CN111434654B - Triazole hexanone biaryl (hetero) ring derivative and preparation method and application thereof - Google Patents
Triazole hexanone biaryl (hetero) ring derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of chemical medicines, and in particular relates to a micromolecule for resisting malignant tumor, blood system malignant diseases, arthritis, multiple sclerosis and immune rejection reaction, a preparation method and application thereof. The invention aims to solve the technical problems that the existing small molecular inhibitor of the dihydrolactic dehydrogenase with high activity and good safety is lack of clinical application to clinical tumor treatment, and the existing small molecular inhibitor of the dihydrolactic dehydrogenase has large toxic and side effects in clinical research. The invention solves the technical problems by providing the triazole and hexanone biaryl (hetero) ring derivative, which is mainly connected with triazole and has different aryl (hetero) rings and different substitutions on hexanone, and the compound provided by the invention has a brand new structure, high anti-malignant tumor activity, remarkably inhibits the activity of the dihydrolactic dehydrogenase and has great value in the development of medicines for treating malignant tumors.
Description
Technical Field
The invention belongs to the field of chemical medicine, and in particular relates to a triazolone biaryl (hetero) ring derivative, a preparation method and application thereof.
Background
The small molecular targeted antitumor drug has definite curative effect and high safety, and can realize accurate treatment for tumor patients, so that the small molecular targeted antitumor drug has become a hot spot and trend in recent years of research and development of tumor drugs.
Dihydroorotate dehydrogenase (dihydroorotate dehydrogenase, DHODH), which is an iron-containing flavin-dependent enzyme, is present in the inner membrane of human mitochondria. It catalyzes the 4 th step reaction in the de novo synthesis pathway of pyrimidine nucleotide in nucleic acid in organism, and is the rate-limiting enzyme for pyrimidine nucleotide synthesis. Pyrimidine nucleotides are necessary for the in vivo synthesis of DNA, RNA, glycoproteins and phospholipids, the synthesis of which is critical for cell proliferation and metabolism. In tumor cells, pyrimidine nucleotides are required in far greater amounts than normal cells, and their synthesis relies mainly on the de novo synthesis pathway. Inhibition of DHODH blocks synthesis of nascent pyrimidine nucleotides, resulting in dysbiosis of DNA (containing adenine and cytosine), RNA (containing uracil and cytosine), glycoproteins, phospholipids, etc., thereby causing cell cycle arrest and inhibiting abnormal proliferation of tumor cells. Studies have shown that DHODH is highly expressed in a variety of tumors and positively correlated with poor prognosis in clinical tumor patients, inhibition of DHODH expression can inhibit tumor proliferation. Therefore, DHODH has become a potential anti-tumor therapeutic target, and has important significance for developing and researching specific inhibitors.
Currently, small molecule inhibitors against DHODH include buquinar (Brequinar), which has a certain antitumor activity, and phase I clinical trials for treating tumors have been performed in 1986, 1988 and 1990, respectively, but the antitumor activity is limited, and the side effects such as bone marrow suppression are large, which have not been clinically approved for malignant tumor treatment. Therefore, the development of high-efficiency low-toxicity DHODH inhibitors for treating tumor has a special significance.
Disclosure of Invention
The invention provides a triazole hexanone biaryl (hetero) ring derivative, the structure of which is shown as the formula I
Wherein X, Y, Z is C or N
R 1 ～R 4 is-H, halogen, -OH and methoxy,
R 5 ～R 9 is-H, halogen, -OH, methoxy, amino, nitro, methoxycarbonyl, trifluoromethoxy, trifluoromethyl, alkyl
R 10 ～R 12 is-H, halogen, -OH, methoxy, alkane, alkene, alkyne.
The triazolone biaryl (hetero) ring derivative according to claim 1, wherein: the structural formula is as follows:
the preparation method of the triazolone biaryl (hetero) ring derivative comprises the following synthetic route
Route one:
R 1 ～R 4 is-H, halogen, -OH and methoxy,
R 5 ～R 9 is-H, halogen, -OH, methoxy, amino, nitro, methoxycarbonyl, trifluoromethoxy, trifluoromethyl, alkyl.
R 10 ～R 12 is-H, halogen, -OH, methoxy, alkane, alkene, alkyne.
The preparation operation steps of the triazol-hexanone biaryl (hetero) ring derivative shown in the formula II comprise:
a. the intermediate 1 is obtained by taking a raw material 1 and catalyzing with different substituted aryl boric acid, wherein the catalyst is [1,1 '-bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride; the alkali is any one of cesium carbonate, potassium carbonate and the like; the reaction temperature is 90-100 ℃; the molar ratio of the raw material 1 to boric acid to alkali to ligand is 1:1.3:6:0.1; the reaction time is 12-24 hours;
b. intermediate 2 is obtained by diazotizing intermediate 1, dropwise adding tetrahydrofuran solution of intermediate 1 into diethyl ether solution of boron trifluoride under the reaction condition of minus fifteen ℃ for reaction for 10-30min, dropwise adding isobutyl tertiary butyl alcohol for reaction for 1-2h, adding isobutyl tertiary butyl alcohol for reaction for 2h, observing that precipitation (dark oily liquid drops) appears, heating the reaction to minus 5, adding 10ml of n-pentane, heating to 25 alkane, and adding 10ml of n-pentane to obtain a solid or dark oily liquid drop product. The product was placed in a new reaction flask, sodium azide and 30ml of acetonitrile solution (acetonitrile: water=3:1) were added, and the reaction was performed for 1-4h;
d. the intermediate 3 is obtained after diazotization of the raw material 1, the operation is carried out, under the reaction condition of minus fifteen ℃ the tetrahydrofuran solution of the raw material 1 is dripped into the diethyl ether solution of boron trifluoride, after the reaction is carried out for 10 to 50min, the tert-butyl alcohol isobutyl ester is dripped, after the reaction is carried out for 1 to 4h, the tert-butyl alcohol isobutyl ester is added for 2h, the occurrence of precipitation (dark oily liquid drops) is observed, the reaction is heated to minus 5 ℃ and 10ml of n-pentane is added, the temperature is further raised to 25 ℃ and 10ml of n-pentane is added, the solid or dark oily liquid drops and a new reaction bottle are taken, then the sodium azide is added, 30ml (acetonitrile: water=3:1) is added, and the reaction is carried out for 1 to 8h;
e. the intermediate 4 is obtained under the catalysis of aryl boric acid with different substitutions of the intermediate 3, and the catalyst is [1,1 '-bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex, and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride; the alkali is any one of cesium carbonate, potassium carbonate and the like; the reaction temperature is 90 palladium; said; the molar ratio of the raw material 1 to boric acid to alkali to ligand is 1:1.3:6:0.1; the reaction time is 12-24 hours;
c. the compounds of formulas 2.1, 2.2 and 2.3 are obtained under the alkalization of an intermediate 2 and a raw material 2 (an intermediate 4 raw material 2), wherein the reaction temperature is 85 degrees; the alkali is 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU); the raw material 2: molar ratio of intermediate 2 to dbu: 1:1.3:0.2, said starting material 4: molar ratio of intermediate 2 to dbu: 1:1.3:0.2. The reaction time is 12h-24h;
Detailed Description
Example 1 preparation of 3.5-difluoro- (3 '-methoxy- [1,1' -biphenyl ])-4-amino (intermediate 1 a)
1g (4.81 mmol) of 4-bromo-3.5-difluoro-aniline and 730mg (4.81 mmol.1 eq) of potassium carbonate (4.82g 24.88mmol 6eq) [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (425.35mg 481mmol 6eq) were placed in a 100ml two-necked flask, and 30ml (dioxane: water=3:1) of nitrogen protection was injected and the reaction was allowed to proceed for 3.5 hours at 80. After the completion of the TLC monitoring reaction, the reaction was distilled under reduced pressure until about 10ml remained, the solution was poured into a separating funnel, extracted 2-3 times with methylene chloride, dried over anhydrous Na2SO4, filtered, distilled under reduced pressure and spun-dried to give a black oily liquid drop, and the liquid drop was purified by petroleum ether: 1 silica gel column chromatography to obtain about 690mg of pale yellow oily liquid with a yield of 61%.
1 H-NMR(400MHz,CDCl 3 ):8.02–7.94(m,4H),7.40–7.33(m,2H),5.27(s,2H),3.87(s, 3H), (ESI, positive ion) m/z:236.20[ M+H ]] + 。
Example 2 preparation of 3.5-difluoro- (2-fluoro- [1,1' -biphenyl ])-4-amino (intermediate 1 b)
1g (4.81 mmol) of 4-bromo-3.5-difluoro-aniline and 730mg (4.81 mmol.1 eq) of potassium o-fluorobenzeneboronic acid (4.82g 24.88mmol 6eq) [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (425.35mg 481mmol 6eq) are placed in a 100ml two-necked flask, and 30ml (dioxane: water=3:1) of nitrogen protection is injected and the reaction is allowed to proceed for 3.5h. After the completion of the TLC monitoring reaction, the reaction was distilled under reduced pressure until about 10ml remained, the solution was poured into a separating funnel, extracted 2-3 times with methylene chloride, dried over anhydrous Na2SO4, filtered, distilled under reduced pressure and spun-dried to give a black oily liquid drop, and the liquid drop was purified by petroleum ether: 1 silica gel column chromatography to obtain light yellow oily liquid of 650mg with a yield of 60%.
1 H-NMR(400MHz,CDCl 3 ) 8.02-7.94 (m, 4H), 7.40-7.33 (m, 2H), 5.27 (s, 2H), (ESI, positive ion) m/z 224.20[ M+H ]] + 。
Example 3 preparation of 2, 6-difluoro-4 '-isopropyl- [1,1' -biphenyl ] -4-aniline (intermediate 1 c)
1g (4.81 mmol) of 4-bromo-2.6-difluoro-aniline and 788mg (4.81 mmol.1 eq) of potassium p-isopropylbenzene borate (4.82g 24.88mmol 6eq) [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (425.35mg 481mmol 6eq) were placed in a 100ml two-necked flask, and 30ml (dioxane: water=3:1) of nitrogen protection was injected and the reaction was allowed to proceed for 3.5 hours. After the completion of the TLC monitoring reaction, the reaction was distilled under reduced pressure until about 10ml remained, the solution was poured into a separating funnel, extracted 2-3 times with methylene chloride, dried over anhydrous Na2SO4, filtered, distilled under reduced pressure and spun-dried to give a black oily liquid drop, and the liquid drop was purified by petroleum ether: 1 silica gel column chromatography to obtain a pale yellow oily liquid of about 690mg in 69% yield.
1 H NMR(400MHz,CDCl 3 ) Delta 7.63-7.54 (m, 4H), 7.38 (d, j=8.2 hz, 2H), 5.27 (s, 2H), 3.00 (dt, j=13.8, 6.9hz, 1H), 1.32 (d, j=6.9 hz, 6H), (ESI, positive ions) m/z 248.20[ m+h ]] + 。
Example 4 preparation of (4 '-amino-2', 6 '-trifluoro [1,1' -biphenyl ] -3-ylmethanol (intermediate 1 d)
1g (4.81 mmol) of 4-bromo-2.6-difluoro-aniline and 820mg (4.81 mmo l.1 eq) of potassium carbonate (4.82g 24.88mmol 6eq) [1,1' -bis (diphenylphosphino) ferrocene (5- (dimethylamino) -2-fluorophenyl) borate]Palladium dichloride (425.35mg 481mmol 6eq) was placed in a 100ml two-necked flask, and 30ml (dioxane: water=3:1) of nitrogen gas was injected for protection, and the reaction was allowed to proceed for 3.5 hours. After the completion of the TLC monitoring reaction, the reaction was distilled under reduced pressure until about 10ml remained, the solution was poured into a separating funnel, extracted 2-3 times with methylene chloride, dried over anhydrous Na2SO4, filtered, distilled under reduced pressure and spun-dried to give a black oily liquid drop, and the liquid drop was purified by petroleum ether: 1 silica gel column chromatography to obtain pale yellow oily liquid of about 570mg, yield 49%. 1 H NMR(400MHz,DMSO-d 6 )δ8.10–7.87(m,2H),7.55(d,J＝6.4Hz,2H),7.43(t,J＝9.6Hz,1H),5.36(t,J＝5.2Hz,1H),4.58(d,J＝4.4Hz,2H),3.66(s,2H).MS m/z(ESI):254.07[M+H] + .
Examples 5, 2',6' -difluoro-N 3 ，N 3 -dimethyl- [1,1' -biphenyl]Preparation of 3,4' -diamine (intermediate 1 e)
1g (4.81 mmol) of 4-bromo-2.6-difluoro-aniline and 740mg (4.81 mmol.1 eq) of potassium carbonate (4.82g 24.88mmol 6eq) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (425.35mg 481mmol 6eq) was placed in a 100ml two-necked flask, and 30ml (dioxane: water=3:1) of nitrogen gas was injected for protection, and the reaction was allowed to proceed for 3.5 hours. After TLC monitoring the reaction was completed, the reaction was distilled under reduced pressure until the remaining about 10ml, pouring the solution into a separating funnel, extracting with dichloromethane for 2-3 times, drying with anhydrous Na2SO4, filtering, distilling under reduced pressure, and spin-drying to obtain black oily liquid drops, and extracting with petroleum ether: 1 silica gel column chromatography to obtain light yellow oily liquid of about 520mg with a yield of 47%. 1 H NMR(400MHz,DMSO-d 6 )δ7.84(d,J＝7.6Hz,2H),7.35(dd,J＝7.6,1.6Hz,1H),6.86(d,J＝5.6Hz,2H),6.81(d,J＝7.6Hz,1H),3.66(s,2H),2.95(s,6H).MS m/z(ESI):249.11[M+H] + .
Example 6 preparation of 3.5-difluoro- (3-methoxy- [1,1' -biphenyl ]) -4-azido (intermediate 2 a)
300mg of 3, 5-difluoro- (3-methoxy- [1,1' -biphenyl) are reacted with]) The product of the last step of 4-aniline (intermediate 1 a) is dissolved in analytically pure tetrahydrofuran (10 ml), slowly dripped into a reaction bottle containing ((1.5 ml) boron trifluoride diethyl ether solution at 15 ℃ below zero, reacted for 5min, and then dripped into 0.9ml of isobutyl tertiary butyl alcohol for 2h, precipitation is observed, the reaction is heated to 5 ℃ below zero and 10ml of n-pentane is added, the temperature is heated to 25 ℃ and 10ml of n-pentane is added, a filter cake is obtained by filtration and placed in a new reaction bottle, 294mg of sodium azide is added, 30ml of acetonitrile (acetonitrile: water=3:1) is injected, and the reaction is carried out for 1h at 80 ℃. After TLC monitoring the reaction, the reaction mixture was distilled under reduced pressure until about 10ml remained, the solution was poured into a separating funnel, extracted 2-3 times with dichloromethane, and anhydrous Na was used 2 SO 4 Drying, filtering, distilling under reduced pressure, and spin-drying to obtain black oily liquid drop, wherein petroleum ether is used for preparing ethyl acetate=15: 1 silica gel column chromatography to obtain pale yellow oily liquid of about 190mg, yield 57%.
1 H-NMR(400MHz,CDCl 3 ) 8.02-7.94 (m, 4H), 7.40-7.33 (m, 2H), 3.87 (s, 3H), (ESI, positive ion) m/z 262.20[ M+H ]] + 。
Example 7 preparation of 3.5-difluoro- (2-fluoro- [1,1' -biphenyl ]) -4-azido (intermediate 2 b)
300mg of 3, 5-difluoro- (2-fluoro- [1,1' -biphenyl) are reacted with]) The product of the last step of 4-aniline (intermediate 1 b) is dissolved in analytically pure tetrahydrofuran (10 ml), slowly dripped into a reaction bottle containing ((1.5 ml) boron trifluoride diethyl ether solution at 15 ℃ below zero, reacted for 5min, and then dripped into 0.9ml of isobutyl tertiary butyl alcohol for 2h, precipitation is observed, the reaction is heated to 5 ℃ below zero and 10ml of n-pentane is added, the temperature is heated to 25 ℃ and 10ml of n-pentane is added, a filter cake is obtained by filtration and placed in a new reaction bottle, 294mg of sodium azide is added, 30ml of acetonitrile (acetonitrile: water=3:1) is injected, and the reaction is carried out for 1h at 80 ℃. After TLC monitoring the reaction, the reaction mixture was distilled under reduced pressure until about 10ml remained, the solution was poured into a separating funnel, extracted 2-3 times with dichloromethane, and anhydrous Na was used 2 SO 4 Drying, filtering, distilling under reduced pressure, and spin-drying to obtain black oily liquid drop, wherein petroleum ether is used for preparing ethyl acetate=15: 1 silica gel column chromatography to obtain light yellow oily liquid of about 210mg, yield 63%.
1 H-NMR(400MHz,CDCl 3 ) 8.02-7.94 (m, 4H), 7.40-7.33 (m, 2H), 5.27 (s, 2H), (ESI, positive ion) m/z 250.10[ M+H ]] + 。
Example 8 preparation of 4-azido-2, 6-difluoro-4 '-isopropyl-1, 1' -biphenyl (intermediate 2 c)
300mg of 2, 6-difluoro-4 '-isopropyl- [1,1' -biphenyl]Dissolving the product of the last step of-4-aniline (intermediate 1 c) in analytically pure tetrahydrofuran (10 ml), slowly dripping the solution into a reaction bottle containing ((1.5 ml) boron trifluoride diethyl ether solution at 15 parts below zero, reacting for 5min, dripping 0.9ml of isobutyl tertiary butyl alcohol, reacting for 2h, observing precipitation, heating the reaction to 5 ℃ below zero, adding 10ml of n-pentane, heating to 25 ℃, adding 10ml of n-pentane, adding a filter cake obtained by filtration, placing the filter cake into a new reaction bottle, adding 294mg of sodium azide, injecting 30ml (acetonitrile: water=3:1), performing reaction at 80 ℃ for 1h.TLC monitoring, performing post-treatment, decompressing and distilling until about 10ml remains, pouring the solution into a separating funnelExtracting with dichloromethane for 2-3 times, anhydrous Na 2 SO 4 Drying, filtering, distilling under reduced pressure, and spin-drying to obtain black oily liquid drop, wherein petroleum ether is used for preparing ethyl acetate=15: 1 silica gel column chromatography to obtain pale yellow oily liquid of about 150mg, yield 48%.
1 H NMR(400MHz,CDCl 3 ) Delta 7.63-7.54 (m, 4H), 7.38 (d, J=8.2 Hz, 2H), 3.00 (dt, J=13.8, 6.9Hz, 1H), 1.32 (d, J=6.9 Hz, 6H), (ESI, positive ions) m/z 274.20[ M+H ]] +
Example 9 preparation of (4 '-azido-2', 6 '-trifluoro [1,1' -biphenyl ] -3-yl) methanol (intermediate 2 d)
300mg of (4 '-amino-2', 6 '-trifluoro [1,1' -biphenyl) are reacted]Dissolving the product of the last step of 3-methyl alcohol (intermediate 1 d) in analytically pure tetrahydrofuran (10 ml), slowly dripping the solution into a reaction bottle containing ((1.5 ml) boron trifluoride diethyl ether solution at 15 parts below zero, reacting for 5min, dripping 0.9ml of isobutyl tertiary butyl alcohol, reacting for 2h, observing that precipitation is observed, heating the reaction to 5 ℃ below zero, adding 10ml of n-pentane, heating to 25 ℃, adding 10ml of n-pentane, adding the filtered filter cake, placing the filter cake into a new reaction bottle, adding 294mg of sodium azide, injecting 30ml (acetonitrile: water=3:1), performing 80 ℃ reaction for 1h.TLC monitoring, performing post-treatment, decompressing and distilling until the residual solution is about 10ml, pouring the solution into a separating funnel, extracting 2-3 times by methylene dichloride, and extracting anhydrous Na 2 SO 4 Drying, filtering, distilling under reduced pressure, and spin-drying to obtain black oily liquid drop, wherein petroleum ether is used for preparing ethyl acetate=15: 1 silica gel column chromatography to obtain pale yellow oily liquid of about 120mg, yield 25%.
1 H NMR(400MHz,DMSO-d 6 )δ7.92–7.85(m,2H),7.59–7.50(m,2H),7.49–7.44(m,2H),5.34(t,J＝5.6Hz,1H),4.60(d,J＝6.4Hz,2H).MS m/z(ESI):236.08[M+H] + 。
Example 10 preparation of 4 '-azido-2', 6 '-difluoro-N, N-dimethyl- [1,1' -biphenyl ] -3-amine (intermediate 2 e)
300mg of 2',6' -difluoro-N 3 ，N 3 -dimethyl- [1,1' -biphenyl]Dissolving the product of the last step of the-3, 4' -diamine (intermediate 1 e) in analytically pure tetrahydrofuran (10 ml), slowly dripping the solution into a reaction bottle containing ((1.5 ml) boron trifluoride diethyl ether solution at 15 ℃ below zero, reacting for 5min, dripping 0.9ml of isobutyl tertiary butyl alcohol, reacting for 2h, observing precipitation, heating the reaction to 5 ℃ below zero, adding 10ml of n-pentane, heating to 25 ℃, adding 10ml of n-pentane, adding the filtered filter cake, placing the filter cake into a new reaction bottle, adding 294mg of sodium azide, injecting 30ml (acetonitrile: water=3:1), reacting for 1h at 80 ℃ after the TLC monitoring reaction is finished, carrying out post-treatment reduced pressure distillation until about 10ml remains, pouring the solution into a separating funnel, extracting 2-3 times by methylene dichloride, and extracting anhydrous Na 2 SO 4 Drying, filtering, distilling under reduced pressure, and spin-drying to obtain black oily liquid drop, wherein petroleum ether is used for preparing ethyl acetate=15: 1 silica gel column chromatography to obtain pale yellow oily liquid of about 140mg, yield 46%.
1 H NMR(400MHz,DMSO-d 6 )δ7.84(d,J＝7.6Hz,2H),7.35(dd,J＝7.6,1.6Hz,1H),6.86(d,J＝5.6Hz,2H),6.81(d,J＝7.6Hz,1H),2.95(s,6H).MS m/z(ESI):275.11[M+H] + 。
Example 11 preparation of 1- (2, 6-difluoro-3 '-methoxy- [1,1' -biphenyl ] -4-yl) -6-isopropyl-1, 5,6, 7-tetrahydro-4H-benzo [ d ] [11,2,3] triazol-4-one (3 a)
3.5-difluoro- (3-methoxy- [1,1' -biphenyl)]) -4-azido (intermediate 2 a) 100mg, 5-isopropyl-1, 3-cyclohexanedione) 59mg was added to 4-6ml acetonitrile and reacted with 80℃for 12h. After TLC monitoring the reaction, the reaction mixture was distilled under reduced pressure until about 10ml remained, the solution was poured into a separating funnel, extracted 2-3 times with dichloromethane, and anhydrous Na was used 2 SO 4 Drying, filtering, distilling under reduced pressure, and spin-drying to obtain black oily liquid drop, and mixing with petroleum ether (ethyl acetate)=15: 1 silica gel column chromatography, the obtained compound brown solid 52mg, yield 34%
1 H NMR(400MHz,CDCl 3 ) Delta 7.42 (d, j=6.4 hz, 1H), 7.36 (t, j=6.4 hz, 1H), 7.31-7.14 (m, 4H), 3.87 (s, 3H), 3.09-2.98 (m, 1H), 2.82 (dd, j=11.2, 4.2hz, 1H), 2.69 (d, j=12.8 hz, 1H), 2.48-2.38 (m, 1H), 2.17 (s, 1H), 1.77 (dd, j=6.4, 6.4hz, 1H), 0.97 (d, j=6.8 hz, 6H), (ESI, positive ions) m/z 406.07[ m+h ]] + 。
Example 12 preparation of 6-isopropyl-1- (2, 2', 6-trifluoro [1,1' -biphenyl ] -4-yl) -1,5,6, 7-tetrahydro-4H-benzo [ d ] [1,2,3] triazol-4-one (3 b)
3.5-difluoro- (2-fluoro- [1,1' -biphenyl)]) -4-azido (intermediate 2 a) 80mg, 5-isopropyl-1, 3-cyclohexanedione) 50mg was added to 4-6ml acetonitrile and reacted with 80℃for 12h. After TLC monitoring the reaction, the reaction mixture was distilled under reduced pressure until about 10ml remained, the solution was poured into a separating funnel, extracted 2-3 times with dichloromethane, and anhydrous Na was used 2 SO 4 Drying, filtering, distilling under reduced pressure, and spin-drying to obtain black oily liquid drop, wherein petroleum ether is used for preparing ethyl acetate=15: 1 silica gel column chromatography separation and purification, the obtained compound brown solid 62mg, yield 50%.
1 H NMR(400MHz,CDCl 3 )δ7.42(d,J＝6.4Hz,1H),7.36(t,J＝6.4Hz,1H),7.31–7.14(m,5H),3.09–2.98(m,1H),2.82(dd,J＝11.2,4.2Hz,1H),2.69(d,J＝12.8Hz,1H),2.48–2.38(m,1H),2.17(s,1H),1.77(dd,J＝6.4,6.4Hz,1H),0.97(d,J＝6.8Hz,6H)。
Example 13 preparation of 1- (2, 6-difluoro-4 '-isopropyl- [1,1' -biphenyl ] -4-yl) -6-isopropyl-1, 5,6, 7-tetrahydro-4H-benzo [ d ] [11,2,3] triazol-4-one (3 c)
50mg of 4-azido-2, 6-difluoro-4 '-isopropyl-1, 1' -biphenyl (intermediate 2 a) 88mg, 5-isopropyl-1, 3-cyclohexanedione) was added4-6ml of acetonitrile was added thereto and reacted with 80℃for 12 hours. After TLC monitoring the reaction, the reaction mixture was distilled under reduced pressure until about 10ml remained, the solution was poured into a separating funnel, extracted 2-3 times with dichloromethane, and anhydrous Na was used 2 SO 4 Drying, filtering, distilling under reduced pressure, and spin-drying to obtain black oily liquid drop, wherein petroleum ether is used for preparing ethyl acetate=15: 1 silica gel column chromatography, the obtained compound brown solid 41mg, yield 31%.
1 H NMR(400MHz,CDCl 3 )δ7.42(d,J＝6.4Hz,1H),7.36(t,J＝6.4Hz,1H),7.31–7.14(m,5H),3.09–2.98(m,1H),2.82(dd,J＝11.2,4.2Hz,1H),2.69(d,J＝12.8Hz,1H),2.48–2.38(m,1H),2.17(s,1H),3.00(dt,J＝13.8,6.9Hz,1H),1.77(dd,J＝6.4,6.4Hz,1H),1.32(d,J＝6.9Hz,6H),0.97(d,J＝6.8Hz,6H)。
Example 14 preparation of 6-isopropyl-1- (2, 2', 6-trifluoro-5 ' - (hydroxymethyl) - [1,1' -biphenyl ] -4-yl) -1,5,6, 7-tetrahydro-4H-benzo [ d ] [1,2,3] triazol-4-one (3 d)
3.5-difluoro- (3-methoxy- [1,1' -biphenyl)]) 50mg of 4-azido (intermediate 2 a) 90mg of 5-isopropyl-1, 3-cyclohexanedione) are added to 4-6ml of acetonitrile and reacted for 12 hours at 80 ℃. After TLC monitoring the reaction, the reaction mixture was distilled under reduced pressure until about 10ml remained, the solution was poured into a separating funnel, extracted 2-3 times with dichloromethane, and anhydrous Na was used 2 SO 4 Drying, filtering, distilling under reduced pressure, and spin-drying to obtain black oily liquid drop, wherein petroleum ether is used for preparing ethyl acetate=15: 1 silica gel column chromatography, the obtained compound brown solid 55mg, yield 41.3%.
1 H NMR(400MHz,CDCl 3 )δ7.42(d,J＝6.4Hz,1H),7.36(t,J＝6.4Hz,1H),7.31–7.11(m,4H),5.34(t,J＝5.6Hz,1H),4.60(d,J＝6.4Hz,2H)，3.09–2.98(m,1H),2.82(dd,J＝11.2,4.2Hz,1H),2.69(d,J＝12.8Hz,1H),2.48–2.38(m,1H),2.17(s,1H),1.77(dd,J＝6.4,6.4Hz,1H),0.97(d,J＝6.8Hz,6H)。
Example 15 preparation of 1- (5 "- (dimethylamino) -2,2", 6-trifluoro [1,1' -biphenyl ] -4-yl) -6-isopropyl-1, 5,6, 7-tetrahydro-4H-benzo [ d ] [1,2,3] triazol-4-one (3 e)
3.5-difluoro- (3-methoxy- [1,1' -biphenyl)]) 50mg of 4-azido (intermediate 2 a) 90mg of 5-isopropyl-1, 3-cyclohexanedione) are added to 4-6ml of acetonitrile and reacted for 12 hours at 80 ℃. After TLC monitoring the reaction, the reaction mixture was distilled under reduced pressure until about 10ml remained, the solution was poured into a separating funnel, extracted 2-3 times with dichloromethane, and anhydrous Na was used 2 SO 4 Drying, filtering, distilling under reduced pressure, and spin-drying to obtain black oily liquid drop, wherein petroleum ether is used for preparing ethyl acetate=15: 1 silica gel column chromatography separation and purification, the obtained compound brown solid 46mg, yield 34.5%.
1 H NMR(400MHz,CDCl 3 )δ7.42(d,J＝6.4Hz,1H),7.36(t,J＝6.4Hz,1H),7.31–7.14(m,5H),3.09–2.98(m,1H),2.95(s,6H),2.82(dd,J＝11.2,4.2Hz,1H),2.69(d,J＝12.8Hz,1H),2.48–2.38(m,1H),2.17(s,1H),1.77(dd,J＝6.4,6.4Hz,1H),0.97(d,J＝6.8Hz,6H)。
EXAMPLE 16 preparation of 1- (2, 2', 6-trifluoro [1,1' -biphenyl ] -4-yl) -1,5,6, 7-tetrahydro-4H-benzo [ d ] [1,2,3] triazol-4-one (4 b)
3.5-difluoro- (2-fluoro- [1,1' -biphenyl)]) -4-azido (intermediate 2 a) 110mg, 5-isopropyl-1, 3-cyclohexanedione) 59mg was added to 4-6ml acetonitrile and reacted with 80℃for 12h. After TLC monitoring the reaction, the reaction mixture was distilled under reduced pressure until about 10ml remained, the solution was poured into a separating funnel, extracted 2-3 times with dichloromethane, and anhydrous Na was used 2 SO 4 Drying, filtering, distilling under reduced pressure, and spin-drying to obtain black oily liquid drop, wherein petroleum ether is used for preparing ethyl acetate=15: 1 silica gel column chromatography, the obtained compound brown solid 41mg, yield 22.4%.
1 H NMR(400MHz,CDCl 3 )δ7.53–7.46(m,1H),7.42(t,J＝7.2Hz,1H),7.26(s,1H),7.26(s,5H),3.16(t,J＝6.1Hz,2H),2.74–2.69(m,2H),2.37–2.28(m,2H)。
Example 17 preparation of 6, 6-dimethyl-1- (2, 2', 6-trifluoro [1,1' -biphenyl ] -4-yl) -1,5,6, 7-tetrahydro-4H-benzo [ d ] [11,2,3] triazol-4-one (5 b)
3.5-difluoro- (2-fluoro- [1,1' -biphenyl)]) 50mg of 4-azido (intermediate 2 a) 90mg of 5-isopropyl-1, 3-cyclohexanedione) are added to 4-6ml of acetonitrile and reacted for 12 hours at 80 ℃. After TLC monitoring the reaction, the reaction mixture was distilled under reduced pressure until about 10ml remained, the solution was poured into a separating funnel, extracted 2-3 times with dichloromethane, and anhydrous Na was used 2 SO 4 Drying, filtering, distilling under reduced pressure, and spin-drying to obtain black oily liquid drop, wherein petroleum ether is used for preparing ethyl acetate=15: 1 silica gel column chromatography, the obtained compound brown solid 67mg, yield 46%.
1 H NMR(400MHz,CDCl 3 )δ7.53–7.46(m,1H),7.42(t,J＝7.2Hz,1H),7.34(d,J＝6.8Hz,1H),7.32–7.21(m,1H),3.01(s,2H),2.58(s,2H),1.20(s,6H)。
Example 18 preparation of 6-phenyl-1- (2, 2', 6-trifluoro- [1,1' -biphenyl ] -4-yl) -1,5,6, 7-tetrahydro-4H-benzo [ d ] [1,2,3] triazol-4-one (6 b)
3.5-difluoro- (2-fluoro- [1,1' -biphenyl)]) 60mg of 4-azido (intermediate 2 a) 90mg of 5-phenyl-1, 3-cyclohexanedione) are added to 4-6ml of acetonitrile and reacted for 12 hours at 80 ℃. After TLC monitoring the reaction, the reaction mixture was distilled under reduced pressure until about 10ml remained, the solution was poured into a separating funnel, extracted 2-3 times with dichloromethane, and anhydrous Na was used 2 SO 4 Drying, filtering, distilling under reduced pressure, and spin-drying to obtain black oily liquid drop, wherein petroleum ether is used for preparing ethyl acetate=15: 1 silica gel column chromatography separation and purification, the obtained compound brown solid 62mg, yield 36%.
1 H NMR(400MHz,CDCl 3 )δ7.51–7.19(m,11H),3.64(dd,J＝13.6,7.4Hz,1H),3.36(d,J＝10.2Hz,2H),3.13–2.87(m,2H)。
Example 19 preparation of 4-oxo-1- (2, 2', 6-trifluoro- [1,1' -biphenyl ] -4-yl) -4,5,6, 7-tetrahydro-1H-benzo [ d ] [1,2,3] triazole-6-carboxylic acid (7 b)
3.5-difluoro- (2-fluoro- [1,1' -biphenyl)]) -4-azido (intermediate 2 a) 90mg, 5-carboxy-1, 3-cyclohexanedione) 55mg was added to 4-6ml acetonitrile and reacted with 80℃for 12h. After TLC monitoring the reaction, the reaction mixture was distilled under reduced pressure until about 10ml remained, the solution was poured into a separating funnel, extracted 2-3 times with dichloromethane, and anhydrous Na was used 2 SO 4 Drying, filtering, distilling under reduced pressure, and spin-drying to obtain black oily liquid drop, wherein petroleum ether is used for preparing ethyl acetate=15: 1 silica gel column chromatography, the obtained compound brown solid 63mg, yield 39%.
1 H NMR(400MHz,DMSO-d 6 )δ7.37(dd,J＝14.2,7.2Hz,2H),7.23–7.12(m,2H),7.32–7.21(m,1H),3.01(s,2H),2.58(s,2H)。
Example 20 in vitro enzyme Activity assay of triazole hexanone biaryl (hetero) ring derivatives of the invention
In vitro enzyme inhibition assays were performed using the test services provided by Shanghai MinIQ company.
1 Experimental method
The purified HsDHODH protein was subjected to a measurement of the activity of the protein (50 mmol. L-1HEPES pH 8.0,150mmol. L) - 1 KCl,0.1%Triton X-100) to 10 nmol.L -1 Adding coenzyme Q and DCIP to final concentrations of 100 and 120 mu mol.L respectively -1 . After mixing, 199. Mu.L of each well was added to a 96-well plate using a discharge gun, followed by incubation at room temperature for 5min, and then 1. Mu.L of substrate DHO was added to each well to a final concentration of 500. Mu. Mol.L -1 . And (3) reading the absorbance at 600nm by using an enzyme-labeled instrument for 6min, and reading every 30 s. Calculating the initial velocity V of the enzymatic reaction 0 The inhibitor activity test is to add inhibitors with different concentrations into the reaction system to calculate the initial velocity V of the enzymatic reaction i By the formula (1-V i /V 0 )×1The inhibition of the compound was calculated at 00%. IC of compound was calculated with software GraphPad Prism 7 50 Values. The experiment uses brequanar as a positive control, and at least 3 replicates are arranged for each experiment.
2 experimental results
The results of the inhibition of the enzyme level in vitro by 1 mu M compound and the inhibition of the enzyme activity by the compound are shown in Table 1
Table 1 shows the results of inhibition of the in vitro enzyme level of the compounds of the present invention
"ND" in Table 1 indicates that no inhibition was measured. "RC" represents the positive control compound brequinar, and it can be seen from Table 1 that the triazole hexanone biaryl (hetero) ring derivative of the present invention shows a better DHODH activity inhibition effect. In particular, compounds 3d and 3e have potent DHODH inhibitory activity, IC 50 The values are 171nM and 39nM, and the inhibition activity is similar.
Example 21 in vitro tumor cell proliferation inhibition assay
The test aims to detect the proliferation inhibition activity of the compound on in vitro tumor cells, and the adopted method is an MTT (tetramethyl azoazole salt) colorimetric method.
1 Experimental materials
1.1 major reagents
RPMI-1640, DMEM high-sugar medium, fetal bovine serum, pancreatin, etc. are purchased from Gibco BRL company (Invitrogen Corporation, USA). Tetramethylazo salt (MTT), dimethyl sulfoxide (DMSO) is a Sigma company (USA) product. In vitro experiments, the compound to be tested is prepared into 50mM stock solution by using 100% DMSO, and the stock solution is stored in a refrigerator at the temperature of minus 20 ℃ in a dark place for standby, and is diluted to the required concentration by using the complete culture solution in the future.
1.2 cell lines and cultures
The human breast cancer cell strain MCF-7, the human colorectal cancer cell strain HCT116, the human liver tumor cell strain HepG2, the human lung cancer cell strain A549 and the human melanin cancer cell strain A375 are all purchased from ATCC company in the United states of America and used for the experimentThis laboratory was kept. All the cell lines were cultured in RPMI-1640 complete medium or DMEM complete medium containing 10% fetal bovine serum, 100U/mL penicillin, 100. Mu.g/mL streptomycin in 5% CO 2 Culturing at 37 ℃.
2 Experimental methods
Cell concentration was adjusted to 4X10 with complete cell culture medium 4 Each ml (48 h cell concentration) was inoculated into a 96-well plate at 0.1 ml/well, and cultured overnight. The next day, medium containing drug at 10 μm concentration was added, 3 duplicate wells were set per concentration gradient, and solvent control and no cell control were set simultaneously, and culture was continued at 37 ℃,5% co 2. After 48h of incubation, 20. Mu.L of MTT reagent with a concentration of 5mg/mL was added to each well, after 2-4 h of incubation, the supernatant was discarded, 150. Mu.L of DMSO was added to each well, and the mixture was mixed by shaking for 15min, absorbance was measured by an enzyme-labeled instrument (lambda 0 was added again) at 570nm, and the average value was obtained.
3.1 experimental results
The inhibition activity of the compounds on the proliferation of MCF-7, HCT116, A549, hepG2 and A375 was tested by the method, and the inhibition effect of the compounds on the proliferation of cells is shown in Table 2.
In vitro proliferation inhibitory Activity of the Compounds of Table 2 against various human tumor cells
"ND" in Table 2 indicates that no inhibition was measured.
The experimental result of the compound in vitro on tumor cell proliferation inhibition shows that compared with a positive compound, the synthesized compounds 3d, 3c and 5b have higher inhibition activity on human lung cancer cells, and the compound 4b also has stronger activity on human colorectal cancer cell lines and human melanoma cell lines. The data show that the triazolone biaryl (hetero) ring derivative has certain inhibition effect on various tumor cell lines.
Claims (3)
1. Triazole hexanone biaryl heterocyclic derivative, the structure of which is shown as follows
R 1 ～R 4 independently-H, halogen;
R 5 ～R 9 independently-H, halogen, -OH, -NH 2 C1-C8 alkyl, C1-C8 alkoxy;
R 10 ～R 12 independently is-H, C-C8 alkyl, phenyl and carboxylic acid.
2. The structural formula of the triazolone biaryl heterocyclic derivative is as follows:
3. use of a triazolone-heteroaromatic derivative according to any one of claims 1 to 2 in the manufacture of a medicament for the treatment of malignant tumours.
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