,123.99,121.82，119.80),122.25,121.29,2×CH-C-CF 3 (116.06,116.04,116.02,115.97)114.62,114.62,114.13,114.13,67.10，40.91,34.82.HR-ESI-MS：m/z＝493.12518[M+H] + ,calcd for C 23 H 21 O 3 N 4 ClF 3 ：493.12488.
Example 16: preparation of TM-16
Figure BDA0003035260180000152
1) Tert-butyl (4-nitrophenylethyl) carbamate
4-Nitrobenzene ethylamine hydrochloride (202mg, 1.0 mmol) was dissolved in 10mL of dichloromethane, and Boc anhydride (218mg, 1.0 mmol) and DMAP (122mg, 1.0 mmol) were added to stir the reaction at room temperature for 5 hours. After the reaction is finished, washing with saturated NaCl, evaporating the organic layer under reduced pressure to dryness to obtain a light yellow product, adding distilled water, stirring, and performing suction filtration to obtain a white solid with the yield of about 92%.
2) Tert-butyl (4-aminophenylethyl) carbamate
The compound tert-butyl (4-nitrophenylethyl) carbamate (266mg, 1.0 mmol) was dissolved in 5ml of methanol, pd/C (80mg, 10%) was added, and after 5 replacements with a hydrogen balloon, protection was continued and stirring was carried out at room temperature for 2 hours. After the reaction, pd/C was removed with celite, and after washing with methanol several times, the solvent was evaporated to dryness under reduced pressure to give 210mg of a white solid with a yield of about 89%.
3) Tert-butyl (4- (isonicotinamide) phenethyl) carbamate
Tert-butyl (4-aminophenylethyl) carbamate (236mg, 1.0 mmol), isonicotinic acid (123mg, 1.0 mmol), HATU (379mg, 1.0 mmol), DIEA (129mg, 1.0 mmol) were weighed out, dissolved in 10mL of a mixed solvent of dichloromethane and DMF (1: 1), and the reaction was stirred at room temperature for about 4 hours. After the reaction is finished, the solvent is evaporated to dryness under reduced pressure, ethyl acetate is added, the mixture is washed by saturated saline solution, an organic layer is concentrated to obtain a crude product, and the crude product is subjected to silica gel column chromatography to obtain a white solid product with the yield of about 65%.
4) N- (4- (2-aminoethyl) phenyl) isonicotinamide
Tert-butyl (4- (isonicotinamide) phenethyl) carbamate (130mg, 0.3mmol) was dissolved in 2mL of dichloromethane, 2.0mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 2h. After the reaction, the residual solvent was distilled off, a saturated aqueous solution of sodium carbonate was added to the reaction system, the system was extracted with ethyl acetate, and the organic layers were combined and concentrated to give a light brown oil with a yield of about 89.2%.
5) N- (4- (2- (3, 4-dichlorophenyl) ureido) ethyl) phenyl) isonicotinamide
The N- (4- (2-aminoethyl) phenyl) isonicotinamide is obtained by reacting 3, 4-dichlorobenzene isocyanate with the same synthetic method and operation as compound 1, and the yield is about 54%. 1 H NMR(400MHz,DMSO-d 6 )δ10.45(s,1H),8.83(s,1H),8.78(dd,J＝4.4,1.8Hz,2H),7.85(dd,J＝4.4,1.8Hz,2H),7.84(s,1H),7.70(dd，J＝6.4，1.6Hz,2H)，7.44(d，J＝8.8Hz，1H)，7.24(dd，J＝6.4,1.6Hz,2H)，7.22(dd，J＝8.8,2.8Hz，1H)，6.27(t,J＝5.6Hz,1H),3.35(td,J＝7.2,5.6Hz,2H),2.73(d,J＝7.2Hz,2H). 13 C NMR(125MHz,DMSO-d 6 )δ163.68,154.62,150.14,150.14,141.83,140.64,136.61,135.15,130.75,130.29,128.79,128.79,121.94,121.44,121.44,120.41,120.41,118.43,117.49,40.52,35.02.HR-ESI-MS：m/z＝429.08813[M+H] + ,calcd for C 21 H 19 O 2 N 4 Cl 2 ：429.08796.
Example 17: preparation of TM-17
Figure BDA0003035260180000161
N- (4- (2-aminoethyl) phenyl) isonicotinamide and 4-chloro-3-trifluoromethylphenyl isocyanate, and the synthesis method and operation are the same as those of compound 16, and the yield is about 52%. 1 H NMR(400MHz,DMSO-d 6 )δ10.45(s,1H)，9.02(s,1H),8.78(dd,J＝4.4,1.6Hz,2H),8.07(d,J＝2.0Hz,1H),7.85(dd,J＝4.4,1.6Hz,2H),7.71(dd,J＝6.8,2.0Hz,2H),7.55(d,J＝2.0Hz,1H),7.54(s,1H)，7.25(dd,J＝6.8,2.0Hz,2H),6.33(t,J＝5.6Hz,1H),3.36(td，J＝7.2,5.6Hz，2H)，2.75(t,J＝7.2Hz,2H). 13 C NMR(125MHz，DMSO-d 6 )δ163.68,154.67,150.14，150.14，141.83，140.03,136.62，135.13，131.72，128.79,128.79,C-CF 3 (126.83,126.54,126.30,126.00),CF 3 (125.86，123.83,121.66,119.45),122.08，121.44，121.44,120.40,120.40,2×CH-C-CF 3 (115.93，115.90,115.85,115.81),40.57,35.03.HR-ESI-MS：m/z＝463.11450[M+H] + ,calcd for C 22 H 19 O 2 N 4 ClF 3 ：463.11431.
Example 18: preparation of TM-18
Figure BDA0003035260180000171
N- (4- (2-aminoethyl) phenyl) -2-morpholinecarboxamide is reacted with 3, 4-dichlorobenzene isocyanate in the same manner and operation as compound 16, with a yield of about 44%. 1 H NMR(400MHz,DMSO-d 6 )δ9.66(s,1H),8.81(s,1H),7.84(d,J＝2.4Hz,1H),7.55(dd,J＝6.4,2.0Hz,2H)，7.43(d，J＝8.8Hz,1H),7.21(dd,J＝8.8,2.4Hz,1H),7.16(dd,J＝6.4，2.0Hz，2H)，6.23(t,J＝5.6Hz,1H),3.66-3.60(m,4H),3.29(td,J＝7.2,5.6Hz,2H),3.10(s,2H),2.70(t,J＝7.2Hz,2H)，2.51-2.48(m,4H). 13 C NMR(125MHz,DMSO-d 6 )δ167.72,154.60，140.63,136.61,134.25,130.74,130.29,128.70,128.70,121.93,119.45,119.45,118.41,117.47,65.94,65.94,61.92,53.04,53.04,40.57,34.97.HR-ESI-MS：m/z＝451.13205[M+H] + ,calcd for C 21 H 25 O 3 N 4 Cl 2 ：451.12982.
Example 19: preparation of TM-19
Figure BDA0003035260180000172
N- (4- (2-aminoethyl) phenyl) -2-morpholinecarboxamide is reacted with 4-chloro-3-trifluoromethylphenyl isocyanate, the synthesis and operation are the same as those of compound 16, and the yield is about 40%. 1 H NMR(400MHz,DMSO-d 6 )δ9.66(s,1H),8.99(s,1H),8.06(d，J＝2.0Hz,1H),7.56(dd,J＝6.4,2.0Hz,2H),7.54(s,2H)，7.17(dd,J＝6.4,2.0Hz,2H),6.28(t,J＝5.6Hz,1H)，3.66-3.61(m，4H),3.30(td,J＝7.2,5.6Hz,2H),3.10(s,2H),2.70(t,J＝7.2Hz,2H),2.51-2.48(m,4H). 13 C NMR(125MHz,DMSO-d 6 )δ167.74,154.65,140.01,136.62,134.25,131.72,128.72,128.72，C-CF 3 (126.78,126.54，126.30,126.05),CF 3 (126.00,123.83,121.66,119.16),122.08,121.11，119.46,119.46,CH-C-CF 3 (115.90,115.85),65.95,65.95,61.93,53.05,53.05,40.61,34.97.HR-ESI-MS：m/z＝485.15747[M+H] + ,calcd for C 22 H 25 O 3 N 4 ClF 3 ：485.15618.
Example 20: preparation of TM-20
Figure BDA0003035260180000181
N- (4- (2-aminoethyl) phenyl) -5-chloro-1H-indole-2-carboxamide is reacted with 3, 4-dichlorophenylisocyanate in the same manner and in the same operation as compound 16 in about 75% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.94(s,1H),10.25(s,1H),8.83(s,1H),7.85(d,J＝2.0Hz,1H),7.77(d,J＝2.8Hz,1H),7.72(dd，J＝6.4,2.0Hz,2H),7.47(d,J＝8.8Hz,1H),7.44(d,J＝8.8Hz,1H),7.40(d,J＝1.6Hz,1H),7.25-7.21(m,4H),6.26(t,J＝5.6Hz,1H),3.34(td，J＝7.2,5.6Hz，2H),2.74(t,J＝7.2Hz,2H). 13 C NMR(125MHz,DMSO-d 6 )δ159.10,154.63,140.65,136.82,135.01,134.60,132.89,130.76,130.30,128.80,128.80,127.92,124.23，123.70,121.95,120.65,120.15,120.15,118.43,117.49,113.85,103.12,40.54,35.02.HR-ESI-MS：m/z＝501.06482[M+H] + ,calcd for C 24 H 20 O 2 N 4 Cl 3 ：501.06464.
Example 21: preparation of TM-21
Figure BDA0003035260180000191
The N- (4- (2-aminoethyl) phenyl) -5-chloro-1H-indole-2-carboxamide is obtained by reacting 4-chloro-3-trifluoromethylphenyl isocyanate, and the synthesis method and operation are the same as those of the compound 16, and the yield is about 43%. 1 H NMR(400MHz,DMSO-d 6 )δ11.93(d,J＝2.0Hz,1H),10.25(s,1H),9.00(s,1H),8.07(d,J＝2.4Hz，1H),7.77(d,J＝2.0Hz，1H),7.73(dd,J＝6.4,2.0Hz,2H),7.55(d,J＝2.0Hz,1H),7.54(s,1H),7.48-7.45(td,J＝8.8,0.8Hz,1H),7.40(dd,J＝2.4,0.8Hz,1H),7.25(dd,J＝6.4,2.0Hz,2H)，7.22(dd,J＝8.8,2.0Hz,1H),6.31(t,J＝5.6Hz,1H),3.36(td,J＝7.2，5.6Hz，2H),2.75(t,J＝7.2Hz,2H). 13 C NMR(125MHz,DMSO-d 6 )δ159.10,154.67,140.01,136.82,135.01,134.58,132.88，131.72,128.80,128.80,127.92,C-CF 3 (126.80，126.54,126.30,126.07),CF 3 (125.88,123.83,121.66,119.40),124.23,123.70,122.09,121.13,120.65,120.15,2×CH-C-CF 3 (115.91,115.86),113.85,103.12，40.58,35.01.HR-ESI-MS：m/z＝535.09161[M+H] + ,calcd for C 25 H 20 O 2 N 4 Cl 2 F 3 ：535.09099.
Example 22: preparation of TM-22
Figure BDA0003035260180000192
N- (4- (2-aminoethyl) phenyl) -5-methylisoxazole-3-carboxamide is reacted with 3, 4-dichlorobenzene isocyanate in the same synthetic method and operation as compound 16, with a yield of about 33%. 1 H NMR(400MHz,DMSO-d 6 )δ10.57(s,1H),8.82(s,1H),7.84(d,J＝2.8Hz,1H),7.71(d,J＝6.8,2.0Hz,2H)，7.44(d,J＝8.8Hz,1H)，7.22(d,J＝8.8Hz,1H),7.21(dd,J＝6.8,2.0Hz,2H),6.65(d,J＝0.8Hz，1H),6.25(t，J＝5.6Hz,1H)，3.34(td,J＝7.2,5.6Hz，2H),2.73(t,J＝7.2Hz，2H),2.49(s,3H). 13 C NMR(125MHz，DMSO-d 6 )δ171.28,159.14,157.14，154.61,140.64,136.09,135.29,130.75,130.29,128.78,128.78,121.94,120.47,120.47,118.42,117.49,101.51,40.48,34.99,11.77.HR-ESI-MS：m/z＝433.08200[M+H] + ,calcd for C 20 H 19 O 3 N 4 Cl 2 ：433.08287.
Example 23: preparation of TM-23 (ZHC-3-8)
Figure BDA0003035260180000201
N- (4- (2-aminoethyl) phenyl) -5-methylisoxazole-3-carboxamide is reacted with 4-chloro-3-trifluoromethylphenylisocyanate in the same manner and in the same operation as compound 16, giving a yield of about 53%. 1 H NMR(400MHz,DMSO-d 6 )δ10.57(s,1H),9.00(s，1H),8.06(d，J＝2.0Hz,1H),7.72(dd,J＝6.8,1.6Hz,2H),7.54(d,J＝2.4Hz,1H),7.54(s,1H),7.22(dd,J＝6.8,1.6Hz,2H),6.65(d,J＝0.8Hz,1H)，6.30(t,J＝5.6Hz,1H)，3.32(td,J＝7.2,5.6Hz,2H),2.74(t,J＝7.2Hz,2H),2.49(s,3H). 13 C NMR(125MHz,DMSO-d 6 )δ171.28,159.14,157.14,154.66,140.01,136.10,135.27，131.72,128.78,128.78,C-CF 3 (126.76,126.54,126.30,126.07),CF 3 (126.00,123.83,121.66,119.55),122.08,121.12,120.47,120.47，CH-C-CF 3 (115.91,115.86),101.51，40.52,34.99,11.77.HR-ESI-MS：m/z＝467.10919[M+H] + ,calcd for C 21 H 19 O 3 N 4 ClF 3 ：467.10923.
Example 24: preparation of TM-24
Figure BDA0003035260180000202
N- (4- (2-aminoethyl) phenyl) furan-2-carboxamide is reacted with 3, 4-dichlorobenzene isocyanate in the same synthetic method and operation as compound 16, with about 48% yield. 1 H NMR(400MHz，DMSO-d 6 )δ10.12(s，1H)，8.82(s,1H),7.93(q,J＝0.8Hz,1H),7.85(d,J＝2.8Hz,1H),7.68(dd,J＝6.8,2.0Hz,2H)，7.44(d，J＝8.0Hz，1H),7.31(dd,J＝3.6,0.8Hz,1H)，7.22(dd,J＝8.0，2.8Hz,1H),7.20(dd,J＝6.8，2.0Hz,2H)，6.70(dd，J＝3.6,2.0Hz,1H),6.25(t，J＝5.6Hz,1H),3.34(td,J＝7.2,5.6Hz,2H),2.72(t,J＝7.2Hz,2H). 13 C NMR(125MHz，DMSO-d 6 )δ156.12,154.79,147.59,145.67，140.81,136.69,134.80,130.92，130.45,128.87,128.87,122.10,120.50,120.50,118.58,117.65,114.63，112.18,40.68，35.15.HR-ESI-MS：m/z＝418.07260[M+H] + ,calcd for C 20 H 18 O 3 N 3 Cl 2 ：418.07197.
Example 25: preparation of TM-25
Figure BDA0003035260180000211
N- (4- (2-aminoethyl) phenyl) furan-2-carboxamide with 4-chloro-3-trifluoro-3The methyl phenyl isocyanate is obtained by reaction, the synthesis method and operation are the same as those of the compound 16, and the yield is about 32%. 1 H NMR(400MHz，DMSO-d 6 )δ10.12(s，1H)，9.00(s，1H)，8.07(d，J＝1.6Hz，1H)，7.93(d，J＝1.2Hz,1H),7.68(d,J＝8.4Hz,2H),7.55(d,J＝2.4Hz,1H),7.54(s,1H),7.31(d,J＝3.2Hz,1H),7.21(d，J＝8.4Hz,2H),6.70(q，J＝1.6Hz,1H)，6.30(t，J＝5.6Hz,1H)，3.34(td，J＝7.2，5.6Hz,2H)，2.73(t,J＝7.2Hz,2H). 13 C NMR(125MHz,DMSO-d 6 )δ155.97,154.67,147.43,145.51,140.02,136.54,134.63,131.72,128.71,128.71,C-CF 3 (126.79,126.55,126.31，126.06)，CF 3 (125.89,123.83,121.66,119.50),122.08，121.12,120.34,120.34,CH-C-CF 3 (115.90,115.86),114.47,112.03,40.56,34.98.HR-ESI-MS：m/z＝452.09891[M+H] + ,calcd for C 21 H 18 O 3 N 3 ClF 3 ：452.09833.
Pharmacological experiments:
experimental example 1: in vitro kinase inhibition Activity assay
The evaluation of the activity of the compounds on the molecular level of CDK8/cyclin C was entrusted to the company Thermo Fisher Scientific (Sammerfei, USA).
In the experiment, the compounds were diluted 100-fold in DMSO solution, with buffer solution (50mM HEPES pH 7.5,0.01% 2 1mM EGTA), the mixture of kinase and antibody and Tracer were mixed, shaken for 30s, and then incubated at room temperature for 60min. Subsequently, the emulsion Ratio (ER, AF647 emulsion (665 nm) to Europium emulsion (615 nm)) was read on a microplate reader and analyzed. In the IC50 assay, compounds were diluted in 3-fold gradients for a total of 10 concentrations tested. Blank control was set in the test and positive control was sorafenib as reference. The results are given as a percentage of "the difference between the ER of the blank and the ER of the test sample" and "the difference between the ER of the blank and the ER of the positive control", a larger percentage indicating better binding of the compound to the kinase. Table 1is the results of the in vitro inhibitory activity of CDK8 kinase of the compounds of the present invention.
TABLE 1 inhibitory Effect of Compounds on CDK8/cyclin C
Figure BDA0003035260180000221
ND: not Determined, not tested.
Experimental example 2: in vitro kinase Selective Activity assay
The compound TM-8 with the highest CDK8 inhibitory activity is selected to test the inhibitory activity of the compound TM-8 on other 24 kinases. 5 of them are CDK subtypes, including CDK1, CDK2, CDK6, CDK7 and CDK9; another 19 kinase families involved are the seven classes GSK3A, BRAF, CAMK4, CLK1, CSNK1D, DAPK1, FGFR1, JAK1, LRRK2, MARK1, MAP2K5, MAPK7, p38 α, MKNK1, MST4, PDK1, PKC α, PTK2, and SRC, respectively. The inhibitory effect of selected compound TM-8 of the invention on 25 kinases including CDK8 at a concentration of 10 μ M is shown in table 2 and figure 1.
TABLE 2 inhibitory Effect of Compound TM-8 on 25 kinases
Figure BDA0003035260180000231
* Each test was repeated twice at a concentration of 10 μ M.
CDK: cyclin dependent kinases (Cyclin dependent kinases); GSK3A: glycogen synthase kinase 3 α (glycogen synthase kinase 3 α); BRAF: sarcoma viral oncogene homolog B1 (v-raf murine sarcococcal oncogene homolog B1); caMK4: calcium/calmodulin-dependent protein kinase 4 (Calcium/calmodulin-dependent protein kinase 4); CLK1: CDC-like kinase 1 (CDC like kinase 1); CSNK1D: tyrosine kinase 1D (Casein kinase 1isoform delta); DAPK1: death-associated protein kinase 1 (Death-associated protein kinase 1); FGFR1: fibroblast Growth Factor Receptor 1 (Fibroblast Growth Factor Receptor-1); JAK1: janus kinase 1 (Janus kinase 1); LRRK2: leucine-rich repeat kinase 2 (Leucine-rich repeat kinase/threonine-protein kinase 2); MARK1: microtubule Affinity modulating Kinase 1 (Microtubule Affinity modulating Kinase 1); MAP2K5: dual specificity mitogen-activated protein kinase kinase5 (Dual specificity mitogen-activated protein kinase 5); MAPK7: mitogen-activated protein kinase 7 (Mitogen-activated protein kinase 7); MAPK14: mitogen-activated protein kinase 14 (Mitogen-activated protein kinase 14); MKNK1: MAP kinase-interacting serine/threonine kinase 1 (MAP kinase-interacting serine/threonine-protein kinase 1); MST4: serine/threonine protein kinase 4 (Mammalian Ste20-like kinase 4); PDK1: 3-phosphoinositide-dependent protein kinase 1 (3-phosphoinositide-dependent protein kinase 1); PRKCA: protein kinase C α (Protein kinase C α); FAK: focal adhesion kinase (Focal adhesion kinase 1); SRC: proto-oncogene tyrosine-protein kinase (proto-oncogene tyrosine-protein kinase).
Experimental example 3: in vitro antitumor cell Activity test (MTT)
Taking tumor cells in logarithmic growth phase, digesting with pancreatin to prepare cell suspension, and inoculating the cell suspension into a 96-well plate according to the number of the cells of about 1500/well, wherein each well is 100 mu L. When tumor cells grow, fresh culture medium of test compounds and corresponding solvent control at different concentrations is added the next day, 100 μ L (DMSO final concentration < 0.1%) is added to each well, and the compound is initially screened to set three doses (0.1 μ M,1 μ M,10 μ M), and single-concentration inhibition rate can also be directly tested. After the test compound addition was complete, incubation was continued for 96h in a 37 ℃ incubator, the supernatant discarded and 200. Mu.L of freshly prepared serum-free medium containing 0.5mg/mL MTT was added to each well. Continuously culturing for 4h, removing the supernatant, adding 200 μ L DMSO into each well to dissolve the precipitate, shaking and mixing uniformly by a micro-oscillator, and measuring Optical Density (OD) value under the condition of 570nm wavelength by a microplate reader. The tumor cells treated by the solvent are taken as a control group, and the inhibition rate of the drug on the tumor cells is calculated according to the following formula.
Inhibition (%) = (control mean OD value-test compound mean OD value)/control mean OD value × 100%. Calculating IC by using logarithm of compound concentration and inhibition rate as regression equation 50 The value is obtained. Table 3 shows the results of the in vitro antitumor cell activities (MTT) of the compounds of the present invention.
TABLE 3 in vitro antitumor cell Activity of part of the Compounds
Figure BDA0003035260180000241

Claims (9)

1. An arylurea compound represented by the following general formula (I) or a physiologically acceptable salt thereof,
Figure FDA0003035260170000011
wherein,
R 1 selected from halogen, trifluoromethyl, having one or more R on the phenyl ring 1 A substituent group;
x and Y are selected from N or C;
R 2 selected from H, CF 3 ﹑F﹑CN﹑NO 2 ﹑NH 2 ﹑N(CH 3 ) 2 C1-C3 alkyl, C1-C3 alkoxy or the following fragments:
Figure FDA0003035260170000012
2. the compound of claim 1, wherein the compound is a compound of formula (IA) or a physiologically acceptable salt thereof:
Figure FDA0003035260170000013
wherein,
R 1 selected from halogen, trifluoromethyl, having one or more R on the phenyl ring 1 A substituent group;
R 2 selected from H, CF 3 ﹑F﹑CN﹑NO 2 ﹑NH 2 ﹑N(CH 3 ) 2 C1-C3 alkyl, C1-C3 alkoxy or the following fragments:
Figure FDA0003035260170000021
3. the compound of claim 1, wherein the compound is a compound of formula (IB) or a physiologically acceptable salt thereof:
Figure FDA0003035260170000022
wherein,
R 1 selected from halogen, trifluoromethyl, having one or more R on the phenyl ring 1 A substituent group;
x and Y are selected from N or C.
4. A compound according to any one of claims 1 to 3, or a physiologically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure FDA0003035260170000023
Figure FDA0003035260170000031
Figure FDA0003035260170000041
5. a process for the preparation of a compound according to any one of claims 1 to 4, comprising the steps of:
the compounds TM-1 to TM-9 were synthesized analogously, for example with compound TM-1, by the following procedure:
Figure FDA0003035260170000042
taking compound TM-14 as an example, the synthesis methods of compounds TM-10, TM-14 and TM-15 are similar and are obtained by synthesizing compounds TM-12 and TM-13, taking compound TM-14 as an example, the preparation process is as follows:
Figure FDA0003035260170000051
the synthesis of compounds TM-16 to TM-25 is similar, taking compound TM-16 as an example, and the preparation process is as follows:
Figure FDA0003035260170000052
6. a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 5 or a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier.
7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is selected from the group consisting of tablets, capsules, pills, injections, sustained release formulations, controlled release formulations, and various microparticle delivery systems.
8. Use of a compound according to any one of claims 1 to 5 or a physiologically acceptable salt thereof in the preparation of a CDK8 inhibitor.
9. Use of a compound according to any one of claims 1 to 5 or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment of tumours.
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CN1440383A (en) * 2000-04-28 2003-09-03 三共株式会社 PPAR gamma modulators
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Publication number Priority date Publication date Assignee Title
CN1440383A (en) * 2000-04-28 2003-09-03 三共株式会社 PPAR gamma modulators
WO2020002969A1 (en) * 2018-06-26 2020-01-02 Zhejiang Vimgreen Pharmaceuticals, Ltd Triazolotriazine derivatives as a2a receptor antagonists
WO2020206608A1 (en) * 2019-04-09 2020-10-15 Ranok Therapeutics (Hangzhou) Co., Ltd. Methods and compositions for targeted protein degradation
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