CN111434654A - 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 medicine, and particularly relates to small molecules for resisting malignant tumors, hematological malignant diseases, arthritis, multiple sclerosis and immune rejection, a preparation method and application thereof. The invention aims to solve the technical problems that the prior dihydrolactate dehydrogenase small-molecular inhibitor with high activity and good safety is lack clinically and is used for clinical tumor treatment on the market, and the prior clinical research on the defect of large toxic and side effects of the dihydrolactate dehydrogenase small-molecular inhibitor is carried out. The invention provides a triazole hexanone biaryl (hetero) ring derivative for solving the technical problems, the derivative is mainly different aryl (hetero) rings connected with triazole and different substitutions on hexanone, and the compound provided by the invention has a brand new structure, high malignant tumor resistance activity, obvious inhibition on the activity of dihydrolactate dehydrogenase and great value in the development of medicaments for treating malignant tumors.
Description
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to a triazolone biaryl (hetero) ring derivative, and a preparation method and application thereof.
Background
The micromolecule targeted anti-tumor medicine has definite curative effect and high safety, and can realize accurate treatment for tumor patients, so the micromolecule targeted anti-tumor medicine becomes a hotspot and trend of research and development of tumor medicines in recent years.
Dihydroorotate dehydrogenase (DHODH) is present in the inner membrane of human mitochondria and is an iron-containing flavin-dependent enzyme. It catalyzes the step 4 reaction in the de novo synthesis pathway of pyrimidine nucleotides in nucleic acids in organisms and is the rate-limiting enzyme of pyrimidine nucleotide synthesis. Pyrimidine nucleotides are essential for the synthesis of DNA, RNA, glycoproteins, and phospholipids in organisms, the synthesis of which is critical for cellular proliferation and metabolism. In tumor cells, pyrimidine nucleotides are required in amounts far greater than normal cells, and their synthesis relies primarily on de novo synthetic pathways. The inhibition of DHODH can block the synthesis of new pyrimidine nucleotide, which causes the biosynthesis of DNA (containing adenine and cytosine), RNA (containing uracil and cytosine), glycoprotein and phospholipid to generate obstacle, thereby causing cell cycle block and inhibiting the abnormal proliferation of tumor cells. The research shows that the DHODH is highly expressed in various tumors, and is positively correlated with poor prognosis of clinical tumor patients, and the inhibition of the DHODH expression can inhibit the tumor proliferation. Therefore, DHODH has become a potential anti-tumor therapeutic target, and the development and research of specific inhibitors aiming at the DHODH have important significance.
Currently, small molecule inhibitors against DHODH include Brequinar (Brequinar), which has a certain antitumor activity, and phase I clinical trials for treating tumors were performed in 1986, 1988, and 1990, respectively, but the antitumor activity was limited, and side effects such as myelosuppression were large, and thus, the DHODH small molecule inhibitors have not been clinically approved for treating malignant tumors. Therefore, the development of a high-efficiency and low-toxicity DHODH inhibitor for treating the tumor is of particular significance.
Disclosure of Invention
The invention provides a triazol hexanone biaryl (hetero) ring derivative with a structure shown as a formula I
Wherein X, Y, Z is C or N
R1～R4is-H, halogen, -OH, methoxy,
R5～R9is-H, halogen, -OH, methoxy, amino, nitro, methoxycarbonyl, trifluoromethoxy, trifluoromethyl, alkyl
R10～R12is-H, halogen, -OH, methoxyl, alkane, alkene, alkyne.
The triazolohexanone biaryl (hetero) cyclic derivative according to claim 1, characterized in that: the structural formula is as follows:
the preparation method of the triazol hexanone biaryl (hetero) ring derivative comprises the following synthetic route
Route one:
R1～R4is-H, halogen, -OH, methoxy,
R5～R9is-H, halogen, -OH, methoxy, amino, nitro, methoxycarbonyl, trifluoromethoxy, trifluoromethyl or alkyl.
R10～R12is-H, halogen, -OH, methoxyl, 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 the raw material 1 and catalyzing with different substituted aryl boric acids, wherein the catalyst is [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex and [1,1' -bis (diphenylphosphino) 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, the boric acid, the alkali and the ligand is 1:1.3: 6: 0.1; the reaction time is 12-24 h;
b. and in the operation, under the reaction condition of minus fifteen ℃, dripping a tetrahydrofuran solution of the intermediate 1 into an ether solution of boron trifluoride, reacting for 10-30min, dripping tert-butyl isobutyl ester into the mixture to react for 1-2h, adding tert-butyl isobutyl ester into the mixture to react for 2h, observing the occurrence of precipitates (deep oily liquid drops), 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 deep oily liquid drop product. Putting the product into a new reaction bottle, adding sodium azide and 30ml of acetonitrile solution (acetonitrile: water is 3:1), and reacting for 1-4h at 80: of reaction time;
d. diazotizing the intermediate 3 in the raw material 1, and then obtaining azide, wherein in the operation, under the condition of reaction at minus fifteen ℃, a tetrahydrofuran solution of the raw material 1 is dripped into an ether solution of boron trifluoride, after the reaction is carried out for 10-50min, isobutyl tert-butoxide is dripped, after the reaction is carried out for 1-4h, isobutyl tert-butoxide is added for reaction for 2h, a precipitate (a deep-color oily liquid drop) is observed, the reaction is heated to minus 5, 10ml of n-pentane is added, then the reaction is heated to 25 alkane, 10ml of n-pentane is added, solid or deep-color oily liquid drops and a new reaction bottle are taken, then sodium azide is added, 30ml of acetonitrile (water: 3:1) is added, and the reaction is carried out for 1-8h at 80;
e. the intermediate 4 is obtained under the catalysis of aryl boric acid which is differently substituted in the intermediate 3, and the catalyst is [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride; the alkali is any one of cesium carbonate, potassium carbonate and the like; the reaction temperature is 90% palladium; the method comprises the following steps of (1); the molar ratio of the raw material 1, the boric acid, the alkali and the ligand is 1:1.3: 6: 0.1; the reaction time is 12-24 h;
c. the compounds of the formulae 2.1, 2.2 and 2.3 are obtained by basification of intermediate 2 and starting material 2 (intermediate 4 starting material 2), the reaction temperature being 85 deg.c; the base is 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU); the raw material 2: intermediate 2 DBU molar ratio: 1:1.3:0.2, the raw material 4: intermediate 2 DBU molar ratio: 1:1.3:0.2. The reaction time is 12-24 h;
Detailed Description
EXAMPLE 1, 3.5-difluoro- (3 '-methoxy- [1,1' -biphenyl ]) -4-amino (intermediate 1a) preparation
1g (4.81mmol) of 4-bromo-3.5-difluoro-aniline and 730mg (4.81mmol.1eq) of m-methoxyphenylboronic acid (4.82g 24.88mmol 6eq) [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (425.35mg 481mmol6eq) were placed in a 100ml two-necked flask, 30ml (dioxane: water ═ 3:1) of nitrogen was injected for protection, after the completion of the reaction was monitored by 80 ℃ reaction 3.5 h.T L C, the post-treatment was distilled under reduced pressure to leave about 10ml, the solution was poured into a separatory funnel, extracted 2-3 times with dichloromethane, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to obtain a black oily liquid drop, and the column chromatography was performed with petroleum ether, ethyl acetate ═ 6: 1 of silica gel to obtain about 690mg of a pale yellow oily liquid with a yield of 61%.
1H-NMR(400MHz,CDCl3) 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, 3.5-difluoro- (2-fluoro- [1,1' -biphenyl ]) -4-amino (intermediate 1b) preparation
1g (4.81mmol) of 4-bromo-3.5-difluoro-aniline and 730mg (4.81mmol.1eq) of o-fluorobenzeneboronic acid (4.82g 24.88mmol 6eq) [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (425.35mg 481mmol6eq) were placed in a 100ml two-necked flask, 30ml (dioxane: water ═ 3:1) of nitrogen was injected for protection, after the completion of the reaction was monitored by 80 ℃ reaction 3.5 h.T L C, the post-treatment was distilled under reduced pressure to leave about 10ml, the solution was poured into a separatory funnel, extracted 2-3 times with dichloromethane, dried over anhydrous Na2SO4, filtered, and dried by distillation under reduced pressure to obtain a black oily liquid drop, and the liquid was separated and purified by a column chromatography using petroleum ether, ethyl acetate ═ 6: 1 silica gel to obtain about 650mg of a pale yellow oily liquid with a yield of 60%.
1H-NMR(400MHz,CDCl3):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-phenylamine (intermediate 1c)
1g (4.81mmol) of 4-bromo-2.6-difluoro-aniline and 788mg (4.81mmol.1eq) of p-isopropylphenylboronic acid (4.82g 24.88mmol 6eq) [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (425.35mg 481mmol6eq) were placed in a 100ml two-necked flask, 30ml (dioxane: water ═ 3:1) of nitrogen was injected for protection, after the completion of the reaction was monitored by 80-protection reaction 3.5 h.T L C, the post-treatment was distilled under reduced pressure to the remaining about 10ml, the solution was poured into a separatory funnel, extracted 2-3 times with dichloromethane, dried over anhydrous Na2SO4, filtered, distilled under reduced pressure to give a black oily droplet, and separated and purified by a column chromatography using petroleum ether: ethyl acetate ═ 6: 1 of silica gel column to give about 690mg of pale yellow oily liquid with a yield of 69%.
1H NMR(400MHz,CDCl3) 7.63-7.54 (M,4H),7.38(d, J ═ 8.2Hz,2H),5.27(s,2H),3.00(dt, J ═ 13.8,6.9Hz,1H),1.32(d, J ═ 6.9Hz,6H). (ESI, positive ion) M/z:248.20[ M + H, 2H ], 1.32 (M, J ═ 6.9Hz,6H)]+。
EXAMPLE 4 preparation of (4 '-amino-2', 6,6 '-trifluoro [1,1' -biphenyl ] -3-ylmethanol (intermediate 1d)
1g (4.81mmol) of 4-bromo-2.6-difluoro-aniline and 820mg (4.81mmol l.1eq) of (5- (dimethylamino) -2-fluorophenyl) boronic acid potassium carbonate (4.82g 24.88mmol 6eq) [1,1' -bis (diphenylphosphino) ferrocene ]]Palladium dichloride (425.35mg, 481mmol, 6eq) is placed in a 100ml two-necked bottle, 30ml (dioxane: water 3:1) is injected for nitrogen protection, after the reaction is monitored to be finished by 3.5 h.T L C under 80 guaranty, the aftertreatment is distilled under reduced pressure until about 10ml of the solution is left, the solution is poured into a separating funnel, extracted for 2-3 times by dichloromethane, dried by anhydrous Na2SO4, filtered, and then is distilled under reduced pressure to be dried to obtain black oily liquid drops, and the black oily liquid drops are obtained by petroleum ether and ethyl acetate 6:1, separating and purifying by silica gel column chromatography to obtain about 570mg of light yellow oily liquid with the yield of 49 percent.1H NMR(400MHz,DMSO-d6)8.10–7.87(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]+.
Example 5, 2', 6' -difluoro-N3，N3-dimethyl- [1,1' -biphenyl]Preparation of (E) -3,4' -diamine (intermediate 1e)
1g (4.81mmol) of 4-bromo-2.6-difluoro-aniline and 740mg (4.81mmol.1eq) of p-isopropylbenzeneboronic acid potassium carbonate (4.82g 24.88mmol 6eq) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (425.35mg 481mmol6eq) is put into a 100ml two-necked bottle, 30ml (dioxane: water: 3:1) is injected for protection of nitrogen, after the reaction is monitored to be finished by the condition of 80-80 ℃ reaction 3.5 h.T L C, the aftertreatment is distilled under reduced pressure until about 10ml of the residual solution is left, the solution is poured into a separating funnel, extracted for 2-3 times by dichloromethane, dried by anhydrous Na2SO4, filtered, distilled under reduced pressure to be dried to obtain black oily liquid drops, and separated and purified by a silica gel column chromatography with petroleum ether and ethyl acetate: 6: 1 to obtain about 520mg of light yellow oily liquid, wherein the yield is 47%.1H NMR(400MHz,DMSO-d6)7.84(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 2a)
300mg of 3.5-difluoro- (3-methoxy- [1,1' -biphenyl)]) The product of the previous step of the reaction of (E) -4-aniline (intermediate 1a) was dissolved in analytically pure tetrahydrofuran (10ml), slowly dropped into a reaction flask containing ((1.5ml) boron trifluoride diethyl etherate solution at-15, reacted for 5min, then dropped with 0.9ml of isobutyl tert-butoxide, reacted for 2h, observed to precipitate, and the reaction was warmed up to the temperature where precipitation was observedAdding 10ml of n-pentane at the temperature of minus 5 ℃, heating to 25 ℃, adding 10ml of n-pentane, adding the n-pentane, filtering, taking a filter cake, placing the filter cake into a new reaction bottle, adding 294mg of sodium azide, injecting 30ml of acetonitrile (water is 3:1), reacting at 80 ℃ for 1 h.T L C, monitoring the reaction, performing after-treatment, distilling under reduced pressure until the residual volume is about 10ml, pouring the solution into a separating funnel, extracting for 2-3 times by using dichloromethane, and using anhydrous Na2SO4Drying, filtering, vacuum distilling, drying to obtain black oily liquid drop, adding petroleum ether, ethyl acetate 15: 1, separating and purifying by silica gel column chromatography to obtain about 190mg of light yellow oily liquid, wherein the yield is 57%.
1H-NMR(400MHz,CDCl3) 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 2b)
300mg of 3.5-difluoro- (2-fluoro- [1,1' -biphenyl)]) Dissolving the product of the previous step of the (4-aniline) (intermediate 1b) in analytically pure tetrahydrofuran (10ml), slowly dripping into a reaction bottle containing boron trifluoride diethyl etherate solution ((1.5ml) at the position below zero 15, reacting for 5min, dripping 0.9ml of tert-butyl isobutyl alcohol, reacting for 2h, observing precipitation, heating to the temperature below zero 5, adding 10ml of n-pentane, heating to the temperature of 25 ℃, adding 10ml of n-pentane, filtering, taking a filter cake, placing the filter cake in a new reaction bottle, adding 294mg of sodium azide, injecting 30ml of acetonitrile (water is 3:1), monitoring the reaction at the temperature of 80 ℃ and 1 h.T L C, performing after-treatment, distilling under reduced pressure to the residual about 10ml, pouring the solution into a separating funnel, extracting for 2-3 times by using dichloromethane, and anhydrous Na2SO4Drying, filtering, vacuum distilling, drying to obtain black oily liquid drop, adding petroleum ether, ethyl acetate 15: 1, performing silica gel column chromatography separation and purification to obtain about 210mg of light yellow oily liquid with the yield of 63 percent.
1H-NMR(400MHz,CDCl3) 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 2c)
300mg of 2, 6-difluoro-4 '-isopropyl- [1,1' -biphenyl]Dissolving the product of the previous step of the (4-aniline) (intermediate 1C) in analytically pure tetrahydrofuran (10ml), slowly dripping into a reaction bottle containing boron trifluoride diethyl etherate solution ((1.5ml) at the position below zero 15, reacting for 5min, dripping 0.9ml of tert-butyl isobutyl alcohol, reacting for 2h, observing precipitation, heating to the temperature below zero 5, adding 10ml of n-pentane, heating to the temperature of 25 ℃, adding 10ml of n-pentane, filtering, taking a filter cake, placing the filter cake in a new reaction bottle, adding 294mg of sodium azide, injecting 30ml of acetonitrile (water is 3:1), monitoring the reaction at the temperature of 80 ℃ and 1 h.T L C, performing after-treatment, distilling under reduced pressure to the residual about 10ml, pouring the solution into a separating funnel, extracting for 2-3 times by using dichloromethane, and anhydrous Na2SO4Drying, filtering, vacuum distilling, drying to obtain black oily liquid drop, adding petroleum ether, ethyl acetate 15: 1, separating and purifying by silica gel column chromatography to obtain light yellow oily liquid of about 150mg with the yield of 48 percent.
1H NMR(400MHz,CDCl3) 7.63-7.54 (M,4H),7.38(d, J ═ 8.2Hz,2H),3.00(dt, J ═ 13.8,6.9Hz,1H),1.32(d, J ═ 6.9Hz,6H) (ESI, positive ion) M/z 274.20[ M + H: (ESI, positive ion): 274.20]+
Example 9 preparation of (4 '-azido-2', 6,6 '-trifluoro [1,1' -biphenyl ] -3-yl) methanol (intermediate 2d)
300mg of (4 '-amino-2', 6,6 '-trifluoro [1,1' -biphenyl)]The product of the previous step of the (E) -3-ylmethanol (intermediate 1d) was dissolved in analytically pure tetrahydrofuran (10ml), slowly dropped into a reaction flask containing ((1.5ml) boron trifluoride diethyl etherate solution at-15, reacted for 5min, then dropped with 0.9ml of isobutyl tert-butoxide, reacted for 2h, observed for precipitation, and the reaction was warmed to-5 ℃ and 10ml of isobutyl tert-butoxide was addedHeating to 25 deg.C, adding 10ml n-pentane, filtering, placing the filter cake in a new reaction bottle, adding 294mg sodium azide, adding 30ml (acetonitrile: water: 3:1), reacting at 80 deg.C for 1 h.T L C, monitoring, distilling under reduced pressure to residual 10ml, pouring the solution into a separating funnel, extracting with dichloromethane for 2-3 times, and adding anhydrous Na2SO4Drying, filtering, vacuum distilling, drying to obtain black oily liquid drop, adding petroleum ether, ethyl acetate 15: 1, separating and purifying by silica gel column chromatography to obtain light yellow oily liquid of about 120mg, wherein the yield is 25%.
1H NMR(400MHz,DMSO-d6)7.92–7.85(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 2e)
Mixing 300mg of 2', 6' -difluoro-N3，N3-dimethyl- [1,1' -biphenyl]Dissolving the product of the previous step of the (E) -3,4' -diamine (intermediate 1e) in analytically pure tetrahydrofuran (10ml), slowly dropping into a reaction flask containing boron trifluoride diethyl etherate solution (1.5ml) at the position below zero 15, reacting for 5min, dropping 0.9ml of isobutyl tert-butoxide, reacting for 2h, observing precipitation, heating to the temperature below zero 5, adding 10ml of n-pentane, further heating to 25 ℃, adding 10ml of n-pentane, filtering, taking the filter cake, placing the filter cake in a new reaction flask, adding 294mg of sodium azide, injecting 30ml (acetonitrile: water: 3:1), monitoring the reaction at 80 ℃ for 1 h.T L C, performing after-treatment, distilling under reduced pressure to obtain about 10ml, pouring the solution into a separating funnel, extracting with dichloromethane for 2-3 times, and anhydrous Na2SO4Drying, filtering, vacuum distilling, drying to obtain black oily liquid drop, adding petroleum ether, ethyl acetate 15: 1, separating and purifying by silica gel column chromatography to obtain about 140mg of light yellow oily liquid with the yield of 46 percent.
1H NMR(400MHz,DMSO-d6)7.84(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 (3a)
3.5-difluoro- (3-methoxy- [1,1' -biphenyl)]) Adding 4-6ml acetonitrile into 100mg of (intermediate 2a) 5-isopropyl-1, 3-cyclohexanedione) 59mg of (E) -4-azido, reacting with 80 ℃ 12 h.T L C, monitoring, distilling under reduced pressure until about 10ml of the solution is left, pouring the solution into a separating funnel, extracting with dichloromethane for 2-3 times, and adding anhydrous Na2SO4Drying, filtering, vacuum distilling, drying to obtain black oily liquid drop, adding petroleum ether, ethyl acetate 15: 1 silica gel column chromatography, and the obtained compound brown solid 52mg with yield 34%
1H NMR(400MHz,CDCl3)7.42(d, J ═ 6.4Hz,1H),7.36(t, J ═ 6.4Hz,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 ═ 12.8Hz,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) (ESI, positive ion) M/z:406.07[ M + H + 6H ], (ESI, positive ion) M/z:406.07[ M + H ═ 6.4Hz,1H ]]+。
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 (3b)
3.5-difluoro- (2-fluoro- [1,1' -biphenyl)]) Adding 4-6ml acetonitrile into 50mg of 4-azido (intermediate 2a) and reacting with 80 ℃ for 12 h.T L C, monitoring, distilling under reduced pressure until about 10ml of the solution is left, pouring the solution into a separating funnel, extracting with dichloromethane for 2-3 times, and adding anhydrous Na2SO4Drying, filtering, vacuum distilling, spin drying to obtain black oily liquid drop, and adding petroleum ether and ethyl acetate15: 1, and performing silica gel column chromatography separation and purification to obtain 62mg of a brown solid of the compound, wherein the yield is 50%.
1H NMR(400MHz,CDCl3)7.42(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 (3c)
Adding 4-6ml acetonitrile into 50mg of 4-azido-2, 6-difluoro-4 '-isopropyl-1, 1' -biphenyl (intermediate 2a)88mg, 5-isopropyl-1, 3-cyclohexanedione), reacting with 12 h.T L C at 80 ℃, monitoring, performing after-treatment, distilling under reduced pressure until about 10ml of solution is remained, pouring the solution into a separating funnel, extracting with dichloromethane for 2-3 times, and adding anhydrous Na2SO4Drying, filtering, vacuum distilling, drying to obtain black oily liquid drop, adding petroleum ether, ethyl acetate 15: purification by silica gel column chromatography 1 gave 41mg of the compound as a brown solid in 31% yield.
1H NMR(400MHz,CDCl3)7.42(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 (3d)
3.5-difluoro- (3-methoxy- [1,1' -biphenyl)])50mg of (e) -4-azido (intermediate 2a)90mg, 5-isopropyl-1, 3-cyclohexanedione) was added to 4-6ml of acetonitrile, andafter the reaction at 80 ℃ of 12 h.T L C is monitored, the post-treatment is carried out by reduced pressure distillation until about 10ml of the solution is left, the solution is poured into a separating funnel and extracted for 2-3 times by dichloromethane, and anhydrous Na2SO4Drying, filtering, vacuum distilling, drying to obtain black oily liquid drop, adding petroleum ether, ethyl acetate 15: 1, and the obtained compound is separated and purified by silica gel column chromatography, and the brown solid of the obtained compound is 55mg, and the yield is 41.3%.
1H NMR(400MHz,CDCl3)7.42(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 (3e)
3.5-difluoro- (3-methoxy- [1,1' -biphenyl)]) Adding 4-6ml acetonitrile into 50mg of 4-azido (intermediate 2a), reacting at 80 ℃ with 12 h.T L C, monitoring, distilling under reduced pressure until about 10ml of the solution is left, pouring the solution into a separating funnel, extracting with dichloromethane for 2-3 times, and adding anhydrous Na2SO4Drying, filtering, vacuum distilling, drying to obtain black oily liquid drop, adding petroleum ether, ethyl acetate 15: purification by silica gel column chromatography 1 gave 46mg of the compound as a brown solid in 34.5% yield.
1H NMR(400MHz,CDCl3)7.42(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 (4b)
3.5-difluoro- (2-fluoro- [1,1' -biphenyl)]) Adding 4-6ml acetonitrile into 59mg of (E) -4-azido (intermediate 2a)110mg, 5-isopropyl-1, 3-cyclohexanedione), reacting at 80 ℃ with 12 h.T L C, monitoring, distilling under reduced pressure until about 10ml of the solution is left, pouring the solution into a separating funnel, extracting with dichloromethane for 2-3 times, and adding anhydrous Na2SO4Drying, filtering, vacuum distilling, drying to obtain black oily liquid drop, adding petroleum ether, ethyl acetate 15: purification by silica gel column chromatography 1 gave 41mg of a brown solid as a 22.4% yield of the compound.
1H NMR(400MHz,CDCl3)7.53–7.46(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 (5b)
3.5-difluoro- (2-fluoro- [1,1' -biphenyl)]) Adding 4-6ml acetonitrile into 50mg of 4-azido (intermediate 2a), reacting at 80 ℃ with 12 h.T L C, monitoring, distilling under reduced pressure until about 10ml of the solution is left, pouring the solution into a separating funnel, extracting with dichloromethane for 2-3 times, and adding anhydrous Na2SO4Drying, filtering, vacuum distilling, drying to obtain black oily liquid drop, adding petroleum ether, ethyl acetate 15: purification by silica gel column chromatography 1 gave 67mg of a brown solid as a 46% yield.
1H NMR(400MHz,CDCl3)7.53–7.46(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 (6b)
3.5-difluoro- (2-fluoro- [1,1' -biphenyl)]) Adding 4-6ml acetonitrile into 60mg of 4-azido (intermediate 2a), reacting at 80 ℃ with 12 h.T L C, monitoring, distilling under reduced pressure until about 10ml of the solution is left, pouring the solution into a separating funnel, extracting with dichloromethane for 2-3 times, and adding anhydrous Na2SO4Drying, filtering, vacuum distilling, drying to obtain black oily liquid drop, adding petroleum ether, ethyl acetate 15: purification by silica gel column chromatography 1 gave 62mg of the compound as a brown solid in 36% yield.
1H NMR(400MHz,CDCl3)7.51–7.19(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 (7b)
3.5-difluoro- (2-fluoro- [1,1' -biphenyl)]) Adding 4-6ml acetonitrile into 55mg of (4-azido) (intermediate 2a), reacting at 80 ℃ with 12 h.T L C, monitoring, distilling under reduced pressure until about 10ml of the solution is left, pouring the solution into a separating funnel, extracting with dichloromethane for 2-3 times, and adding anhydrous Na2SO4Drying, filtering, vacuum distilling, drying to obtain black oily liquid drop, adding petroleum ether, ethyl acetate 15: purification by silica gel column chromatography 1 gave 63mg of the compound as a brown solid in 39% yield.
1H NMR(400MHz,DMSO-d6)7.37(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 triazolone biaryl (hetero) Ring derivatives of the invention
The in vitro enzyme activity inhibition assay was performed using the test services provided by Shanghai Ruizi.
1 method of experiment
The purified HsDHODH protein was assayed for viability (50 mmol. L-1 HEPES pH 8.0,150 mmol. L)- 1KCl, 0.1% Triton X-100) to 10 nmol. L-1Adding coenzyme Q and DCIP to final concentrations of 100 and 120. mu. mol. L-1After mixing, add 199. mu. L per well to a 96-well plate using a line gun, incubate at room temperature for 5min, then add 1. mu. L substrate DHO per well to a final concentration of 500. mu. mol. L-1. And reading the light absorption value at 600nm by using a microplate reader for 6min in total, and reading every 30 s. Calculation of the initial velocity V of the enzymatic reaction0The inhibitor activity test is to add different concentrations of inhibitor into the reaction system and calculate the initial speed V of the enzymatic reactioniBy the formula (1-V)i/V0) × 100% inhibition calculated for Compounds Using the software GraphPad Prism 7 IC of the Compounds50The value is obtained. The experiment uses brequinar as a positive control, and at least 3 parallels are arranged in each experiment.
2 results of the experiment
The results of the detection by the method show that 1 mu M compound inhibits the level of in vitro enzyme, and the results of the inhibition effect of the compound on the enzyme activity are shown in Table 1
Table 1 shows the results of in vitro enzyme level inhibition of the compounds of the present invention
"ND" in Table 1 indicates that no inhibitory effect was measured. "RC" represents a positive control compound brequinar, and as can be seen from Table 7, the triazolone biaryl (hetero) ring derivative of the present invention shows a good inhibitory effect on DHODH activity. In particular, compounds 3d, 3e have potent DHODH inhibitory activity, IC50The values are 171nM and 39nM, and the inhibitory activity of the better effect is similar.
Example 21 in vitro tumor cell proliferation inhibition assay
The experiment aims at detecting the proliferation inhibition activity of the compound on in vitro tumor cells, and the adopted method is an MTT (tetramethyl azozolium) colorimetric method.
1 materials of the experiment
1.1 Primary reagents
RPMI-1640, DMEM high-sugar medium, fetal bovine serum, pancreatin and the like are purchased from Gibco BR L company (Invitrogen corporation, USA), tetramethylazoazolium salt (MTT) and dimethyl sulfoxide (DMSO) are products of Sigma company (USA). in an in vitro experiment, a 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-20 ℃ in a dark place for standby, and is diluted to a required concentration by using the complete culture solution when in use.
1.2 cell lines and culture
The human breast cancer cell strain MCF-7, the human colorectal cancer cell strain HCT116, the human hepatoma cell strain HepG2, the human lung cancer cell strain A549 and the human melanoma cell strain A375 which are purchased from American ATCC company and stored in the laboratory are all cultured in 5 percent CO with RPMI-1640 complete culture medium or DMEM complete culture medium containing 10 percent fetal calf serum, 100U/m L penicillin and 100 mu g/m L streptomycin2And cultured at 37 ℃.
2 method of experiment
Cell concentration was adjusted to 4X10 with complete cell culture medium4The cell concentration of each well (48 h) is inoculated on a 96-well plate according to 0.1 ml/well, the culture is carried out overnight, the next day, a culture medium containing 10 mu M concentration drug is added, 3 multiple wells are arranged on each concentration gradient, a solvent control group and a blank control group without cells are arranged at the same time, the culture is continued under the conditions of 37 ℃ and 5% CO2, after 48h of culture, 20 mu L of MTT reagent with the concentration of 5mg/M L is added into each well, after 2-4 h of culture, supernatant is discarded, DMSO150 mu L is added into each well, the mixture is uniformly mixed for 15min by shaking, the absorbance is measured by an enzyme-labeling instrument (lambda is added by 570 nm), the average value is obtained, the relative cell proliferation inhibition rate is expressed by the average value (control group A570-experiment group A570/control group A570 × 100%. the experimental data is expressed by the average value, and the inhibition rate of the compound on the cell proliferation inhibition is expressed by the inhibition rate.
3.1 results of the experiment
The proliferation inhibition activity of the compound on MCF-7, HCT116, A549, HepG2 and A375 is detected by adopting the method, and the cell proliferation inhibition effect result of the compound is shown in Table 2.
TABLE 2 inhibition of proliferation of various human tumor cells in vitro by the compounds
"ND" in Table 2 indicates that no inhibitory effect was measured.
The experimental results of the compound in vitro tumor cell proliferation inhibition show that compared with the 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 strains.
Claims (10)
1. The structure of the triazol hexanone biaryl (hetero) ring derivative is shown as the formula I
R1～R4When is-H, halogen, -OH, -NH2、-NO2C1-C8 alkyl, C1-C8 alkoxy, -CF3C1-C8 alkenyl or C1-C8 ester group;
R5～R9independently is-H, halogen, -OH, -NH2、-NO2C1-C8 alkyl, C1-C8 alkoxy, -CF3、-OCF3C1-C8 alkenyl or C1-C8 ester group;
R10～R12independently C1-C8 alkyl, substituted phenyl substituted C1-C8 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-4; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1-C8 alkyl, C1-C8 alkoxy, phenyl,
-CF3、-OCF3Or C1-C8 alkenyl and carboxyl.
2. The triazolohexanone biaryl (hetero) cyclic derivative according to claim 1
R1～R4When is-H, halogen, -OH, -NH2、-NO2C1-C4 alkyl, C1-C4 alkoxy, -CF3C1-C4 alkenyl or C1-C4 ester group;
R5～R9independently is-H, halogen, -OH, -NH2、-NO2C1-C4 alkyl, C1-C4 alkoxy, -CF3、-OCF3C1-C4 alkenyl or C1-C4 ester group;
R10～R12independently C1-C4 alkyl, substituted phenyl substituted C1-C4 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-4; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, phenyl,
-CF3、-OCF3Or C1-C4 alkenyl and carboxyl
Preferably, the first and second liquid crystal materials are,
R1～R4when is-H, halogen, -OH, -NH2、-NO2C1-C4 alkyl, C1-C4 alkoxy, -CF3
R5～R9Independently is-H, halogen, -OH, -NH2、-NO2C1-C4 alkyl, C1-C4 alkoxy, -CF3、-OCF3Or C1-C4 ester group;
R10～R12independently C1-C4 alkyl, substituted phenyl substituted C1-C4 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-4; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, phenyl,
-CF3、-OCF3Or C1-C4 alkenyl and carboxyl
It is further preferred that the first and second liquid crystal compositions,
R1～R4when is-H, halogen, -OH, -NH2、-NO2C1-C4 alkyl, C1-C4 alkoxy, -CF3
R5～R9Independently is-H, halogen, -OH, -NH2、-NO2C1-C4 alkyl, C1-C4 alkoxy, -CF3、-OCF3
R10～R12Independently C1-C4 alkyl, substituted phenyl substituted C1-C4 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-4; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, phenyl,
-CF3、-OCF3Or C1-C4 alkenyl, carboxyl
Preferably, the first and second liquid crystal materials are,
R1～R4when is-H, halogen, -OH, -NH2、-NO2C1-C4 alkyl, C1-C4 alkoxy
R5～R9Independently is-H, halogen, -OH, -NH2、-NO2C1-C4 alkyl, C1-C4 alkoxy, -CF3、-OCF3
R10～R12Independently C1-C4 alkyl, substituted phenyl substituted C1-C4 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-4; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1EC4 alkyl, C1-C4 alkoxy, phenyl,
-CF3、-OCF3Or C1-C4 alkenyl and carboxyl.
Preferably, the first and second liquid crystal materials are,
R1～R4when is-H, halogen, -OH, -NH2、-NO2C1-C4 alkyl, C1-C4 alkoxy
R5～R9Independently is-H, halogen, -OH, -NH2、-NO2C1-C4 alkyl, C1-C4 alkoxy, -CF3、-OCF3
R10～R12Independently C1-C4 alkyl, substituted phenyl substituted C1-C4 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-2; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, phenyl and carboxyl
Preferably, the first and second liquid crystal materials are,
R1～R4when is-H, halogen, -OH, -NH2、-NO2C1-C4 alkyl, C1-C4 alkoxy
R5～R9Independently is-H, halogen, -OH, -NH2、-NO2C1-C4 alkyl, C1-C4 alkoxy, -CF3、-OCF3
R10～R12Independently C1-C4 alkyl, substituted phenyl substituted C1-C4 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-2; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, phenyl and carboxyl
Preferably, the first and second liquid crystal materials are,
R1～R4when is-H, halogen, -OH, -NH2、-NO2C1-C4 alkaneOxy radical
R5～R9Independently is-H, halogen, -OH, -NH2、-NO2C1-C4 alkyl, C1-C4 alkoxy, -CF3、-OCF3
R10～R12Independently C1-C4 alkyl, substituted phenyl substituted C1-C4 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-2; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, phenyl and carboxyl
Preferably, the first and second liquid crystal materials are,
R1～R4when is-H, halogen, -OH, -NH2、-NO2C1-C4 alkoxy
R5～R9Independently is-H, halogen, -OH, -NH2、-NO2C1-C4 alkyl, C1-C4 alkoxy, -CF3、-OCF3
R10～R12Independently C1-C4 alkyl, substituted phenyl substituted C1-C4 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-2; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, phenyl and carboxyl
Most preferably, the first and second substrates are,
R1～R4when is-H, halogen, -OH, -NH2、-NO2C1-C4 alkoxy
R5～R9Independently is-H, halogen, -OH, -NH2、-NO2C1-C4 alkyl, C1-C4 alkoxy, -CF3、-OCF3
R10～R12Independently H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, phenyl and carboxyl.
3. A triazolohexanone biaryl (hetero) cyclic derivative having the structural formula:
4. a pharmaceutically acceptable salt or hydrate of a triazolohexanone biaryl (hetero) cyclic derivative according to any one of claims 1 to 2.
5. A prodrug of a triazolohexanone biaryl (hetero) ring derivative according to any one of claims 1 to 2.
6. A composition comprising the triazolohexanone biaryl (hetero) cyclic derivative according to any one of claims 1 to 2, the salt or hydrate according to claim 4 or the prodrug according to claim 5, and pharmaceutically acceptable auxiliary components.
7. Use of a triazolohexanone biaryl (hetero) cyclic derivative according to any one of claims 1 to 2, a salt or hydrate according to claim 12, a prodrug according to claim 5 or a composition according to claim 6 in the preparation of a diltiazem lactate dehydrogenase inhibitor; preferably, the use of the above-mentioned triazolohexanone biaryl (hetero) cyclic derivative, its salt or hydrate for the preparation of a diispropyl lactate dehydrogenase inhibitor.
8. Use of a triazolohexanone biaryl (hetero) cyclic derivative according to any one of claims 1 to 2, a salt or hydrate according to claim 12, a prodrug according to claim 5 or a composition according to claim 6 for the preparation of a medicament for the treatment of malignant tumors.
9. Use of a pyrimido morpholine derivative according to any one of claims 1 to 2, a salt or hydrate according to claim 12, a prodrug according to claim 5 or a composition according to claim 6 for the manufacture of a medicament for the treatment of acute leukemia.
10. Use of a triazolohexanone biaryl (hetero) cyclic derivative according to any one of claims 1 to 2, a salt or hydrate according to claim 12, a prodrug according to claim 5 or a composition according to claim 6 for the preparation of a medicament for the treatment of rheumatoid arthritis, multiple sclerosis and immune rejection.
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| CN114560816A (en) * | 2022-03-11 | 2022-05-31 | 四川大学华西医院 | Triazole biaryl (hetero) ring derivative and preparation method and application thereof |
| CN115246783A (en) * | 2021-04-26 | 2022-10-28 | 中国科学院上海药物研究所 | 1,3-cyclohexanedione compound and pharmaceutical composition and application thereof |
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