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WO2007095812A1 - Substituted [1,3,5] triazine compounds, their processes for preparation and uses thereof - Google Patents

Substituted [1,3,5] triazine compounds, their processes for preparation and uses thereof Download PDF

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Publication number
WO2007095812A1
WO2007095812A1 PCT/CN2006/003428 CN2006003428W WO2007095812A1 WO 2007095812 A1 WO2007095812 A1 WO 2007095812A1 CN 2006003428 W CN2006003428 W CN 2006003428W WO 2007095812 A1 WO2007095812 A1 WO 2007095812A1
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WIPO (PCT)
Prior art keywords
substituted
triazine
diamine
phenyl
piperazin
Prior art date
Application number
PCT/CN2006/003428
Other languages
French (fr)
Chinese (zh)
Inventor
Hong Liu
Hualiang Jiang
Xu Shen
Jian Ding
Xingzu Zhu
Liping Lin
Mingfang Zheng
Mingyue Zheng
Yu Zhou
Xinquan Ji
Haibin Luo
Xiaomin Luo
Jianhua Shen
Kaixian Chen
Original Assignee
Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Priority claimed from CN 200610057786 external-priority patent/CN1970552A/en
Application filed by Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences filed Critical Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Publication of WO2007095812A1 publication Critical patent/WO2007095812A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and in particular to substituted [1,3,5]triazine compounds and preparation methods thereof and Applications, and pharmaceutical compositions comprising the substituted [1,3,5]triazine compounds.
  • BACKGROUND OF THE INVENTION The pathogenesis of many diseases involves the involvement of inflammatory mediators, some inflammatory diseases (such as rheumatoid arthritis, rheumatic fever, osteoarthritis), asthma, chronic obstructive pulmonary disease, trauma, burns, endotoxin shock, Alzheimer's disease, even heart failure, has the involvement of inflammatory mediators.
  • AA acetylcholine
  • PGs prostaglandins
  • LTs leukotrienes
  • the first metabolic pathway includes the following series of reactions: Membrane phospholipids via phospholipase
  • a 2 (PLA 2 ) produces free arachidonic acid (AA), and AA is converted to prostaglandin G 2 (PG 2 ) by the action of cyclooxygenase (COX-1 and COX- 2 ), and its peroxidase activity proceeds.
  • the product is converted to prostaglandin H 2 (PGH 2 ), a tissue-specific isozyme that metabolizes PGH 2 to other forms of prostaglandins or thromboxane A 2 (TxA 2 ).
  • AA is metabolized to leukotrienes (LTs) by the action of 5-lipoxygenase.
  • glucocorticoid anti-inflammatory drugs are often used in the early stage, but long-term use of these drugs can cause complications such as adrenal cortical function decline.
  • phenylbutazone was used clinically, and the concept of non-steroidal anti-inflammatory drugs (SAID) was first proposed internationally.
  • NSAIDs with anti-inflammatory and analgesic effects emerged, such as indomethacin and ibuprofen, which are still widely used in clinical practice.
  • COX-2 is expressed in normal tissues and is a constituent protein of normal cells; and COX-2 is an induced form of enzymes, mainly in inflammatory cells, such as endothelial cells, macrophages, and synovial fibroblasts after tissue damage. Expression in dendritic cells, chondrocytes and osteoblasts.
  • COX-2 and COX-1 have similar active binding sites for AA or NSAID; COX-2 can be induced by various factors in inflammatory tissues, and its level will rise sharply at 8-10 times, causing inflammation sites. Increased levels of PGE 2 , PGI 2 , and PGEi promote inflammatory responses and tissue damage.
  • JR Vane et al. pointed out that the effective therapeutic effect of NSAID on inflammation stems from its inhibition of COX-2, which is attributed to inhibition of COX-1. Therefore, since the 1990s, the search for COX-2 selective inhibitors has become an important way to discover new anti-inflammatory drugs. However, COX-2 selective inhibitors have a cardiovascular safety hazard.
  • Classical NSAIDs such as aspirin, indomethacin, and diclofenac are COX selective inhibitors, generally do not contribute to 5-LOX metabolism, they not only affect the synthesis of PGs that have protective effects on the gastric mucosa, but also Single inhibition of COX-2 leads to increased metabolic activity of LOX, causing imbalance of AA metabolism, promoting the synthesis of LTs, thereby promoting leukocyte chemotaxis and increasing vascular permeability. Place In order to propose the need for a comprehensive anti-inflammatory drug with a toxic side effect, COX and 5-LOX should be simultaneously inhibited.
  • COX-2/5-LOX dual inhibitors to achieve synergistic anti-inflammatory purposes is the focus of research on anti-inflammatory drugs for medical workers at home and abroad in recent years.
  • NS AIDs especially selective COX-2 inhibitors (such as celecoxib), act synergistically with other chemotherapeutic drugs to treat rectal cancer.
  • selective 5-LOX inhibitors and COX-2/5-LOX dual inhibitors have been much less studied in rectal cancer.
  • COX-2 selective inhibitors or COX-2/5-LOX dual inhibitors as antitumor drugs and/or their auxiliary drugs will be more and more affected in the field of cancer treatment, especially the prevention and treatment of colorectal cancer.
  • Computer-Aided Drug Design has become an important method and tool for modern drug research and development, adding computer-aided drug design, especially computer-aided combination chemical library design, to the cycle of new drug research. It can shorten the cycle of new drug research, save research and development costs, and improve the hit rate of new drug screening.
  • Computer-Aided Drug Design is a new technology in medicinal chemistry and synthetic chemistry in recent years, which can rapidly generate a large number of molecular structures for high-throughput screening.
  • Structural biology also The original basic research entered the applied research stage.
  • Some substituted [1,3,5] triazine compounds have certain inhibitory activities on human intestinal cancer cells, HT-29 and HCT-116, and similar structures of morpholine triazines have been found to Intestinal cancer cell lines HT-29 and HCT-116 have strong inhibition Activity, a few compounds IC 5G up to nM grade; in addition, morpholine triazines also showed better epidermal growth factor receptor (EGFR) inhibitory activity; compounds that received cell chromosome teratogenicity test performed well, no teratogenicity Thus, the present invention has been completed.
  • EGFR epidermal growth factor receptor
  • the present invention provides a substituted [1,3,5]triazine compound which has a dual inhibitor action and an EGFR enzyme inhibitor action on COX-2/5-LOX.
  • a further object of the present invention is to provide a process for the preparation of the above compounds.
  • a further object of the invention is to provide the use of the above compounds.
  • a further object of the present invention is to provide a pharmaceutical composition comprising the above compound.
  • a further object of the invention is to provide the use of the above pharmaceutical compositions.
  • the present invention provides a substituted [1,3,5]triazine compound having a structure represented by the formula (I), a pharmaceutically acceptable salt thereof, and a solvate or hydrate thereof:
  • R 2 , R 3 and R 4 are each independently hydrogen, Q-C 8 linear or branched hydrocarbon, substituted or unsubstituted aryl, aralkyl, C r C 4 alkaryl, aroyl,
  • the aryl group is selected from the group consisting of phenyl, naphthyl and biphenyl, and the substituents are from 1 to 4 selected from the group consisting of halogen, d-linear or branched hydrocarbon, an aryl group, a nitro group, an amino group, a hydroxyl group, a hydroxy group, Group of trifluoromethyl, trifluoromethoxy, carboxy, C!-alkoxy, fluorenyl, C r C 4 alkylthio, C r C 4 alkane, C r C 4 alkoxycarbonyl, sulfonyl Group; and
  • Re and R 7 are each independently selected from the group consisting of hydrogen, halogen, d-linear or branched hydrocarbon, cyano, nitro, amino, hydroxy, hydroxydecyl, trifluoromethyl, trifluoromethoxy, carboxy, dC 4 alkoxy, mercapto, - C 4 alkylthio, -C 4 acyl, and sulfonyl groups group;
  • Y is CH 2, 0, S, or the RN, wherein R is hydrogen, - C a linear or branched hydrocarbon group, a hydroxyl group, an OC4 hydroxyalkyl group, a group, a C, a C 4 alkylcarbonyl group, a C!-alkoxycarbonyl group, a decanoyl group;
  • m, n are each independently 0, 1 , 2 Or 3, or R 5 is selected from the group consisting of a hydroxyl group, an amino group, a substituted amino group, a Ci-
  • R 8 is hydrogen, hydroxy, aryl, heteroaryl ring, heteroalicyclic or C 2 -C 6 alkenyl.
  • the compound according to the invention may be: ⁇ , ⁇ '-diphenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine;-Chloro-p-sulfonyl-p-phenyl-indole,-phenyl-[1,3,5]-triazine-2,4-diamine; ⁇ -p-sulfonylphenyl-indole, -phenyl-6- (piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; ⁇ -o-methylsulfonylphenyl-indole,-phenyl-6-(piperazin-1- Substituted)-[1,3,5]-triazine -2,4-diamine; N-m-methanesulfonylphenyl-N,-phenyl-6-(piperazin-1-substituted)
  • the present invention also provides a process for the preparation of the above compound, which comprises the steps of: (1) the compound of the formula (II) in an alkaline solvent at 0-50. Reacts with a substituted amine at C temperature, lsT, N
  • R x is hydrogen, halogen, hydroxy, decyl, -C 4 hydrocarbylamine, or C r C 4 aminoalkyl
  • R y and R z are respectively hydrogen, halogen, -C4 aminoalkyl, or dC 4 halogenated a hydrocarbon group to give a compound of the formula (III):
  • R 2 , R x and R y are the same as defined in the formulae (1) and (II);
  • the compound of the formula (III) is used in an alkaline solvent at 20-100.
  • the compound represented by the formula (IV) is obtained by reacting with a substituted amine, a substituted arylamine, a substituted arylalkylamine, an alcohol or a thiol at a C temperature:
  • a salt formation reaction or a solvate or a hydrate is formed by a conventional method in the art as needed.
  • the method according to the present invention wherein the alkaline solvent described in the step (1) and the step (2) is an alkali solution prepared by using an inert solvent selected from the group consisting of pyridine, triethylamine, 4-diamine.
  • the base is one or more selected from the group consisting of pyridine, triethylamine, 4-di
  • DMAP guanamine pyridine
  • the substituted [1,3,5]triazine compound or a pharmaceutically acceptable salt thereof or a solvate or hydrate thereof according to the present invention can be used as a cyclooxygenase inhibitor, a 5-lipoxygenase inhibitor, Double inhibitors of cyclooxygenase and 5-lipoxygenase, and EGFR enzyme inhibitors.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the formula (I) as an active ingredient, the pharmaceutical composition comprising a therapeutically effective amount of the substitution as shown in the formula (I) [1, 3, 5]
  • the pharmaceutically acceptable carrier includes an ion exchanger, aluminum oxide, aluminum stearate, lecithin, serum protein, a buffer substance such as phosphate, glycerin, sorbic acid, potassium sorbate, a partial glyceride of a saturated plant fatty acid.
  • the above pharmaceutical composition can be used for the prevention and/or treatment of inflammatory diseases, and for the prevention and/or treatment and/or adjuvant treatment of tumor diseases, particularly intestinal cancer.
  • composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal , intraventricular, intrasternal and intracranial injections or Enter, or use an explant reservoir.
  • oral or intramuscular injection, intraperitoneal or intravenous administration is preferred for the treatment of inflammation.
  • the dosage and method of use of the compounds of the invention depends on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and Subjective judgment of the doctor.
  • the recommended dose is 5 mg to 10 mg/kg daily, and the maintenance dose can be reduced to 3 mg/kg per day.
  • Gelling agent 0.25g / grain. Injection 0.25g/5ml.
  • Oral solution 5g / 50ml.
  • the substituted [1,3,5]triazine compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof at the COX-2 and 5-LOX enzyme levels and the overall animal level (carrageenan-induced A series of models of mouse foot swelling, carrageenan-induced rat foot swelling, diterpene-induced mouse auricular inflammation model, rat adjuvant arthritis primary, secondary lesion model) In the study, both showed significant anti-inflammatory activity. It has good safety to Ames test and mouse micronucleus test, and has no toxic side effects on gastrointestinal tract. It is biocompatible for in vivo treatment.
  • the pharmaceutical composition of the present invention can be used for the prevention and/or treatment of inflammatory diseases and has a good therapeutic effect.
  • DRAWINGS Figure 1 is a graph showing the binding kinetics of substituted [1,3,5]triazine compounds with cyclooxygenase (COX-1 and COX-2).
  • Figures 1-1 and 1-2, Figures 1-3 and 1-4, Figures 1-5 and 1-6, Figures 1-7 and 1-8, and Figures 1-9 and 1-10 represent positive compound, compound B, compound B52, B58 compound, and K D values of compound 61 in combination with COX-2 and COX-1's.
  • Figure 1 shows the binding kinetics of the substituted [1,3,5]triazine compound to 5-lipoxygenase (5-LOX).
  • the instrument used is BIACORE3000 and the analysis software is Kinetic Analysis in the Application Wizard.
  • FIG. 2-1 and 2-2 show the K D of the positive compound ETYA and the compound B62 combined with 5-LOX, respectively.
  • Figure 3 is a photograph of the section of the gastrointestinal side effects test report of each group.
  • Figure 3-1 shows the negative control
  • Figure 3-2 shows indomethacin
  • Figure 3-3 shows the compound Celecoxib
  • Figure 3-4 shows compound B62
  • Figure 3-5 shows compound B68.
  • the solution is thoroughly mixed, then plated, dried, and activated at 100 ⁇ 110 oC for 1 ⁇ 2 hours, then stored in a desiccator for UV light ( ⁇ : 254 nm); column chromatography uses 200 mesh to 300 mesh column Analysis of silica gel (produced by Qingdao Ocean Chemical Plant).
  • Example 1 Synthesis of aniline monosubstituted tripolychloroazine (4,6-dichlorophenyl-[1,3,5]-triazin-2-amine) In a 50 ml eggplant-shaped flask, 4.726 g of tripolychloro The oxazine was dissolved in 20 ml of 1,4-dioxane, and an aqueous solution of 2.337 ml of aniline and 1.03 g of NaOH was slowly added dropwise with stirring, and the reaction was stirred for 6 hours; water was added thereto, and the mixture was filtered, washed with water, and evaporated. . Mp 136-138 0 C.
  • Example 2 Synthesis of aniline disubstituted tripolychloroazine (6-chloro-N,N,-diphenyl-[1,3,5]-triazine-2,4-diamine) in a 50 ml eggplant bottle 0.421 g of chloralazine was dissolved in 5 ml of 1,4-dioxane, and 0.42 ml of an aqueous solution of aniline and 0.2 g of NaOH was added thereto with stirring at room temperature; and the reaction was stirred at 20 to 100 ° C overnight. Filtration and washing with water to give a white solid (yield). Mp l97 °C.
  • LREI (m/z): 426 (M+), 384, 370, 358 (100), 299, 144, 119, 92, 77, 56.
  • HREI Calculated value (calculated as C 19 H 22 N 8 0 2 S) 426.1597; found 426.1584.
  • 6-chlorophenyl-N,-p-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-sulfonylphenyl -N,-Phenyl-[1,3,5]-triazine-2,4-diamine, morpholine, m.p. Mp 178-180 0 C.
  • 6-chloro-p-fluorophenyl-N 6-chloro-p-fluorophenyl-N,-p-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-p-sulfonylphenyl- N,-Phenyl-[1,3,5]-triazine-2,4-diamine, morpholine, m.p. Mp 198-199. C.
  • N,-dibenzyl-6-chloro-[1,3,5]-tri-2,4-diamine in place of 6-chloro-p-methylsulfonylphenyl-N,-phenyl-[1 3,5]-triazine-2,4-diamine, morpholine, m.p. Mp 134 ⁇ 136 0 C o ! HNMR (300Mz, CDCI3, TMS) ⁇ (ppm): 7.23-7.3 l(m, 10H); 5.17(Br-s, 2H); 4.57(d 5 J 5.7 Hz, 4H); 3.66-3.73 (m, 8H). LREI (m/z): 376 ( ⁇ ), 73 (100).
  • Example 69 Synthesis of 2-chloro-4,6-di(morpholine-4-substituted)-[1,3,5]-triazine (Compound C188) Operation was carried out as in Example 2 except that morpholine was used in place of aniline. , the title compound was obtained as a white solid. Mp 175. C. ! HNMR (300Mz, CDC1 3, TMS) ⁇ (ppm): 3.70 ⁇ 3.78 (m, 16H).
  • Example 76 2-[4-(4,6-Diphenylamino-[1,3,5]-triazine-2-substituted) piperazin-1-substituted]ethanol (Compound C193) was synthesized except 6- Chloro-N,N,-diphenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-methylsulfonylphenyl-N,-phenyl-[1 , 3,5]-triazine- 2,4-diamine, 2-(piperazin-1-substituted)ethanol, in place of piperazine.
  • Example 79 N-(3,4-Dimethoxy)phenyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5-triazine-2,4-di synthesis of the amine (compound C73) except that 6-chloro -N- (3,4- two Yue yloxy) -N-phenyl, - phenyl - [1,3,5] - triazine - 2, 4 - two The amine was replaced by an amine instead of 6-chloro-N-p-sulfonylphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine, morpholine instead of piperazine.
  • Example 81 N-p-Methylthiophenyl-6-(morpholin-4-substituted)-N,-p-p-phenyl-[1,3,5]-triazine-2,4-diamine (compound)
  • the synthesis of C19) is in addition to 6-chloro-N-p-methylthiophenyl-N,-p-phenylene-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N.
  • - sulfonylphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine, morpholine in place of piperazine was operated as in Example 5 to give the title compound as white powder. Solid.
  • Example 82 6-(morpholine-4-substituted)-N-phenyl-N,-(pyridin-4-substituted)-[1,3,5]-triazine-2,4-di Synthesis of the amine (compound C20) except 6-chloro-N-phenyl-N,-(pyridin-4-substituted)-[1,3,5]-triazine-2,4-diamine instead of 6-chloro
  • the title compound was obtained as a powdery solid, m. m. m. m. . . .
  • Real horse method Binding experiments of compounds with cyclooxygenase (COX-1 and COX-2) were carried out at room temperature using BIACORE 3000 (BIACORE AB, Uppsala, Sweden) (Amersham).
  • the chip and buffer solution were as follows: CM5 chip, EDC, NHS, ethanolamine, HBS-EP (purchased from BIACORE AB (Uppsala, Sweden)) 0 Procedure: Dissolve the piperazine triazine compound in DMSO and dilute with HBS-EP To the corresponding concentrations (0.625, 1.25, 2.5, 5.0 and 10.0 ⁇ ), the DMSO content was 0.4%.
  • the purified protein is attached to the chip by amino coupling.
  • the dynamics of the BIACORE 3000 kinetic analysis Wizard was used for data collection and analysis.
  • Test compounds were prepared by the Shanghai Institute of Drug Research Center for Drug Discovery and Design (DDDC) synthesis laboratory.
  • P-day compounds Celecoxib and ETYA eicosa-5, 8, 11-tetraynoic acid
  • 5-LOX enzyme DDDC biological laboratory eukaryotic system expression preparation.
  • Test Example 2 Inhibition of neutrophil release of leukotriene B4 in isolated rat Experimental reagent: Type II glycogen (Sigma-Aldrich Co, 10K154), indomethacin
  • Test animals SD rats, clean grade, male or female, weighing 200 ⁇ 20 g (commercially available).
  • Experimental equipment Thermometer, Multiskan spectrum, constant temperature water bath, etc.
  • Experimental methods and data analysis :
  • the collected cells were adjusted to 5 X 10 6 /mL with Hanks balanced salt buffer, and dispensed in 0.5 mL, 37.
  • C was incubated for 10 min, and L-cysteine (10 mM), indomethacin (1 mg/L) and test compounds at various concentrations (50, 5, 0.5 ⁇ ), 37 were added in sequence. After incubating for 30 min, the calcium ionophore A23187 (5 ⁇ ), 37 was added. C continued to incubate for 30 min, immediately after 4.
  • C centrifuge at 14000 r/min for 5 minutes, and store the supernatant at -70. C spare.
  • the final concentration of the solvent in the reaction system is ⁇ 0.21%.
  • the cell extract was diluted with the buffer of the commercial EIA kit, and then added to the 96-well microtiter plate. Two replicate wells were set for each sample, and the test was repeated twice, and incubated at 4 ° C overnight. The force was applied to the developer, and the absorbance was measured at 412 nm after 90 minutes in the dark, and the content of LTB 4 in the sample was measured according to the standard curve established by the standard.
  • the concentration of LTB 4 in each treated sample is represented by mean SEM.
  • the formula for calculating the inhibition rate of neutrophils to 1 ⁇ 3 ⁇ 4 4 is:
  • Inhibition rate (solvent tube concentration - sample tube concentration) / solvent tube concentration xlOO%
  • the IC 5 G value of LTB 4 released from rat neutrophils (5 x 10 6 /ml) stimulated by calcium ionophore A23187 was further tested by the test method for compounds B62, B68, C72 and the positive control Zileuton. , 1.52 ⁇ , 31.12 ⁇ , 11.78 ⁇ and 0.86 ⁇ , respectively.
  • mice male healthy mice weighing 22-25 g.
  • mice Male healthy mice weighing 22-25 g were randomly divided into groups of 10 each. Negative (CMC sodium, sodium carboxymethylcellulose aqueous solution) and positive ( p -indomethacin, 5 mg/kg) control group were set. The test drug was dissolved in the CMC solution, and the amount of the drug was 50 mg/kg. Dosing (intraperitoneal injection or gavage) 30 minutes before the onset of inflammation. The mice were then fixed in a rat rack, the hind limbs were straightened, and 0.2% carrageenan (Can'ageenin) 20 ⁇ l was injected into the ankle of the mice with a 4 gauge syringe.
  • CMC sodium, sodium carboxymethylcellulose aqueous solution Positive (p -indomethacin, 5 mg/kg) control group were set.
  • the test drug was dissolved in the CMC solution, and the amount of the drug was 50 mg/kg. Dosing (intraperitoneal injection or gavage) 30 minutes before the onset of inflammation
  • mice were sacrificed 4 hours after the inflammation, and the left and right hind limbs were cut along the joints of the hind limbs.
  • the differences between the drug-administered group, the control group and the positive drug control group were compared.
  • the mean value, SD, P value and percent inhibition were determined by statistical analysis. (See Table 3).
  • Test Example 4 Anti-inflammatory drug screening pharmacodynamics experiment (II) Experimental animals: male Wister rats, weighing 150-180 g; male mice, weighing 26-30 g. Experimental methods and observation indicators: Experiment 1. Rat foot and carrageenan-induced swelling method. Male Wister rats weighing 150-180 g were randomly divided into groups of 10 rats each. A negative (CMC aqueous solution) and a positive (indomethacin 3.6 mg/kg) control group were set. The test drug was dissolved in the CMC solution, and the amount of each of the 15 compounds was 15 mg/kg. Administered by intragastric administration 60 minutes before the onset of inflammation.
  • mice Male SD rats weighing 180 ⁇ 20 g were randomly divided into groups of 10 rats each. A negative (CMC aqueous solution) and a positive (indomethacin 0.3 mg/kg) control group were set.
  • the test drug is dissolved in CMC solution, B62 large dose 30mg/kg, medium dose lOmg/kg, low dose 3mg/kg, B68 large dose 100mg/kg, medium dose 50mg/kg, low dose 25mg/kg. It was administered by intragastric administration 60 minutes before the onset of inflammation.
  • FCA Freund's complete adjuvant
  • Negative control 10 7.30 ⁇ 2.18 Positive control 10 3.90 ⁇ 1.02 46.58% Small dose (lmg/kg) 10 7.70 ⁇ 1.27 -5.48% Small dose (3mg/kg) 10 4.80 ⁇ 2.26* 34.25% Medium dose 4.05 ⁇ 2.72** 44.52 %
  • mice male SD rats
  • Test drugs indomethacin, Celecoxib, B62, B68
  • Experimental methods and observation indicators Male Sprague-Dawley rats weighing 200-220 g were randomly selected, with 10 rats in each group. Negative and positive control groups were set. Administered by gavage, once a day for 4 consecutive days, during which no control was given to food or water. The animals were sacrificed 24 hours after the last administration, and the stomach and small intestine were taken out. The mouth was made in the longitudinal direction of the small bend. The stomach and small intestine were washed with running water, and the stomach was opened with the index finger to check the stomach damage and record. One or more lesions (bleeding point, erosion, ulceration, or perforation) are considered positive.
  • Test Example 6 Compound B and B62 bacterial back mutation test
  • TA97 9-aminoacridine TA98 manufactured by Sigma Chemical Company lnc: 2-Nitroflucrene TA100 manufactured by Aldrich Chemical Company lnc: Methyl methanesulfonate TA102 manufactured by Sigma Chemical Company lnc: Mitomycin C TA1535 manufactured by KYOWAHAKKO KOGYO CO.LTD.: Sodium azide by Merck produce
  • TA97, TA98, TA100 2-aminofluorene produced by Sigma Chemical Company lnc
  • TA1535 Cyclophosphamide for injection is produced by Shanghai Hualian Pharmaceutical Co., Ltd.: Salmonella typhimurium histidine auxotrophic mutant.
  • the identification includes: histidine auxotrophy, lipopolysaccharide barrier defect (rfa), UV repair defect O uvrB, except TA102), and R-factor.
  • TA97 TA98, and TA100 have a ⁇ plasmid with ampicillin resistance, TA102 with ⁇ and pAQl plasmids, and ampicillin and tetracycline. Those who have passed the above-mentioned identification, the spontaneous mutation number meets the required strain, and the bacteria are added as a mutagenized experimental strain.
  • Toxicity prediction of 5 strains Toxicity evaluation criteria: First, it was observed that the bacterial growth background was toxic if it became thinner or disappeared than the negative control group. Second, the average number of regressions per count compared to the negative control is toxic if the return variable is significantly reduced or dose dependent.
  • Aroclor 1254-induced rat liver S 9 was prepared with about 200 grams of body weight Sprague -Dawley rats, intraperitoneal injection of Aroclor 1254 (Dainippon Pharmaceutical Co., Ltd.) 500 mg / kg, the fifth day of sacrifice, the liver was removed and rinsed under sterile conditions Immediately irrigate with 4 C 0.15M KCl, then add 0.15M KC1 4 C homogenate at a ratio of 3 ml/g wet weight, centrifuge at 9000 xg, and take the supernatant as s 9 and store in liquid nitrogen. The frozen s 9 was slowly melted before the experiment, using the newly prepared S 9 Mix each time.
  • Pre-culture is used to measure the mutagenic effect of drug metabolism activation.
  • the composition of the test top layer is:
  • the measured drug solution, bacterial solution, and S 9 mixture were subjected to 25 minutes and 35 minutes. After shaking and incubating, the experiment was carried out according to the standard plate infiltration method. Each dose group was set to 3 i, and each strain was counted in the absence of drug metabolism or by the drug-based activation system (-S 9 or +S 9 ). The number of colonies was X-SD. Effective experiment acceptance criteria:
  • a positive (negative) control must fall within or close to the historical background data of the laboratory or be consistent with the literature.
  • Results evaluation criteria 1. The return mutation value of all test groups was 2 times lower than that of the negative control group and was negative. The recovery mutation value of any test group was 4 times greater than that of the negative control group, and the pretest and the conclusion of the main test were consistent, and it was judged as positive.
  • test compounds B and B62 meet the guidelines.
  • the negative and positive recovery mutation rates are consistent with the background data of the laboratory, and there is no pollution in the experiment. This experiment is valid for evaluation.
  • Compound B is - S 9 test system a concentration of 50 ( ⁇ g / i, of the TA97, TA98, TA102 strain inhibitory effect when a dose of 50, 5, 0.5, when 0.05 ⁇ ⁇ / dish without suppression. There was no mutagenic effect and the results are shown in Table 13.
  • the compound ⁇ has a bacteriostatic effect on TA97, TA98, TA100, TA102, TA1535 and 5 strains in 5000 and 1000 g/Jni in the +S 9 experimental system.
  • the dose is 500 ⁇ ⁇ /, it has a bacteriostatic effect on ⁇ 97, ⁇ 98, ⁇ 102, and 3 strains. 50, 5 ⁇ no bacteriostatic or mutagenic effect.
  • Compound B62 has a bacteriostatic effect on TA97, TA98, TA 100, TA102, and 4 strains in the -S 9 and + S 9 experimental systems at a concentration of 500 ( ⁇ g / dish).
  • 500 ⁇ g / dish
  • TA1535 strain dose 5000, 1000, 500, 50, 5 g / no inhibition of the growth of bacterial colonies, no mutagenic effects. See Table 15 and Table 16 .
  • B and B62 have no mutagenicity and no mutagenicity under the conditions of this experiment.
  • Table 13 B without the action of the S 9 metabolic system i show change test for Salmonella typhimurium
  • TA97, TA98, TA100 2-aminofluorene (50 g/i)
  • TA102 1 ,8-dihydroxyanthraquinone (50 g/ ⁇ 111 )
  • TA 1535 cyclophosphamide 200 ⁇ g/ m ⁇ Table 14.B via the S 9 metabolic system
  • the dosage of colonies and reverting colonies of Salmonella typhimurium is ⁇ ⁇ / ⁇ ⁇ 97 ⁇ 98 TA100 TA102 TA1535
  • TA102 Muitomycin C (0.5 g/ ⁇ )
  • TA100 2-aminofluorene (50 ⁇ )
  • TA102 1 ,8-dihydroxyanthraquinone (50 g/dish)
  • TA1535 Cyclophosphamide 200
  • Solvent control 0.5% sodium carboxymethyl cellulose.
  • mice 90 ICR mice (?45, $45) were provided by the Shanghai Real-face Animal Center of the Chinese Academy of Sciences, and the certificate of conformity: Laboratory Animal Quality Certificate No. SCXK (Shanghai) 2002-0010.
  • the mice were adaptively reared in the animal room of Shanghai Institute of Materia Medica, Chinese Academy of Sciences for three days.
  • the body weight was 18 ⁇ 22 grams, and they were randomly divided into groups according to their body weight. 14 samples (?7, ⁇ 7) were used as one dose group.
  • the control group consisted of 10 rats (? 5, $ 5).
  • the feed was purchased from Sino-British joint venture Sipper - Bikai Experimental Animals Co., Ltd. Free water intake, feeding temperature is 23 ⁇ 2.
  • C humidity is 60 ⁇ 10%.
  • the selected doses are 2000, 1000, 500, 250, 125 mg/kg 5 dose groups, each group Fourteen, male and female, were administered intragastrically once a day for two consecutive days, and the death of the animals was recorded. As a result, the mice did not die after administration of the high dose of 2000 mg/kg (Table 1).
  • the mouse LD50 is greater than 2000 mg/kg.
  • the selected doses are 2000, 1000, 500, 250, 125 mg/kg 5 dose groups, each group
  • the mouse LD50 is approximately 1000 mg/kg.
  • the highest dose of B62 was selected as 2000 mg/kg, and another 1000, 500 mg/kg dose group, one solvent control group and one positive control group.
  • the highest dose of B68 was selected as 500 mg/kg, and another 250 doses of 250 and 125 mg/kg were administered.
  • Agent distance 0.5 times the highest dose.
  • Dosing volume 0.2 ml/10 g. .
  • the test substance can be sampled two or more times at a time point between 12 and 24 hours after the last administration.
  • Mice were intragastrically administered B62: 2000, 1000, 500 mg/kg/day and the negative control group for 2 days; B68: 500, 250, 125 mg/kg/day and the negative control group were administered continuously for 2 days.
  • the positive control group was intraperitoneally injected (60 mg/kg) and sampled 24 hours after the last administration.
  • the bilateral femurs were removed, washed with inactivated calf serum, centrifuged, dispersed cell smears, air-dried and fixed by Giemsa staining and microscopic examination.
  • mice must meet the criteria in accordance with the guidelines.
  • the highest dose must be greater than 1/2 LD 50 if there is no serious physical illness or severe bone marrow toxicity.
  • micronucleus rate of mouse bone marrow polychromatic erythrocytes caused by positive and negative controls must fall within or close to the historical background data of this laboratory or be consistent with the literature.
  • the PCE/NCE ratio in the drug-administered group was in the appropriate range and there was no obvious bone marrow cytotoxicity.
  • the nuclear rate of the test substance in all dose groups is similar to the micronucleus rate of the negative control group, or not more than 2 times, it can be judged as negative. 2. Any increase in the nucleus rate of the nucleus induced by the test substance was 4 times higher than that of the negative control group.
  • the statistical difference is significant, it should be compared with the historical negative control data 95% upper limit, if it is less than still can be judged as negative. When it is greater than the dose relationship, the micronucleus rate increases with the dose, and the statistical difference is judged to be positive.
  • mice were intragastrically administered with B62 for 2 consecutive days.
  • the micronucleus rate of the 2000, 1000, and 500 mg/kg/day dose groups was similar to the negative control group at 24 h after the last administration. There was no significant difference.
  • Table 17 The mice were intragastrically administered with B62 for 2 consecutive days.
  • the micronucleus rate of the 2000, 1000, and 500 mg/kg/day dose groups was similar to the negative control group at 24 h after the last administration. There was no significant difference.
  • Table 17 The mice were intragastrically administered with B62 for 2 consecutive days.
  • the micronucleus rate of the 2000, 1000, and 500 mg/kg/day dose groups was similar to the negative control group at 24 h after the last administration. There was no significant difference.
  • mice were intragastrically administered B68 twice, at the time point of 24 h after the last administration.
  • the micronucleus rate of the three dose groups of 125, 250, and 500 mg/kg/day was similar to that of the negative control group, and there was no significant difference.
  • the results are shown in Table 18.
  • Test Example 8 Compound ⁇ Inducing Chromosomal Aberration in Cultured Mammalian Cells The purpose of the experiment was to observe the chromosomal aberration and to observe whether the compound ⁇ caused damage to the chromosome of CHL cells in vitro. Preparation method:
  • Cyclophosphamide (Shanghai Twelfth Pharmaceutical Product) as a metabolic activation system
  • CHL cells serve as sputum cells for the effect of B on chromosomes.
  • CHL cells were introduced by the Shanghai Institute of Drug Control and the mycoplasma test was negative.
  • RPMI1640 (GIBCO product) cells plus 15% calf serum were placed at 37. C, 5% C0 2 incubator for monolayer cell culture.
  • the IC 5Q value was measured to be 1.82 ⁇ ⁇ / ⁇ , which was diluted as the highest dose, and the final concentration was 1.82, 0.91, 0.455 g/ml.
  • the metabolic activation experiment was continued for 6 h after changing to fresh medium for 24 h.
  • the non-metabolic activation group and the metabolic activation group were harvested for 24 hours to prepare specimens.
  • Inoculate CHL cells each containing approximately 1xlO 5 37 cells.
  • the test substance solution was added so that the final concentration in the culture solution was 1.82, 0.91, and 0.455 g/ml.
  • Each of the three dose groups and the negative control group the positive control group.
  • Non-metabolic activation was performed at 24 h to collect cells.
  • 0.1 ml of S 9 mixture was added, and three dose groups and a negative and positive control group were also measured. After 6 hours of culture, the fresh medium was changed, and the cells were further cultured until 24 hours to collect the cells.
  • Color body preparation
  • Colchicine 0.2 g/ml was added 3 h before the cells were collected, then trypsinized, centrifuged, and the supernatant was decanted. After being treated with 0.075M KC1 hypotonic solution, it was fixed in sterol: water acetic acid (3:1) fixative. Take a few drops of the drop on the clean glass, Giemsa staining, microscopic examination.
  • the highest concentration should meet the requirements of China's guiding principles. This will achieve the highest concentration allowed by solubility or toxicity.
  • the negative control value should be within the 99% confidence limit of the previous negative control background data in this laboratory.
  • Negative Negative if all the test groups have a distortion rate below 4.9%. Positive: If the test group has at least one group that meets the positive criteria and is dose dependent or repeatable, it can be judged as a positive result. If the result is not certain, the test should be repeated. Experimental result
  • (+S 9 ) group The final concentration of compound B was 1.82, 0.91, 0.455 g/ml and the chromosome aberration rates of the negative control group were: 2%, 4% and 3%, respectively. In the experiment, the chromosomal aberration rate of the high, medium and low dose groups was ⁇ 5%, which was negative. The positive drug cyclophosphamide 24h induced distortion rate was 13% positive (see Table 19). Table 19 Chromosomal aberration rate of Compound B in CHL cells (+S 9 group)
  • Distortion type b-fracture; p-polyploid; t-triple body; q-four-body; a-deficient; e-exchange; f-fragmentation; d-double centromere; g-crack; r- Ring; 1-lost; tr-translocation
  • a cell chromosome aberration occurs in the n-type, and the distortion rate is calculated as 1 time.
  • test substance was formulated into a corresponding concentration with 0.5% CMC-Na, so that the dose groups of each dose group were equal in volume and were ready for use.
  • mice 60 Kunming mice ($30, ⁇ 30) were provided by the Shanghai Experimental Animal Center of the Chinese Academy of Sciences, and the certificate of compliance was: No. 005 of the Chinese Medicine. Adapted to feeding in a week. Feed purchase free Shanghai Shilin Technology Co., Ltd. Free water intake, feeding temperature 23 soil 2 . C. Body weight: The body weight is 18-22 grams when administered. Gender: Male and female. Number of animals per group: Randomly grouped by body weight, one dose per 10 groups during the experiment. Dosage
  • Dose setting According to the preliminary experimental results, the highest dose was determined to be 4082 mg/kg, which was decreased by 0.7, which was 6 dose groups of 686, 980, 1400, 2000, 2857, 4082 mg/kg; 0.7; each animal receives volume: gavage volume: 0.2 ml / g body weight,
  • mice were administered intragastrically.
  • mice were randomly divided into 6 groups according to body weight, with 10 mice in each group. The body weight distribution of each group was similar. After the administration, all aspects of the animal's reaction were observed, and the dead animals were dissected. Check the internal organs and record the number of deaths per day.
  • Toxic reaction Observe the appearance, behavior, eating, feces, etc. of the mice, and the dead animals are subjected to autopsy. At the end of the experiment on the 15th day, the surviving mice were dissected, and the lesions of the heart, lung, liver, spleen, kidney and other organs were examined visually.
  • mice After 30 minutes of oral administration, the mice showed decreased activity, paroxysmal tremor, gait, and began to die about 1 hour after the drug. Most deaths occur within 4 hours. The toxicity is proportional to the dose. There was no obvious abnormality in the visual examination of the organs of the mice. Surviving mice were dissected on the 15th day, and no obvious lesions were seen in the internal organs. The deaths are listed in the table below.
  • Test object logarithm animal death animal mortality probability single LD50 and dose number rate 95% confidence limit (mg/kg) (x) (only) (only) (%) (Y) (mg/kg)
  • the LD 5Q is calculated by the Bliss method as follows:
  • mice After 30 minutes of oral administration, the mice showed decreased activity, paroxysmal tremor, gait, and began to die about 1 hour after the drug. Most deaths occur within 4 hours.
  • the toxicity is proportional to the dose.
  • the survivors were all dissected on the 15th day, and no obvious lesions were seen in the viscera. Mortality was determined by Bliss method to obtain LD 5 Q: 2315 mg/kg;
  • the 95% confidence limit is 1790 ⁇ 2993 mg/kg.
  • Test Example 10 Cell level test compound EGFR inhibitory activity
  • Cells SPCA1 human lung cancer cells; stimulating factor: hEGF: human epidermal growth factor (R and D Catalog: 236-EG); medium: DMEM F12 1 : l (GIBCO); calf serum (Hangzhou Sijiqing); DMSO; MTT ( 5g / l ) Real ⁇ r method: MTT
  • the inhibition rate of proliferation in the negative control group was 0, and the other concentrations were compared with it, and the inhibition rate was calculated as follows: (Control group OD value - experimental group OD value) / control group OD value X 100% III.
  • this experiment established a hEGF stimulation group for the crude screening drug. Fine screening was performed to identify new and strong tyrosine kinase inhibitors that inhibited cell proliferation and had the lowest concentration.
  • the cells were seeded in a 96-well plate with DMEM/F12 medium containing 10% serum, and the cell density was 1 10 4 /well;
  • the drug was diluted as above with serum-free DMEM/F 12 containing 10 ng/ml hEGF as a solvent, and the negative control was serum-free DMEM/F12 containing 10 ng/ml hEGF.
  • the preparation method of the substituted [1,3,5]triazine compound of the present invention has the advantages of mild reaction conditions, abundant raw materials, easy handling and post-treatment.
  • Substituted [1,3,5]triazine compounds of the present invention in computer virtual screening and binding experiments of cyclooxygenase and 5-lipoxygenase (COX-1, COX-2 and 5-LOX) and pharmacological tests in animals These compounds were confirmed to be dual inhibitors of cyclooxygenase and 5-lipoxygenase (COX-2 and 5-LOX), which have good preventive and therapeutic effects on experimental inflammation, and Ames experiments and mice.
  • the micronucleus test has better safety and the side effects on the gastrointestinal tract are significantly weakened.
  • the compound of the present invention has low toxicity. It has good safety to Ames test and mouse micronucleus test, and has no toxic side effect on gastrointestinal tract.
  • the substituted [1,3,5]triazine of the present invention The compound showed good inhibitory activity in an in vitro screening test of anti-tumor cell line HCT-116 human intestinal cancer and HT-29 human intestinal cancer, and many compounds appeared as potent inhibitors.
  • the compound of the present invention is in EGFR cells. ⁇ -level inhibition was also shown in the test. Activity t due to jtb, the present invention. J m
  • the compounds of the invention are also useful in the prevention and/or treatment and/or adjuvant treatment of neoplastic diseases.

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Abstract

This invention discloses the substituted [1,3,5] triazine compounds of following formula, their pharmaceutically acceptable salts and solvates or hydrates, the pharmaceutical compositions containing the compounds and the uses thereof. The compositions of the present invention may be used for the prevention and/or treatment of inflammation diseases, which have good effect. The substituted [1,3,5] triazine compounds or their pharmaceutically acceptable salts show remarkable EGFR enzyme inhibitory activity and antitumor activity in a serious of selective tests of EGFR enzyme level and tumor cell level (human HT-29 and HCT-116). So The compositions of the present invention may be used for the prevention and/or treatment and/or aid treatment of tumor diseases.

Description

取代〖1，3，5]三嗪类化合物及其制备方法和应用 技术领域 本发明涉及药物化学和药物治疗学领域，具体涉及取代 [1,3,5]三嗪 类化合物及其制备方法和应用，以及包括该取代 [1,3，5]三嗪类化合物的 药物组合物。 背景技术 许多疾病的发病过程都有炎症介质的参与， 一些炎症性疾病 （如 类风湿关节炎、 风湿热、 骨关节炎）、 哮喘、 慢性阻塞性肺部疾患、 创 伤、 烧伤、 内毒素休克、 阿尔茨海默病， 甚至心衰等都有炎症介质的 参与。 考虑到介质的复杂性和多样性， 单一介质不是炎症紊乱病理生 理学的全部原因。 因此， 能同时干扰多个介质或酶活性的化合物可能 比单一活性的化合物对炎症更有影响。 多种炎症介质中， 花生四烯酸 FIELD OF THE INVENTION The present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and in particular to substituted [1,3,5]triazine compounds and preparation methods thereof and Applications, and pharmaceutical compositions comprising the substituted [1,3,5]triazine compounds. BACKGROUND OF THE INVENTION The pathogenesis of many diseases involves the involvement of inflammatory mediators, some inflammatory diseases (such as rheumatoid arthritis, rheumatic fever, osteoarthritis), asthma, chronic obstructive pulmonary disease, trauma, burns, endotoxin shock, Alzheimer's disease, even heart failure, has the involvement of inflammatory mediators. Given the complexity and diversity of the media, a single medium is not the full cause of the pathophysiology of inflammatory disorders. Thus, a compound that can interfere with multiple media or enzymatic activities at the same time may have a greater impact on inflammation than a single active compound. Among a variety of inflammatory mediators, arachidonic acid
( Arachidonic Acid, AA )的代谢产物前列腺素（ PGs )和白三烯（ LTs ) 是两个重要的炎症介质。 AA 的代谢有如下两条途径： （1) 环氧合酶(Arachidonic Acid, AA) metabolite prostaglandins (PGs) and leukotrienes (LTs) are two important inflammatory mediators. There are two pathways for AA metabolism: (1) Cyclooxygenase
( COX )代谢途径， 即 AA在 COX的催化下经一系列反应代谢转变成 PGs; (2)脂氧酶（5_LOX )代谢途径， 即 AA在 5-LOX的催化下代谢 转变成 LTs。 因此， 阻断 AA的这两个代谢途径就能抑制炎症介质 PGs 和 LTs的生成， 从而达到治疗或減弱炎症的目的。 'Arachidonic acid (COX) pathway, i.e. after the AA COX catalyzed series of reactions metabolized into PGs; (2) Lipoxygenase (5 _LOX) pathway, i.e. under catalytic AA metabolism of 5-LOX into LTs. Therefore, blocking these two metabolic pathways of AA can inhibit the production of inflammatory mediators PGs and LTs, thereby achieving the purpose of treating or attenuating inflammation. 'Arachidonic acid
COX-1 cox-2 COX-1 cox-2
Figure imgf000004_0001
Figure imgf000004_0001
PGF2a 其中， 第一条代谢途径包括以下一系列反应： 膜磷脂经由磷脂酶Among PGF 2a , the first metabolic pathway includes the following series of reactions: Membrane phospholipids via phospholipase
A2 (PLA2)产生游离花生四烯酸 (AA)， AA经环氧合酶 (COX-1和 COX- 2) 的作用转化为前列腺素 G2 (PG2), 其过氧化酶活性接着将其产物转化 为前列腺素 H2(PGH2), 组织特异性的同功酶将 PGH2代谢为前列腺素 的其它形式或血栓烷 A2(TxA2)。 同时， AA在 5-脂氧酶的作用下代谢 为白三烯 (LTs)。 对于炎症的治疗， 早期人们多用糖皮质激素类抗炎药（SAID ), 但 长期服用这类药物易引起肾上腺皮质功能衰退等并发症。 1952年保泰 松用于临床， 国际上首次提出非甾体抗炎药 ( SAID)这一概念。在随后 的二三十年间涌现出一大批具有抗炎镇痛作用的 NSAID, 如目前仍在 临床上广泛应用的吲哚美辛、 布洛芬等， 该类药物在世界医药产量中 一直居领先地位。 然而， 长期应用 NSAID会引起胃肠道特别是胃粘膜 的损害， 表现为点状出血、 弥漫性浅表粘膜糜烂、 局部深溃疡、 大出 血甚至穿孔。 1991年， COX-2的发现为 NSAID的研究开辟了一个新方向。 研 究表明： COX-1在正常组织中表达，是正常细胞的组成蛋白；而 COX-2 是酶的诱导形式， 主要在炎症细胞， 如组织损伤后的内皮细胞、 巨噬 细胞、 滑液纤维细胞、树状细胞、软骨细胞及成骨细胞中表达。 COX- 2 与 COX-1对 AA或 NSAID有相似的活性结合部位； COX-2在炎症组 织中可被多种因子所诱导，其水平将以 8~10倍的速度剧涨， 引起炎症 部位的 PGE2、 PGI2和 PGEi的含量增加， 促进了炎症反应和组织损伤。 1994年， J. R. Vane等指出， NSAID对炎症的有效治疗作用源于其对 COX-2的抑制， 而不良反应归于对 COX-1 的抑制。 因此， 90年代以 来， 寻找 COX-2选择性抑制剂已成为发现新型抗炎药物的重要途径。 但是， COX-2选择性抑制剂在心血管方面存在的安全隐患。 研究表明， 在 AA的两条代谢途径中存在一定的平衡制约关系， 即 当 COX的活性受到抑制时， 5-LOX的活性增强，使更多 AA进入 5- LOX 代谢途径产生 LTs。 同样， 当 5-LOX 的活性受到抑制时， 则有更多的 AA进入 COX代谢途径使 PG生成增加， 结果都使炎症加重。 因此，单 纯抑制其中一条代谢途径都将引起大量的 AA进入另一条代谢途径， 从而造成炎症进一步发展。 经典的 NSAIDs如阿斯匹林、 吲哚美辛、 双氯芬酸等都是 COX选择性抑制剂， 一般对 5-LOX代谢不起作用， 它们不仅影响对胃黏膜有保护作用的 PGs的合成， 而且由于单一的抑 制 COX-2以致于导致 LOX代谢活性增高， 引起 AA代谢失衡， 促进 LTs物质的合成增加， 从而促进白细胞趋化聚集， 增加血管通透性。 所 以提出需要一个作用全面且毒副作用小的抗炎药，应对 COX和 5-LOX 同时产生抑制作用。 因而设计 COX-2/5-LOX双重抑制剂以达到协同消 炎的目的， 是近年来国内外医药工作者的抗炎药物的重点研究方向。 近来研究发现 NS AIDs特别是选择性的 COX-2抑制剂（如 celecoxib 等)作为增效作用与其它化学治疗药物分子共同作用，可以治疗直肠癌。 相对于 COX-2抑制剂在直肠癌上的研究， 选择性的 5-LOX抑制剂和 COX-2/5-LOX双重抑制剂在直肠癌上的研究要少的多。 然而， COX-2 选择性抑制剂或 COX-2/5-LOX双重抑制剂作为抗肿瘤药物和 /或其辅 助药物在肿瘤治疗领域， 尤其是直肠结肠癌的防治上将越来越多的受 到关注， 并将成为今后研究的热点。 近年来， "计算机辅助药物设计" （Computer-Aided Drug Design, CADD)已成为现代药物研究与开发的一个重要方法和工具， 将计算机 辅助药物设计特别是计算机辅助组合化学库设计加入新药研究的循 环， 能缩短新药研究的周期， 节省研究与开发费用， 提高新药筛选的 命中率。 "组合化学，， （Combinatorial Chemistry)是近年来药物化学和合 成化学中出现的一项新技术， 能够迅速产生大量分子结构以进行高通 量筛选 (High Throughput Screening)。 "结构生物学" 也从原来的基础研 究进入应用研究阶段， 其中的一个主要应用领域是在分子和原子结构 水平上研究药物与靶蛋白的相互作用， 测定药物-蛋白质复合物的晶 体结构 , 为新化合物的设计和先导化合物的结构改造提供有益的结构 信息。 发明内容 本发明的发明人在中国专利申请 CN 200310109187.0中公开了哌 嗪三嗪类化合物的合成制备方法及含此类化合物的药物组合物， 发现 了具有全新结构的哌、秦三嗪类化合物对 COX-2酶具有很好的结合， 解 离常数达 10_6并对小鼠角叉菜胶性足肿胀模型有很好的抗炎作用。 并 且，根据 COX-1、 COX-2和 5-LOX的三维结构（其中 COX-1和 COX- 2 有晶体结构， 5-LOX的三维结构用同源蛋白模建方法构建）， 综合运用 计算机辅助药物分子设计、 组合化学、 分子生物学和结构生物学方法， 进一步寻找具有 COX-2/5- LOX双重抑制剂作用的先导化合物，并针对 其药理作用进行结构优化， 从而在上述专利发明的基础上发现： （1) 某 些哌嗪三嗪类化合物对 COX-2酶和 5-LOX酶均具有很好的结合作用， 解离常数达 10-6; 对其中 Ν-取代芳基 -Ν，-取代芳基 -6- (哌嗪小取 代) -[1，3,5]-三嗪 -2，4-二胺类化合物进行了各种药理试验，发现这类化合 物在大鼠足跖角叉菜胶致肿模型、 小鼠耳二曱苯致炎模型、 大鼠佐剂 性关节炎 (预防原发病变)模型和大鼠佐剂性关节炎 (预防继发病变)模型 上均有很好的抗炎作用； 并在 Ames实验和小鼠微核实验中显示较好的 安全性， 对胃肠道无毒副作用。 （2)—些取代 [1,3,5]三嗪类化合物对人 肠癌细胞枒、 HT-29和 HCT-116有一定的抑制活性， 同时发现类似结构 的吗啉三嗪类化合物对人肠癌细胞株 HT-29和 HCT-116却有强效抑制 活性， 少数化合物 IC5G达 nM级； 另外吗啉三嗪类化合物还表现有较 好的表皮生长因子受体 (EGFR)抑制活性； 接受细胞染色体致畸试验的 化合物表现良好， 均没有致畸性， 从而完成了本发明。 因此，本发明的目的是提供一种对 COX-2/5-LOX具有双重抑制剂 作用和 EGFR酶抑制剂作用的取代 [1,3,5]三嗪类化合物。 本发明的再一目的是提供上述化合物的制备方法。 本发明再一目的是提供上述化合物的应用。 本发明的再一目的是提供包括上述化合物的药物组合物。 本发明的再一目的是提供上述药物组合物的应用。 根据本发明的技术方案， 本发明提供了一种具有式 （I )所示结构 的取代 [1，3,5]三嗪类化合物、 其药学上可接受的盐及溶剂合物或水合 物： A 2 (PLA 2 ) produces free arachidonic acid (AA), and AA is converted to prostaglandin G 2 (PG 2 ) by the action of cyclooxygenase (COX-1 and COX- 2 ), and its peroxidase activity proceeds. The product is converted to prostaglandin H 2 (PGH 2 ), a tissue-specific isozyme that metabolizes PGH 2 to other forms of prostaglandins or thromboxane A 2 (TxA 2 ). At the same time, AA is metabolized to leukotrienes (LTs) by the action of 5-lipoxygenase. For the treatment of inflammation, glucocorticoid anti-inflammatory drugs (SAID) are often used in the early stage, but long-term use of these drugs can cause complications such as adrenal cortical function decline. In 1952, phenylbutazone was used clinically, and the concept of non-steroidal anti-inflammatory drugs (SAID) was first proposed internationally. In the next two or three decades, a large number of NSAIDs with anti-inflammatory and analgesic effects emerged, such as indomethacin and ibuprofen, which are still widely used in clinical practice. These drugs have been leading the world in pharmaceutical production. status. However, long-term use of NSAID can cause damage to the gastrointestinal tract, especially the gastric mucosa, manifested as punctate hemorrhage, diffuse superficial mucosal erosion, local deep ulcer, massive bleeding and even perforation. In 1991, the discovery of COX-2 opened up a new direction for NSAID research. Studies have shown that: COX-1 is expressed in normal tissues and is a constituent protein of normal cells; and COX-2 is an induced form of enzymes, mainly in inflammatory cells, such as endothelial cells, macrophages, and synovial fibroblasts after tissue damage. Expression in dendritic cells, chondrocytes and osteoblasts. COX-2 and COX-1 have similar active binding sites for AA or NSAID; COX-2 can be induced by various factors in inflammatory tissues, and its level will rise sharply at 8-10 times, causing inflammation sites. Increased levels of PGE 2 , PGI 2 , and PGEi promote inflammatory responses and tissue damage. In 1994, JR Vane et al. pointed out that the effective therapeutic effect of NSAID on inflammation stems from its inhibition of COX-2, which is attributed to inhibition of COX-1. Therefore, since the 1990s, the search for COX-2 selective inhibitors has become an important way to discover new anti-inflammatory drugs. However, COX-2 selective inhibitors have a cardiovascular safety hazard. Studies have shown that there are certain equilibrium constraints in the two metabolic pathways of AA, that is, when the activity of COX is inhibited, the activity of 5-LOX is enhanced, and more AA enters the 5-LOX metabolic pathway to produce LTs. Similarly, when the activity of 5-LOX is inhibited, more AA enters the COX metabolic pathway and increases PG production, resulting in increased inflammation. Therefore, simply inhibiting one of the metabolic pathways will cause a large amount of AA to enter another metabolic pathway, resulting in further development of inflammation. Classical NSAIDs such as aspirin, indomethacin, and diclofenac are COX selective inhibitors, generally do not contribute to 5-LOX metabolism, they not only affect the synthesis of PGs that have protective effects on the gastric mucosa, but also Single inhibition of COX-2 leads to increased metabolic activity of LOX, causing imbalance of AA metabolism, promoting the synthesis of LTs, thereby promoting leukocyte chemotaxis and increasing vascular permeability. Place In order to propose the need for a comprehensive anti-inflammatory drug with a toxic side effect, COX and 5-LOX should be simultaneously inhibited. Therefore, the design of COX-2/5-LOX dual inhibitors to achieve synergistic anti-inflammatory purposes is the focus of research on anti-inflammatory drugs for medical workers at home and abroad in recent years. Recent studies have found that NS AIDs, especially selective COX-2 inhibitors (such as celecoxib), act synergistically with other chemotherapeutic drugs to treat rectal cancer. Compared to COX-2 inhibitors in rectal cancer, selective 5-LOX inhibitors and COX-2/5-LOX dual inhibitors have been much less studied in rectal cancer. However, COX-2 selective inhibitors or COX-2/5-LOX dual inhibitors as antitumor drugs and/or their auxiliary drugs will be more and more affected in the field of cancer treatment, especially the prevention and treatment of colorectal cancer. Concerns will be a hot topic for future research. In recent years, "Computer-Aided Drug Design" (CADD) has become an important method and tool for modern drug research and development, adding computer-aided drug design, especially computer-aided combination chemical library design, to the cycle of new drug research. It can shorten the cycle of new drug research, save research and development costs, and improve the hit rate of new drug screening. "Combinatorial Chemistry" is a new technology in medicinal chemistry and synthetic chemistry in recent years, which can rapidly generate a large number of molecular structures for high-throughput screening. "Structural biology" also The original basic research entered the applied research stage. One of the main application areas was to study the interaction between drugs and target proteins at the molecular and atomic structure level, and to determine the crystals of drug-protein complexes. The bulk structure provides useful structural information for the design of new compounds and structural modification of lead compounds. SUMMARY OF THE INVENTION The inventors of the present invention disclosed in the Chinese patent application CN 200310109187.0 a synthetic preparation method of piperazine triazine compounds and a pharmaceutical composition containing the same, and found a piperidine and a triazine compound having a completely new structure. COX-2 enzyme has good binding, dissociation constant of 10_ 6 mice and carrageenan paw edema model has a good anti-inflammatory effect. Moreover, based on the three-dimensional structure of COX-1, COX-2 and 5-LOX (where COX-1 and COX-2 have a crystal structure, and the three-dimensional structure of 5-LOX is constructed by a homologous protein modeling method), computer aided Drug molecular design, combinatorial chemistry, molecular biology and structural biology methods, further searching for lead compounds with dual inhibitors of COX-2/5-LOX, and structural optimization for their pharmacological effects, thereby laying the foundation for the above patented invention discovery: (1) certain piperazine triazine compounds for COX-2 enzyme, and 5-LOX enzymes have a good binding, dissociation constant of 10-6; substituted aryl group of Ν- -v wherein, -Substituted aryl-6-(piperazine small substituted)-[1,3,5]-triazine-2,4-diamine compounds were subjected to various pharmacological tests and found to be in the rat's ankle angle The model of the forkworm gum swelling, the mouse ear dioxin-induced inflammation model, the rat adjuvant arthritis (preventive primary lesion) model, and the rat adjuvant arthritis (preventive secondary lesion) model are very Good anti-inflammatory effect; and showed good safety in the Ames test and mouse micronucleus test, on the gastrointestinal tract No toxic side effects. (2) Some substituted [1,3,5] triazine compounds have certain inhibitory activities on human intestinal cancer cells, HT-29 and HCT-116, and similar structures of morpholine triazines have been found to Intestinal cancer cell lines HT-29 and HCT-116 have strong inhibition Activity, a few compounds IC 5G up to nM grade; in addition, morpholine triazines also showed better epidermal growth factor receptor (EGFR) inhibitory activity; compounds that received cell chromosome teratogenicity test performed well, no teratogenicity Thus, the present invention has been completed. Accordingly, it is an object of the present invention to provide a substituted [1,3,5]triazine compound which has a dual inhibitor action and an EGFR enzyme inhibitor action on COX-2/5-LOX. A further object of the present invention is to provide a process for the preparation of the above compounds. A further object of the invention is to provide the use of the above compounds. A further object of the present invention is to provide a pharmaceutical composition comprising the above compound. A further object of the invention is to provide the use of the above pharmaceutical compositions. According to a technical solution of the present invention, the present invention provides a substituted [1,3,5]triazine compound having a structure represented by the formula (I), a pharmaceutically acceptable salt thereof, and a solvate or hydrate thereof:
Figure imgf000008_0001
Figure imgf000008_0001
( I ) 其中， 、 R2、 R3和 R4各自独立地为氢、 Q- C8直链或支链烃基、 取代 或未取代的芳基、 芳烷基、 CrC4烷芳基、 芳酰基， 其中芳基选自苯基、 萘基和联苯基，取代基为 1-4个选自包括卤素、 d- 直链或支链烃基、 氛基、 硝基、 氨基、 羟基、 羟曱基、 三氟甲基、 三氟曱氧基、 羧基、 C!- 烷氧基、 巯基、 CrC4烷硫基、 CrC4烷欺基、 CrC4烷氧羰基、 磺酰基的组的基团； 并且 (I) Wherein, R 2 , R 3 and R 4 are each independently hydrogen, Q-C 8 linear or branched hydrocarbon, substituted or unsubstituted aryl, aralkyl, C r C 4 alkaryl, aroyl, Wherein the aryl group is selected from the group consisting of phenyl, naphthyl and biphenyl, and the substituents are from 1 to 4 selected from the group consisting of halogen, d-linear or branched hydrocarbon, an aryl group, a nitro group, an amino group, a hydroxyl group, a hydroxy group, Group of trifluoromethyl, trifluoromethoxy, carboxy, C!-alkoxy, fluorenyl, C r C 4 alkylthio, C r C 4 alkane, C r C 4 alkoxycarbonyl, sulfonyl Group; and
Figure imgf000009_0001
其中 Re和 R7各自独立地为选自 包括氢、 卤素、 d- 直链或支链烃基、 氰基、 硝基、 氨基、 羟基、 羟 曱基、 三氟甲基、 三氟曱氧基、 羧基、 d-C4烷氧基、 巯基、 - C4烷 硫基、 -C4酰基、 和磺酰基的组的基团； Y为 CH2 、 0、 S、 或 RN, 其中 R为氢、 - C4直链或支链烃基、羟基、 OC4羟烷基、 基、 C,-C4 烷羰基、 C!- 烷氧羰基、 磧酰基的基团； m, n各自独立地为 0, 1 , 2 或 3 , 或者， R5选自羟基、氨基、取代氨基、 Ci-C6烷基、 d- 烷羟基、
Figure imgf000009_0001
Wherein Re and R 7 are each independently selected from the group consisting of hydrogen, halogen, d-linear or branched hydrocarbon, cyano, nitro, amino, hydroxy, hydroxydecyl, trifluoromethyl, trifluoromethoxy, carboxy, dC 4 alkoxy, mercapto, - C 4 alkylthio, -C 4 acyl, and sulfonyl groups group; Y is CH 2, 0, S, or the RN, wherein R is hydrogen, - C a linear or branched hydrocarbon group, a hydroxyl group, an OC4 hydroxyalkyl group, a group, a C, a C 4 alkylcarbonyl group, a C!-alkoxycarbonyl group, a decanoyl group; m, n are each independently 0, 1 , 2 Or 3, or R 5 is selected from the group consisting of a hydroxyl group, an amino group, a substituted amino group, a Ci-C 6 alkyl group, a d-alkylhydroxy group,
-C(0)R8、 -(CH2)XR8、 -CH2CH=CHR8、 -C(0)OR8或 -S(0)2R8, 其中， x 为 0、 1、 2或 3; R8为氢、 羟基、 芳基、 杂芳环基、 杂脂环基或 C2-C6 烯基。 -C(0)R 8 , -(CH 2 ) X R 8 , -CH 2 CH=CHR 8 , -C(0)OR 8 or -S(0) 2 R 8 , where x is 0, 1, 2 or 3; R 8 is hydrogen, hydroxy, aryl, heteroaryl ring, heteroalicyclic or C 2 -C 6 alkenyl.
优选地， 根据本发明的化合物可以为： Ν,Ν'-二苯基 -6- (哌嗪 -1-取 代) -[1，3,5]-三嗪 -2,4-二胺； 6-氯 对曱磺酰基笨基 -Ν，-苯基 -[1,3,5]-三嗪 -2,4-二胺； Ν-对曱磺酰基苯基 -Ν，-苯基 -6- (哌嗪 -1-取代 )-[1，3,5]-三嗪 -2,4-二胺； Ν-邻甲磺酰基苯基 -Ν，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2，4-二胺； N-间甲磺酰基苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺； 4-(6-氯 -4-苯胺基 -[1,3,5]-三嗪 -2-氨基)苯磺酰胺； 4-(4-苯胺 基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2-氨基)苯磺酰胺； 2-(4-苯胺基 -6- (哌嗪 -1-取代 )-[1，3，5]-三嗪 -2-氨基）苯磺酰胺； 3-(4-苯胺基 -6- (哌嗪 - 1-取 代 )-[1,3,5]-三嗪- 2-氨基）苯磺酰胺； N-萘基 -N，-苯基 -6- (哌嗪 - 1-取 代 )-[1,3,5]-三嗪 -2,4-二胺； N, N，-二萘基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4-二胺； N-联苯基 -N，-苯基 -6- (哌嗪 -1-取代) -[1，3，5]-三嗪 -2,4-二胺； N, N，-二联苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺； N-苯基 -6- (哌嗪 -1-取代) -N，-对三氟曱氧基苯基 -[1，3,5]-三嗪 -2,4-二胺; N-苯基 -6- (哌嗪 小取代) -N，-邻三氟甲氧基苯基 -[1,3，5]-三嗪 -2,4-二胺; N-苯基 -6- (哌嗪 -1-取代) -N，-间三氟甲氧基苯基 -[1,3，5]-三嗪 -2，4-二胺; 6- (哌嗪 - 1-取 代) -N， N，-对三氟曱氧基苯基 -[1，3,5]-三嗪 -2，4-二胺; 6- (哌嗪 -1-取代) -N， N，-邻三氟曱氧基苯基 -[1，3,5]-三嗪 -2,4-二胺; 6- (哌嗪 -1-取代) -N， N，-间 三氟曱氧基苯基 -[1，3,5]-三嗪 -2，4-二胺; N-对溴苯基 -N，-苯基 -6- (哌嗪 -1- 取代） -[ 1 ,3 ,5]-三嗪 -2，4-二胺； N-邻溴苯基 - N，-苯基 - 6-(哌嗪 - 1 -取 代 )-[1,3,5]-三嗪 -2,4-二胺； N-间溴苯基 -N，-苯基 -6- (哌嗪 - 1-取代 )-[1,3，5]- 三嗪- 2，4-二胺； N, N，-二间溴苯基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4-二 胺； Ν, Ν'-二间溴苯基 -6- (哌嗪 -1-取代) -[1，3,5]-三嗪 -2,4-二胺； Ν, Ν，-二 间溴苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺； Ν-苯基 -6- (哌嗪 -1-取 代) -Ν，-对曱苯基- [1，3，5]-三嗪 -2，4-二胺; Ν-苯基 -6- (哌嗪 -1-取代) -Ν'-邻 曱苯基- [1,3，5]-三嗪 -2,4-二胺; Ν-苯基 -6- (哌嗪小取代) -Ν，-间曱苯基- [1,3,5]-三嗪 -2，4-二胺; Ν, Ν，-二间甲基苯基 -6- (哌。秦 -1-取代) -[1，3，5]-三嗪 -2,4-二胺； Ν, Ν，-二邻曱基苯基 -6- (哌，秦 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺； Ν, Ν，-二对甲基苯基 -6- (哌嗪小取代 )-[1,3,5]-三嗪 -2，4-二胺； Ν-对氯苯 基 -Ν，-苯基 -6- (哌嗪 -1-取代 )-[1,3，5]-三嗪 -2，4-二胺； Ν-邻氯苯基 -Ν，-苯基 - 6 - (哌嗪 -1-取代) -[1,3,5]-三嗪 -2，4-二胺； Ν-间氯苯基 -Ν，-苯基 -6- (哌嗪小 取代) -[1，3,5]-三嗪 -2，4-二胺； Ν, Ν'-二间氯苯基 -6- (哌嗪小取代 )-[1,3,5]- 三嗪 -2,4-二胺； Ν， Ν，-二邻氯苯基 -6- (哌嗪 -1-取代 )-[1,3，5]-三嗪 -2，4-二 胺； N, N，-二对氯苯基 -6- (哌嗪 -1-取代) -[1，3,5]-三嗪 -2,4-二胺； N-间氟 苯基 -N，-苯基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4-二； N-邻氟苯基 -N，-苯基 -6- (哌咯 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺； N, N，-二对氟苯基 -6- (哌嗪小 取代 )-[1,3,5]-三嗪 -2,4-二胺； N, N，-二邻氟苯基 -6- (哌嗪 -1-取代) -[1，3,5]- 三嗪 -2,4-二胺； N， N，-二间氟苯基 -6- (哌。秦 -1-取代 )-[1,3,5]-三嗪 -2,4-二 胺； N-对甲氧基苯基 -N，-苯基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4-二胺； N-邻曱氧基苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺； N-间 曱氧基苯基 -N，-苯基 -6- (哌嗪小取代 )-[1，3,5]-三嗪 -2,4-二胺； N, N，-二对 曱氧基苯基- 6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4-二胺; N, N，-二邻曱氧基苯 基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2，4-二胺； N, N，-二间甲氧基苯基 -6- (哌 嗪- 1-取代) -[1,3,5]-三嗪 -2,4-二胺； N-对硝基苯基 -N，-苯基 -6- (哌嗪小取 代 )-[ 1 ,3 ,5]-三嗪 -2，4-二胺； N-邻硝基苯基 -N，-苯基 -6-(哌嗪- 1 -取 代）-[1 ,3,5]-三嗪 -2,4-二胺； N-间硝基苯基 -N，-苯基 -6-(哌嗪 - 1 -取 代 )-[1，3,5]-三嗪 -2，4-二胺； N, N，-二间硝基苯基 -6- (哌嗪 -1-取代) -[1,3,5]- 三嗪 -2,4-二胺； N, N，-二邻硝基苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4- 二胺； N, N，-二对硝基苯基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4-二胺； N-(3,4-二曱氧基)苯基 -N，-苯基 -6- (哌嗪小取代 )-[1,3，5]-三嗪 -2,4-二胺； N-(2，3-二曱氧基)苯基 -N，-苯基- 6- (哌嗪小取代 )-[1,3,5]-三嗪 -2,4-二胺； N-(2,4-二曱氧基)苯基 -N，-苯基 -6- (哌嗪小取代 )-[1，3,5]-三嗪 -2,4-二胺； N- (2,5-二甲氧基)苯基 -N，-苯基- 6- (哌嗪小取代 )- [1,3，5]-三嗪 -2，4-二胺； N-(2，6-二曱氧基)苯基 -Ν'-苯基 -6- (哌嗪小取代 )-[1，3,5]-三嗪 -2,4-二胺； Ν-(3,5-二甲氧基)苯基 -Ν，-苯基 -6- (哌嗪小取代 )-[1,3,5]-三嗪- 2,4-二胺； Ν, Ν，-二 (3,4-二曱氧基)苯基 -6- (哌嗪小取代 )-[1，3，5]-三嗪- 2,4-二胺； Ν， Ν，-二 (2,3-二曱氧基)苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪- 2,4-二胺； Ν, Ν，- 二 (2,4-二甲氧基)苯基 -6- (哌嗪小取代 )-[1，3,5]-三嗪 -2，4-二胺； Ν， Ν，-二 (2,5-二曱氧基)苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2，4-二胺； Ν, Ν，-二 (2,6-二曱氧基)苯基 -6- (哌嗪小取代 )-[1，3,5]-三嗪 -2，4-二胺； Ν, Ν，-二 (3,5-二曱氧基)苯基 -6- (哌嗪小取代 )-[1,3,5]-三嗪 -2,4-二胺； Ν-(2，3-二氢 苯并 [1,4]二恶 -6-取代) -N，-苯基 -6- (哌嗪小取代) -[1,3,5]-三嗪 -2，4-二胺； N, N，-(2,3-二氢苯并 [1,4]二恶 -6-取代) -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4- 二胺； 4-(4-对甲氧基苯胺基 -6- (哌嗪小取代 )-[1,3,5]-三嗪 -2-氨基)苯磺酰 胺； 4- (4-邻甲氧基苯胺基 -6- (哌嗪 -1-取代 )-[1，3,5]-三嗪 -2-氨基)苯磺酰 胺； 4-(4-间甲氧基苯胺基 -6- (哌。秦 -1-取代) -[1,3,5]-三嗪 -2-氨基)苯磺酰 胺； 3-(4-间甲氧基苯胺基 -6- (哌嗪 -1-取代) -[1，3,5]-三嗪 -2-氨基)苯磺酰 胺； 3-(4-邻甲氧基苯胺基 -6- (哌喚 -1-取代) -[1，3,5]-三嗪 -2-氨基)苯磺酰 胺； 3-(4-对曱氧基苯胺基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2-氨基)苯磺酰 胺； 2- (4-对曱氧基苯胺基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2-氨基)苯磺酰 胺； 2- (4-邻曱氧基苯胺基- 6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2-氨基)苯磺酰 胺； 2- (4-间甲氧基苯胺基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2-氨基)苯磺酰 胺； N-对乙氧基苯基 -N，-苯基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2，4-二胺； N-邻乙氧基苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1，3,5]-三嗪 -2,4-二胺； N-间 乙氧基苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1，3,5]-三嗪 -2，4-二胺； N-(3,4-二 曱基)苯基 -N，-苯基 -6- (哌嗪小取代 )-[1,3,5]-三嗪 -2,4-二胺； N-(2,3-二曱 基)苯基 -N，-苯基 -6- (哌嗪 -1-取代) -[1，3,5]-三嗪 -2,4-二胺； N- (2,4-二曱基) 苯基— N，-苯基 -6- (哌嗪 -1-取代 )-[1，3,5]-三嗪 -2，4-二胺； N-(2，5-二甲基)苯 基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1,3，5]-三嗪 -2，4-二胺； N-(2,6-二曱基)苯基 — N，-苯基 -6- (哌嗪 -1-取代 )-[1，3,5]-三嗪 -2,4-二胺； N-(3，5-二曱基)苯基 — N，-苯基 -6- (哌 -1-取代) -[1，3,5]-三嗪 -2,4-二胺； N， N，-二 (3,4-二曱基) 苯基 -6- (哌嗪 -1-取代 )-[1，3,5]-三嗪 -2,4-二胺； N, N，-二 (2,3-二曱基)苯基 -6- (哌嗪 - 1-取代) -[1，3，5]-三嗪 -2,4-二胺； N, N，-二 (2,4-二甲基)苯基 -6- (哌 嗪 -1-取代 )-[1,3，5]-三嗪 -2,4-二胺； N, N，-二 (2，5-二甲基)苯基 -6- (哌嗪 -1- 取代 )-[1，3,5]-三嗪 -2,4-二胺； N, N，-二 (2,6-二曱基)苯基 -6- (哌嗪 -1-取 代 )-[1,3,5]-三嗪 -2,4-二胺； N, N，-二 (3,5-二甲基）苯基 -6- (哌嗪 -1-取 代 )-[1,3,5]-三嗪 -2，4-二胺； N-对曱硫基苯基 -N，-苯基 -6- (哌嗪 -1-取 代 )-[1,3,5]-三嗪 -2,4-二胺； N-邻甲硫基苯基 -N，-苯基 -6- (哌嗪 -1-取 代) -[1,3，5]-三嗪 -2，4-二胺； N-间曱硫基苯基 -N，-苯基 -6- (哌嗪 -1-取 代) -[1,3，5]-三嗪 -2,4-二胺； 4-(4-苯胺基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2- 取代氨基)苯硫酚；3-(4-苯胺基 -6- (哌嗪小取代 )-[1,3,5]-三嗪 -2-取代氨基) ^^酚； 2-(4-苯胺基 -6- (哌嗪小取代 )-[1，3,5]-三嗪 -2-取代氨基)苯硫酚； 4-(4-苯胺基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2-取代氨基)苯酚； 3-(4-苯胺基 -6 -(哌嗪- 1 -取代 )-[ 1 ,3 ,5]-三嗪 -2-取代氨基)苯酚； 2-(4-苯胺基 -6- (哌嗪- 1 - 取代) -[1,3,5]-三嗪 -2-取代氨基)苯酚； N-对甲苯基 -N，-对甲硫基苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺； N-邻曱苯基 -N，-对曱硫基苯基 -6- (哌嗪 -1-取代) -[1,3，5]-三嗪 -2,4-二胺； N-间曱苯基 -N，-对曱硫基苯基 -6- (哌嗪 -1-取代) -[1,3，5]-三嗪 -2,4-二胺； N-苄基 -N，-苯基 -6- (哌嗪小取 代 )-[1,3,5]-三嗪 -2，4-二胺； N, N，-二苄基 -6- (哌嗪 -1-取代 )-[1,3，5]-三嗪 - 2，4-二胺； N-(3,4-二氯)苯基 -N，-苯基 -6- (哌嗪 -1-取代) -[1，3,5]-三嗪 -2,4- 二胺； N-(2,3-二氯)苯基 -N，-苯基 -6- (哌嗪 -1-取代) -[1，3,5]-三嗪- 2，4-二胺； N-(2,4-二氯）苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2，4-二胺； N-(2,5-二氯）苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺； N-(2,6-二氯）苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2，4-二胺； N-(3，5-二氯)苯基 -N，-苯基 -6- (哌嗪小取代 )-[1,3,5]-三嗪 -2,4-二胺； N，N，- 二苯基 -6-(4-对甲^磺酰基哌嗪 -1-取代 )-[1,3，5]-三嗪 -2，4-二胺； Ν,Ν'-二 苯基 _6-(4-甲磺酰基哌嗪小取代) -[1,3，5]-三嗪 -2，4-二胺； Ν,Ν'-二苯基 -6-(4-乙酰基哌嗪 -1-取代) -[1，3,5]-三嗪 -2,4-二胺； Ν,Ν'-二苯基 -6-(4-乙氧 羰基哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4-二胺; Ν-对曱氧基苯基 -Ν，-苯基 -6-(4- 对曱苯磺酰基哌嗪 -1-取代) -[1，3，5]-三嗪 -2,4-二胺； Ν-对曱氧基苯基 -Ν，- 苯基 -6- (4-曱磺酰基哌嗪 -1-取代) -[1，3,5]-三嗪 -2，4-二胺； Ν-对甲氧基苯 基 -Ν，-苯基 -6-(4-乙酰基哌嗪小取代 )-[1，3,5]-三嗪 -2,4-二胺; Ν-对曱氧基 苯基 -Ν，-苯基 -6-(4-乙氧羰基哌嗪 -1-取代) -[1，3,5]-三嗪 -2,4-二胺； 4-[4- 苯胺— 6— (4-曱磺酰基哌嗪 -1-取代) -[1,3,5]-三嗪 -2-氨基]苯磺酰胺； 4- [4- 苯胺 _6— (4-对曱苯磺酰基哌嗪 -1-取代) -[1，3,5]-三嗪 -2-氨基]苯磺酰胺； 4- [4-苯胺 -6-(4-乙酰基哌嗪 -1-取代 )-[1,3，5]-三嗪 -2-氨基]苯磺酰胺； 4-[4- 苯胺 _6-(4-乙氧羰基哌嗪 -1-取代 )-[1，3,5]-三嗪 -2-氨基]苯磺酰胺； 6- (吗啉 -4-取代) -N,N，-二苯基 -[1,3，5]-三嗪 -2，4-二胺； N-对氯苯基 -6- (吗啉 -4-取 代) -N，-苯基- [1,3,5]-三嗪 -2,4-二胺； N-邻氯苯基 -6- (吗啉 -4-取代) -N，-苯 基- [1,3,5]-三嗪 -2,4-二胺； N-间氯苯基 -6- (吗啉 -4-取代) -N，-苯基 -[1,3,5]- 三嗪- 2，4-二胺； N, N，-二间氯苯基 -6- (吗啉 - 4-取代 )-[1,3，5]-三嗪- 2，4-二 胺； Ν, Ν'-二邻氯苯基 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪 -2,4-二胺； Ν, Ν，-二 对氯苯基 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪 _2，4-二胺； Ν-邻甲氧基苯基 -6- (吗 淋― 4—取代) -Ν，-苯基 -[1,3,5]-三嗪 -2,4-二胺； Ν-间甲氧基苯基 -6- (吗啉 -4- 取代) -Ν，-苯基 -[1,3，5]-三嗪 -2,4-二胺； Ν-对甲氧基苯基 -6- (吗啉 -4-取 代) -Ν，-苯基 -[1,3,5]-三嗪 -2,4-二胺； Ν,Ν'-二对甲氧基苯基 -6- (吗啉 -4-取 代）-[1,3,5]-三嗪- 2，4-二胺； Ν，Ν，-二邻曱氧基苯基 -6- (吗啉 -4-取 代）-[1,3，5]-三嗪 -2,4-二胺； Ν，Ν，-二间甲氧基苯基 -6- (吗啉 -4-取 代 )-[1,3，5]-三嗪 -2，4-二胺； 6- (吗啉 -4-取代) -Ν-苯基 -Ν，-对三氟曱氧基苯 基- [1,3，5]-三嗪 -2，4-二胺； 6- (吗啉 -4-取代) -Ν-苯基 -Ν，-邻三氟曱氧基苯 基- [1,3,5]-三嗪 -2，4-二胺； 6- (吗啉 -4-取代) 苯基 -Ν，-间三氟曱氧基苯 基- [1,3,5]-三嗪 -2,4-二胺； Ν-对溴苯基 -6- (吗啉 -4-取代) -Ν，-苯基 -[1,3,5]- 三嗪 -2,4-二胺； Ν-邻溴苯基 -6- (吗啉 -4-取代) -Ν，-苯基- [1,3，5]-三嗪 -2,4- 二胺； Ν-间溴苯基- 6- (吗啉 -4-取代) -Ν，-苯基 -[1，3,5]-三嗪- 2,4-二胺； Ν- 对乙氧基苯基 -6- (吗啉 -4-取代) -Ν，-苯基 -[1，3，5]-三嗪 -2，4-二胺； 4- (6- (吗 啉 _4-取代) -4-苯胺基 -[1,3,5]-三嗪 -2-氨基)苯曱酰胺； 3-(6- (吗啉 -4-取 代) -4-苯胺基 -[1,3,5]-三嗪 -2-氨基)苯曱酰胺； 2-(6- (吗啉 -4-取代) -4-苯胺 基 -[1,3，5]-三嗪 -2-氨基)笨甲酰胺； Ν-对氟苯基 -Ν，-对甲氧基苯基 -6- (吗 啉 _4-取代) -[1,3,5]-三嗪 -2,4-二胺； Ν-对氟苯基 -6- (吗淋 -4-取代) -Ν，-对三 氟甲氧基苯基 -[1 ,3,5]-三嗪 -2,4-二胺； Ν-对氟苯基 -6- (吗啉 -4-取代) -Ν，- 苯基 -[1，3,5]-三嗪 -2,4-二胺； Ν-(3,4-二甲氧基)苯基 -6- (吗啉 -4-取代) -Ν，- 苯基— [1,3，5]-三嗪 -2,4-二胺； Ν-(2，3-二甲氧基)苯基 -6- (吗啉 -4-取代) -Ν，- 苯基— [1,3,5]-三嗪 -2,4-二胺； Ν-(2，4-二甲氧基)苯基 -6- (吗啉 -4-取代) -Ν，- 苯基— [1,3,5]-三嗪 -2,4-二胺； Ν-(2，5-二曱氧基)苯基 -6- (吗啉 -4-取代) -Ν，- 苯基— [1，3,5]-三嗪 -2,4-二胺； Ν-(2,6-二甲氧基)苯基 -6- (吗啉 - 4-取代) -Ν，- 苯基— [1,3,5]-三嗪 -2,4-二胺； N-(3,5-二曱氧基)苯基 -6- (吗啉 -4-取代) - N，- 苯基 [1,3,5]-三嗪 -2,4-二胺； 4-(4-苯胺基 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪 -2-氨基)苯磺酰胺； 3-(4-苯胺基 -6- (吗啉 -4-取代) -[1,3，5]-三嗪 -2-氨基)苯 磺酰胺； 2-(4-苯胺基 -6- (吗啉 -4-取代) -[1,3，5]-三嗪 -2-氨基)苯磺酰胺； 4-(4-对曱氧基苯胺基 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪 -2-氨基)苯磺酰胺； N-对甲氧基苯基 -N，-(2- (吗啉 -4-取代）乙基) -N"-苯基 -[1 ,3,5]-三嗪- 2,4,6- 三胺； N-(2- (吗淋 -4-取代）乙基) -N，,N，，-二苯基 -[1,3,5]-三嗪 -2,4,6-三胺； N-苄基 -N，-(2- (吗啉 -4-取代）乙基) -N，，-苯基 -[1,3,5]-三嗪 -2,4，6-三胺； N- 苄基 -6- (吗啉 -4-取代) -N，-苯基 -[1，3，5]-三嗪 -2,4-二胺； N-对曱氧基苄基 -6- (吗啉 -4-取代) -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺； N-邻甲氧基苄基 -6- (吗 啉 _4—取代) -N，-苯基 -[1，3,5]-三嗪 -2,4-二胺； N-间曱氧基苄基 -6- (吗啉 -4- 取代) -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺； N-苄基 -6- (吗啉 -4-取代) -N，-对甲 苯基- [1,3,5]-三嗪 -2,4-二胺； 4-(4-苄胺基 -6- (吗啉 -4-取代) -[1,3,5]-三嗪 -2- 氨基)苯磺酰胺； N-苄基 -N，-对曱氧基苯基 -6- (吗啉 -4-取代) -[1，3,5]-三嗪 -2,4-二胺； N-苄基 -N，-对氟苯基 -6- (吗啉 -4-取代) -[1,3,5]-三嗪 -2,4-二胺； N-苄基 -N，-邻氟苯基 -6- (吗啉 -4-取代) -[1，3,5]-三嗪 -2,4-二胺； N-苄基 -N，- 间氟苯基 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪- 2,4-二胺； Ν,Ν'-二苄基 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪 -2，4-二胺； 2-[4,6-二苯胺基 -[1,3，5]-三嗪 -2-氨基]乙 醇； 3-[4，6-二苯胺基 -[1,3，5]-三嗪 -2-氨基]丙醇； 2-[4,6-二苯胺基 -[1,3,5]- 三嗪 _2_氨基〗乙胺； 2-[4-对曱氧基苯胺基 _6_苯胺基 -[1,3，5]-三嗪 _2_氨基] 乙醇； 3_[4-对甲氧基苯胺基 -6-苯胺基 -[1，3,5]-三嗪 -2-氨基]丙醇； 2-[4- 对曱氧基苯胺基 -6-笨胺基 -[1，3，5]-三嗪 -2-氨基]乙胺； 2-[4-苄胺基 -6-苯 胺基- [1，3,5]-三嗪 -2-氨基]乙醇； 3-[4-苄胺基 -6-苯胺基 -[1,3,5]-三嗪 -2-氨 基]丙醇； 2-[4-苄胺基 -6-苯胺基 -[1，3,5]-三嗪 -2-氨基]乙胺； 4，6-二 (吗啉 -4-取代) -Ν-苯基 -[1,3,5]-三嗪 -2-胺； 4-[4,6-二 (吗啉 -4-取代) - [1,3,5]-三嗪 -2-氨基]苯磺酰^; Ν-对曱氧基苯基 -4,6-二 (吗啉 -4-取代) -[1,3，5]-三嗪 -2- 胺； Ν-对氟苯基 -4，6-二 (吗啉 -4-取代) -[1，3，5]-三嗪 -2-胺； Ν-苄基 -4,6-二 (吗啉— 4—取代 )_[1，3,5]-三嗪 _2_胺； 4-氯 _6_ (吗啉 _4_取代) -Ν-苯基 -[1，3,5]- 三嗪 _2_胺； 4-[4-氯 -6- (吗啉 -4-取代) -[1,3,5]-三嗪 -2-氨基]苯磺酰胺； 4- 氯 对甲氧基苯基 -6- (吗啉 -4-取代 )-[1,3，5]-三嗪 -2-胺； 4-氯 邻曱氧 基苯基 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪 -2-胺； 4-氯 -N-间曱氧基苯基 -6- (吗 啉 _4-取代) -[1,3，5]-三嗪 -2-胺； 4-氯 -N-对氟苯基 -6- (吗啉 -4-取代 )-[1,3,5]- 三嗪 -2-胺； N-苄基 -4-氯 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪 -2-胺； 2-氯 -4,6- 二 (吗啉 _4-取代) -[1,3,5]-三嗪； 2-甲氧基 -4,6-二 (吗啉 -4-取代) -[1,3,5]-三 嗪； N-苄基 -4-甲氧基 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪 -2-胺； N-苄基 -4-乙 氧基 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪 -2-胺； 2, 4, 6-三 (吗啉 -4-取代) -[1,3,5]- 三嗪； 4-曱氧基 -N-对甲氧基苯基 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪 -2-胺； 2-[4_(4,6-二对曱氧基苯胺基 -[1,3，5]-三嗪 -2-取代)哌嗪小取代]乙醇； 2_[4-(4-对曱氧基苯胺基 -6-苯胺基 -[1,3,5]-三嗪 -2-取代)哌嗪 -1-取代]乙 醇； 2-[4-(4，6-二苯胺基 -[1,3,5]-三嗪 -2-取代)哌嗪 -1-取代]乙醇； N-对甲 硫基苯基 _6_ (吗啉 _4_取代) -N，-对曱苯基 -[1，3,5]-三嗪 -2,4-二胺； N-对曱 硫基苯基— 6- (吗啉 -4-取代) -N，-对曱氧基苯基 -[1,3,5]-三嗪 -2,4-二胺； N- 对曱硫基苯基 -6- (吗啉 -4-取代) -N，-苯基 -[1,3，5]-三嗪 -2,4-二胺； N-邻曱 硫基苯基 -6- (吗啉 -4-取代) -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺； N-间曱硫基 苯基 -6- (吗啉 -4-取代) -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺； 6- (吗啉 -4-取 代) -N-苯基 -Ν'- (吡啶 -4-取代 )-[1,3,5]-三嗪 -2,4-二胺； 6- (吗啉 -4-取 代) -Ν- (吡啶 -4-取代) -Ν'-对甲苯基 -[1，3,5]-三嗪 -2,4-二胺； 6- (吗啉 -4-取 代) -Ν- (吡啶 -4-取代) -Ν'-邻曱苯基 -[1,3,5]-三嗪 -2,4-二胺； 6- (吗啉 -4-取 代) -Ν- (吡啶 -4-取代) -Ν'-间曱苯基 -[1，3,5]-三嗪 -2，4-二胺； Ν-对甲氧基苯 基 -6- (吗啉 -4-取代) -Ν，- (吡啶 -4-取代 )-[1,3,5]-三嗪 -2,4-二胺; Ν-邻曱氧基 苯基 _6- (吗啉 -4-取代) -Ν，- (吡啶 -4-取代 )-[1,3,5]-三嗪 -2，4-二胺； 或 Ν-间 曱氧基苯基 -6- (吗啉 -4-取代) -Ν，- (吡啶 -4-取代) -[1,3,5]-三嗪 -2,4-二胺。 Preferably, the compound according to the invention may be: Ν,Ν'-diphenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine;-Chloro-p-sulfonyl-p-phenyl-indole,-phenyl-[1,3,5]-triazine-2,4-diamine; Ν-p-sulfonylphenyl-indole, -phenyl-6- (piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-o-methylsulfonylphenyl-indole,-phenyl-6-(piperazin-1- Substituted)-[1,3,5]-triazine -2,4-diamine; N-m-methanesulfonylphenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-di Amine; 4-(6-chloro-4-anilino-[1,3,5]-triazin-2-amino)benzenesulfonamide; 4-(4-anilino-6-(piperazine-1-substituted) -[1,3,5]-triazin-2-amino)benzenesulfonamide; 2-(4-anilino-6-(piperazin-1-substituted)-[1,3,5]-triazine 2-amino)benzenesulfonamide; 3-(4-anilino-6-(piperazine-1-substituted)-[1,3,5]-triazine-2-amino)benzenesulfonamide; N-naphthalene -N,-phenyl-6-(piperazine-1-substituted)-[1,3,5]-triazine-2,4-diamine; N, N,-dinaphthyl-6- (piperider Pyrazin-1-substituted) -[1,3,5]-triazine-2,4-diamine; N-biphenyl-N,-phenyl-6-(piperazin-1-substituted)-[1 , 3,5]-triazine-2,4-diamine; N, N,-diphenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2, 4-diamine; N-phenyl-6-(piperazin-1-substituted)-N,-p-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine N-phenyl-6-(piperazine small substituted)-N,-o-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine; N-phenyl- 6-(piperazin-1-substituted)-N,-m-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine; 6-(piperazine- 1-substituted ) -N, N,- Trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine; 6-(piperazin-1-substituted)-N,N,-o-trifluoromethoxyphenyl -[1,3,5]-triazine-2,4-diamine; 6-(piperazin-1-substituted)-N,N,-m-trifluoromethoxyphenyl-[1,3,5 ]-triazine-2,4-diamine; N-p-bromophenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4 -diamine; N-o-bromophenyl-N,-phenyl-6-(piperazine- 1 -substituted)-[1,3,5]-triazine-2,4-diamine; N-interbromine phenyl-N,-phenyl-6-(piperazine-1-substituted)-[1,3,5]-triazine-2,4-diamine; N,N,-di-bromophenyl-6 - (piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν, Ν'-di-bromophenyl-6-(piperazin-1-substituted) [1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine,-di-bromophenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine -2,4-diamine; Ν-phenyl-6-(piperazin-1-substituted)-indole, p-p-phenyl-[1,3,5]-triazine-2,4-diamine; Ν-Phenyl-6-(piperazin-1-substituted)-Ν'-o-phenylene-[1,3,5]-triazine-2,4-diamine; Ν-phenyl-6- ( Piperazine small substituted) - hydrazine, - m-phenylene-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine, -di-m-methylphenyl-6- (piperider. Qin-1-substituted) -[1,3,5]-triazine-2,4-diamine; oxime, fluorene,-di-nonylphenyl-6-(piperidin, qin-1-substituted)-[ 1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine, -di-p-methylphenyl-6-(piperazine small substituted)-[1,3,5]-triazine-2 , 4-diamine; Ν-p-chlorophenyl-hydrazine, -phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; o-Chlorophenyl-indole, -phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-m-chlorophenyl-indole,- Phenyl-6-(piperazine small substituted)-[1,3,5]-triazine-2,4-diamine; Ν, Ν'-di-chlorophenyl-6-(piperazine small substitution)- [1,3,5]-triazine-2,4-diamine; Ν, Ν,-di-o-chlorophenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine -2,4-two Amine; N, N,-di-p-chlorophenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-m-fluorophenyl-N ,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-di; N-o-fluorophenyl-N,-phenyl-6- (piperider咯-1-substituted)-[1,3,5]-triazine-2,4-diamine; N, N,-di-p-fluorophenyl-6-(piperazine small substitution)-[1,3, 5]-triazine-2,4-diamine; N, N,-di-fluorophenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4- Diamine; N, N,-di-fluorophenyl-6-(piperidinyl-l-substituted)-[1,3,5]-triazine-2,4-diamine; N-p-methoxy phenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-o-decyloxyphenyl-N,- Phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-metamethoxyphenyl-N,-phenyl-6- ( Piperazine small substituted)-[1,3,5]-triazine-2,4-diamine; N, N,-di-p-methoxyphenyl-6-(piperazin-1-substituted)-[1 ,3,5]-triazine-2,4-diamine; N,N,-di-o-decyloxyphenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine -2,4-diamine; N, N,-di-m-methoxyphenyl-6-(piperazine-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-p-nitrophenyl-N,-phenyl-6- ( Small substituted azine)-[1,3,5]-triazine-2,4-diamine; N-o-nitrophenyl-N,-phenyl-6-(piperazine- 1 -substituted)-[1 ,3,5]-triazine-2,4-diamine; N-m-nitrophenyl-N,-phenyl-6-(piperazine- 1 -substituted)-[1,3,5]-three Pyrazine-2,4-diamine; N, N,-di-nitrophenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N, N,-di-nitrophenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N, N,-di-nitro Phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(3,4-dimethoxy)phenyl-N,- Phenyl-6-(piperazine small substituted)-[1,3,5]-triazine-2,4-diamine; N-(2,3-dimethoxy)phenyl-N,-phenyl - 6- (piperazine small substitution)-[1,3,5]-triazine-2,4-diamine; N-(2,4-dimethoxy)phenyl-N,-phenyl-6 - (piperazine small substitution)-[1,3,5]-triazine-2,4-diamine; N-(2,5-dimethoxy)phenyl-N,-phenyl- 6- ( Piperazine small substituted)-[1,3,5]-triazine-2,4-diamine; N-(2,6-dimethoxy)phenyl-fluorene-phenyl-6- (piperazine) Small substituted)-[1,3,5]-triazine-2,4-diamine; Ν-(3,5-dimethoxy)phenyl-indole, -phenyl-6- (piperazine small substitution) )-[1,3,5]-triazine- 2,4- Amine; hydrazine, bis(3,4-dimethoxy)phenyl-6-(piperazine small substituted)-[1,3,5]-triazine-2,4-diamine; Ν,-bis(2,3-dimethoxy)phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine, - bis(2,4-dimethoxy)phenyl-6-(piperazine small substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine, -di(2) ,5-dimethoxy)phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine, -di(2,6 -dimethoxy)phenyl-6-(piperazine small substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine, -di(3,5-dioxine Phenyl-6-(piperazine small substituted)-[1,3,5]-triazine-2,4-diamine; Ν-(2,3-dihydro Benzo[1,4]dioxin-6-substituted)-N,-phenyl-6-(piperazine small substituted)-[1,3,5]-triazine-2,4-diamine; N, N,-(2,3-dihydrobenzo[1,4]dioxin-6-substituted)-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4 - diamine; 4-(4-p-methoxyanilino-6-(piperazine small substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide; 4- (4-o- Methoxyanilino-6-(piperazin-1-substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide; 4-(4-m-methoxyanilino-6- (Peptide. Qin-1-substituted) -[1,3,5]-triazin-2-amino)benzenesulfonamide; 3-(4-m-methoxyanilino-6-(piperazine-1-substituted) -[1,3,5]-triazin-2-amino)benzenesulfonamide; 3-(4-o-methoxyanilino-6-(piperacin-1-substituted)-[1,3,5 ]-Triazine-2-amino)benzenesulfonamide; 3-(4-p-methoxyanilino-6-(piperazin-1-substituted)-[1,3,5]-triazine-2-amino Benzenesulfonamide; 2-(4-p-methoxyanilino-6-(piperazin-1-substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide; 2- 4-o-methoxyanilino-6-(piperazin-1-substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide; 2-(4-m-methoxyanilinyl) -6-(piperazin-1-substituted)-[1,3,5]-triazin-2-amino)benzenesulfonyl N-p-ethoxyphenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-o-ethoxy Phenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-m-ethoxyphenyl-N, -phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(3,4-dimercapto)phenyl-N,- Phenyl-6-(piperazine small substituted)-[1,3,5]-triazine-2,4-diamine; N-(2,3-diindenyl)phenyl-N,-phenyl- 6-(Piperazine-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(2,4-dimercapto)phenyl-N,-phenyl-6 - (piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(2,5-dimethyl)phenyl-N,-phenyl-6- (piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(2,6-dimercapto)phenyl-N,-phenyl-6- ( Piperazine-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(3,5-dimercapto)phenyl-N,-phenyl-6- (piperidin -1-substituted) -[1,3,5]-triazine-2,4-diamine; N, N,-bis(3,4-dimercapto)phenyl-6-(piperazin-1- Substituted)-[1,3,5]-triazine-2,4-diamine; N,N,-bis(2,3-dimercapto)phenyl-6-(piperazine-1- 1-substituted) [1,3,5]-triazine-2,4-diamine; N, N,-di (2,4- Dimethyl)phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N, N,-bis(2,5-dimethyl Phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N, N,-bis(2,6-dimercapto)phenyl -6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N, N,-bis(3,5-dimethyl)phenyl-6- (piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-p-thiophenyl-N,-phenyl-6- (piperazin-1- Substituted)-[1,3,5]-triazine-2,4-diamine; N-o-methylthiophenyl-N,-phenyl-6-(piperazin-1-substituted)-[1, 3,5]-triazine-2,4-diamine; N-m-decylthiophenyl-N,-phenyl-6- (piperazine-1-take Generation]-[1,3,5]-triazine-2,4-diamine; 4-(4-anilino-6-(piperazin-1-substituted)-[1,3,5]-triazine -2-substituted amino) thiophenol; 3-(4-anilino-6-(piperazine small substituted)-[1,3,5]-triazine-2-substituted amino)^^ phenol; 2-( 4-anilino-6-(piperazine small substituted)-[1,3,5]-triazine-2-substituted amino)thiophenol; 4-(4-anilino-6-(piperazin-1- Substituted) -[1,3,5]-triazine-2-substituted amino)phenol; 3-(4-anilino-6-(piperazine- 1 -substituted)-[ 1 ,3 ,5]-triazine 2-substituted amino)phenol; 2-(4-anilino-6-(piperazine- 1 -substituted)-[1,3,5]-triazine-2-substituted amino)phenol; N-p-tolyl -N,-p-methylthiophenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-o-phenylene-N-- P-thiophenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-m-decylphenyl-N,-p-thiol Phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-benzyl-N,-phenyl-6- (piperazine small substitution) )-[1,3,5]-triazine-2,4-diamine; N, N,-dibenzyl-6-(piperazin-1-substituted)-[1,3,5]-triazine - 2,4-diamine; N-(3,4-dichloro)phenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-three Azin-2,4-diamine; N-(2,3-dichloro)phenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine- 2,4-diamine; N-(2,4-dichloro)phenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2, 4-diamine; N-(2,5-dichloro)phenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4- Diamine; N-(2,6-dichloro)phenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine N-(3,5-Dichloro)phenyl-N,-phenyl-6-(piperazine small substituted)-[1,3,5]-triazine-2,4-diamine; N,N ,-Diphenyl-6-(4-p-methylsulfonylpiperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν,Ν'-diphenyl _6-(4-methanesulfonylpiperazine small substitution)-[1,3,5]-triazine-2,4-diamine; hydrazine, Ν'-diphenyl-6-(4-acetylperidine Pyrazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, Ν'-diphenyl-6-(4-ethoxycarbonylpiperazine-1-substituted) [1,3,5]-triazine-2,4-diamine; Ν-p-nonyloxyphenyl-indole,-phenyl-6-(4-p-nonylbenzenesulfonylpiperazin-1-substituted) -[1,3,5]-triazine-2,4-diamine; Ν-p-nonyloxyphenyl-indole,-phenyl-6-(4-oxasulfonylpiperazin-1-substituted) [1,3,5]-triazine-2,4-diamine Ν-p-methoxyphenyl-oxime,-phenyl-6-(4-acetylpiperazine small substituted)-[1,3,5]-triazine-2,4-diamine; Ν-曱Oxyphenyl-indole, -phenyl-6-(4-ethoxycarbonylpiperazine-1-substituted)-[1,3,5]-triazine-2,4-diamine; 4-[4- Aniline-6-(4-oxasulfonylpiperazin-1-substituted)-[1,3,5]-triazin-2-amino]benzenesulfonamide; 4-[4-aniline_6- (4-pair Benzenesulfonyl piperazine-1-substituted)-[1,3,5]-triazin-2-amino]benzenesulfonamide; 4-[4-aniline-6-(4-acetylpiperazine-1- Substituted)-[1,3,5]-triazin-2-amino]benzenesulfonamide; 4-[4-aniline_6-(4-ethoxycarbonylpiperazine-1-substituted)-[1,3, 5]-triazin-2-amino]benzenesulfonamide; 6-(morpholine -4-substituted) -N,N,-diphenyl-[1,3,5]-triazine-2,4-diamine; N-p-chlorophenyl-6-(morpholin-4-substituted) -N,-phenyl-[1,3,5]-triazine-2,4-diamine; N-o-chlorophenyl-6-(morpholin-4-substituted)-N,-phenyl-[ 1,3,5]-triazine-2,4-diamine; N-m-chlorophenyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5]- Oxazine-2,4-diamine; N,N,-di-chlorophenyl-6-(morpholine-4-substituted)-[1,3,5]-triazine-2,4-diamine; , Ν'-di-o-chlorophenyl-6-(morpholin-4-substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine,-di-p-chlorophenyl- 6-(morpholine-4-substituted)-[1,3,5]-triazine_2,4-diamine; Ν-o-methoxyphenyl-6- (Nipride-4-substituted)-Ν ,-phenyl-[1,3,5]-triazine-2,4-diamine; Ν-m-methoxyphenyl-6-(morpholin-4-substituted)-indole,-phenyl-[ 1,3,5]-triazine-2,4-diamine; Ν-p-methoxyphenyl-6-(morpholin-4-substituted)-indole,-phenyl-[1,3,5] -triazine-2,4-diamine; Ν,Ν'-di-p-methoxyphenyl-6-(morpholin-4-substituted)-[1,3,5]-triazine-2,4- Diamine; hydrazine, hydrazine, -di-o-hydroxyphenyl-6-(morpholin-4-substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine, - Di-methoxybenzene -6-(morpholine-4-substituted)-[1,3,5]-triazine-2,4-diamine; 6-(morpholin-4-substituted)-indole-phenyl-indole,- p-Trifluorodecyloxyphenyl-[1,3,5]-triazine-2,4-diamine; 6-(morpholine-4-substituted)-fluorenyl-phenyl-indole--trifluoroanthracene Oxyphenyl-[1,3,5]-triazine-2,4-diamine; 6-(morpholin-4-substituted)phenyl-indole,-m-trifluoromethoxyphenyl-[1 ,3,5]-triazine-2,4-diamine; Ν-p-bromophenyl-6-(morpholin-4-substituted)-indole,-phenyl-[1,3,5]-triazine -2,4-diamine; Ν-o-bromophenyl-6-(morpholin-4-substituted)-indole,-phenyl-[1,3,5]-triazine-2,4-diamine; Ν-m-bromophenyl-6-(morpholin-4-substituted)-indole,-phenyl-[1,3,5]-triazine-2,4-diamine; Ν-p-ethoxyphenyl -6-(morpholine-4-substituted)-indole,-phenyl-[1,3,5]-triazine-2,4-diamine; 4-(6-(morpholine-4-substituted)- 4-anilino-[1,3,5]-triazin-2-amino)benzamide; 3-(6-(morpholin-4-substituted)-4-anilino-[1,3,5] -triazin-2-amino)phenyl hydrazide; 2-(6-(morpholin-4-substituted)-4-anilino-[1,3,5]-triazin-2-amino)benzamide; Ν-p-fluorophenyl-indole,-p-methoxyphenyl-6-(morpholine-4-substituted)-[1,3,5]-triazine-2,4-di Amine; p-fluorophenyl-6-(norlin-4-substituted)-indole, p-trifluoromethoxyphenyl-[1 ,3,5]-triazine-2,4-diamine; Ν-p-fluorophenyl-6-(morpholin-4-substituted)-indole,-phenyl-[1,3,5]-triazine-2,4-diamine; Ν-(3,4-di Methoxy)phenyl-6-(morpholin-4-substituted)-indole,-phenyl-[1,3,5]-triazine-2,4-diamine; Ν-(2,3-di Methoxy)phenyl-6-(morpholin-4-substituted)-indole,-phenyl-[1,3,5]-triazine-2,4-diamine; Ν-(2,4-di Methoxy)phenyl-6-(morpholin-4-substituted)-indole,-phenyl-[1,3,5]-triazine-2,4-diamine; Ν-(2,5-di曱oxy)phenyl-6-(morpholin-4-substituted)-indole,-phenyl-[1,3,5]-triazine-2,4-diamine; Ν-(2,6-di Methoxy)phenyl-6-(morpholine-4-substituted)-Ν,- Phenyl — [1,3,5]-triazine-2,4-diamine; N-(3,5-dimethoxy)phenyl-6-(morpholin-4-substituted)-N,- Phenyl[1,3,5]-triazine-2,4-diamine; 4-(4-anilino-6-(morpholin-4-substituted)-[1,3,5]-triazine- 2-amino)benzenesulfonamide; 3-(4-anilino-6-(morpholin-4-substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide; 2-(4 -anilino-6-(morpholin-4-substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide; 4-(4-p-nonyloxyanilin-6- (?啉-4-substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide; N-p-methoxyphenyl-N,-(2-(morpholin-4-substituted) -N"-Phenyl-[1 ,3,5]-triazine- 2,4,6-triamine; N-(2-(Nylin-4-substituted)ethyl)-N,,N ,,-diphenyl-[1,3,5]-triazine-2,4,6-triamine; N-benzyl-N,-(2-(morpholin-4-substituted)ethyl)- N,,-phenyl-[1,3,5]-triazine-2,4,6-triamine; N-benzyl-6-(morpholin-4-substituted)-N,-phenyl-[ 1,3,5]-triazine-2,4-diamine; N-p-methoxybenzyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5] -triazine-2,4-diamine; N-o-methoxybenzyl-6-(morpholine-4-substituted)-N,-phenyl-[1,3,5]-triazine-2, 4-diamine; N-metamethoxy -6-(morpholine-4-substituted)-N,-phenyl-[1,3,5]-triazine-2,4-diamine; N-benzyl-6-(morpholin-4- Substituted) -N,-p-tolyl-[1,3,5]-triazine-2,4-diamine; 4-(4-benzylamino-6-(morpholin-4-substituted)-[1 ,3,5]-triazin-2-amino)benzenesulfonamide; N-benzyl-N,-p-methoxyphenyl-6-(morpholin-4-substituted)-[1,3,5] -triazine-2,4-diamine; N-benzyl-N,-p-fluorophenyl-6-(morpholin-4-substituted)-[1,3,5]-triazine-2,4- Diamine; N-benzyl-N,-o-fluorophenyl-6-(morpholin-4-substituted)-[1,3,5]-triazine-2,4-diamine; N-benzyl- N,-m-fluorophenyl-6-(morpholin-4-substituted)-[1,3,5]-triazine-2,4-diamine; Ν,Ν'-dibenzyl-6- (啉-4-substituted)-[1,3,5]-triazine-2,4-diamine; 2-[4,6-diphenylamino-[1,3,5]-triazine-2-amino ]ethanol; 3-[4,6-diphenylamino-[1,3,5]-triazin-2-amino]propanol; 2-[4,6-diphenylamino-[1,3,5] - triazine _ _ 2-amino-〖ethylamine; 2 - [4 - anilino group of Yue _ _ anilino-6 - [1,3, 5] - triazin-2 _ _ amino] ethanol; 3 _ [4 - P-methoxyanilino-6-anilino-[1,3,5]-triazin-2-amino]propanol; 2-[4-p-methoxyanilino-6-phenylamino-[1 , 3,5]-triazin-2-amino]ethylamine; 2-[4-benzylamino-6-anilino-[1,3,5]-triazin-2-amino]ethanol; 3-[4 -benzylamino-6-anilino-[1,3,5]-triazin-2-amino]propanol; 2-[4-benzylamino-6-anilino-[1,3,5]- Triazine-2-amino]ethylamine; 4,6-di(morpholine-4-substituted)-fluorenyl-phenyl-[1,3,5]-triazin-2-amine; 4-[4,6 - bis(morpholine-4-substituted)-[1,3,5]-triazin-2-amino]benzenesulfonyl^; Ν-p-methoxyphenyl-4,6-di(morpholine-4) -substituted) -[1,3,5]-triazin-2-amine; fluorenyl-p-fluorophenyl-4,6-di(morpholine-4-substituted)-[1,3,5]-triazine 2-amine; Ν--benzyl-4,6-bis (morpholino - 4 - substituted) _ [1, 3, 5] - triazin-amine _ 2 _; _ 6 _ 4-chloro (4-morpholinyl _ _Substitution) -Ν-phenyl-[1, 3 , 5 ]- Triazine _ 2 -amine; 4-[4-chloro-6-(morpholin-4-substituted)-[1,3,5]-triazin-2-amino]benzenesulfonamide; 4-chloro-p-methoxy Phenyl-6-(morpholin-4-substituted)-[1,3,5]-triazin-2-amine; 4-chloro-o-decyloxyphenyl-6-(morpholin-4-substituted) -[1,3,5]-triazin-2-amine; 4-chloro-N-metamethoxyphenyl-6-(morpholine-4-substituted)-[1,3,5]-triazine 2-amine; 4-chloro-N-p-fluorophenyl-6-(morpholin-4-substituted)-[1,3,5]-triazin-2-amine; N-benzyl-4-chloro -6-(morpholine-4-substituted)-[1,3,5]-triazin-2-amine; 2-chloro-4,6-di(morpholine-4-substituted)-[1,3, 5]-triazine; 2-methoxy-4,6-di(morpholine-4-substituted)-[1,3,5]-triazine; N-benzyl-4-methoxy-6- (morpholine-4-substituted)-[1,3,5]-triazin-2-amine; N-benzyl-4-ethoxy-6-(morpholin-4-substituted)-[1,3 ,5]-triazin-2-amine; 2,4,6-tris(morpholin-4-substituted)-[1,3,5]-triazine; 4-decyloxy-N-p-methoxy Phenyl-6-(morpholin-4-substituted)-[1,3,5]-triazin-2-amine; 2 -[ 4 _( 4 ,6-di-p-methoxyanilino-[1, 3,5]-triazine-2-substituted) piperazine small substitution] ethanol; 2 _[4-(4-p-methoxyanilino-6-anilino-[1,3,5]-triazine- 2-substituted) piperazine-1-substituted]ethanol; 2-[4-(4,6-di Amino - [1,3,5] - triazin-2-substituted) piperazine-1-substituted] ethanol; N-to-methylthiophenyl _ 6 _ (_ 4 _ substituted morpholine) -N, - P-phenyl-[1,3,5]-triazine-2,4-diamine; N-p-thiophenyl-6-(morpholin-4-substituted)-N,-p-oxyl Phenyl-[1,3,5]-triazine-2,4-diamine; N-p-thiophenyl-6-(morpholin-4-substituted)-N,-phenyl-[1, 3,5]-triazine-2,4-diamine; N-o-nonylthiophenyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5]-three Pyrazine-2,4-diamine; N-m-decylthiophenyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5]-triazine-2,4- Diamine; 6-(morpholin-4-substituted)-N-phenyl-indole'-(pyridin-4-substituted)-[1,3,5]-triazine-2,4-diamine; 6- (morpholine-4-substituted)-Ν-(pyridyl-4-substituted)-Ν'-p-tolyl-[1,3,5]-triazine-2,4-diamine; 6-(morpholine- 4-substituted) -Ν-(pyridyl-4-substituted)-Ν'-o-phenylene-[1,3,5]-triazine-2,4-diamine; 6-(morpholin-4-substituted -Ν-(pyridyl-4-substituted)-Ν'- m-phenyl-[1,3,5]-triazine-2,4-diamine; Ν-p-methoxyphenyl-6- ( Morpholine-4-substituted) -Ν,-(pyridyl-4-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-o-methoxyphenyl _6- ( Porphyrin-4 -substituted) - hydrazine, - (pyridine-4-substituted)-[1,3,5]-triazine-2,4-diamine; or fluorenyl-metamethoxyphenyl-6- (morpholine-4 - substituted) - hydrazine, - (pyridine-4-substituted) - [1,3,5]-triazine-2,4-diamine.
本发明还提供了制备上述化合物的方法，该方法包括以下步骤：（1) 将通式 (II)所示化合物在碱性溶剂中于 0-50。C温度下与取代胺反应， lsT、N The present invention also provides a process for the preparation of the above compound, which comprises the steps of: (1) the compound of the formula (II) in an alkaline solvent at 0-50. Reacts with a substituted amine at C temperature, lsT, N
R、,z N R
Figure imgf000017_0001
R, z NR
Figure imgf000017_0001
其中， Rx为氢、 卤素、 羟基、 巯基、 -C4烃基胺、 或 CrC4氨烷基; Ry和 Rz分别为氢、 卤素、 -C4氨烷基、 或 d-C4卤代烃基， 从而得到 通式 (III)所示化合物： Wherein R x is hydrogen, halogen, hydroxy, decyl, -C 4 hydrocarbylamine, or C r C 4 aminoalkyl; R y and R z are respectively hydrogen, halogen, -C4 aminoalkyl, or dC 4 halogenated a hydrocarbon group to give a compound of the formula (III):
Figure imgf000017_0002
Figure imgf000017_0002
(ΠΙ)  (ΠΙ)
其中， 、 R2、 Rx和 Ry与通式 (1)、 （II)中定义相同； Wherein, R 2 , R x and R y are the same as defined in the formulae (1) and (II);
(2)将通式 (III)所示化合物在碱性溶剂中于 20-100。C 温度下与取 代胺、 取代芳胺、 取代芳基烷胺、 醇或硫醇等反应， 得到通式 (IV)所示 化合物：  (2) The compound of the formula (III) is used in an alkaline solvent at 20-100. The compound represented by the formula (IV) is obtained by reacting with a substituted amine, a substituted arylamine, a substituted arylalkylamine, an alcohol or a thiol at a C temperature:
Figure imgf000017_0003
Figure imgf000017_0003
(IV) 其中， R!、 R2、 R3、 与通式 (I)中定义相同， Rx与通式（II ) 中定 义相同； (IV) Wherein R!, R 2 , R 3 are the same as defined in the formula (I), and R x is the same as defined in the formula (II);
(3)在 0-120°C下、 在碱性溶剂中， 将通式 (IV)所示化合物与取代 脂环胺、 取代芳基胺、 取代芳基烷胺、 醇或硫醇进行反应， 得到式 (I) 所示化合物；  (3) reacting a compound of the formula (IV) with a substituted alicyclic amine, a substituted arylamine, a substituted arylalkylamine, an alcohol or a thiol at 0-120 ° C in an alkaline solvent. Obtaining a compound of formula (I);
(4)根据需要， 通过本领域常规方法进行成盐反应， 或形成溶剂合 物或水合物。 根据本发明的方法， 其中， 步骤 (1)和步骤 (2)中所述的碱性溶剂是 用惰性溶剂配制的碱溶液， 所述碱选自包括吡啶、 三乙胺、 4-二曱胺基 吡啶、 二异丙基乙胺的有机碱和包括複酸钠、 碳酸钾、 氢氧化钠、 氢 氧化钾的无机碱的组， 所述惰性溶剂为一种或多种选自包括四氢呋喃、 乙醚 (Et20)、 二曱基曱酰胺、 乙二醇二曱醚、 乙二醇二乙醚、 二氧六环 的组的溶剂。 根据本发明的方法， 其中， 步骤 (3)中所述的碱性溶剂是用极性有 机溶剂配制的碱溶液， 所述极性有机溶剂为一种或多种选自包括二曱 基曱酰胺、 二曱基亚砜、 二氧六环、 乙醇、 曱醇、 丙酮、 乙酸乙酯和 四氢呋喃的组的溶剂； 所述碱为一种或多种选自包括吡啶、 三乙胺、 4-二曱胺基吡啶 (DMAP)、 二异丙基乙胺的有机碱和包括碳酸钠、 碳酸 钾、 氢氧化钠、 氢氧化钾的无机碱的組的碱。 根据本发明的取代 [1,3,5]三嗪类化合物或其药学上可接受的盐或 它们的溶剂合物或水合物可作为环氧合酶抑制剂、 5-脂氧酶抑制剂、环 氧合酶和 5-脂氧酶双重抑制剂、 和 EGFR酶抑制剂。 根据本发明的取代 [1，3,5]三嗪类化合物或其药学上可接受的盐或 用于预防和 /或治疗和 /或辅助治疗癌症、 尤其肠癌。 本发明还提供了一种以式（I )所示化合物作为活性组分的药物组 合物，所述药物组合物包含治疗有效量的如式 (I)所示的取代 [1，3,5]三嗪 类化合物或其药学上可接受的盐或它们的溶剂合物或水合物和至少一 种药学上可接受的载体。 所述药学上可接受的载体包括离子交换剂、 氧化铝、 硬脂酸铝、 卵磷脂、 血清蛋白、 緩冲物质如磷酸盐、 甘油、 山梨酸、 山梨酸钾、 饱和植物脂肪酸的部分甘油酯混合物、 水， 盐或 电解质、 磷酸氢二钠、 磷酸氢钾、 氯化钠、 锌盐、 胶态氧化硅、 三硅 酸镁、 聚乙烯吡咯烷酮、 纤维素物质、 聚乙二醇、 羧甲基纤维素钠、 聚丙烯酸酯、 蜂蜡和羊毛脂， 但并不限于此。 上述药物组合物可以用于预防和 /或治疗炎症性疾病， 并且预防和 / 或治疗和 /或辅助治疗肿瘤疾病、 尤其肠癌。 本发明化合物的药物组合物可以下面的任意方式施用： 口服， 喷 雾吸入， 直肠用药， 鼻腔用药， 颊部用药， 局部用药， 非肠道用药， 如皮下、 静脉、 肌内、 腹膜内、 鞘内、 心室内、 胸骨内和颅内注射或 输入， 或借助一种外植储器用药。 其中治疗炎症时优选口服或肌肉注 射， 腹膜内或静脉内给药方式。 另外需要指出，本发明化合物的使用剂量和使用方法取决于诸多因 素,包括患者的年龄、 体重、 性别、 自然健康状况、 营养状况、 化合物 的活性强度、 服用时间、 代谢速率、 病症的严重程度以及诊治医师的 主观判断。 例如， 建议剂量为开始每日 5mg ~ 10mg/kg, 维持量可减至 每日 3mg/kg。胶嚢剂： 0.25g/粒。注射液 0.25g/5ml。 口服溶液： 5g/50ml。 本发明的式 (I)所示取代 [1,3，5]三嗪类化合物或其药学上可接受的 盐在 COX-2和 5-LOX酶水平和动物整体水平（角叉菜胶诱导的小鼠足 跖肿胀模型、 角叉菜胶诱导的大鼠足跖肿胀模型、 二曱苯诱导的小鼠 耳廓炎症模型、 大鼠佐剂性关节炎原发、 继发病变模型） 的一系列研 究中， 均显示显著的抗炎活性。对 Ames实验和小鼠微核实验有较好的 安全性， 对胃肠道的无毒副作用， 用于体内治疗具有生物相容性。 本 发明的药物组合物可以用于预防和 /或治疗炎症疾病， 有良好的疗效。 本发明的式 (I)所示取代 [1,3，5]三嗪类化合物或其药学上可接受的 盐在 EGFR酶水平和肿瘤株细胞水平 (人肠癌 HT-29和 HCT- 116)的一系 列筛选试验中， 显示显著的 EGFR酶抑制活性和抗肿瘤活性。 因此， 本发明的药物组合物还可以用于肿瘤疾病的预防和 /或治疗和 /或辅助 治疗， 有良好的疗效。 附图说明 图 1为取代 [1,3,5]三嗪类化合物与环氧合酶 (COX-1和 COX-2) 的 结合动力学曲线。 所用仪器为 BIACORE3000, 分析软件为 Application Wizard中的 Kinetic Analysis。测定时环氧合酶 2蛋白固定在 CM5芯片 上。 其中， 图 1-1和 1-2、 图 1-3和 1-4、 图 1-5和 1-6、 图 1-7和 1-8、 以及图 1-9和图 1-10分別表示阳性化合物、 化合物 B、 化合物 B52、 化合物 B58、 和化合物 61与 COX-2和 COX-1结合的 KD值。 图 1显示取代 [1,3,5]三嗪类化合物与 5-脂氧酶 (5- LOX) 的结合动 力学曲线。所用仪器为 BIACORE3000,分析软件为 Application Wizard 中的 Kinetic Analysis。测定时 5-脂氧酶蛋白固定在 CM5芯片上。其中， 图 2-1和图 2-2分别表示阳性化合物 ETYA和化合物 B62与 5-LOX结 合的 KD。 图 3 为胃肠道副作用实验报告各组切片情况的照片。 其中图 3-1 为阴性对照， 图 3-2为吲哚美辛， 图 3-3为化合物 Celecoxib, 图 3-4 为化合物 B62, 图 3-5为化合物 B68。 (4) A salt formation reaction or a solvate or a hydrate is formed by a conventional method in the art as needed. The method according to the present invention, wherein the alkaline solvent described in the step (1) and the step (2) is an alkali solution prepared by using an inert solvent selected from the group consisting of pyridine, triethylamine, 4-diamine. An organic base of pyridine, diisopropylethylamine, and a group of inorganic bases including sodium complexate, potassium carbonate, sodium hydroxide, potassium hydroxide, wherein the inert solvent is one or more selected from the group consisting of tetrahydrofuran and diethyl ether. A solvent of the group of (Et 2 0), dimethyl hydrazide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane. The method according to the present invention, wherein the alkaline solvent described in the step (3) is an alkali solution prepared by using a polar organic solvent, and the polar organic solvent is one or more selected from the group consisting of dinonyl amides. a solvent of the group of dimercaptosulfoxide, dioxane, ethanol, decyl alcohol, acetone, ethyl acetate and tetrahydrofuran; the base is one or more selected from the group consisting of pyridine, triethylamine, 4-di A base of a group of guanamine pyridine (DMAP), an organic base of diisopropylethylamine, and an inorganic base including sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide. The substituted [1,3,5]triazine compound or a pharmaceutically acceptable salt thereof or a solvate or hydrate thereof according to the present invention can be used as a cyclooxygenase inhibitor, a 5-lipoxygenase inhibitor, Double inhibitors of cyclooxygenase and 5-lipoxygenase, and EGFR enzyme inhibitors. A substituted [1,3,5]triazine compound or a pharmaceutically acceptable salt thereof according to the invention or for the prevention and/or treatment and/or adjuvant treatment of cancer, in particular intestinal cancer. The present invention also provides a pharmaceutical composition comprising the compound of the formula (I) as an active ingredient, the pharmaceutical composition comprising a therapeutically effective amount of the substitution as shown in the formula (I) [1, 3, 5] A triazine compound or a pharmaceutically acceptable salt thereof or a solvate or hydrate thereof and at least one pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier includes an ion exchanger, aluminum oxide, aluminum stearate, lecithin, serum protein, a buffer substance such as phosphate, glycerin, sorbic acid, potassium sorbate, a partial glyceride of a saturated plant fatty acid. Mixture, water, salt or electrolyte, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, carboxymethyl Cellulose sodium, polyacrylate, beeswax and lanolin, but are not limited thereto. The above pharmaceutical composition can be used for the prevention and/or treatment of inflammatory diseases, and for the prevention and/or treatment and/or adjuvant treatment of tumor diseases, particularly intestinal cancer. The pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal , intraventricular, intrasternal and intracranial injections or Enter, or use an explant reservoir. Among them, oral or intramuscular injection, intraperitoneal or intravenous administration is preferred for the treatment of inflammation. It should also be noted that the dosage and method of use of the compounds of the invention depends on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and Subjective judgment of the doctor. For example, the recommended dose is 5 mg to 10 mg/kg daily, and the maintenance dose can be reduced to 3 mg/kg per day. Gelling agent: 0.25g / grain. Injection 0.25g/5ml. Oral solution: 5g / 50ml. The substituted [1,3,5]triazine compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof at the COX-2 and 5-LOX enzyme levels and the overall animal level (carrageenan-induced A series of models of mouse foot swelling, carrageenan-induced rat foot swelling, diterpene-induced mouse auricular inflammation model, rat adjuvant arthritis primary, secondary lesion model) In the study, both showed significant anti-inflammatory activity. It has good safety to Ames test and mouse micronucleus test, and has no toxic side effects on gastrointestinal tract. It is biocompatible for in vivo treatment. The pharmaceutical composition of the present invention can be used for the prevention and/or treatment of inflammatory diseases and has a good therapeutic effect. The substituted [1,3,5]triazine compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof at the EGFR enzyme level and the tumor cell level (human intestinal cancer HT-29 and HCT-116) In a series of screening assays, significant EGFR enzyme inhibitory activity and antitumor activity were shown. Therefore, the pharmaceutical composition of the present invention can also be used for the prevention and/or treatment and/or adjuvant treatment of tumor diseases, and has a good therapeutic effect. DRAWINGS Figure 1 is a graph showing the binding kinetics of substituted [1,3,5]triazine compounds with cyclooxygenase (COX-1 and COX-2). The instrument used was BIACORE3000 and the analysis software was Kinetic Analysis in the Application Wizard. The cyclooxygenase 2 protein was immobilized on the CM5 chip at the time of measurement. Wherein, Figures 1-1 and 1-2, Figures 1-3 and 1-4, Figures 1-5 and 1-6, Figures 1-7 and 1-8, and Figures 1-9 and 1-10 represent positive compound, compound B, compound B52, B58 compound, and K D values of compound 61 in combination with COX-2 and COX-1's. Figure 1 shows the binding kinetics of the substituted [1,3,5]triazine compound to 5-lipoxygenase (5-LOX). The instrument used is BIACORE3000 and the analysis software is Kinetic Analysis in the Application Wizard. The 5-lipoxygenase protein was immobilized on the CM5 chip at the time of measurement. Among them, Figures 2-1 and 2-2 show the K D of the positive compound ETYA and the compound B62 combined with 5-LOX, respectively. Figure 3 is a photograph of the section of the gastrointestinal side effects test report of each group. Figure 3-1 shows the negative control, Figure 3-2 shows indomethacin, Figure 3-3 shows the compound Celecoxib, Figure 3-4 shows compound B62, and Figure 3-5 shows compound B68.
具体实施方式 下面进一步用实施例说明式 (I)化合物的制备， 但这些实施例绝不 是对本发明的任何限制。 核磁共振谱在 BrukerAM-400上测定，质谱在 MAT-95型质谱仪上 进行。 元素分析由中科院上海药物研究所分析室完成。 熔点在电热熔 点管或 b型熔点管上测定， 温度计未经校正； 簿层层析 (TLC)采用硅胶 GF254(青岛海洋化工厂生产)与浓度为 0.8%的羧甲基纤维素钠蒸馏水 溶液充分搅匀后铺板， 晾干， 经 100~110 oC活化 1〜2小时后于干燥器 内保存备用， 紫外灯 (λ: 254 nm)显色； 柱层析采用 200目〜 300目柱 层析硅胶 (青岛海洋化工厂生产）。 实施例 1 苯胺单取代三聚氯嗪（4，6-二氯 苯基 -[1，3，5]-三嗪 -2- 胺)的合成 在 50ml茄形瓶中， 将 4.726 g三聚氯嗪溶于 20ml 1，4-二氧六环， 搅拌下緩慢滴入 2.337 ml苯胺和 1.03gNaOH的水溶液， 搅拌反应 6小 时；加入水水后抽滤，水洗得标题化合物 3.259g,产率 53%。 Mp 136-138 0C。 实施例 2 苯胺二取代三聚氯嗪 （6-氯 -N，N，-二苯基 -[1，3，5]-三嗪 -2,4-二胺） 的合成 在 50ml茄形瓶中， 将 0.421g三聚氯嗪溶于 5 ml 1,4-二氧六环， 室温搅拌下加入 0.42ml苯胺和 0.2gNaOH的水溶液； 在 20-100 °C搅拌 反应过夜。 抽滤， 水洗得灰白色固体（粗品）， 干燥后得标题化合物为 0.515g, 产率 76% (粗）。 Mp l97 °C。 BEST MODE FOR CARRYING OUT THE INVENTION The preparation of the compound of the formula (I) is further illustrated by the following examples, but these examples are in no way intended to limit the invention. Nuclear magnetic resonance spectra were measured on a Bruker AM-400 and mass spectra were performed on a MAT-95 mass spectrometer. Elemental analysis was completed by the Analytical Laboratory of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. The melting point is determined on an electric melting point tube or a b-type melting point tube, and the thermometer is uncorrected; the layer chromatography (TLC) uses silica gel GF254 (produced by Qingdao Ocean Chemical Plant) and 0.8% sodium carboxymethyl cellulose distilled water. The solution is thoroughly mixed, then plated, dried, and activated at 100~110 oC for 1~2 hours, then stored in a desiccator for UV light (λ: 254 nm); column chromatography uses 200 mesh to 300 mesh column Analysis of silica gel (produced by Qingdao Ocean Chemical Plant). Example 1 Synthesis of aniline monosubstituted tripolychloroazine (4,6-dichlorophenyl-[1,3,5]-triazin-2-amine) In a 50 ml eggplant-shaped flask, 4.726 g of tripolychloro The oxazine was dissolved in 20 ml of 1,4-dioxane, and an aqueous solution of 2.337 ml of aniline and 1.03 g of NaOH was slowly added dropwise with stirring, and the reaction was stirred for 6 hours; water was added thereto, and the mixture was filtered, washed with water, and evaporated. . Mp 136-138 0 C. Example 2 Synthesis of aniline disubstituted tripolychloroazine (6-chloro-N,N,-diphenyl-[1,3,5]-triazine-2,4-diamine) in a 50 ml eggplant bottle 0.421 g of chloralazine was dissolved in 5 ml of 1,4-dioxane, and 0.42 ml of an aqueous solution of aniline and 0.2 g of NaOH was added thereto with stirring at room temperature; and the reaction was stirred at 20 to 100 ° C overnight. Filtration and washing with water to give a white solid (yield). Mp l97 °C.
实施例 3 N，N，-二苯基 -6- (哌嗪 -1-取代 )-[1，3，5]-三嗪 -2,4-二胺 (化合 物 B)的合成  Example 3 Synthesis of N,N,-diphenyl-6-(piperazine-1-substituted)-[1,3,5]-triazine-2,4-diamine (Compound B)
在 100ml茄形瓶中，将 2,915g六水合哌嗪溶于丁酮，加入 1.117g苯 胺二取代三聚氯嗪，在 -40 - 40°C和碱性条件下搅拌 5小时 (或加热回流 2-3 小时)。 停止反应， 加入冷水后析出白色沉淀， 抽滤。 将干燥后的 白色晶体经柱层析分离得标题化合物 0.702g， 产率 54%。 Mp 189〜192 oC。 iHNMR ( 400Mz, CDC13 ,TMS ) δ (ppm): 2.40(br-s, 1H); 2.9 l(t, J=4.92Hz, 4H); 3.83(t, J=4.92Hz, 4H); 7.04(t, J=7.38Hz, 2H); 7.10(br-s, 2H); 7.30(t, J=7.91Hz， 4H); 7.55(t, J=7.70Hz, 4H). LREI(m/z): 347(M+), 291(50), 279(100), 220, 144, 119, 92, 77, 56。 In a 100 ml eggplant-shaped flask, 2,915 g of piperazine hexahydrate was dissolved in methyl ethyl ketone, 1.17 g of aniline disubstituted chloralazine was added, and the mixture was stirred at -40 to 40 ° C for 5 hours under alkaline conditions (or heated under reflux 2). -3 hours). The reaction was stopped, and after adding cold water, a white precipitate was precipitated and suction filtered. The white crystals after drying were separated by column chromatography to give the title compound 0.702 g, yield 54%. Mp 189~192 oC. iHNMR (400Mz, CDC1 3 , TMS) δ (ppm): 2.40 (br-s, 1H); 2.9 l (t, J = 4.92 Hz, 4H); 3.83 (t, J = 4.92 Hz, 4H); 7.04 ( t, J = 7.38 Hz, 2H); 7.10 (br-s, 2H); 7.30 (t, J = 7.91 Hz, 4H); 7.55 (t, J = 7.70 Hz, 4H). LREI (m/z): 347 (M+), 291 (50), 279 (100), 220, 144, 119, 92, 77, 56.
实施例 4 6-氯 -N-对甲磺酰基苯基 -N，-苯基 -[1，3，5]-三嗪 -2,4-二胺的合 成 Example 4 Synthesis of 6-chloro-N-p-methanesulfonylphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine
在 50ml茄形瓶中， 将 0.400g对苯胺单取代三聚氯嗪溶于 15ml丙 酮， 室温搅拌下用恒压滴液漏斗往其中緩慢滴入 0.248g对曱磺酰基苯 胺的 10ml丙酮溶液； 滴完后再加入 0.080g氢氧化钠的 10ml水溶液， 室温搅拌 2小时后体系浑浊， 回流反应过夜， 析出白色沉淀， 抽滤得 粗品， 柱层析 (EA/PE=1 :1; Rf= 0.26)提纯得纯品标题化合物 0.170g, 产率 27%。  In a 50 ml eggplant-shaped flask, 0.400 g of p-aniline monosubstituted tripolychloropyrazine was dissolved in 15 ml of acetone, and a solution of 0.248 g of p-sulfonylaniline in 10 ml of acetone was slowly added dropwise thereto with a constant pressure dropping funnel at room temperature; After completion, a solution of 0.080 g of sodium hydroxide in 10 ml of water was added, and after stirring at room temperature for 2 hours, the system was turbid, and the reaction was refluxed overnight, and a white precipitate was precipitated, which was filtered with suction to give a crude product, EtOAc (EtOAc/EtOAc: Purification of the pure title compound 0.170 g, yield 27%.
实施例 5 N-对甲磺酰基苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1，3，5]-三嗪 Example 5 N-p-Methanesulfonylphenyl-N,-phenyl-6-(piperazine-1-substituted)-[1,3,5]-triazine
-2,4-二胺 (化合物 B51)的合成 Synthesis of -2,4-diamine (Compound B51)
在 50ml茄形瓶中， 将 0.250g(1.29mmol)六水合哌嗪溶于约 20ml 丙酮， 室温搅拌下用恒压滴液漏斗往其中緩慢滴入 0.160g(0.426mmol) 6-氯 -N-对甲磺酰基苯基 -N，-苯基 -[1,3，5]-三嗪 -2,4-二胺的 8ml 丙酮溶 液； 滴完后继续室温搅拌 3〜4小时， 减压蒸去适量丙酮， 搅拌下加入 足量冷水， 析出白色沉淀， 抽滤， 反复水洗至中性； 所得粗品干燥后 柱层析提纯得标题化合物 0.102g, 产率 56%。 Mp 166 170。C。 'HNMR ( 400Mz, CD3OD，TMS ) δ (ppm): 7.95(d, J=8.8Hz, 2H); 7.83(d, J=8.8Hz， 2H); 7.65(d, J=8.8Hz5 2H); 7.30(t, J=7.8Hz, 2H); 7.02(t, J=7.6Hz 1H); 3.85(t, J=5.2Hz, 4H); 3.10(s， 3H); 2.85(t, J=5.2Hz, 4H)。 LREI(m/z): 425(M+), 357(100)。 In a 50 ml eggplant-shaped flask, 0.250 g (1.29 mmol) of piperazine hexahydrate was dissolved in about 20 ml of acetone, and 0.160 g (0.426 mmol) of 6-chloro-N- was slowly added dropwise thereto with a constant pressure dropping funnel while stirring at room temperature. a solution of methanesulfonylphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine in 8 ml of acetone; after completion of the dropwise addition, stirring at room temperature for 3 to 4 hours, and evaporating under reduced pressure The amount of acetone was added, and a sufficient amount of cold water was added under stirring to precipitate a white precipitate, which was filtered with suction and washed with water to neutral. The obtained crude product was dried and purified by column chromatography to give the title compound 0.102 g, yield 56%. Mp 166 170. C. 'HNMR (400Mz, CD3OD, TMS) δ (ppm): 7.95 (d, J = 8.8 Hz, 2H); 7.83 (d, J = 8.8 Hz, 2H); 7.65 (d, J = 8.8 Hz 5 2H); 7.30 (t, J = 7.8 Hz, 2H); 7.02 (t, J = 7.6 Hz 1H); 3.85 (t, J = 5.2 Hz, 4H); 3.10 (s, 3H); 2.85 (t, J = 5.2 Hz, 4H). LREI (m/z): 425 (M+), 357 (100).
实施例 6 4-(4-苯胺基 -6- (哌嗪 -1-取代 )-[1，3，5]-三嗪 -2-氨基)苯橫酰胺 (化合物 B52)的合成 Example 6 Synthesis of 4-(4-anilino-6-(piperazin-1-substituted)-[1,3,5]-triazine-2-amino)benzene amide (Compound B52)
除了用 4-(6-氯 -4-苯胺基 -[1，3,5]-三嗪 -2-氨基)苯横酰胺代替 6-氯 -N-对甲磺酰基苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺夕卜，按实施例 5操作， 得到标题化合物白色粉末状固体，产率 83%。 Mp 209-211 °C。 ipi MR ( 400Mz, CD3OD, TMS ) δ (ppm): 2.88(t, J=5.12Hz, 4H); 3.84(t, J=5.12Hz, 4H); 7.01(t, J=7.42Hz, 1H); 7.29(t, J=7.42Hz, 2H); 7.65(d, J=8.66Hz, 2H); 7.78(d, J=8.93Hz, 2H); 7.88(d, J=8.93Hz, 2H)。 13CNMR(400Mz, DMSO-d6) δ (ppm): 164.5, 164, 143.5, 140, 136， 128.5, 126， 122, 120.5, 119.5, 46, 44。 LREI(m/z): 426(M+), 384, 370, 358(100), 299, 144, 119, 92, 77， 56。 HREI: 计算值 （以 C19H22N802S 计） 426.1597; 实测值 426.1584。 IR(cm-1): 3374.9, 2950.6, 1577.5， 1533.2, 1500.4, 1417.4, 1317.2, 1269.0, 1228.5, 1155.2, 1099.2, 879.4, 835.0, 804.2, 694.3， 586.3, 540.0。 In addition to 4-(6-chloro-4-anilino-[1,3,5]-triazin-2-amino)benzene amide instead of 6-chloro-N-p-methylsulfonylphenyl-N,-benzene The benzyl-[1,3,5]-triazine-2,4-diamine was treated as Example 5 to give the title compound as a white powder. Mp 209-211 °C. Ipi MR (400Mz, CD 3 OD, TMS ) δ (ppm): 2.88 (t, J=5.12Hz, 4H); 3.84(t, J=5.12Hz, 4H); 7.01(t, J=7.42Hz, 1H 7.29 (t, J = 7.42 Hz, 2H); 7.65 (d, J = 8.66 Hz, 2H); 7.78 (d, J = 8.93 Hz, 2H); 7.88 (d, J = 8.93 Hz, 2H). 13 C NMR (400 Mz, DMSO-d6) δ (ppm): 164.5, 164, 143.5, 140, 136, 128.5, 126, 122, 120.5, 119.5, 46, 44. LREI (m/z): 426 (M+), 384, 370, 358 (100), 299, 144, 119, 92, 77, 56. HREI: Calculated value (calculated as C 19 H 22 N 8 0 2 S) 426.1597; found 426.1584. IR (cm -1 ): 3374.9, 2950.6, 1577.5, 1533.2, 1500.4, 1417.4, 1317.2, 1269.0, 1228.5, 1155.2, 1099.2, 879.4, 835.0, 804.2, 694.3, 586.3, 540.0.
实施例 7 N-苯基 -6- (哌"秦 -1-取代) -N，-对三氟甲氧基苯基 -〖1，3，5】-三嗪 -2,4-二胺 (化合物 B53)的合成 Example 7 N-Phenyl-6-(piperidinyl-1-substituted)-N,-p-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine ( Synthesis of Compound B53)
除了用 6-氯 苯基 -N，-对三氟曱氧基苯基 -[1，3，5]-三嗪 -2,4-二胺代 替 6-氯 -N-对甲磺酰基苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺外， 按实施例 5操作， 得到标题化合物白色粉末状固体， 产率 65%。 Mp 89〜91 °C。 1HNMR ( 400Mz， DMCO-d6 ,TMS ) δ (ppm): 7,90(d, J=9.07Hz， 2H); 7.73(d, J=7.97Hz, 2H); 7.28(t, J=7.97Hz ,2H); 7.23(t, J=8,80Hz, 2H); 6.98(t, J=7.43Hz, 1H); 4.0 l(t, J=5.2Hz, 4H); 3.15(t, J=5.2Hz, 4H)。 In addition to 6-chlorophenyl-N,-p-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-methylsulfonylphenyl -N,-Phenyl-[1,3,5]-triazine-2,4-diamine, the title compound was obtained as a white powder. Mp 89~91 °C. 1 H NMR (400 Mz, DMCO-d6, TMS) δ (ppm): 7,90 (d, J = 9.07 Hz, 2H); 7.73(d, J=7.97Hz, 2H); 7.28(t, J=7.97Hz, 2H); 7.23(t, J=8,80Hz, 2H); 6.98(t, J=7.43Hz, 1H); 4.0 l (t, J = 5.2 Hz, 4H); 3.15 (t, J = 5.2 Hz, 4H).
实施例 8 N-对溴苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1，3，5】-三嗪 -2，4-二胺 (化合物 B54)的合成 Example 8 Synthesis of N-p-bromophenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine (Compound B54)
除了用 6-氯 -N-对溴苯基 -N，-苯基- [1,3,5]-三嗪 -2,4-二胺代替 6-氯 -N -对甲磺酰基苯基 -N，-苯基 -[1,3，5]-三嗪 -2，4-二胺夕卜，按实施例 5操作， 得到标题化合物白色粉末状固体。 Mp 220 222 °C。 iH MR ( 400Mz, DMSO-d6，TMS ) δ (ppm): 7.74(m, 4H); 7.43(d, J=9.0Hz， 2H); 7.28(t, J=8.1Hz ,2H); 6.96(t, J=7.2Hz, 1H); 3.69(t， J=4.8Hz, 4H); 2,72(t， J=4.8Hz, 4H)。  In addition to 6-chloro-N-p-bromophenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-methanesulfonylphenyl- N,-Phenyl-[1,3,5]-triazine-2,4-diamine, the title compound was obtained as white powder. Mp 220 222 °C. iH MR (400Mz, DMSO-d6, TMS) δ (ppm): 7.74 (m, 4H); 7.43 (d, J = 9.0 Hz, 2H); 7.28 (t, J = 8.1 Hz, 2H); 6.96 (t , J = 7.2 Hz, 1H); 3.69 (t, J = 4.8 Hz, 4H); 2, 72 (t, J = 4.8 Hz, 4H).
实施例 9 N-苯基 -6- (哌嗪 -1-取代) -N，-对甲苯基-【1，3，5】-三嗪 -2,4-二胺 (化合物 B55)的合成 Example 9 Synthesis of N-phenyl-6-(piperazine-1-substituted)-N,-p-tolyl-[1,3,5]-triazine-2,4-diamine (Compound B55)
除了用 6-氯 苯基 -N，-对甲苯基 - [1，3,5]-三嗪 -2，4-二胺代替 6-氯 -N-对甲磺酰基苯基 -N，-苯基 -[1，3,5]-三嗪 -2,4-二胺外， 按实施例 5操作 得到标题化合物白色粉末状固体。 Mp 197-199 °C。 iHNM ( 400Mz, CDCls，TMS ) δ (ppm): 7.58(d, J=Hz, 2H); 7.44(d, J=Hz, 2H); 7.32(t, J=Hz， 2H); 7.14(d, J=Hz, 2H); 7.02(t, J=Hz II- I); 3.82(t, J=5.2Hz, 4H); 2.92(t, J=5.2Hz, 4H); 2.32(s, 3H)。  In addition to 6-chlorophenyl-N,-p-tolyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-methylsulfonylphenyl-N,-benzene The title compound was obtained as a white powdery solid. m. m. Mp 197-199 °C. iHNM (400Mz, CDCls, TMS) δ (ppm): 7.58(d, J=Hz, 2H); 7.44(d, J=Hz, 2H); 7.32(t, J=Hz, 2H); 7.14(d, J = Hz, 2H); 7.02 (t, J = Hz II - I); 3.82 (t, J = 5.2 Hz, 4H); 2.92 (t, J = 5.2 Hz, 4H); 2.32 (s, 3H).
实施例 10 N-对氯苯基 -N，-苯基 -6- (派噪 -1-取代 )-[1，3，5】-三嗪 -2，4-二胺 (化合物 B56)的合成 Example 10 Synthesis of N-p-Chlorophenyl-N,-phenyl-6-(Passon-1 -substituted)-[1,3,5]-triazine-2,4-diamine (Compound B56)
除了用 6-氯 对氯苯基 -N，-苯基- [1,3，5]-三嗪 -2，4-二胺代替 6-氯 对曱磺酰基苯基 -N，-苯基 -[1，3,5]-三嗪 -2,4-二胺夕卜，按实施例 5操作， 得到标题化合物白色粉末状固体。 Mp 208~211 °C。 1HNMR ( 400Mz, CDCI3，TMS ) δ (ppm): 7.55(d, J=Hz, 2H); 7.5 l(d, J=Hz， 2H); 7.32(t, J=Hz, 2H); 7.26(d, J=Hz， 2H); 7.06(t, J=Hz IH); 3.80(t, J=5.2Hz, 4H); 2.92(t, J=5.2Hz, 4H)。 In addition to 6-chloro-p-chlorophenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-p-sulfonylphenyl-N,-phenyl- [1,3,5]-triazine-2,4-diamine, operating as in Example 5, The title compound was obtained as a white powdery solid. Mp 208~211 °C. 1 H NMR ( 400 Mz, CDCI 3 , TMS ) δ (ppm): 7.55 (d, J = Hz, 2H); 7.5 l (d, J = Hz, 2H); 7.32 (t, J = Hz, 2H); 7.26 ( d, J = Hz, 2H); 7.06 (t, J = Hz IH); 3.80 (t, J = 5.2 Hz, 4H); 2.92 (t, J = 5.2 Hz, 4H).
实施例 11 N-间氟苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1，3，5]-三嗪 -2,4-二胺 (化合物 B57)的合成 Example 11 Synthesis of N-m-Fluorophenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine (Compound B57)
除了用 6-氯 -N-间氟苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺代替 6-氯 -N-对甲磺酰基苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺夕卜，按实施例 5操作， 得到标题化合物白色粉末状固体。 Mp 86~93 °C。 iHNMR OOMz, DMCO-d6 ,TMS ) δ (ppm): 7.75(d, J=Hz, 2H); 7.43(dd, J=Hz, 2H); 7.28(t, J=Hz, 2H); 7.28(s, IH); 6.98(t, J=Hz IH); 6.71(td, J=Hz, IH); 3.79(t, J-5.2Hz, 4H) 2.81(t, J=5.2Hz, 4H)。  In addition to 6-chloro-N-m-fluorophenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-methylsulfonylphenyl- N,-Phenyl-[1,3,5]-triazine-2,4-diamine, the title compound was obtained as white powder. Mp 86~93 °C. iHNMR OOMz, DMCO-d6, TMS) δ (ppm): 7.75 (d, J=Hz, 2H); 7.43 (dd, J=Hz, 2H); 7.28(t, J=Hz, 2H); 7.28(s , IH); 6.98 (t, J = Hz IH); 6.71 (td, J = Hz, IH); 3.79 (t, J-5.2 Hz, 4H) 2.81 (t, J = 5.2 Hz, 4H).
实施例 12 N-对甲氧基苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1，3，5卜三嗪 -2,4- 二胺 (化合物 B58)的合成 Example 12 N-p-Methoxyphenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5-triazine-2,4-diamine (Compound B58) Synthesis
除了用 6-氯 -N-对曱氧基苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺代替 6- 氯- N-对曱磺酰基苯基- N，-苯基 -[1，3,5]-三嗪- 2,4-二胺外， 按实施例 5操 作，得到标题化合物白色粉末状固体。 Mp 198-199 °C。 !HNMR( 400Mz， CDCI3 ,TMS ) δ (ppm): 2.9 l(t, J=5.0Hz, 4H); 3.80(t， J=5.0Hz, 4H); 6.86(d, J=Hz, 2H); 6.94(br-s, IH); 7.02(t, J=Hz, IH); 7.02(s， IH); 7.29(t, J=Hz, 2H); 7.43(d, J=5.0Hz, 2H); 7.55(d, 2H)。 13CNMR(400Mz， DMSO-d6) δ (ppm):54.0, 55.9, 65.2(-OCH3), 123.9, 130.0, 132.0, 138.1, 143.5， 150.2, 164.4, 174.0, 174.8。 LREI(m/z): 377(1^), 321, 309(100), 250, 149, 119， 92: 77。 HREI: 计算值（以 C2。H23N70计） 377.1964; 实测值 377.1952。 IR(cm_1): 3322.8, 2950.6, 2856.1， 1608.4, 1581.4, 1538.9, 1494.6, 1436.7, 1376.9, 1359.6, 1272.8, 1236.2, 1027.9, 806.1, 750.2. 分析计算值 (以 C20H23N7O计 ) (%): C, 63.64; H, 6.14; N, 25.98。 实测值： C, 63.71; H, 6.17; N, 25.53。 In addition to 6-chloro-N-p-methoxyphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-sulfonylbenzene The title compound was obtained as a white powdery solid. m. m. Mp 198-199 °C. ! HNMR (400Mz, CDCI3, TMS ) δ (ppm): 2.9 l (t, J = 5.0Hz, 4H); 3.80 (t, J = 5.0Hz, 4H); 6.86 (d, J = Hz, 2H); 6.94(br-s, IH); 7.02(t, J=Hz, IH); 7.02(s, IH); 7.29(t, J=Hz, 2H); 7.43(d, J=5.0Hz, 2H); 7.55 (d, 2H). 13 C NMR (400 Mz, DMSO-d6) δ (ppm): 54.0, 55.9, 65.2 (-OCH3), 123.9, 130.0, 132.0, 138.1, 143.5, 150.2, 164.4, 174.0, 174.8. LREI(m/z): 377(1^), 321, 309(100), 250, 149, 119, 92: 77. HREI: Calculated value (calculated as C 2 .H 23 N 7 0) 377.1964; found 377.1952. IR (cm _1 ): 3322.8, 2950.6, 2856.1, 1608.4, 1581.4, 1538.9, 1494.6, 1436.7, 1376.9, 1359.6, 1272.8, 1236.2, 1027.9, 806.1, 750.2. Analytical calculations (calculated as C 20 H 23 N 7 O) (%): C, 63.64; H, 6.14; N, 25.98. Found: C, 63.71; H, 6.17; N, 25.53.
实施例 13 N-间溴苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1，3，5]-三嗪 -2，4-二胺 (化合物 B59)的合成 Example 13 Synthesis of N-m-bromophenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine (Compound B59)
除了用 6-氯 间溴苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺代替 6-氯 -N-对曱磺酰基苯基 -Ν'-苯基 -[1,3,5]-三嗪 -2，4-二胺夕卜，按实施例 5操作， 得到标题化合物白色粉末状固体。 Mp 89〜92 °C。 iHNMR OOMz, CDC13 ,TMS ) δ (ppm): 7.98(s, IH); 7.54(dd， J=8.6&1.0Hz, 2H); 7.30(m, 3H); 7.14(m， 4H);7.05(t, J=7.6Hz, IH); 3.80(t, J=5.2Hz, 4H) 2.90(t, In addition to 6-chloro-bromophenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-sulfonylphenyl-Ν'- Phenyl-[1,3,5]-triazine-2,4-diamine, the title compound was obtained as white powder. Mp 89~92 °C. iHNMR OOMz, CDC1 3 , TMS ) δ (ppm): 7.98 (s, IH); 7.54 (dd, J = 8.6 & 1.0 Hz, 2H); 7.30 (m, 3H); 7.14 (m, 4H); 7.05 ( t, J=7.6Hz, IH); 3.80(t, J=5.2Hz, 4H) 2.90(t,
J=5.2Hz, 4H)。 J = 5.2 Hz, 4H).
实施例 14 N-对硝基苯基 -N，-苯基- 6- (哌"秦 -1-取代 )-[1,3，5]-三嗪 -2,4- 二胺 (化合物 B60)的合成 Example 14 N-p-Nitrophenyl-N,-phenyl-6-(pipe "Hin-1-substituted"-[1,3,5]-triazine-2,4-diamine (Compound B60) Synthesis
除了用 6-氯 对硝基苯基 -N，-苯基 -[1,3,5]-三嗪 -2，4-二胺代替 6-氯 -N-对甲磺酰基苯基 -N，-苯基 -[1,3，5]-三嗪 -2,4-二胺夕卜，按实施例 5操作， 得到标题化合物白色粉末状固体。 Mp 246〜247 QC。 iHNMR ( 400Mz， DMCO-d6 ,TMS ) δ (ppm): 2.81(t,J=5.2Hz,4H); 3.80(t5J=5.2Hz, 4H); 7.01(t, J=7.4Hz, IH); 7.30(t, J=8.0Hz, 2H); 7.75(d,J=8.0Hz, 2H); In addition to 6-chloro-p-nitrophenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-methylsulfonylphenyl-N, -Phenyl-[1,3,5]-triazine-2,4-diamine, the title compound was obtained as a white powder. Mp 246~247 Q C. iHNMR (400Mz, DMCO-d6, TMS) δ (ppm): 2.81 (t, J = 5.2 Hz, 4H); 3.80 (t 5 J = 5.2 Hz, 4H); 7.01 (t, J = 7.4 Hz, IH) ; 7.30 (t, J = 8.0 Hz, 2H); 7.75 (d, J = 8.0 Hz, 2H);
8.08(dJ=9.2Hz,lH); 8.18(d, J=9.2Hz, 2H)。 8.08 (dJ = 9.2 Hz, lH); 8.18 (d, J = 9.2 Hz, 2H).
实施例 15 N-(3，4-二甲氧基)苯基 -N，-苯基 -6- (哌"秦 -1-取代 )-〖1，3，5]-三 嗪 -2,4-二胺 (化合物 B61)的合成 Example 15 N-(3,4-Dimethoxy)phenyl-N,-phenyl-6- (piperidinyl-1-substituted)-[1,3,5]-three Synthesis of azine-2,4-diamine (Compound B61)
除了用 6-氯 -N-(3,4-二曱氧基)苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺 代替 6-氯 -N-对甲磺酰基苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺外， 按实施 例 5操作， 得到标题化合物白色粉末状固体。 Mp 97〜100 °C。 iHNMR ( 400Mz， CDC13 TMS ) δ (ppm): 2.80(t, J=5.1Hz， 4H); 3.79(t， J=5.1Hz, 4H); 3.79(s, 6H); 6.86(d, J=8.7Hz, 1H); 6.95(t, J=8.7Hz, 1H); 7.15(d, J=8.9Hz, 1H); 7.25(t, J=7.4Hz, 2H); 7.52(s, 1H); 7.78 (d, J=7.7Hz, 2H)。 LREI(m/z): 407(]ν ), 351, 339(100), 323, 280， 144,119, 92, 77，56。 In addition to 6-chloro-N-(3,4-dimethoxy)phenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N The title compound was obtained as a white powdery solid. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Mp 97~100 °C. iHNMR (400Mz, CDC1 3 TMS) δ (ppm): 2.80 (t, J = 5.1 Hz, 4H); 3.79 (t, J = 5.1 Hz, 4H); 3.79 (s, 6H); 6.86 (d, J = 8.7 Hz, 1H); 6.95 (t, J = 8.7 Hz, 1H); 7.15 (d, J = 8.9 Hz, 1H); 7.25 (t, J = 7.4 Hz, 2H); 7.52 (s, 1H); 7.78 (d, J = 7.7 Hz, 2H). LREI (m/z): 407 (] ν ), 351, 339 (100), 323, 280, 144, 119, 92, 77, 56.
实施例 16 N-(2，3-二氢苯并〖1，4】二恶 -6-取代) -N，-苯基 -6- (哌嗪 -1-取 代 )-[1，3，5] -三嗪 -2，4-二胺 (化合物 B62)的合成 Example 16 N-(2,3-Dihydrobenzo[1,4]dioxin-6-substituted)-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5 Synthesis of Triazine-2,4-Diamine (Compound B62)
除了用 6-氯 -N-(2,3-二氢苯并 [1,4]二恶 -6-取代) -N，-苯基- [1,3,5]-三 嗪 -2,4-二胺代替 6-氯 对甲磺酰基苯基 -N，-苯基 -[1,3，5]-三嗪 -2,4-二胺 夕卜，按实施例 5操作，得到标题化合物白色粉末状固体。 Mp 105-109。C。 !HNMR ( 400Mz, DMCO-d6， TMS ) δ (ppm): 2.79(t5 J=4.9Hz, 4H);3.75(t, J=4.8Hz, 4H); 4.25(m, 4H); 6.74(d5 J=8.8Hz, 1H); 6.95(t, J=7.3Hz, 1H); 7.10(dd, J=8.8 and 2.6Hz5 1H); 7.25(t, J=7.4Hz， 2H); 7.43(s, 1H); 7.78(d, J=7.7Hz, 2H) o In addition to 6-chloro-N-(2,3-dihydrobenzo[1,4]dioxin-6-substituted)-N,-phenyl-[1,3,5]-triazine-2,4 -Diamine in place of 6-chloro-p-methylsulfonylphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine, as in Example 5 to give the title compound white Powdered solid. Mp 105-109. C. !HNMR (400Mz, DMCO-d6, TMS) δ (ppm): 2.79 (t 5 J=4.9Hz, 4H); 3.75 (t, J=4.8Hz, 4H); 4.25(m, 4H); 6.74(d 5 J = 8.8 Hz, 1H); 6.95 (t, J = 7.3 Hz, 1H); 7.10 (dd, J = 8.8 and 2.6 Hz 5 1H); 7.25 (t, J = 7.4 Hz, 2H); 7.43 (s , 1H); 7.78(d, J=7.7Hz, 2H) o
实施例 17 4-(4-对甲氧基苯胺基 -6- (哌嗪 -1-取代 )-[1，3，5]-三嗪 -2-氨基） 苯磺酰胺 (化合物 的合成 Example 17 4-(4-p-methoxyanilino-6-(piperazin-1-substituted)-[1,3,5]-triazine-2-amino)benzenesulfonamide (synthesis of compound
除了用 4-(6-氯 -4-对曱氧基苯胺基 -[1,3,5]-三嗪 -2-氨基)苯磺酰胺代 替 6-氯 对曱磺酰基苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺外， 按实施例 5操作， 得到标题化合物白色粉末状固体。 Mp 251~254 °C。 ^!NMR ( 400Mz, DMSO-d6 ,TMS ) δ (ppm): (not split clear) 2.75(s, 4H); 3.70(s, 4H); 3.75(s, 3H); 6.89(d, J=6.8Hz， 2H); 7.12 (s， 1H); 7.60(d, J=9.4Hz, 2H); 7.70(d, J=8.8 Hz, 2H); 7.92(d5 J=8.5Hz, 2H)。 In addition to 4-(6-chloro-4-p-methoxyanilino-[1,3,5]-triazin-2-amino)benzenesulfonamide instead of 6-chloro-p-sulfonylphenyl-N,- The title compound was obtained as a white powdery solid, m. m. Mp 251~254 °C. ^!NMR (400Mz, DMSO-d6, TMS) δ (ppm): (not split clear) 2.75(s, 4H); 3.70(s, 4H); 3.75(s, 3H); 6.89(d, J=6.8Hz, 2H 7.12 (s, 1H); 7.60 (d, J = 9.4 Hz, 2H); 7.70 (d, J = 8.8 Hz, 2H); 7.92 (d 5 J = 8.5 Hz, 2H).
实施例 18 N-对乙氧基苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1，3，5】-三嗪 -2，4- 二胺 (化合物 B64)的合成 Example 18 N-p-ethoxyphenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine (Compound B64) Synthesis
除了用 6-氯 -N-对乙氧基苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺代替 6- 氯 对曱磺酰基笨基 -N，-苯基 -[1，3,5]-三嗪 -2,4-二胺外， 按实施例 5操 作，得到标题化合物白色粉末状固体。 Mp 185-187 °C。 'ΗΝΜΐΚ 400Μζ, DMSO-d6 , TMS ) δ (ppm): 1.38(t， J=7.0Hz，3H); 2.80(t, J=5.0 Hz, 4H); 3.78(t, J=5.0Hz, 4H); 4.02 (q, J=6.8Hz, 2H); 6.85(d, J=6.8 Hz, 2H); 6.95(t, J=7.2Hz， 1H); 7.26(t, J=7.6Hz, 2H); 7.64(d, J=7.2Hz, 2H); 7.79(d, J=7.6Hz: 2H)。 In addition to 6-chloro-N-p-ethoxyphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-p-sulfonyl-phenyl-N The title compound was obtained as a white powdery solid. m. m. Mp 185-187 °C. 'ΗΝΜΐΚ 400Μζ, DMSO-d6, TMS) δ (ppm): 1.38 (t, J=7.0 Hz, 3H); 2.80 (t, J=5.0 Hz, 4H); 3.78 (t, J=5.0 Hz, 4H) ; 4.02 (q, J = 6.8 Hz, 2H); 6.85 (d, J = 6.8 Hz, 2H); 6.95 (t, J = 7.2 Hz, 1H); 7.26 (t, J = 7.6 Hz, 2H); 7.64 (d, J = 7.2 Hz, 2H); 7.79 (d, J = 7.6 Hz : 2H).
实施例 19 N-(3，4-二甲基)苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5卜三嗪 -2,4-二胺 (化合物 B65)的合成 Example 19 N-(3,4-Dimethyl)phenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5-triazine-2,4-diamine Synthesis of (Compound B65)
除了用 6-氯 -N-(3,4-二甲基)苯基 -N，-苯基 -[1,3,5]-三嗪- 2,4-二胺代 替 6-氯 -N-对曱磺酰基苯基 -Ν'-苯基 -[1,3,5]-三嗪 -2，4-二胺外， 按实施例 5操作， 得到标题化合物白色粉末状固体。 Mp l85~187 °C。 'HNMR ( 400Mz, DMSO-d6， TMS ) δ (ppm): 2.19(s,3H); 2.21(s,3H); 3.75(s,3H); 2.79(t, J=5.2Hz54H); 3.75(t, =4.8 Hz,4H); 6.95(t, 1H); 7.01 (d, In addition to 6-chloro-N-(3,4-dimethyl)phenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N- The title compound was obtained as a white powdery solid. m. m. Compound Compound Compound Compound Compound Compound Compound Compound Mp l85~187 °C. 'HNMR (400Mz, DMSO-d6, TMS) δ (ppm): 2.19 (s, 3H); 2.21 (s, 3H); 3.75 (s, 3H); 2.79 (t, J = 5.2 Hz 5 4H); (t, =4.8 Hz, 4H); 6.95(t, 1H); 7.01 (d,
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Figure imgf000030_0003
lt'C00/900ZN3/13d Z18S60/L00Z OAV 合物 B70)的合成 lt'C00/900ZN3/13d Z18S60/L00Z OAV Synthesis of Compound B70)
除了用 N-苄基 -6-氯 -N，-苯基 -[1，3，5]-三嗪 -2，4-二胺代替 6-氯 -N-对 曱磺酰基苯基 -N，-苯基 -[1,3,5]-三嗪 -2，4-二胺外， 按实施例 5操作， 得 到标题化合物白色粉末状固体。 Mp 72-75 °C。 1HNMR ( 400Mz, CDCI3 ,TMS ) δ (ppm): 7.53(dd, J=8.4&0.8Hz, 2H); 7.30(m, 7H); 6.95(t, J=7.2Hz, IH); 6.90(s, IH); 5.30(s， lH);4.60(d, J=6Hz, 2H); 3.78(s, 4H); 2.85(t, J=5.Hz, 4H)。 In addition to N-benzyl-6-chloro-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-sulfonylphenyl-N, The title compound was obtained as a white powdery solid. m. m. Mp 72-75 °C. 1 H NMR ( 400 Mz, CDCI 3 , TMS ) δ (ppm): 7.53 (dd, J = 8.4 & 0.8 Hz, 2H); 7.30 (m, 7H); 6.95 (t, J = 7.2 Hz, IH); 6.90 (s , IH); 5.30 (s, lH); 4.60 (d, J = 6 Hz, 2H); 3.78 (s, 4H); 2.85 (t, J = 5. Hz, 4H).
实施例 24 N-(3，4-二氯）苯基 -N，-苯基 -6- (哌嗪 -1-取代) -[1，3，5】-三嗪 -2,4-二胺 (化合物 B75)的合成 Example 24 N-(3,4-Dichloro)phenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine Synthesis of (Compound B75)
除了用 6-氯 -N-(3,4-二氯)苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺代替 6-氯- N-对甲磺酰基苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺外， 按实施例 5 操作， 得到标题化合物白色粉末状固体。 Mp 107-109 。C。 iHNMR ( 400Mz, CDCI3，TMS ) δ (ppm): 7.94(d， J=2.4Hz, IH); 7.54(d, J=7.6I_Iz， 2H); 7.34(t, J=8Hz, 3H); 7.23(dd, J=8.4 & 2.4Hz, IH); 7.07(t, J=7.2Hz, IH); 6.92(s, IH); 6.90(s， IH); 3.82(t, J=4.8Hz, 4H); 2.94(t, J=4.8Hz, 4H)。  In addition to 6-chloro-N-(3,4-dichloro)phenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-pair The title compound was obtained as a white powdery solid. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Mp 107-109. C. iHNMR (400Mz, CDCI3, TMS) δ (ppm): 7.94 (d, J = 2.4 Hz, IH); 7.54 (d, J = 7.6 I_Iz, 2H); 7.34 (t, J = 8 Hz, 3H); 7.23 ( Dd, J = 8.4 & 2.4 Hz, IH); 7.07 (t, J = 7.2 Hz, IH); 6.92 (s, IH); 6.90 (s, IH); 3.82 (t, J = 4.8 Hz, 4H); 2.94 (t, J = 4.8 Hz, 4H).
实施例 25 N-对氟苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1，3，5]-三嗪 -2,4-二胺 (化合物 B76)的合成 Example 25 Synthesis of N-p-fluorophenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine (Compound B76)
除了用 6-氯 对氟苯基 -Ν，-苯基 -[1,3，5]-三嗪 -2,4-二胺代替 6-氯 -Ν-对曱磺酰基苯基 -Ν，-苯基 -[1,3,5]-三嗪 -2,4-二胺夕卜，按实施例 5操作， 得到标题化合物白色粉末状固体。 Mp 191-192 °C。 'HNMR OOMz, CDCI3 ,TMS ) δ (ppm): 7.55(dd, J=8.8&1.2Hz, 2H); 7.49(m, 2H); 7.3 l(t, J=8.4Hz, 2H); 7.02(m, 3H); 6.87(s, IH); 6.83(s, IH); 3.81(t， J=5.2Hz, 4H); 2.92(t, J=5.2Hz, 4H)。 In addition to 6-chloro-p-fluorophenyl-indole,-phenyl-[1,3,5]-triazine-2,4-diamine in place of 6-chloro-indole-p-sulfonylphenyl-indole,- Phenyl-[1,3,5]-triazine-2,4-diamine, the title compound was obtained as white powder. Mp 191-192 °C. 'HNMR OOMz, CDCI3, TMS) δ (ppm): 7.55 (dd, J = 8.8 & 1.2 Hz, 2H); 7.49 (m, 2H); 7.3 l (t, J = 8.4 Hz, 2H); 7.02 (m , 3H); 6.87(s, IH); 6.83(s, IH); 3.81(t, J=5.2Hz, 4H); 2.92 (t, J = 5.2 Hz, 4H).
实施例 26 N-间甲 苯基 -N，-苯基 -6- (哌嗪 -1-取代) - [1，3，5】-三嗪 -2,4- 二胺 (化合物 B77)的合成 EXAMPLE 26 Synthesis of N-m-Methoxyphenyl-N,-phenyl-6-(piperazine-1-substituted)-[1,3,5]-triazine-2,4-diamine (Compound B77)
除了用 6-氯 -N-间曱氧基苯基 -N，-苯基 -[1,3，5]-三嗪 -2,4-二胺代替 6- 氯 _N_对甲磺酰基苯基-N，-苯基— [ ^]-三嗪 -2，4-二胺外， 按实施例 5操 作， 得到标题化合物白色粉末状固体。 Mp 85〜88 °C。 iHNMR OOMz, CDC13 ,TMS ) δ (ppm): 7.56(d, J=7.6Hz, 2H); 7.34(m, 3H); 7.20(t, J=8.0Hz, 1H); 7.03(t, J=6.8Hz, 2H); 6.92(s, 2H); 6.60(dd, J=8.4 & 2.8Hz, 1H); 3.83(t, J=5.2Hz, 4H); 3.80(s, 3H); 2.93(t, J=5.2Hz, 4H)。 In addition to 6-chloro-N-metamethoxyphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro- N- p-methanesulfonylbenzene The title compound was obtained as a white powdery solid. m. m. Mp 85~88 °C. iHNMR OOMz, CDC1 3 , TMS ) δ (ppm): 7.56 (d, J = 7.6 Hz, 2H); 7.34 (m, 3H); 7.20 (t, J = 8.0 Hz, 1H); 7.03 (t, J = 6.8 Hz, 2H); 6.92 (s, 2H); 6.60 (dd, J = 8.4 & 2.8 Hz, 1H); 3.83 (t, J = 5.2 Hz, 4H); 3.80 (s, 3H); 2.93 (t, J = 5.2 Hz, 4H).
实施例 27 N，N，-二苄基 -6- (哌嗪 -1-取代 )-[1，3，5]-三嗪 -2,4-二胺 (化合物 B69)的合成 除了用 Ν,Ν'-二苄基 - 6-氯 -[1,3，5]-三嗪 -2，4-二胺代替 6-氯 -Ν-对曱磺 酰基苯基 -Ν，-苯基 -[1，3，5]-三嗪 -2,4-二胺外, 按实施例 5操作， 得到标 题化合物无色粘稠状固体。 1HNMR ( 400Mz， CDC13 ,TMS ) δ (ppm): 7.18-7.28(m, 10H); 4.40(s, 4H); 3.58(t, J=4.4Hz, 4H); 2.62(t, J=4.4Hz, 4H). Example 27 Synthesis of N,N,-dibenzyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine (Compound B69) In addition to hydrazine, Ν'-Dibenzyl-6-chloro-[1,3,5]-triazine-2,4-diamine in place of 6-chloro-indole-p-sulfonylphenyl-indole,-phenyl-[1 The title compound was obtained as a colorless viscous solid, m. m. 1 H NMR ( 400 Mz, CDC1 3 , TMS ) δ (ppm): 7.18-7.28 (m, 10H); 4.40 (s, 4H); 3.58 (t, J = 4.4 Hz, 4H); 2.62 (t, J = 4.4 Hz, 4H).
实施例 28 N，N，-二苯基 -6-(4-对甲苯磺酰基哌嗪 -1-取代 )-[1，3，5]-三嗪 -2，4-二胺 (化合物 B81)的合成 Example 28 N,N,-Diphenyl-6-(4-p-toluenesulfonylpiperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine (Compound B81) Synthesis
将 200mg Ν,Ν'-二苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2，4-二胺溶于 10ml无水吡啶中，冰浴搅拌下，分批加入对曱苯磺酰氯 120mg, 3小时 后往体系加入适量冰水， 搅拌一刻钟后抽滤得黄绿色固体粗品， 经柱 层析提纯， 得到纯品白色粉末 260mg。 收率 90%。 Mp 214-218 °C。 1HNMR( 400Mz, DMCO-d6 ,TMS ) δ (ppm): 7.72(d, J=7.6Hz, 2H); 7.65(d, J=7.6Hz, 2H); 7.43(d, J=8Hz, 2H); 7.25(t, J=7.6Hz, 4H); 6.95(t, J=7.6Hz, 2H); 3.90(t, J=5.2Hz， 4H); 2.93(t, J=5.2Hz， 4H); 2.38(s, 3H)。 LREI(m/z): 501(M+), 346(100)。 ' 200 mg of hydrazine, Ν'-diphenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine was dissolved in 10 ml of anhydrous pyridine and stirred in an ice bath. Then, 120 mg of p-phenylenesulfonyl chloride was added in portions, and after 3 hours, an appropriate amount of ice water was added to the system, and after stirring for a quarter of an hour, the crude product was obtained as a yellow-green solid, which was purified by column chromatography to obtain 260 mg of pure white powder. The yield was 90%. Mp 214-218 °C. 1 H NMR (400 Mz, DMCO-d6, TMS) δ (ppm): 7.72 (d, J = 7.6 Hz, 2H); 7.65 (d, J = 7.6 Hz, 2H); 7.43 (d, J = 8 Hz, 2H) 7.25(t, J=7.6Hz, 4H); 6.95(t, J=7.6Hz, 2H); 3.90(t, J=5.2Hz, 4H); 2.93(t, J=5.2Hz, 4H); 2.38 (s, 3H). LREI (m/z): 501 (M+), 346 (100). '
实施例 29 N-对甲氧基苯基 -N，-苯基 -6-(4-对甲苯磺酰基哌嚓 -1 -取 代) -[1，3,5卜三嗪 -2，4-二胺 (化合物 B82)的合成 Example 29 N-p-methoxyphenyl-N,-phenyl-6-(4-p-toluenesulfonylpiperidin-1 -substituted)-[1,3,5-triazine-2,4-di Synthesis of Amine (Compound B82)
除了用 N-对甲氧基苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4- 二胺代替 Ν,Ν，-二苯基 -6- (派"秦小取代) -[1,3，5]-三嗪 -2,4-二胺外，按实施 例 28操作，得到标题化合物白色粉末状固体。 Mp 114-117 °C。 ^INMR ( 400Mz， CDC13 ,TMS ) δ (ppm): 7.62(d, J=8.4Hz, 2H); 7.47(d, J=7.6Hz, 2H); 7.36(d, J=8.8Hz， 2H); 7.30(m， 4H); 7.02(t, J=7.6Hz, 1H); 6.84(d, J-6.8Hz, 2H); 3.91(t, J=5.2Hz, 4H); 3.80(s, 3H); 3.01(t, J=5.2Hz, 4H); 2.40(s, 3H)。 In addition to N-p-methoxyphenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine in place of hydrazine, hydrazine, The title compound was obtained as a white powdery solid. m.p. m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m - 117 ° C. ^INMR ( 400 Mz, CDC1 3 , TMS ) δ (ppm): 7.62 (d, J = 8.4 Hz, 2H); 7.47 (d, J = 7.6 Hz, 2H); 7.36 (d, J = 8.8 Hz, 2H); 7.30 (m, 4H); 7.02 (t, J = 7.6 Hz, 1H); 6.84 (d, J-6.8 Hz, 2H); 3.91 (t, J = 5.2 Hz, 4H); 3.80 (s, 3H); 3.01 (t, J = 5.2 Hz, 4H); 2.40 (s, 3H).
实施例 30 N-对曱氧基苯基 -N，-苯基 -6-(4-曱磺酰基哌嗪 -1-取 代 )-[1，3，5]-三嗪 -2,4-二胺 (化合物 B83)的合成 Example 30 N-p-methoxyphenyl-N,-phenyl-6-(4-oxasulfonylpiperazin-1-substituted)-[1,3,5]-triazine-2,4-di Synthesis of Amine (Compound B83)
除了用曱磺酰氯代替对甲苯磺酰氯外， 按实施例 29操作， 得到标 题化合物白色粉末状固体。 Mp 212-214 °C。 ifiNMR ( 400Mz, CDCI3，TMS ) δ (ppm): 7.52(d, J=8.4Hz， 2H); 7.42(d, J=6.8Hz, 2H); 7.3 l(t, J=7.6Hz， 2H); 7.05(t, J=7.6Hz, IH); 6.95(s, 1H); 6.87(d, J=6.8Hz, 2H); 6.85(s, IH); 3.95(t, J=4.8Hz, 4H); 3.80(s, 3H); 3.25(t, J=4.8Hz, 4H); 2.77(s, 3H)。  The title compound was obtained as a white powdery solid, m. m. Mp 212-214 °C. IfiNMR (400Mz, CDCI3, TMS) δ (ppm): 7.52 (d, J = 8.4 Hz, 2H); 7.42 (d, J = 6.8 Hz, 2H); 7.3 l (t, J = 7.6 Hz, 2H); 7.05(t, J=7.6Hz, IH); 6.95(s, 1H); 6.87(d, J=6.8Hz, 2H); 6.85(s, IH); 3.95(t, J=4.8Hz, 4H); 3.80(s, 3H); 3.25(t, J=4.8Hz, 4H); 2.77(s, 3H).
实施例 31 N，N，-二苯基 -6-(4-甲磺酰基哌嗪 -1-取代 )-[1，3，5]-三嗪 -2,4- 二胺 (化合物 B84)的合成 Example 31 N,N,-Diphenyl-6-(4-methanesulfonylpiperazin-1-substituted)-[1,3,5]-triazine-2,4- Synthesis of diamine (compound B84)
除了用甲磺酰氯代替对曱苯磺酰氯外， 按实施例 28操作， 得到标 题化合物。 Mp 216 218。C。 1HNMR ( 400Mz, CDC13 ,TMS ) δ (ppm): 7.55(d, J=7.6Hz, 4H); 7.33(t, J=7.6Hz, 4H); 7.07(t, J=7.6Hz, 2H); 6.95(s, 2H); 3.97(t, J=4.8Hz， 4H); 3.27(t, J=4.8Hz, 4H); 2.80(s, 3H)。 The title compound was obtained according to the procedure of m. m. Mp 216 218. C. 1 H NMR ( 400 Mz, CDC1 3 , TMS ) δ (ppm): 7.55 (d, J = 7.6 Hz, 4H); 7.33 (t, J = 7.6 Hz, 4H); 7.07 (t, J = 7.6 Hz, 2H) ; 6.95 (s, 2H); 3.97 (t, J = 4.8 Hz, 4H); 3.27 (t, J = 4.8 Hz, 4H); 2.80 (s, 3H).
实施例 32 4-[4-苯胺 -6-(4-甲磺酰基哌嗪 -1-取代 )-[1，3，5卜三嗪 -2-氨基] 酰胺 (化合物 B85)的合成 Example 32 Synthesis of 4-[4-aniline-6-(4-methanesulfonylpiperazine-1-substituted)-[1,3,5-triazine-2-amino]amide (Compound B85)
除了用 4-(4-苯胺基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 _2_氨基)苯磺酰胺 代替 Ν,Ν，-二苯基 -6- (哌嗪 -1-取代) -[1，3，5]-三嗪- 2,4-二胺外， 按实施例 30操作， 得到标题化合物白色粉末状固体。 Mp 247〜252 °C。 'HNMR ( 400Mz, DMSO-d6 ,TMS ) δ (ppm): 9.60(s， 1H); 9.33(s, 1H); 7.92(d, J=9.2Hz, 2H); 7.72(d, J=9.2Hz, 4H); 7.3 l(t, J=8.0Hz, 2H); 7.16(s, 2H); 7.02(t, J=7.6Hz, 1H); 3.91(t, J=5.2Hz, 4H); 3.22(t, J=5.2Hz, 4H); 2.91(s, 3H)。 Except that 4- (4 - anilino-6- (piperazin-1-substituted) - [1, 3, 5] - triazin-2 _ _ amino) benzenesulfonamide instead of Ν, Ν, - diphenyl -6 - (Piperazine-1-substituted)-[1,3,5]-triazine- 2,4-diamine. Mp 247~252 °C. 'HNMR (400Mz, DMSO-d6, TMS) δ (ppm): 9.60(s, 1H); 9.33(s, 1H); 7.92(d, J=9.2Hz, 2H); 7.72(d, J=9.2Hz , 4H); 7.3 l(t, J=8.0Hz, 2H); 7.16(s, 2H); 7.02(t, J=7.6Hz, 1H); 3.91(t, J=5.2Hz, 4H); 3.22( t, J = 5.2 Hz, 4H); 2.91 (s, 3H).
实施例 33 4-[4-苯胺基 -6-(4-乙酰基哌嗪 -1-取代 )-[1，3，5]-三嗪 -2- ^】 酰胺 (化合物 B196)的合成 Example 33 Synthesis of 4-[4-anilino-6-(4-acetylpiperazine-1-substituted)-[1,3,5]-triazine-2-()amide (Compound B196)
除了用 4-(4-笨胺基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2-氨基)苯磺酰胺 代替 Ν,Ν'-二苯基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2，4-二胺，乙酰氯代替对 甲苯磺酰氯外， 按实施例 28操作， 得到标题化合物白色粉末状固体。 1HNMR ( 300Mz， DMSO-d6 ,TMS ) δ (ppm): 7.93(d, J=8.7Hz, 2H); 7.69-7.24(m, 4H); 7.3 l(t, J=7.5Hz5 2H); 7.00(t, J=7.5Hz, 1H); 3.73- 3.82(m， 4H); 3.54(m, 4H); 2.06(s, 3H)。 实施例 34 4-[4-苯胺基 -6-(4-乙氧羰基哌嗪 -1-取代) -[1，3，5】-三嗪 -2-氨 基]^ 酰胺 (化合物 B197)的合成 In addition to 4-(4-aminoamino-6-(piperazin-1-substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide instead of hydrazine, Ν'-diphenyl- 6-(Piperazine-1-substituted)-[1,3,5]-triazine-2,4-diamine, acetyl chloride in place of p-toluenesulfonyl chloride. solid. 1 HNMR (300Mz, DMSO-d6 , TMS) δ (ppm): 7.93 (d, J = 8.7Hz, 2H); 7.69-7.24 (m, 4H); 7.3 l (t, J = 7.5Hz 5 2H); 7.00 (t, J = 7.5 Hz, 1H); 3.73- 3.82 (m, 4H); 3.54 (m, 4H); 2.06 (s, 3H). Example 34 Synthesis of 4-[4-anilino-6-(4-ethoxycarbonylpiperazine-1-substituted)-[1,3,5]-triazin-2-amino]-amide (Compound B197)
除了用 4-(4-苯胺基 -6- (哌嗪小取代 )-[1,3,5]-三嗪 -2-氨基)苯磺酰胺 代替 Ν,Ν' -二苯基 -6- (哌嗪- 1 -取代 )-[1 ,3 ,5]-三嗪 -2,4-二胺，溴乙酸乙酯代 替对甲苯磺酰氯外， 按实施例 28操作， 得到标题化合物白色粉末状固 体。 iHNMR ( 300Mz, DMSO-d6，TMS ) δ (ppm): 7.93(d, J=8.1Hz, 2H); 7.69-7.74(m, 4H); 7.3 l(t, J=7.8Hz， 2H); 7.01 (t, J=7.2Hz, 1H); 4.10(q, J=7.2Hz, 2H); 3.79(m,4H); 2.59(m,4H); 1.20(t, J=7.2Hz, 3H)。  In addition to 4-(4-anilino-6-(piperazine small substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide instead of hydrazine, Ν'-diphenyl-6- ( Piperazine-1 -substituted)-[1,3,5]-triazine-2,4-diamine, ethyl bromoacetate, m.p. . iHNMR (300Mz, DMSO-d6, TMS) δ (ppm): 7.93 (d, J = 8.1 Hz, 2H); 7.69-7.74 (m, 4H); 7.3 l (t, J = 7.8 Hz, 2H); 7.01 (t, J = 7.2 Hz, 1H); 4.10 (q, J = 7.2 Hz, 2H); 3.79 (m, 4H); 2.59 (m, 4H); 1.20 (t, J = 7.2 Hz, 3H).
实施例 35 N-对氯苯基 -6- (吗啉 -4-取代) -N，-苯基 -[1，3，5】-三嗪 -2，4-二胺 (化合物 C151)的合成 Example 35 Synthesis of N-p-chlorophenyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5]-triazine-2,4-diamine (Compound C151)
除了用 6-氯 对氯苯基 -N，-苯基 -[1,3,5]-三嗪 -2，4-二胺代替 6-氯 对曱磺酰基苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺， 吗啉代替哌嗪外， 按实施例 5操作，得到标题化合物白色粉末状固体。 Mp 226 QC。 'I-INMR (300Mz, CDC13, TMS) δ (ppm): 7.55(d, J=7.8Hz, 2H); 7.50(d, J=6.6Hz, 2H); 7.33(t, J=7.8Hz, 2H); 7.27(dd, J=1.5 & 7.2Hz, 2H); 7.08(t, J=7.2Hz 1H); 7.02(Br-s,2H); 3.74~3.84(m, 8H)。 In addition to 6-chloro-p-chlorophenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-p-sulfonylphenyl-N,-phenyl- The title compound was obtained as a white powdery solid, m. m. Mp 226 Q C. 'I-INMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.55 (d, J = 7.8 Hz, 2H); 7.50 (d, J = 6.6 Hz, 2H); 7.33 (t, J = 7.8 Hz, 2H); 7.27 (dd, J=1.5 & 7.2 Hz, 2H); 7.08 (t, J = 7.2 Hz 1H); 7.02 (Br-s, 2H); 3.74~3.84 (m, 8H).
实施例 36 N-邻甲氧基苯基 -6- (吗啉 -4-取代) -N，-苯基 -[1，3，5〗-三嗪 -2,4- 二胺 (化合物 C152)的合成 Example 36 N-o-methoxyphenyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5-triazine-2,4-diamine (compound C152) Synthesis
除了用 6-氯 -N-邻甲氧基苯基 -N，-苯基 -[1，3，5]-三嗪 -2，4-二胺代替 6- 氯 对曱磺酰基苯基 -Ν'-苯基 -[1,3，5]-三嗪 -2,4-二胺，吗啉代替哌嗪外， 按实施例 5操作， 得到标题化合物白色粉末状固体。 Mp 162 ~ 163 QC。 lHNMR (300Mz, DMSO- d6， TMS) δ (ppm): 8.13(Br-s, 1H); 7.74(Br-s5 1H); 7.70(d, J=8.1Hz, 2H); 7.26(t, J=8.1Hz, 2H); 7.05(d, J=3.6Hz, 2H);In addition to 6-chloro-N-o-methoxyphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-p-sulfonylphenyl-oxime The title compound was obtained as a white powdery solid, m. m. m. Mp 162 ~ 163 Q C. l HNMR (300Mz, DMSO-d6, TMS) δ (ppm): 8.13 (Br-s, 1H); 7.74 (Br-s 5 1H); 7.70 (d, J = 8.1 Hz, 2H); 7.26 (t, J = 8.1 Hz, 2H); 7.05 (d, J = 3.6 Hz, 2H);
6.92-6.98(m, 2H); 3.86(s, 3H); 3.73 (m, 4H); 3.66 (m, 4H)。 6.92-6.98 (m, 2H); 3.86 (s, 3H); 3.73 (m, 4H); 3.66 (m, 4H).
实施例 37 N-间甲氧基苯基 -6- (吗啉 -4-取代) -N，-苯基 -[1，3,5】-三嗪 -2,4- 二胺 (化合物 C153)的合成 Example 37 N-Methoxyphenyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5]-triazine-2,4-diamine (Compound C153) Synthesis
除了用 6-氯 -N-间甲氧基苯基 -N，-苯基- [1,3,5]-三嗪 -2，4-二胺代替 6- 氯— N_对曱磺酰基苯基-N，-苯基 _[l53，5]_三嗪 2,4—二胺，吗啉代替哌。秦外， 按实施例 5操作，得到标题化合物白色粉末状固体。 Mp 164 °C。 'I-INMR (300Mz, DMSO-d6, TMS) δ (ppm): 7.75(d, J=7.5Hz, 2H); 7.43 (s, 1H); 7.27(m, 3H); 7.17(t, J=8.1Hz， 1H); 6.96(t, J=7.5Hz, 1H); 6.55(d, J=7.5Hz, 1H); 3.65-3.75 (m, 11H)。 In addition to 6-chloro-N-m-methoxyphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-sulfonylbenzene yl -N, - phenyl _ [l53, 5] _ triazine-2,4-diamine, piperazine instead of morpholine. The title compound was obtained as a white powdery solid. Mp 164 °C. 'I-INMR (300Mz, DMSO-d6, TMS) δ (ppm): 7.75 (d, J = 7.5 Hz, 2H); 7.43 (s, 1H); 7.27 (m, 3H); 7.17 (t, J = 8.1 Hz, 1H); 6.96 (t, J = 7.5 Hz, 1H); 6.55 (d, J = 7.5 Hz, 1H); 3.65-3.75 (m, 11H).
实施例 38 N，N，-二对曱氧基苯基 -6- (吗啉 -4-取代 )-[1，3，5】-三嗪 -2,4-二 胺 (化合物 C154)的合成 Example 38 Synthesis of N,N,-di-p-methoxyphenyl-6-(morpholin-4-substituted)-[1,3,5]-triazine-2,4-diamine (Compound C154)
除了用 6-氯 -Ν,Ν，-二对曱氧基苯基 -[1，3,5]-三嗪 -2,4-二胺代替 6-氯 -Ν-对曱磺酰基苯基 -Ν，-苯基 -[1,3,5]-三嗪 -2，4-二胺， 吗啉代替哌嗪外， 按实施例 5操作， 得到标题化合物白色粉末状固体。 Mp 192 193 DC。 !HNMR (300Mz, CDC13, TMS) δ (ppm): 7.42(d5 J=8.7Hz, 4H); 6.86(d, J=8.7Hz， 4H); 6.78(s, 2H); 3.72-3.80 (m, 14H)。 In addition to 6-chloro-indole, hydrazine, -di-p-methoxyphenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-indole-p-sulfonylphenyl- The title compound was obtained as a white powdery solid, m.p.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Mp 192 193 D C. ! HNMR (300Mz, CDC1 3, TMS) δ (ppm): 7.42 (d 5 J = 8.7Hz, 4H); 6.86 (d, J = 8.7Hz, 4H); 6.78 (s, 2H); 3.72-3.80 ( m, 14H).
实施例 39 6- (吗啉 -4-取代) -N-苯基 -N，-对三氟甲氧基苯基- [1,3,5]- =- 嗪 -2,4-二胺 (化合物 C155)的合成 Example 39 6-(morpholine-4-substituted)-N-phenyl-N,-p-trifluoromethoxyphenyl-[1,3,5]- =-azine-2,4-diamine ( Synthesis of Compound C155)
除了用 6-氯 苯基 -N，-对三氟曱氧基苯基- [1,3，5]-三嗪 -2，4-二胺 代替 6-氯 -N-对曱磺酰基苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺， 吗啉代替 哌嗪外， 按实施例 5 操作， 得到标题化合物白色粉末状固体。 Mp 178-180 0C。 1HNMR (300MzJ DMSO-d6, TMS) δ (ppm): 7.85(d, J=9.0Hz, 2H); 7.72(d, J=7.8Hz5 2H); 7.28(m， 4H); 6.97(t, J=7.5Hz, IH); 3.64-3.85 (m, 8H)。 In addition to 6-chlorophenyl-N,-p-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-sulfonylphenyl -N,-Phenyl-[1,3,5]-triazine-2,4-diamine, morpholine, m.p. Mp 178-180 0 C. 1 H NMR (300 Mz J DMSO-d6, TMS) δ (ppm): 7.85 (d, J = 9.0 Hz, 2H); 7.72 (d, J = 7.8 Hz 5 2H); 7.28 (m, 4H); , J = 7.5 Hz, IH); 3.64-3.85 (m, 8H).
实施例 40 N-对溴苯基 -6- (吗啉 -4-取代) -N，-苯基 -[1，3，5】-三嗪 -2,4-二胺 (化合物 C156)的合成 Example 40 Synthesis of N-p-P-Phenylphenyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5]-triazine-2,4-diamine (Compound C156)
除了用 N-对溴苯基 -6-氯 -N 苯基 -[1,3,5]-三嗪 -2,4-二胺代替 6-氯 - N-对曱磺酰基苯基 -N，-苯基 -[1,3，5]-三嗪 -2,4-二胺， 吗啉代替哌嗪外， 按实施例 5操作， 得到标题化合物白色粉末状固体。 Mp 227~228 °C。 !HNMR (300Mz, DMSO-d6, TMS) δ (ppm): 7.73(m, 4H); 7.43(d, J=9.0Hz, 2H); 7.29(t, J=7.8Hz, 2H); 6.98(t, J=7.5Hz, IH); 3.65-3.74 (m， 8H)。 In addition to replacing N-p-bromophenyl-6-chloro-N-phenyl-[1,3,5]-triazine-2,4-diamine with 6-chloro-N-p-sulfonylphenyl-N, - phenyl-[1,3,5]-triazine-2,4-diamine, morpholine, m.p. Mp 227~228 °C. ! HNMR (300Mz, DMSO-d6 , TMS) δ (ppm): 7.73 (m, 4H); 7.43 (d, J = 9.0Hz, 2H); 7.29 (t, J = 7.8Hz, 2H); 6.98 (t , J = 7.5 Hz, IH); 3.65-3.74 (m, 8H).
实施例 41 N-对乙氧基苯基 -6- (吗啉 -4-取代) -N，-苯基 -[1，3，5】-三嗪 -2,4- 二胺 (化合物 C157)的合成 Example 41 N-p-Ethoxyphenyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5]-triazine-2,4-diamine (Compound C157) Synthesis
除了用 6-氯- N-对乙氧基苯基 -N，-苯基 -[1，3，5]-三嗪 -2,4-二胺代替 6-氯- N-对曱磺酰基苯基 -N，-笨基 -[1，3,5]-三嗪 -2，4-二胺， 吗啉代替哌嗪 夕卜，按实施例 5操作，得到标题化合物白色粉末状固体。 Mp 174-175 。C。 !HNMR (300Mz, DMSO-d6, TMS) δ (ppm): 7.74(d, J=7.8Hz, 2H); 7.59(d, J=9.0Hz, 2H); 7.27(t, J=7.8Hz， 2H); 6.95(t, J=7.2Hz, IH); 6.85(d, J=9.0Hz, 2H); 3.98(q? J=6.9Hz, 2H); 3.64-3.73 (m， 8H); 1.31(t, J=6.9Hz, 3H)。 In addition to 6-chloro-N-p-ethoxyphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-sulfonylbenzene The title compound was obtained as a white powdery solid. m.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Mp 174-175. C. ! HNMR (300Mz, DMSO-d6 , TMS) δ (ppm): 7.74 (d, J = 7.8Hz, 2H); 7.59 (d, J = 9.0Hz, 2H); 7.27 (t, J = 7.8Hz, 2H 6.95(t, J=7.2Hz, IH); 6.85(d, J=9.0Hz, 2H); 3.98(q ? J=6.9Hz, 2H); 3.64-3.73 (m, 8H); 1.31(t , J=6.9Hz, 3H).
实施例 42 4-(6- (吗啉 -4-取代) -4-笨胺基 -〖1，3，5]-三嗪 -2-^ 苯甲酰胺 (化合物 C158)的合成 Example 42 Synthesis of 4-(6-(morpholine-4-substituted)-4-phenylamino-[1,3,5]-triazine-2-(benzoic acid) (Compound C158)
除了用 4-(6-氯 -4-苯胺基 -[1,3,5]-三嗪 -2-氨基)苯曱酰胺代替 6-氯 -N -对曱磺酰基苯基 -N， -笨基 -[ 1 ,3,5]-三嗪 -2,4-二胺， 吗啉代替哌嗪外， 按实施例 5操作， 得到标题化合物白色粉末状固体。 Mp 222〜223 °C。 ]HNMR (300Mz, DMSO-d6, TMS) δ (ppm): 7.78~7.85(m, 5H); 7.73(d, J=8.1Hz, 2H); 7.30(t, J=8.1Hz, 2H); 7.18(s, IH); 6.99(t, J=7.5Hz, IH); 3.65-3.76 (m, 8H)。 In addition to 4-(6-chloro-4-anilino-[1,3,5]-triazin-2-amino)benzamide instead of 6-chloro-N-p-sulfonylphenyl-N, - stupid Base-[1,3,5]-triazine-2,4-diamine, morpholine instead of piperazine, The title compound was obtained as a white powdery solid. Mp 222~223 °C. ] HNMR (300Mz, DMSO-d6 , TMS) δ (ppm): 7.78 ~ 7.85 (m, 5H); 7.73 (d, J = 8.1Hz, 2H); 7.30 (t, J = 8.1Hz, 2H); 7.18 (s, IH); 6.99 (t, J = 7.5 Hz, IH); 3.65-3.76 (m, 8H).
实施例 43 N-对氟苯基 -N，-对曱氧基苯基 -6- (吗啉 -4-取代) -[1，3，5】-三嗪 -2,4-二胺 (化合物 C159)的合成 Example 43 N-p-fluorophenyl-N,-p-methoxyphenyl-6-(morpholin-4-substituted)-[1,3,5]-triazine-2,4-diamine (compound) Synthesis of C159)
除了用 6-氯 -N-对氟苯基 -N，-对曱氧基苯基 -[1,3,5]-三嗪 -2,4-二胺代 替 6-氯 -N-对甲磺酰基苯基 -N，-苯基 -[1,3，5]-三嗪 -2,4-二胺， 吗啉代替哌 嗪外，按实施例 5操作，得到标题化合物白色粉末状固体。 Mp 200-201 0C。！HNMR (300Mz, CDC13, TMS) δ (ppm): 7.47(m, 2H); 7.41(d, J=9.0Hz, 2H); 6.70(t, J=8.7Hz, 2H); 6.87(d, J=9.3Hz, 2H); 6.82(s, IH); 6.77(s, IH); 3.71-3.81 (m, 8H)。 In addition to 6-chloro-N-p-fluorophenyl-N,-p-methoxyphenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-methylsulfonate The title compound was obtained as a white powdery solid. m.j.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Mp 200-201 0 C. ! HNMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.47 (m, 2H); 7.41 (d, J = 9.0 Hz, 2H); 6.70 (t, J = 8.7 Hz, 2H); 6.87 (d, J = 9.3 Hz, 2H); 6.82 (s, IH); 6.77 (s, IH); 3.71-3.81 (m, 8H).
实施例 44 N-对氟苯基 -6- (吗啉 -4-取代) -N，-对三氟甲氧基苯基- [1,3,5]-三嗪 -2,4-二胺 (化合物 C160)的合成 Example 44 N-p-fluorophenyl-6-(morpholin-4-substituted)-N,-p-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine Synthesis of (Compound C160)
除了用 6-氯 对氟苯基 -N，-对三氟曱氧基苯基 -[1,3,5]-三嗪 -2,4-二 胺代替 6-氯 对曱磺酰基苯基 -N，-苯基 -[1，3,5]-三嗪 -2，4-二胺， 吗啉代 替哌嗪外， 按实施例 5 操作， 得到标题化合物白色粉末状固体。 Mp 198-199。C。 iHNMR (300Mz， CDC13, TMS) δ (ppm): 7.55(d, J=9.3Hz, 2H); 7.47(m, 2H); 7.15(d5 J=8.7Hz， 2H); 7.01(t, J=9.0Hz, 2H); 6.88(s, IH); 6.80(s, IH); 3.73-3.82 (m, 8H)。 . In addition to 6-chloro-p-fluorophenyl-N,-p-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-p-sulfonylphenyl- N,-Phenyl-[1,3,5]-triazine-2,4-diamine, morpholine, m.p. Mp 198-199. C. iHNMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.55 (d, J = 9.3 Hz, 2H); 7.47 (m, 2H); 7.15 (d 5 J = 8.7 Hz, 2H); 7.01 (t, J = 9.0 Hz, 2H); 6.88 (s, IH); 6.80 (s, IH); 3.73-3.82 (m, 8H). .
实施例 45 N-对氟苯基 -6- (吗啉 -4-取代) -N，-苯基 -[1，3，5]-三嗪 -2,4-二胺 (化合物 C161)的合成 除了用 6-氯- N-对氟苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺代替 6-氯 对甲磺酰基苯基 -N，-苯基 -[ 1 ,3 ,5]-三嗪 -2，4-二胺， 吗啉代替哌嗪外， 按实施例 5操作， 得到标题化合物白色粉末状固体。 Mp 210-211。C。 'HNMR (300Mz, CDC13, TMS) δ (ppm): 7.54(dd, J=1.2 & 8.7Hz, 2H); 7.48(m， 2H); 7.3 l(t, J=8.4Hz, 2H); 6.97〜7.08(m, 3H); 6.96(s， IH); 6.91(s， IH); 3.73-3.82 (m, 8H)。 Example 45 Synthesis of N-p-fluorophenyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5]-triazine-2,4-diamine (Compound C161) In addition to 6-chloro-N-p-fluorophenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-methanesulfonylphenyl-N,- Phenyl-[1,3,5]-triazine-2,4-diamine, morpholine, m.p. Mp 210-211. C. 'HNMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.54 (dd, J = 1.2 & 8.7 Hz, 2H); 7.48 (m, 2H); 7.3 l (t, J = 8.4 Hz, 2H); 6.97 ~7.08 (m, 3H); 6.96 (s, IH); 6.91 (s, IH); 3.73-3.82 (m, 8H).
实施例 46 4-(4-对甲氧基苯胺基 -6- (吗啉 -4-取代 )-〖1，3，5]-三嗪 -2- J 酰胺 (化合物 C162)的合成 Example 46 Synthesis of 4-(4-p-methoxyanilino-6-(morpholine-4-substituted)-[1,3,5]-triazine-2-J amide (Compound C162)
除了用 4-(6-氯 -4-对曱氧基苯胺基 -[1,3,5]-三嗪 -2-氨基)苯磺酰胺代 替 6-氯 -N-对曱磺酰基苯基 -Ν'-苯基 -[1，3,5]-三嗪 -2，4-二胺， 吗啉代替哌 嗪外，按实施例 5操作，得到标题化合物白色粉末状固体。 Mp 257-258 0C。 iHNM (300Mz, DMSO-d6, TMS) δ (ppm): 7.91(d, J=7.2Hz, 2H); 7.68(d5 J=8.7Hz， 2H); 7.57(d, J=8.7Hz, 2H) 6.88(t5 J=7.2Hz, 2H); 3.73(m, 7H); 3.65(m5 4H)。 In addition to 4-(6-chloro-4-p-methoxyanilino-[1,3,5]-triazin-2-amino)benzenesulfonamide instead of 6-chloro-N-p-sulfonylphenyl- The title compound was obtained as a white powdery solid, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Mp 257-258 0 C. iHNM (300Mz, DMSO-d6, TMS) δ (ppm): 7.91 (d, J = 7.2 Hz, 2H); 7.68 (d 5 J = 8.7 Hz, 2H); 7.57 (d, J = 8.7 Hz, 2H) 6.88 (t 5 J = 7.2 Hz, 2H); 3.73 (m, 7H); 3.65 (m 5 4H).
实施例 47 N-对甲氧基苯基 -N，-(2- (吗啉 -4-取代）乙基) -N，，-苯基 -[1 ,3,5] -三"秦 -2，4，6-三胺 (化合物 C163)的合成 Example 47 N-p-Methoxyphenyl-N,-(2-(morpholin-4-substituted)ethyl)-N,,-phenyl-[1,3,5]-tri"Qin-2 Synthesis of 4,6-triamine (compound C163)
除了用 6-氯- N-对曱氧基苯基 -N，-苯基- [1，3，5]-三嗪 -2，4-二胺代替 6-氯 对曱磺酰基苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺， 2- (吗啉 -4-取代) 乙胺代替哌"秦外， 按实施例 5操作， 得到标题化合物白色粉末状固体。 Mp 147-148 0C。 1HNMR (300Mz, CDC13, TMS) δ (ppm): 7.57(d, J=7.2Hz, 2H); 7.45(d, J=8.7Hz5 2H); 7.30(t, J=8.7Hz, 2H); 7.04(t, J=7.2Hz, IH); 6.89(Br-s, IH); 6.87(d, J=9.0Hz, 2H); 6.85(Br-s, IH); 5.54(t, J=7.2Hz, IH); 3.81(s, 3H); 3.71(t, J=4.8Hz, 4H); 3.51(q, J=5.7Hz, 2H); 2.56(t, J=5.4Hz, 2H); 2.47(t, J=4.5Hz, 4H)。 LREI(m/z): 421(1^), 309(100)。 In addition to 6-chloro-N-p-methoxyphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine in place of 6-chloro-p-sulfonylphenyl-N ,-Phenyl-[1,3,5]-triazine-2,4-diamine, 2-(morpholine-4-substituted) ethylamine in place of the pipette, as described in Example 5, to give the title compound White powdery solid. Mp 147-148 0 C. 1 HNMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.57 (d, J = 7.2 Hz, 2H); 7.45 (d, J = 8.7 Hz 5 2H) 7.30 (t, J = 8.7 Hz, 2H); 7.04 (t, J = 7.2 Hz, IH); 6.89 (Br-s, IH); 6.87 (d, J = 9.0 Hz, 2H); 6.85 (Br- s, IH); 5.54(t, J=7.2Hz, IH); 3.81(s, 3H); 3.71(t, J=4.8Hz, 4H); 3.51(q, J=5.7Hz, 2H); 2.56(t, J=5.4Hz, 2H); 2.47(t, J=4.5 Hz, 4H). LREI (m/z): 421 (1^), 309 (100).
实施例 48 N-(2- (吗啉 -4-取代)乙基) -N，，N，，-二苯基 -[1，3，5]-三嗪 -2,4,6- 三胺 (化合物 C164)的合成 Example 48 N-(2-(morpholine-4-substituted)ethyl)-N,,N,,-diphenyl-[1,3,5]-triazine-2,4,6-triamine Synthesis of (Compound C164)
除了用 6-氯 -N，N，-二苯基 -[1,3,5]-三嗪 -2,4-二胺代替 6-氯 -N-对曱磺 酰基苯基 -N，-苯基 -[1，3，5]-三嗪 -2，4-二胺， 2- (吗啉 -4-取代）乙胺代替哌嗪 外，按实施例 5操作，得到标题化合物白色粉末状固体。 Mp 167-168 °C。 !HNMR (300Mz, CDC13， TMS) δ (ppm): 7.59(d, J=7.2Hz, 4H); 7.34(t, J=7.5Hz, 4H); 7.07(t, J=7.2Hz， 2H); 6.96(s, 2H); 5.58(t, J=6.0Hz, IH); 3.74(t， J=4.8Hz, 4H); 3.55(q， J=5.7Hz, 2H); 2.59(t， J=6.0Hz, 2H); 2.50(t, J=4.8Hz, 4H)。 LREI(m/z): 391(M")， 279(100)。 In addition to 6-chloro-N,N,-diphenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-sulfonylphenyl-N,-benzene The title compound was obtained as a white powdery solid, m. m. . Mp 167-168 °C. ! HNMR (300Mz, CDC1 3, TMS) δ (ppm): 7.59 (d, J = 7.2Hz, 4H); 7.34 (t, J = 7.5Hz, 4H); 7.07 (t, J = 7.2Hz, 2H) ; 6.96(s, 2H); 5.58(t, J=6.0Hz, IH); 3.74(t, J=4.8Hz, 4H); 3.55(q, J=5.7Hz, 2H); 2.59(t, J= 6.0 Hz, 2H); 2.50 (t, J = 4.8 Hz, 4H). LREI (m/z): 391 (M"), 279 (100).
实施例 49 N-苄基 -N，-(2- (吗啉 -4-取代）乙基) -N，，-苯基 -【1,3，5】-三嗪 -2，4，6-三胺 (化合物 C165)的合成 Example 49 N-Benzyl-N,-(2-(morpholin-4-substituted)ethyl)-N,,-phenyl-[1,3,5]-triazine-2,4,6- Synthesis of Triamine (Compound C165)
除了用 N-苄基 -6-氯 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺代替 6-氯 -N-对 曱磺酰基苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺， 2- (吗啉 -4-取代)乙胺代替 哌嗪外，按实施例 5操作，得到标题化合物粘稠油状物。 iHNMR (300Mz, CDC13, TMS) δ (ppm): 7.54(m, 2H); 7.04~7.34(m, 7H); 7.01(t, J=7.2Hz, IH); 6.87(Br-s, IH); 5.44(t, J=7.2Hz， IH); 5.38(Br-s, IH); 4.62(d, J=5.7Hz, 2H); 3.71(t, J=4.8Hz, 4H); 3.49(q, J=5.7Hz, 2H); 2.54(t, J=6.0Hz, 2H); 2.46(t, J=4.8Hz， 4H)。 In addition to N-benzyl-6-chloro-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-sulfonylphenyl-N, -Phenyl-[1,3,5]-triazine-2,4-diamine, 2-(morpholin-4-substituted)ethylamine in place of piperazine, as in Example 5 to give the title compound as thick Oily. iHNMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.54 (m, 2H); 7.04~7.34 (m, 7H); 7.01 (t, J = 7.2 Hz, IH); 6.87 (Br-s, IH) ; 5.44 (t, J = 7.2 Hz, IH); 5.38 (Br-s, IH); 4.62 (d, J = 5.7 Hz, 2H); 3.71 (t, J = 4.8 Hz, 4H); 3.49 (q, J = 5.7 Hz, 2H); 2.54 (t, J = 6.0 Hz, 2H); 2.46 (t, J = 4.8 Hz, 4H).
实施例 50 N-苄基 -6- (吗啉 -4-取代) -N，-苯基 -[1,3，5]-三嗪 -2,4-二胺 (化 合物 C166)的合成 除了用 N-苄基 -6-氯 -N，-苯基 -[1,3，5]-三嗪 -2,4-二胺代替 6-氯 -N-对 甲磺酰基苯基 -N，-苯基 -[1，3，5]-三嗪 -2,4-二胺， 吗啉代替哌嗪外， 按实 施例 5 操作， 得到标题化合物白色固体。 Mp 121-123 °C。 'HNMR (300Mz, CDC13， TMS) δ (ppm): 7.53(d, J=8.7Hz, 2H); 7.25~7.34(m, 7H); 7.01(t, J=7.2Hz, IH); 6.87(s, IH); 5.31(Br-s, IH); 4.6 l(d, J=5.7Hz, 2H);3.69~3.77 (m, 8H)。 Example 50 Synthesis of N-Benzyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5]-triazine-2,4-diamine (Compound C166) In place of N-benzyl-6-chloro-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-methylsulfonylphenyl-N, - phenyl-[1,3,5]-triazine-2,4-diamine, morpholine, m.p. Mp 121-123 °C. 'HNMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.53 (d, J=8.7Hz, 2H); 7.25~7.34(m, 7H); 7.01(t, J=7.2Hz, IH); 6.87( s, IH); 5.31 (Br-s, IH); 4.6 l (d, J = 5.7 Hz, 2H); 3.69 to 3.77 (m, 8H).
实施例 51 N-苄基 -6- (吗啉 -4-取代) -N，-对甲苯基 -〖1，3，5]-三嗪 -2,4-二胺 (化合物 C167)的合成 Example 51 Synthesis of N-benzyl-6-(morpholine-4-substituted)-N,-p-tolyl-[1,3,5]-triazine-2,4-diamine (Compound C167)
除了用 N-苄基 -6-氯 -N，-对曱苯基 -[1，3，5]-三嗪 -2，4-二胺代替 6-氯 -N-对甲磺酰基苯基 -Ν'-苯基 -[1,3,5]-三嗪 -2，4-二胺， 吗啉代替哌嗪外， 按实施例 5 操作， 得到标题化合物白色粘稠固体。 iHN R (300Μζ, DMSO-d6, TMS) δ (ppm): 7.73(d, J=7.8Hz, IH); 7.63(d, J=8.1Hz, IH); 7.22(m, 4H); 7.11(d, J=8.1Hz， IH); 6.89(t， J=7.2Hz， IH); 4.42(d, J=13.2Hz, 2H); 3.60-3.67 (m, 8H); 2.25(s, 3H)。  In addition to N-benzyl-6-chloro-N,-p-phenylene-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-methylsulfonylphenyl- The title compound was obtained as a white viscous solid, m.j.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj iHN R (300 Μζ, DMSO-d6, TMS) δ (ppm): 7.73 (d, J = 7.8 Hz, IH); 7.63 (d, J = 8.1 Hz, IH); 7.22 (m, 4H); 7.11 (d) , J = 8.1 Hz, IH); 6.89 (t, J = 7.2 Hz, IH); 4.42 (d, J = 13.2 Hz, 2H); 3.60-3.67 (m, 8H); 2.25 (s, 3H).
实施例 52 4-(4-苄胺基 -6- (吗啉 -4-取代) -〖1，3，5]-三嗪 -2- J 苯磺酰胺 (化合物 C168)的合成 Example 52 Synthesis of 4-(4-benzylamino-6-(morpholine-4-substituted)-[1,3,5]-triazine-2-J benzenesulfonamide (Compound C168)
除了用 4-(4-苄胺基 -6-氯 -[1,3,5]-三嗪 -2-氨基)苯磺酰胺代替 6-氯 对甲磺酰基苯基 -N，-苯基 -[1,3,5]-三嗪 -2，4-二胺， 吗啉代替哌嗪外， 按实施例 5操作， 得到标题化合物白色粘稠固体。 Mp 205-206 °C。 In addition to 4-(4-benzylamino-6-chloro-[1,3,5]-triazin-2-amino)benzenesulfonamide instead of 6-chloro-methanesulfonylphenyl-N,-phenyl- The title compound was obtained as a white viscous solid, m. m. Mp 205-206 °C.
'HNMR (300Mz, DMSO-d6, TMS) δ (ppm): 7.89(d, J=8.7Hz, IH); 7.75(d,'HNMR (300Mz, DMSO-d6, TMS) δ (ppm): 7.89 (d, J = 8.7 Hz, IH); 7.75 (d,
J=8.7Hz, IH); 7.63(m， 2H); 7.17~731(m, 5H); 4.46(d? J=12Hz, 2H);J=8.7Hz, IH); 7.63(m, 2H); 7.17~731(m, 5H); 4.46(d ? J=12Hz, 2H);
3.59-3.66 (m, 8H)。 实施例 53 N-苄基 -N，-对甲 苯基 -6- (吗啉 -4-取代 )-[1,3，5〗-三嗪 -2,4- 二胺 (化合物 C169)的合成 3.59-3.66 (m, 8H). Example 53 Synthesis of N-Benzyl-N,-p-tolyl-6-(morpholine-4-substituted)-[1,3,5-triazine-2,4-diamine (Compound C169)
除了用 N-苄基 -6-氯 -N，-对曱氧基苯基 -[1,3,5]-三嗪- 2,4-二胺代替 6- 氯— N_对曱磺酰基苯基-N，-苯基 _[1，3,5]-三嗪- 2,4-二胺，吗啉代替哌嗪外， 按实施例 5操作， 得到标题化合物白色固体。 Mp l52〜： 153 DC。 ^INMR (300Mz, CDC13, TMS) δ (ppm): 7.40(d, J=9.0Hz, 2H); 7.26~7.33(m, 5H); 6.83(d, J=9.0Hz, 2H); 6.75(Br-s, 1H); 5.27(Br-s， 1H); 4.59(d, J=5.7Hz, 2H);In addition to N-benzyl-6-chloro-N,-p-methoxyphenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-sulfonylbenzene The title compound was obtained as a white solid, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Mp l52~: 153 D C. ^INMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.40 (d, J = 9.0 Hz, 2H); 7.26~7.33 (m, 5H); 6.83 (d, J = 9.0 Hz, 2H); 6.75 ( Br-s, 1H); 5.27 (Br-s, 1H); 4.59 (d, J = 5.7 Hz, 2H);
3.68- 3.78 (m, 11H)。 3.68- 3.78 (m, 11H).
实施例 54 N-苄基 -N，-对氟苯基 -6- (吗啉 -4-取代) -[1，3，5]-三嗪 -2，4-二胺 (化合物 C170)的合成 Example 54 Synthesis of N-Benzyl-N,-p-fluorophenyl-6-(morpholin-4-substituted)-[1,3,5]-triazine-2,4-diamine (Compound C170)
除了用 N-苄基 -6-氯 -N，-对氟苯基 -[1,3，5]-三嗪 -2,4-二胺代替 6-氯 _N_对曱磺酰基苯基 _N，_苯基 _[1,3，5]-三嗪 -2,4-二胺， 吗啉代替哌嗪外， 按实施例 5操作， 得到标题化合物白色固体。 Mp l43〜： L44°C。 -INMR (300Mz, CDC13, TMS) δ (ppm): 7.45(m, 2H); 7.25~7.33(m, 5H); 6.96(t, J=8.7Hz, 2H); 6.78(s, 1H); 5.28(t, J=5.7Hz, 1H); 4.59(d, J=6.0Hz, 21- I);In addition to using N-benzyl-6-chloro-N,-p-fluorophenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro- N- p-sulfonylphenyl- The title compound was obtained as a white solid. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Mp l43~: L44°C. -INMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.45 (m, 2H); 7.25~7.33 (m, 5H); 6.96 (t, J = 8.7 Hz, 2H); 6.78 (s, 1H); 5.28 (t, J = 5.7 Hz, 1H); 4.59 (d, J = 6.0 Hz, 21-I);
3.69- 3.76 (m, 8H)。 3.69- 3.76 (m, 8H).
实施例 55 N，N，-二苄基 -6- (吗啉 -4-取代 )-〖1，3，5】-三嗪 -2,4-二胺 (化合物 C176)的合成 Example 55 Synthesis of N,N,-dibenzyl-6-(morpholine-4-substituted)-[1,3,5]-triazine-2,4-diamine (Compound C176)
除了用 N, N，-二苄基 -6-氯 -[1,3,5]-三 -2，4-二胺代替 6-氯 对甲 磺酰基苯基 -N，-苯基 -[1,3,5]-三嗪 -2，4-二胺， 吗啉代替哌嗪外， 按实施 例 5操作，得到标题化合物白色固体。 Mp 134~1360Co !HNMR (300Mz, CDCI3, TMS) δ (ppm): 7.23-7.3 l(m, 10H); 5.17(Br-s, 2H); 4.57(d5 J=5.7Hz, 4H); 3.66-3.73 (m, 8H)。 LREI(m/z): 376(^), 73(100)。 In addition to N, N,-dibenzyl-6-chloro-[1,3,5]-tri-2,4-diamine in place of 6-chloro-p-methylsulfonylphenyl-N,-phenyl-[1 3,5]-triazine-2,4-diamine, morpholine, m.p. Mp 134~136 0 C o ! HNMR (300Mz, CDCI3, TMS) δ (ppm): 7.23-7.3 l(m, 10H); 5.17(Br-s, 2H); 4.57(d 5 J = 5.7 Hz, 4H); 3.66-3.73 (m, 8H). LREI (m/z): 376 (^), 73 (100).
实施例 56 2- [4，6-二苯胺基 -[1，3，5]-三嗪 -2- JL】乙醇 (化合物 C177)的 合成 Example 56 Synthesis of 2-[4,6-diphenylamino-[1,3,5]-triazine-2-JL]ethanol (Compound C177)
除了用 6-氯 -N, N，-二苯基 -[1,3，5]-三嗪 -2,4-二胺代替 6-氯 -N-对曱 磺酰基苯基 -N，-苯基 -[1,3,5]-三嗪- 2,4-二胺， 2-氨基乙醇代替哌嗪外，按 实施例 5 操作， 得到标题化合物白色固体。 Mp 182~183°C。 iHNMR (300Mz, DMSO-d6, TMS) δ (ppm): 7.80(d, J=8.1Hz, 4H); 7.25(t, J=7.8Hz, 4H); 6.94(t, J=7.5Hz, 3H); 3.54(t, J=6.0Hz, 2H); 3.38(q, J=5.7Hz, 2H)。 LREI(m/z): 322(1^), 304(100)。  In addition to 6-chloro-N,N,-diphenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-sulfonylphenyl-N,-benzene The title compound was obtained as a white solid, m. m. Mp 182~183 °C. iHNMR (300Mz, DMSO-d6, TMS) δ (ppm): 7.80 (d, J = 8.1 Hz, 4H); 7.25 (t, J = 7.8 Hz, 4H); 6.94 (t, J = 7.5 Hz, 3H) ; 3.54 (t, J = 6.0 Hz, 2H); 3.38 (q, J = 5.7 Hz, 2H). LREI (m/z): 322 (1^), 304 (100).
实施例 57 2-[4-对曱氧基苯胺基 -6-苯胺基 -[1，3，5]-三嗪 -2-氨基]乙醇 (化合物 C179)的合成 Example 57 Synthesis of 2-[4-p-methoxyanilino-6-anilino-[1,3,5]-triazine-2-amino]ethanol (Compound C179)
除了用 6-氯 对曱氡基苯基 -N，-苯基 -[1,3,5]-三嗪 -2，4-二胺代替 6- 氯— N_对曱磺酰基苯基— N，-苯基 -[1,3,5〗-三嗪 -2,4-二胺， 2-氨基乙醇代替 哌嗪外， 按实施例 5操作， 得到标题化合物白色固体。 Mp l73〜174°C。 'HNMR (300Mz, CDC13， TMS) δ (ppm): 7.55(d， J=8.7Hz, 2H); 7.42(d， J=9.0Hz, 2H); 7.3 l(t, J=7.5Hz, 2H); 7.06(t， J=7.5Hz, 1H); 6.86(d, J=7.8Hz, 2H); 6.79(s， 1H); 6.70(s, 1H); 5.45(t, J=5.4Hz, 1H); 3.78~3.82(m, 51- I); 3.58(q， J=5.1Hz，2H)。 LREI(m/z): 352(ΐν )， 321(100)。 In addition to 6-chloro-p-nonylphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro- N- p-sulfonylphenyl-N The title compound was obtained as a white solid. m. m. Compound Compound Compound Compound Compound Compound Mp l73~174 °C. 'HNMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.55 (d, J = 8.7 Hz, 2H); 7.42 (d, J = 9.0 Hz, 2H); 7.3 l (t, J = 7.5 Hz, 2H 7.06(t, J=7.5Hz, 1H); 6.86(d, J=7.8Hz, 2H); 6.79(s, 1H); 6.70(s, 1H); 5.45(t, J=5.4Hz, 1H ); 3.78~3.82(m, 51-I); 3.58(q, J=5.1Hz, 2H). LREI (m/z): 352 (ΐν), 321 (100).
实施例 58 2-【4-苄胺基 -6-苯胺基 -【1，3，5]-三嗪 _2_氨基]乙醇 (化合物 C180)的合成 Synthesis of 2 _ _ triazine amino] ethanol (Compound C180) - A Example 58 2 - [4-benzyloxy-6-anilino - [1,3, 5]
除了用 N-苄基 -6-氯 -N，-苯基 -[1,3，5]-三嗪- 2，4-二胺代替 6-氯 对 曱磺酰基苯基 - N，-苯基 -[1,3，5]-三嗪 -2,4-二胺， 2-氨基乙醇代替哌嗪外， 按实施例 5操作，得到标题化合物粘稠状固体。 'HNMR (300Mz, CDC13, TMS) δ (ppm): 7.49(d, J=8.4Hz, 2H); 7.22-7.3 l(m, 7H); 7.01(t, J=7.5Hz, lH);4.56(d, J=6.0Hz， 2H); 3.73(m, 2H); 3.52(m, 2H)。 LREI(m/z): 336(]^), 305(100)。 In addition to N-benzyl-6-chloro-N,-phenyl-[1,3,5]-triazine-2,4-diamine in place of 6-chloro-p-sulfonylphenyl-N,-phenyl -[1,3,5]-triazine-2,4-diamine, 2-aminoethanol instead of piperazine The title compound was obtained as a viscous solid. 'HNMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.49 (d, J = 8.4 Hz, 2H); 7.22-7.3 l(m, 7H); 7.01 (t, J = 7.5 Hz, lH); 4.56 (d, J = 6.0 Hz, 2H); 3.73 (m, 2H); 3.52 (m, 2H). LREI(m/z): 336(]^), 305(100).
实施例 59 4,6-二 (吗啉 -4-取代) -N-苯基 -[1,3，5】-三嗪 -2-胺 (化合物 C171) 的合成 Example 59 Synthesis of 4,6-bis(morpholine-4-substituted)-N-phenyl-[1,3,5]-triazine-2-amine (Compound C171)
除了用 4,6-二氯 苯基 -[1，3,5]-三嗪 -2-胺代替 6-氯 -N-对曱磺酰基 苯基 -N，-苯基 -[1,3，5]-三嗪 -2，4-二胺， 吗啉代替哌溱外， 按实施例 5操 作，得到标题化合物白色固体。 Mp 168~170°Co lHNMR (300Mz, CDC13, TMS) δ (ppm): 7.55(d, J=10.4Hz, 2H); 7.30(t, J=9.6Hz, 2H); 7.02(t, J=10.0Hz, 1H); 6.74(s, 1H); 3.78(m, 8H); 3.73 (m, 8H)。 In addition to 4,6-dichlorophenyl-[1,3,5]-triazin-2-amine instead of 6-chloro-N-p-sulfonylphenyl-N,-phenyl-[1,3, 5)-Triazine-2,4-diamine, morpholine in EtOAc (EtOAc) Mp 168~170°Co l HNMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.55 (d, J = 10.4 Hz, 2H); 7.30 (t, J = 9.6 Hz, 2H); 7.02 (t, J =10.0 Hz, 1H); 6.74 (s, 1H); 3.78 (m, 8H); 3.73 (m, 8H).
实施例 60 4-【4，6-二 (吗啉 -4-取代 )-[1，3，5]-三嗪 ^苯磺酰胺 (化合 物 C172)的合成 Example 60 Synthesis of 4-[4,6-bis(morpholine-4-substituted)-[1,3,5]-triazinebenzenesulfonamide (Compound C172)
除了用 4-[4,6-二氯 -[1,3,5]-三嗪 -2-氨基]苯磺酰胺代替 6-氯 对甲 磺酰基苯基 -N，-苯基 -[1，3，5]-三嗪 -2，4-二胺， 吗啉代替哌嗪外， 按实施 例 5操作，得到标题化合物白色固体。 Mp 300°C以上。 'HNMR pOOMz, DMSO-d6， TMS) δ (ppm): 7.84(d， J=9.0Hz, 2H); 7.71(d， J=8.7Hz, 2H); 3.71(m, 8H); 3.64 (m, 8H)。  In addition to 4-[4,6-dichloro-[1,3,5]-triazin-2-amino]benzenesulfonamide instead of 6-chloro-p-methylsulfonylphenyl-N,-phenyl-[1, 3,5]-triazine-2,4-diamine, morpholine, m.p. Mp 300 ° C or more. 'HNMR pOOMz, DMSO-d6, TMS) δ (ppm): 7.84 (d, J = 9.0 Hz, 2H); 7.71 (d, J = 8.7 Hz, 2H); 3.71 (m, 8H); 3.64 (m, 8H).
实施例 61 N-对曱氧基苯基 -4,6-二 (吗啉 -4-取代 )-〖1，3,5]-三嗪 -2-胺 (化 合物 C173)的合成 Example 61 Synthesis of N-p-methoxyphenyl- 4,6-di(morpholine-4-substituted)-[1,3,5]-triazine-2-amine (Compound C173)
除了用 4,6-二氯 -N-对甲氧基苯基 -[1,3,5]-三嗪 -2-胺代替 6-氯- N-对 甲磺酰基苯基 -N，-苯基- [1,3，5]-三嗪- 2,4-二胺， 吗啉代替哌嗪外， 按实 施例 5操作，得到标题化合物白色固体。 Mp
Figure imgf000045_0001
pOOMz, DMSO-d6, TMS) δ (ppm): 7.55(d, J=9.0Hz， 2H); 6.84 (d, J=6.6Hz, 2H); 3.60~3.70(m, 19H)。 In addition to 4,6-dichloro-N-p-methoxyphenyl-[1,3,5]-triazin-2-amine instead of 6-chloro-N-p-methylsulfonylphenyl-N,-benzene Base-[1,3,5]-triazine-2,4-diamine, morpholine instead of piperazine The title compound was obtained as a white solid. Mp
Figure imgf000045_0001
pOOMz, DMSO-d6, TMS) δ (ppm): 7.55 (d, J = 9.0 Hz, 2H); 6.84 (d, J = 6.6 Hz, 2H); 3.60 to 3.70 (m, 19H).
实施例 62 N-对氟苯基 -4，6-二 (吗啉 -4-取代 )-[1，3，5]-三嗪 -2-胺 (化合物 C174)的合成 Example 62 Synthesis of N-p-fluorophenyl- 4,6-di(morpholine-4-substituted)-[1,3,5]-triazine-2-amine (Compound C174)
除了用 4,6-二氯- N-对氣苯基 -[1，3,5]-三嗪 -2-胺代替 6-氯 对曱磺 酰基苯基 -N，-苯基 -[1，3，5]-三嗪 -2，4-二胺， 吗啉代替哌嗪外，按实施例 5 操作， 得到标题化合物白色固体。 Mp 199〜200°C。 iHNMR (300Mz, CDC13, TMS) δ (ppm): 7.48(m, 2H); 7.01 (t， J=8.4Hz, 2H); 3.71~3.81(m, 16H)„ In addition to 4,6-dichloro-N-p-phenyl-[1,3,5]-triazin-2-amine instead of 6-chloro-p-sulfonylphenyl-N,-phenyl-[1, 3,5]-triazine-2,4-diamine, morpholine, m.p. Mp 199~200 °C. iHNMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.48 (m, 2H); 7.01 (t, J = 8.4 Hz, 2H); 3.71~3.81 (m, 16H) „
实施例 63 N-苄基 -4,6-二 (吗啉 -4-取代 )-[1，3，5]-三嗪 -2-胺 (化合物 C175) 的合成的合成 Example 63 Synthesis of N-benzyl-4,6-di(morpholine-4-substituted)-[1,3,5]-triazine-2-amine (Compound C175)
除了用 4,6-二氯 -N-苄基 -[1，3,5]-三嗪 -2-胺代替 6-氯 对甲磺酰基 苯基 -N，-苯基 -[1,3,5]-三嗪 -2，4-二胺， 吗啉代替哌嗪外， 按实施例 5搡 作，得到标题化合物白色固体。 Mp 160〜161°C。 XHNMR (300Mz, CDC13, TMS) δ (ppm): 7.36(t5 J=6.6Hz, 1H); 7.17~7.29(m, 5H); 4.40 (d, J=6.3Hz， 2H); 3.55~3.61(m, 16H)。 In addition to 4,6-dichloro-N-benzyl-[1,3,5]-triazin-2-amine instead of 6-chloro-methanesulfonylphenyl-N,-phenyl-[1,3, 5)-Triazine-2,4-diamine, morpholine, m.p. Mp 160 ~ 161 ° C. X HNMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.36 (t 5 J=6.6Hz, 1H); 7.17~7.29(m, 5H); 4.40 (d, J=6.3Hz, 2H); 3.55~ 3.61 (m, 16H).
实施例 64 4-氯 -6- (吗啉 -4-取代) -N-苯基 -[1，3，5]-三嗪 -2-胺 (化合物 C181)的合成 EXAMPLE 64 Synthesis of 4-chloro-6-(morpholine-4-substituted)-N-phenyl-[1,3,5]-triazine-2-amine (Compound C181)
除了用吗啉代替对曱磺酰基苯胺外， 按实施例 4操作， 得到标题 化合物白色固体。 Mp 198~1990Co lBNMR (300Mz, CDC13, TMS) δ (ppm): 7.53(d, J=8.1Hz, 2H); 7.37(t, J=8.1Hz, 2H); 7.26(s, 1H); 7.14(t， J=7.5Hz, IH); 3.87(m5 4H); 3.77(m, 4H)。 LREI(m/z): 291(Μζ 100)。 The title compound was obtained as a white solid, m. Mp 198~199 0 C o l BNMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.53 (d, J=8.1Hz, 2H); 7.37(t, J=8.1Hz, 2H); 7.26(s, 1H); 7.14(t, J = 7.5 Hz, IH); 3.87 (m 5 4H); 3.77 (m, 4H). LREI (m/z): 291 (Μζ 100).
实施例 65 4-[4-氯 -6- (吗啉 -4-取代 )-[1，3，5]-三嗪 -2- J^]^ 酰胺 (化合 物 C182)的合成 Example 65 Synthesis of 4-[4-chloro-6-(morpholine-4-substituted)-[1,3,5]-triazine-2-J^]^amide (Compound C182)
除了用 4-[4，6-二氯 -[1,3,5]-三嗪 -2-氨基]苯磺酰胺代替 4,6-二氯 -N- 苯基 -[1,3,5]-三嗪 -2-胺，吗啉代替对甲磺酰基苯胺外，按实施例 4操作， 得到标题化合物白色固体。 Mp 300°C以上。 ^NMR (300Mz5 DMSO-d6, TMS) δ (ppm): 7.55〜7.83(m, 4H); 3.64〜3.77(m, 8H)。 In place of 4-,4-dichloro-N-phenyl-[1,3,5] The title compound was obtained as a white solid. m. m. Mp 300 ° C or more. ^NMR (300Mz 5 DMSO-d6, TMS) δ (ppm): 7.55~7.83 (m, 4H); 3.64~3.77 (m, 8H).
实施例 66 4-氯 -N-对甲氧基苯基 -6- (吗啉 -4-取代 )-[1，3，5】-三嗪 -2-胺 (化 合物 C183)的合成 Example 66 Synthesis of 4-chloro-N-p-methoxyphenyl-6-(morpholine-4-substituted)-[1,3,5]-triazine-2-amine (Compound C183)
除了用 4, 6-二氯 -N-对甲氧基苯基 -[1,3,5]-三嗪 -2-胺代替 4,6-二氯 -N-苯基- [1，3,5]-三嗪 -2-胺， 吗啉代替对甲磺酰基苯胺外， 按实施例 4 操作， 得到标题化合物白色固体。 Mp 164〜165°C。 ifiNMR (300Mz, CDC13, TMS) δ (ppm): 7.39(d, J=9.0Hz, 2H); 7.10(s, IH); 6.90(d, J=8.7Hz, 2H); 3.72〜3.85(m， 11H)。 ' In addition to 4,6-dichloro-N-p-methoxyphenyl-[1,3,5]-triazin-2-amine instead of 4,6-dichloro-N-phenyl-[1,3, 5)-Triazin-2-amine, morpholine, m.p. Mp 164~165 °C. IfiNMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.39 (d, J = 9.0 Hz, 2H); 7.10 (s, IH); 6.90 (d, J = 8.7 Hz, 2H); 3.72~3.85 (m) , 11H). '
实施例 67 4-氯 -N-对氟苯基 -6- (吗 #-4-取代 )-[1，3，5]-三嗪 -2-胺 (化合物 C184)的合成 Example 67 Synthesis of 4-chloro-N-p-fluorophenyl-6-(? #-4-substituted)-[1,3,5]-triazine-2-amine (Compound C184)
除了用 4, 6-二氯 -N-对氟苯基 -[1,3,5]-三嗪 -2-胺代替 4,6-二氯 -N-苯 基 -[1,3,5]-三嗪 -2-胺， 吗淋代替对曱磺酰基苯胺外， 按实施例 4操作， 得到标题化合物白色固体。 Mp 234~235°C。 iH MR (300Mz, CDC13， TMS) δ (ppm): 7.42~7.47(m, 2H); 7.04(t, J=8.7Hz, 2H); 3.72~3.86(m, 8H)。 In addition to 4,6-dichloro-N-p-fluorophenyl-[1,3,5]-triazin-2-amine instead of 4,6-dichloro-N-phenyl-[1,3,5] - Triazine-2-amine, m.p. Mp 234~235 °C. iH MR (300Mz, CDC1 3 , TMS) δ (ppm): 7.42~7.47(m, 2H); 7.04(t, J=8.7Hz, 2H); 3.72~3.86(m, 8H).
实施例 68 N-苄基 -4-氯 -6- (吗啉 -4-取代 )-[1，3,5]-三嗪 -2-胺 (化合物 C185)的合成 Example 68 N-Benzyl-4-chloro-6-(morpholin-4-substituted)-[1,3,5]-triazin-2-amine (compound) Synthesis of C185)
除了用 N-苄基 -4, 6-二氯 -[1,3,5]-三嗪 -2-胺代替 4,6-二氯 苯基 -[1,3,5]-三嗪 -2-胺， 吗啉代替对甲磺酰基苯胺外， 按实施例 4操作， 得 到标题化合物白色固体。 Mp 169〜： 170°C。 1HNMR (300Mz, DMSO- d6, TMS) δ (ppm): 7.23~7.33(m， 5H) 4.45(d, J=6.3Hz, 2H); 3.56〜3.67(m， 8H)。 In addition to N-benzyl-4,6-dichloro-[1,3,5]-triazin-2-amine in place of 4,6-dichlorophenyl-[1,3,5]-triazine-2 The title compound was obtained as a white solid. m. Mp 169~: 170 °C. 1 HNMR (300Mz, DMSO- d6, TMS) δ (ppm): 7.23 ~ 7.33 (m, 5H) 4.45 (d, J = 6.3Hz, 2H); 3.56~3.67 (m, 8H).
实施例 69 2-氯 -4,6-二 (吗啉 -4-取代) -[1，3，5]-三嗪 (化合物 C188)的合成 除了用吗啉代替苯胺外， 按实施例 2操作， 得到标题化合物白色 固体。 Mp 175。C。 !HNMR (300Mz, CDC13, TMS) δ (ppm): 3.70~3.78(m, 16H)。 Example 69 Synthesis of 2-chloro-4,6-di(morpholine-4-substituted)-[1,3,5]-triazine (Compound C188) Operation was carried out as in Example 2 except that morpholine was used in place of aniline. , the title compound was obtained as a white solid. Mp 175. C. ! HNMR (300Mz, CDC1 3, TMS) δ (ppm): 3.70 ~ 3.78 (m, 16H).
实施例 70 2-甲氧基 -4，6-二 (吗啉 -4-取代 )-〖1，3，5】-三嗪 (化合物 C186)的 合成 Example 70 Synthesis of 2-methoxy-4,6-di(morpholine-4-substituted)-[1,3,5]-triazine (Compound C186)
除了用 2-氯 -4，6-二 (吗啉 -4-取代) -[1，3，5]-三嗪代替 6-氯 -N-对甲磺 酰基苯基 -N，-苯基- [1,3,5]-三嗪 -2,4-二胺， 甲醇钠代替哌嗪， 曱醇代替 丙酮外， 按实施例 5操作， 得到标题化合物白色固体。 Mp l61~162°C。 1HNMR (300Mz, CDC13, TMS) δ (ppm): 3.90(s, 3H); 3.70~3.82(m, 16H)。 实施例 71 N-苄基 -4-甲氧基 -6- (吗啉 -4-取代 )-[1，3，5]-三嗪 -2-胺 (化合物 C187)的合成 In addition to 2-chloro-4,6-di(morpholine-4-substituted)-[1,3,5]-triazine in place of 6-chloro-N-p-methylsulfonylphenyl-N,-phenyl- [1,3,5]-Triazine-2,4-diamine, sodium methoxide instead of piperazine, and decyl alcohol. Mp l61~162 °C. 1 H NMR ( 300 Mz, CDC1 3 , TMS) δ (ppm): 3.90 (s, 3H); 3.70~3.82 (m, 16H). Example 71 Synthesis of N-Benzyl-4-methoxy-6-(morpholin-4-substituted)-[1,3,5]-triazin-2-amine (Compound C187)
除了用 N-苄基 -4-氯 -6- (吗啉 -4-取代) -[1,3,5]-三嗪 -2-胺代替 6-氯 对甲磺酰基苯基 -N，-苯基 -[1，3，5]-三嗪 -2,4-二胺， 曱醇钠代替哌漆， 甲 醇代替丙酮外， 按实施例 5 操作， 得到标题化合物白色固体。 Mp 174~175。C。 iHNMR (300Mz, CDC13, TMS) δ (ppm): 7.27~7.35(m, 5H);In addition to N-benzyl-4-chloro-6-(morpholin-4-substituted)-[1,3,5]-triazin-2-amine instead of 6-chloro-methanesulfonylphenyl-N,- Phenyl-[1,3,5]-triazine-2,4-diamine, sodium decoxide was added in place of the piper paint, and methanol was used instead of acetone to give the title compound as a white solid. Mp 174~175. C. iHNMR (300Mz, CDC1 3 , TMS) δ (ppm): 7.27~7.35(m, 5H);
4.61(s, 2H); 3.67~3.90(m, 11H)。 LREI(m/z): 301(1^， 100)。 4.61(s, 2H); 3.67~3.90(m, 11H). LREI (m/z): 301 (1^, 100).
实施例 72 2，4，6-三 (吗 ~4-'取代) -[1，3，5】-三嗪 (化合物 C189)的合成 Example 72 Synthesis of 2,4,6-tris(?~4-'substituted)-[1,3,5]-triazine (Compound C189)
除了用吗淋代替苯胺外， 按实施例 2操作， 得到标题化合物白色 固体。 Mp 273°C 挥发。 (300Mz, CDC13, TMS) δ (ppm): 3.69〜3.78( n, 24H)。 The title compound was obtained as a white solid. Mp 273 ° C volatilization. (300Mz, CDC1 3 , TMS) δ (ppm): 3.69 to 3.78 (n, 24H).
实施例 73 4-甲氧基 -N-对甲氧基苯基 -6- (吗啉 -4-取代 )-【1,3，5】-三 "2- 胺 (化合物 C190)的合成 Example 73 Synthesis of 4-methoxy-N-p-methoxyphenyl-6-(morpholine-4-substituted)-[1,3,5]-tris "2-amine (Compound C190)
除了用 4-氯- N-对曱氧基苯基 -6- (吗淋 -4-取代 )-[1,3,5]-三嗪- 2-胺代 替 6-氯 -N-对曱磺酰基苯基 -N，-苯基 -[1，3，5〗-三嗪 -2,4-二胺， 甲醇钠代替 哌嗪， 曱醇代替丙酮外， 按实施例 5操作， 得到标题化合物白色固体。 Mp 164〜1650C。 !HNMR (300Mz, CDC13, TMS) δ (ppm): 7.44(d, J=9.0Hz, 2H); 6.87(d5 J=9.0Hz, 2H); 3.91(s, 3H); 3.81(m, 7H); 3.72(m, 4H)。 In addition to 4-chloro-N-p-methoxyphenyl-6-(morphine-4-substituted)-[1,3,5]-triazine-2-amine instead of 6-chloro-N-p-sulfonate Acylphenyl-N,-phenyl-[1,3,5-triazine-2,4-diamine, sodium methoxide in place of piperazine, and decyl alcohol in place of acetone, was operated as in Example 5 to give the title compound white. solid. Mp 164~165 0 C. ! HNMR (300Mz, CDC1 3, TMS) δ (ppm): 7.44 (d, J = 9.0Hz, 2H); 6.87 (d 5 J = 9.0Hz, 2H); 3.91 (s, 3H); 3.81 (m, 7H); 3.72 (m, 4H).
实施例 74 2-〖4-(4，6-二对甲 苯胺基 -〖1，3，5卜三嗪 -2-取代)哌嗪 -1- 取代]乙醇 (化合物 C191)的合成 Example 74 2-Synthesis of 4-(4,6-di-p-anilino-[1,3,5-triazine-2-substituted)piperazine-1-substituted]ethanol (Compound C191)
除了用 6-氯 -Ν,Ν，-二对曱氧基苯基 -[1,3,5]-三嗪 -2,4-二胺代替 6-氯 -Ν-对甲磺酰基苯基 -Ν，-苯基 -[1,3，5]-三嗪 -2,4_二胺， 2- (哌嗪 -1-取代）乙 醇代替哌嗪外， 按实施例 5操作， 得到标题化合物白色粉末状固体。 Mp 172-173 °C。 ]HNMR( 300Mz, CDC13, TMS ) δ (ppm): 7.44(d, J=9.3Hz, 4H); 6.86(d, J=9.0Hz, 4H); 3.84(m, 10H); 3.68(t, J=6.8Hz, 2H); 2.54~2.61(m5 6H)。 In addition to 6-chloro-indole, hydrazine, -di-p-methoxyphenyl-[1,3,5]-triazine-2,4-diamine in place of 6-chloro-indole-p-methylsulfonylphenyl- v, - phenyl - [1,3,5] - triazine - 2, 4 _ diamine, 2- (piperazin-1-substituted) ethanol instead of piperazine, the procedure described by Example 5, to give the title compound as a white Powdered solid. Mp 172-173 °C. ] HNMR (300Mz, CDC1 3, TMS) δ (ppm): 7.44 (d, J = 9.3Hz, 4H); 6.86 (d, J = 9.0Hz, 4H); 3.84 (m, 10H); 3.68 (t, J = 6.8 Hz, 2H); 2.54 to 2.61 (m 5 6H).
实施例 75 2-〖4-(4-对甲氧基苯胺基 -6-苯胺基 -〖1，3,5]-三嗪 -2-取代)哌 漆_1 -取代】乙醇 (化合物 C192)的合成 Example 75 2-[4-(4-p-methoxyanilino-6-anilino-[1,3,5]-triazine-2-substituted) piperidine Synthesis of Paint_1 - Substituted] Ethanol (Compound C192)
除了用 6-氯 -N-对甲氧基苯基 -N-苯基 -[1，3，5〗-三嗪 -2,4-二胺代替 6- 氯 _N-对甲磺酰基苯基 -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺， 2- (哌嗪 -1-取代） 乙醇代替哌嗪外， 按实施例 5 操作， 得到标题化合物粘稠油状物。 'HNMR ( 300Mz, CDC13, TMS ) δ (ppm): 7.54(d, J=8.7Hz, 2H); 7.44(d, J=6.6Hz, 2H); 7.30(t, J=8.1Hz, 2H); 7.03(t, J=7.8Hz, IH); 7.02(s, IH); 6.93(s, IH); 6.86(d, J=7.2Hz, 2H); 3.87(t, J=5.1Hz, 2H); 3.80(s, 3H); 3.69(t, J=5.7Hz, 2H) 3.00(s， 2H); 2.58~2.64(m, 6H)。 In addition to 6-chloro-N-p-methoxyphenyl-N-phenyl-[1,3,5-triazine-2,4-diamine instead of 6-chloro-N-p-methylsulfonylphenyl -N,-Phenyl-[1,3,5]-triazine-2,4-diamine, 2-(piperazin-1-substituted) ethanol in place of piperazine, operated as in Example 5 to give the title compound Viscous oil. 'HNMR (300Mz, CDC1 3 , TMS ) δ (ppm): 7.54 (d, J = 8.7 Hz, 2H); 7.44 (d, J = 6.6 Hz, 2H); 7.30 (t, J = 8.1 Hz, 2H) ; 7.03(t, J=7.8Hz, IH); 7.02(s, IH); 6.93(s, IH); 6.86(d, J=7.2Hz, 2H); 3.87(t, J=5.1Hz, 2H) 3.80(s, 3H); 3.69(t, J=5.7Hz, 2H) 3.00(s, 2H); 2.58~2.64(m, 6H).
实施例 76 2-〖4-(4，6-二苯胺基 -[1，3，5]-三嗪 -2-取代)哌嗪 -1-取代]乙醇 (化合物 C193)的合成 除了用 6-氯 -N，N，-二苯基 -[1，3,5]-三嗪 -2,4-二胺代替 6-氯 -N-对甲磺 酰基苯基— N，-苯基 -[1，3，5]-三嗪- 2,4-二胺， 2- (哌嗪 -1-取代）乙醇代替哌嗪 夕卜，按实施例 5操作，得到标题化合物白色粉末状固体。 Mp 151-152 °Co 'HNMR ( 300Mz, CDC13, TMS ) δ (ppm): 7.57(d, J=9.0Hz, 4H); 7.33(t, J=8.4Hz, 4H); 7.06(t, J=7.2Hz, 2H); 6.98(s, 2H); 3.88(t, J=5.1Hz, 4H); 3.69(t, J=7.2Hz, 2H); 2.90(s, IH); 2.56-2.63 (m, 6H)。 Example 76 2-[4-(4,6-Diphenylamino-[1,3,5]-triazine-2-substituted) piperazin-1-substituted]ethanol (Compound C193) was synthesized except 6- Chloro-N,N,-diphenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-methylsulfonylphenyl-N,-phenyl-[1 , 3,5]-triazine- 2,4-diamine, 2-(piperazin-1-substituted)ethanol, in place of piperazine. Mp 151-152 °Co 'HNMR (300Mz, CDC1 3 , TMS ) δ (ppm): 7.57 (d, J = 9.0 Hz, 4H); 7.33 (t, J = 8.4 Hz, 4H); 7.06 (t, J = 7.2 Hz, 2H); 6.98 (s, 2H); 3.88 (t, J = 5.1 Hz, 4H); 3.69 (t, J = 7.2 Hz, 2H); 2.90 (s, IH); 2.56-2.63 (m , 6H).
实施例 77 6- (吗 "4-取代) -N，N，-二苯基 -[1，3，5]-三嗪 -2,4-二胺 (化合物 C71)的合成 Example 77 Synthesis of 6-(? "4-substituted)-N,N,-diphenyl-[1,3,5]-triazine-2,4-diamine (Compound C71)
除了用 6-氯- Ν,Ν'-二苯基 -[1，3，5]-三嗪 -2,4-二胺代替 6-氯 -N-对曱磺 酰基苯基 -Ν，-苯基 -[1,3,5]-三嗪 -2,4-二胺， 吗淋代替哌嗪外， 按实施例 5 操作， 得到标题化合物白色粉末状固体。 Mp 195-197 QC。 'HNMR (400Mz, CDC13, TMS) δ (ppm): 7.55(d, J=7.8Hz, 4H); 7.32(t, J=6.8Hz, 4H); 7.05(t, J=7.8Hz, 2H); 6.88 (s, 2H); 3.82(t, J=4.8Hz, 4H); 3.75(t, J=4.8Hz, 4H)。 LREI(m/z): 348( 100 % )。 实施例 78 N-对甲！ ^苯基 -6- (吗啉 -4-取代) -N，-苯基 -[1，3，5]-三嗪 -2,4- 二胺 (化合物 C72)的合成 In addition to 6-chloro-indole, Ν'-diphenyl-[1,3,5]-triazine-2,4-diamine in place of 6-chloro-N-p-sulfonylphenyl-indole,-benzene The title compound was obtained as a white powdery solid, m. m. Mp 195-197 Q C. 'HNMR (400Mz, CDC1 3 , TMS) δ (ppm): 7.55 (d, J = 7.8 Hz, 4H); 7.32 (t, J = 6.8 Hz, 4H); 7.05 (t, J = 7.8 Hz, 2H); 6.88 (s, 2H); 3.82 (t, J = 4.8 Hz, 4H); 3.75 (t, J = 4.8 Hz, 4H). LREI (m/z): 348 (100%). Example 78 N-pair! Synthesis of phenyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5]-triazine-2,4-diamine (compound C72)
除了用 N-对甲氧基苯基 -6-氯 -N，-苯基 -[1,3，5]-三嗪 -2，4-二胺代替 6- 氯 -N-对曱磺酰基苯基 -N，-苯基 -[1,3，5]-三嗪 -2，4-二胺，吗啉代替哌嗪外， 按实施例 5操作， 得到标题化合物白色粉末状固体。 Mp 198-200 DC。 'HNMR (400MZ, CDC13, TMS) δ (ppm): 7.55(d, J=7.6Hz, 2H); 7.45(d, J=7.2Hz, 2H); 7.30(t, J=7.6Hz, 2H); 7.05(t, J=7.6Hz, IH); 6.91(s, IH); 6.88(4 J=6.8Hz, 2H); 6.81(s, IH); 3.81(m, 7H); 3.75(t, J=4.8Hz, 4H)。 LREI(m/z): 378(]^, 100 % )。 In addition to N-p-methoxyphenyl-6-chloro-N,-phenyl-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N-p-sulfonylbenzene The title compound was obtained as a white powdery solid. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Mp 198-200 D C. 'HNMR (400MZ, CDC1 3 , TMS) δ (ppm): 7.55 (d, J = 7.6 Hz, 2H); 7.45 (d, J = 7.2 Hz, 2H); 7.30 (t, J = 7.6 Hz, 2H) ; 7.05(t, J=7.6Hz, IH); 6.91(s, IH); 6.88(4 J=6.8Hz, 2H); 6.81(s, IH); 3.81(m, 7H); 3.75(t, J =4.8 Hz, 4H). LREI(m/z): 378(]^, 100 % ).
实施例 79 N-(3，4-二甲氧基)苯基 -6- (吗啉 -4-取代) -N，-苯基— [1，3，5卜三 嗪 -2,4-二胺 (化合物 C73)的合成 除了用 6-氯 -N-(3,4-二曱氧基)苯基 -N，-苯基 -[1，3,5]-三嗪 -2,4-二胺 代替 6-氯 -N-对曱磺酰基苯基 -N，-苯基 -[1,3,5]-三嗪 -2，4-二胺， 吗啉代替 哌嗪外， 按实施例 5 操作， 得到标题化合物白色粉末状固体。 Mp 132-135 。C。 1HNMR ( 400Mz, CDC13 TMS ) δ (ppm): 7.53(dd, J=7.6&0.8Hz, 2H); 7.30(t, J=7.6Hz, 2H); 7.23(s, IH); 7.04(t, J=7.2Hz, IH); 6.95(dd, J=8.4 & 2.4Hz, 2H); 6.91(s, IH); 6.82(d, J=8.4Hz, IH); 3.87(s, 3H); 3.82(m, 7H); 3.73(t5 J=5.2Hz, 4H)。 LREI(m/z): 408(1^", 100 % )0 实施例 80 4-(4-苯胺基 -6- (吗啉 -4-取代 )-[1，3，5]-三嗪 -2- J ^ 酰胺 (化合物 C74)的合成 除了用 4-(6-氯 -4-苯胺基 -[1，3,5]-三嗪 -2-氨基)苯磺酰胺代替 6-氯 -N-对甲磺酰基苯基 -N，-苯基 -[1,3，5]-三嗪 -2,4-二胺， 吗啉代替哌嗪外， 按实施例 5操作， 得到标题化合物白色粉末状固体， 产率 92%。 Mp 245-248 °Co 'ΗΝΜΙΚ 400Mz, DMCO-d6, TMS ) δ (ppm): 7.95(d, J=8.8Hz， 2H); 7.78(d, J=8.8Hz, 2H); 7.74(d， J=8.8Hz, 2H); 7.29(t, J=7.6Hz, 2H); 7.00(t, J=7.6Hz， 1H); 3.79(t, J=4.8Hz, 1H); 3.68(t， J=4.8Hz, 4H)。 LREI(m/z): 427(M+， 100 % )。 Example 79 N-(3,4-Dimethoxy)phenyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5-triazine-2,4-di synthesis of the amine (compound C73) except that 6-chloro -N- (3,4- two Yue yloxy) -N-phenyl, - phenyl - [1,3,5] - triazine - 2, 4 - two The amine was replaced by an amine instead of 6-chloro-N-p-sulfonylphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine, morpholine instead of piperazine. The title compound was obtained as a white powdery solid. Mp 132-135. C. 1 H NMR ( 400 Mz, CDC1 3 TMS ) δ (ppm): 7.53 (dd, J = 7.6 & 0.8 Hz, 2H); 7.30 (t, J = 7.6 Hz, 2H); 7.23 (s, IH); 7.04 (t , J = 7.2 Hz, IH); 6.95 (dd, J = 8.4 & 2.4 Hz, 2H); 6.91 (s, IH); 6.82 (d, J = 8.4 Hz, IH); 3.87 (s, 3H); 3.82 (m, 7H); 3.73 (t 5 J = 5.2 Hz, 4H). LREI(m/z): 408(1^", 100 % ) 0 Example 80 Synthesis of 4-(4-anilino-6-(morpholin-4-substituted)-[1,3,5]-triazine-2-J amide (Compound C74) except 4-(6 -Chloro-4-anilino-[1,3,5]-triazin-2-amino)benzenesulfonamide instead of 6-chloro-N-p-methylsulfonylphenyl-N,-phenyl-[1,3 5,-Triazine-2,4-diamine, morpholine in place of piperazine, the title compound was obtained as a white powdery solid (yield: 92%) Mp 245-248 °Co 'ΗΝΜΙΚ 400Mz, DMCO-d6, TMS) δ (ppm): 7.95 (d, J = 8.8 Hz, 2H); 7.78 (d, J = 8.8 Hz, 2H); 7.74 (d, J = 8.8 Hz, 2H); 7.29 (t , J = 7.6 Hz, 2H); 7.00 (t, J = 7.6 Hz, 1H); 3.79 (t, J = 4.8 Hz, 1H); 3.68 (t, J = 4.8 Hz, 4H). LREI (m/z): 427 (M+, 100%).
实施例 81 N-对甲硫基苯基 -6- (吗啉 -4-取代) -N，-对曱苯基 -[1，3，5]-三嗪 -2,4-二胺 (化合物 C19)的合成 除了用 6-氯 -N-对甲硫基苯基 -N，-对曱苯基 -[1,3,5]-三嗪 -2,4-二胺代 替 6-氯 -N-对曱磺酰基苯基 -N，-苯基 -[1,3，5]-三嗪 -2，4-二胺， 吗啉代替哌 嗪外， 按实施例 5 操作， 得到标题化合物白色粉末状固体。 lHNMR (300Mz, DMSO-d6， TMS) δ (ppm): 7.70(d, J=8.1Hz, 2H); 7.59(d, J=7.5Hz， 2H) 7.20(d5 J=8.7Hz， 2H); 7.07(d, J=8.4Hz, 2H); 3.64~3.73(m, 8H); 2.44(s, 3H); 2.25(s3 3H)。 LREI(m/z): 408(1^", 100)。 Example 81 N-p-Methylthiophenyl-6-(morpholin-4-substituted)-N,-p-p-phenyl-[1,3,5]-triazine-2,4-diamine (compound) The synthesis of C19) is in addition to 6-chloro-N-p-methylthiophenyl-N,-p-phenylene-[1,3,5]-triazine-2,4-diamine instead of 6-chloro-N. - sulfonylphenyl-N,-phenyl-[1,3,5]-triazine-2,4-diamine, morpholine in place of piperazine, was operated as in Example 5 to give the title compound as white powder. Solid. l HNMR (300Mz, DMSO-d6, TMS) δ (ppm): 7.70 (d, J = 8.1 Hz, 2H); 7.59 (d, J = 7.5 Hz, 2H) 7.20 (d 5 J = 8.7 Hz, 2H) ; 7.07(d, J=8.4Hz, 2H); 3.64~3.73(m, 8H); 2.44(s, 3H); 2.25(s 3 3H). LREI (m/z): 408 (1^", 100).
实施例 82 6- (吗啉 -4-取代) -N-苯基 -N，- (吡啶 -4-取代 )-[1，3，5]-三嗪 -2，4-二 胺 (化合物 C20)的合成 除了用 6-氯 -N-苯基 -N，- (吡啶 -4-取代 )-[1,3,5]-三嗪 -2,4-二胺代替 6- 氯 对甲磺酰基苯基 -N，-苯基 -[1 ,3,5]-三嗪 -2，4-二胺，吗啉代替哌嗪外， 按实施例 5 操作， 得到标题化合物粉末状固体。 iHNMR (300Mz, DMSO-d6, TMS) δ (ppm): 8.48(d, J=8.7Hz, 2H); 7.10(d, J=8.1Hz, 2H); 7.01(d， J=7.8Hz, 2H); 6.68(t， J=7.5Hz， 2H); 6.50(d, J=7.8Hz, 2H); 3.67(m， 4H); 2.92(m， 4H)。 LREI(ra/z): 349(ΐν ,扇)。 Example 82 6-(morpholine-4-substituted)-N-phenyl-N,-(pyridin-4-substituted)-[1,3,5]-triazine-2,4-di Synthesis of the amine (compound C20) except 6-chloro-N-phenyl-N,-(pyridin-4-substituted)-[1,3,5]-triazine-2,4-diamine instead of 6-chloro The title compound was obtained as a powdery solid, m. m. m. m. m. . iHNMR (300Mz, DMSO-d6, TMS) δ (ppm): 8.48 (d, J = 8.7 Hz, 2H); 7.10 (d, J = 8.1 Hz, 2H); 7.01 (d, J = 7.8 Hz, 2H) ; 6.68 (t, J = 7.5 Hz, 2H); 6.50 (d, J = 7.8 Hz, 2H); 3.67 (m, 4H); 2.92 (m, 4H). LREI (ra/z): 349 (ΐν, fan).
试验例 1 Test example 1
实验 1、 利用表面等离子共振 (Surface Plasmon Resonance, SPR) 生物传感技术 Biacore 3000研究根据本发明制备的取代 [1,3,5]三嗪类 化合物与环氧合酶 (COX-1和 COX-2)的相互作用（图 1)  Experiment 1. Using a Surface Plasmon Resonance (SPR) biosensing technique Biacore 3000 to study the substituted [1,3,5]triazines and cyclooxygenases (COX-1 and COX- prepared according to the present invention). 2) Interaction (Figure 1)
实马 方法： 采用 BIACORE3000(BIACORE AB, Uppsala, Sweden)(Amersham) , 在室温下完成化合物与环氧合酶（COX-1和 COX-2)的结合实验。 芯片 和緩冲溶液如下： CM5 芯片， EDC, NHS , 乙醇胺， HBS-EP (购自 BIACORE AB公司（Uppsala, Sweden)) 0 操作步驟： 将哌嗪三嗪类化合物用 DMSO溶解， 以 HBS-EP稀释 至相应浓度 (0.625, 1.25， 2.5, 5.0和 10.0 μΜ)， DMSO的含量为 0.4 %。 将纯化的蛋白通过氨基偶联法连接到芯片上。 用 BIACORE 3000的动 力学分析 Wizard进行动力学实验， 进行数据的收集和分析。 Real horse method: Binding experiments of compounds with cyclooxygenase (COX-1 and COX-2) were carried out at room temperature using BIACORE 3000 (BIACORE AB, Uppsala, Sweden) (Amersham). The chip and buffer solution were as follows: CM5 chip, EDC, NHS, ethanolamine, HBS-EP (purchased from BIACORE AB (Uppsala, Sweden)) 0 Procedure: Dissolve the piperazine triazine compound in DMSO and dilute with HBS-EP To the corresponding concentrations (0.625, 1.25, 2.5, 5.0 and 10.0 μΜ), the DMSO content was 0.4%. The purified protein is attached to the chip by amino coupling. The dynamics of the BIACORE 3000 kinetic analysis Wizard was used for data collection and analysis.
根据 1： 1 Langmuir binding model分析数据，得到的一系列结果如 表 1所示。  According to the 1: 1 Langmuir binding model analysis data, a series of results are shown in Table 1.
表 1、哌嗪三嗪类化合物与环氧合酶 (COX-1和 COX-2)结合的动力学常 〕/:/il£ 8si90 Table 1. Kinetics of binding of piperazine triazines to cyclooxygenase (COX-1 and COX-2) ]/:/il£ 8si90
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B71 9.2x10"4 l.l xlO"3
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B71 9.2x10" 4 ll xlO" 3
Figure imgf000054_0001
B75 2.97x10"5 2.4xl0"3 B75 2.97x10" 5 2.4xl0" 3
B81 2.39xl0"6 1.25 l0"5 B81 2.39xl0" 6 1.25 l0" 5
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B83 7.66xl0"6 1.35xlO"5
Figure imgf000054_0002
B83 7.66xl0" 6 1.35xlO" 5
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实验 2. 基于表面等离子共振生物传感技术（SPR )的 5-L0X酶作 用活性试验 (图 2)  Experiment 2. 5-L0X enzyme activity assay based on surface plasmon resonance biosensing (SPR) (Fig. 2)
样品来源： 测试化合物由上海药物研究所药物发现与设计中心 ( DDDC ) 合成实验室制备， P日性化合物 Celecoxib 和 ETYA(eicosa-5 ,8, 11 -tetraynoic acid)从 Calbiochem公司购置。 5-LOX酶， DDDC生物实验室真核系统表达制备。  Sample Source: Test compounds were prepared by the Shanghai Institute of Drug Research Center for Drug Discovery and Design (DDDC) synthesis laboratory. P-day compounds Celecoxib and ETYA (eicosa-5, 8, 11-tetraynoic acid) were purchased from Calbiochem. 5-LOX enzyme, DDDC biological laboratory eukaryotic system expression preparation.
仪器设备： Biacore S51 仪器， 瑞典 Biacore公司。  Equipment: Biacore S51 instrument, Biacore, Sweden.
实验条件： 温度： 25°C; 酶溶解緩冲液： PBS„化合物浓度 (图 2): 阳性化合物 ETYA依次为 3.125e-6; 6.25e-6; 12.5e-6; 25e-6; 50e-6 M;化 合物 B52依次为 1.6807e-6, 2.401e-6, 3.43e-6, 4.9e-6, 7.0e-6, 10.0e-6 M。  Experimental conditions: Temperature: 25 ° C; Enzyme solubilization buffer: PBS „ compound concentration (Fig. 2): The positive compound ETYA was 3.125e-6 in sequence; 6.25e-6; 12.5e-6; 25e-6; 50e- 6 M; Compound B52 was 1.6807e-6, 2.401e-6, 3.43e-6, 4.9e-6, 7.0e-6, 10.0e-6 M in sequence.
实验结果： 1. Celecoxib: 本系统未能检测到 Celecoxib能与 5-LOX ®条作用的 信息。 （未见相关文献报道 Celecoxib具有 5 - LOX酶抑制活性)。 Experimental results: 1. Celecoxib: This system failed to detect information about the role of Celecoxib with the 5-LOX ® strip. (No relevant literature reports that Celecoxib has 5-LOX enzyme inhibitory activity).
2. ETYA和化合物 B62与 5-脂氧酶的结合试验显示其解离常数分 别为： ETYA: KD = 3.4 x 10_6M; B62: KD = 5.08 x 1(T6 M (见图 2)。 ETYA的结果与文献艮道值相符。 2. The binding experiments of ETYA and compound B62 with 5-lipoxygenase showed that the dissociation constants were: ETYA: K D = 3.4 x 10 _6 M; B62: K D = 5.08 x 1 (T 6 M (see Figure 2) The results of ETYA are consistent with the literature values.
试验例 2 离体大鼠中性粒细胞释放白三浠 B4的抑制作用试验 实验试剂： II型糖原（Sigma-Aldrich Co, 10K154), 吲哚美辛  Test Example 2 Inhibition of neutrophil release of leukotriene B4 in isolated rat Experimental reagent: Type II glycogen (Sigma-Aldrich Co, 10K154), indomethacin
(Sigma-Aldrich Co, 061K1368), A23187(Sigma-Aldrich Co), L-半胱氨酸 (上海康达氨基酸厂， 批号： 20030601), 齐留通原料药（北京昭衍新药 研究中心， 纯度为 99.8%, 批号为 20020902)。 LTB4 EIA测定试剂盒 (Cayman Chemical Company, 批号为 121237)。 (Sigma-Aldrich Co, 061K1368), A23187 (Sigma-Aldrich Co), L-cysteine (Shanghai Kangda Amino Acid Factory, Batch No.: 20030601), Qiliutong API (Beijing Zhaoyan New Drug Research Center, purity is 99.8%, batch number is 20020902). LTB 4 EIA assay kit (Cayman Chemical Company, lot number 121237).
试验动物： SD大鼠， 清洁级，雌雄不拘，体重 200±20 g (市售可得）。 实验仪器： 酶标仪（Thermo, Multiskan spectrum), 恒温水浴箱等。 实验方法与数据分析：  Test animals: SD rats, clean grade, male or female, weighing 200 ± 20 g (commercially available). Experimental equipment: Thermometer, Multiskan spectrum, constant temperature water bath, etc. Experimental methods and data analysis:
1 大鼠白细胞悬液的制备  1 Preparation of rat leukocyte suspension
取正常大鼠， 0.2 %糖原 20 mL/kg进行腹腔注射 (ip), 16h后股动脉 放血处死大鼠， 每只大鼠用 Hanks平衡盐緩冲液 10 mL进行腹腔灌洗， 收集月复腔内灌洗液， 2000 r/min离心 10 min, 沉淀细胞加入冷冻蒸馏水 5 mL溶解红细胞， 1 min后立即加入等体积的 1.8%氯化钠溶液， 2000 r/min 离心 5 min， 沉淀细胞用 Hanks平衡盐緩冲液悬浮洗潦 2次。 台盼蓝排除 染色， 细胞活性>95%, Wright-Giemsa染色， 形态学观察中性粒细胞比 例>80 % , 其余为单核细胞。 2 白三錄 B4的生成 Normal rats, 0.2% glycogen 20 mL / kg for intraperitoneal injection (ip), 16h after the femoral artery bleeding excised rats, each rat with Hanks balanced salt buffer 10 mL for peritoneal lavage, collected monthly recovery The lavage fluid was centrifuged at 2000 r/min for 10 min. The precipitated cells were added to 5 mL of frozen distilled water to dissolve the red blood cells. Immediately after 1 min, an equal volume of 1.8% sodium chloride solution was added and centrifuged at 2000 r/min for 5 min to precipitate the cells. The Hanks balanced salt buffer was washed twice with 2 times. Trypan blue was excluded from staining, cell activity was >95%, Wright-Giemsa staining, morphological observation of neutrophil ratio >80%, and the rest were monocytes. 2 White three record B 4 generation
用 Hanks平衡盐緩冲液将上述收集的细胞调整到 5 X 106/mL , 按 0.5mL分装， 37。C孵育 10min， 依次加入 L-半胱氨酸（ 10mM ) , 吲哚 美辛 （lmg/L ) 以及各浓度受试化合物 （50, 5 , 0.5μΜ ) , 37。C孵育 30min后， 加入钙离子载体 A23187 ( 5μΜ ) , 37。C继续孵育 30min后， 立即于 4。C、 14000 r/min离心 5分钟， 上清保存于 -70。C备用。 反应体系 内溶媒终浓度≤0.21%。 The collected cells were adjusted to 5 X 10 6 /mL with Hanks balanced salt buffer, and dispensed in 0.5 mL, 37. C was incubated for 10 min, and L-cysteine (10 mM), indomethacin (1 mg/L) and test compounds at various concentrations (50, 5, 0.5 μΜ), 37 were added in sequence. After incubating for 30 min, the calcium ionophore A23187 (5 μΜ), 37 was added. C continued to incubate for 30 min, immediately after 4. C, centrifuge at 14000 r/min for 5 minutes, and store the supernatant at -70. C spare. The final concentration of the solvent in the reaction system is ≤ 0.21%.
3 白三烯 B4的测定 3 Determination of leukotriene B 4
根据试剂盒说明 ,将细胞提取液用商业 EIA试剂盒的緩冲液稀释后， 加入 96孔酶标板， 每个样本设两个复孔， 并重复检测两次， 4°C孵育过 夜， 次日力 p入显色剂， 避光反应 90min后于 412nm处检测吸光度， 并根 据用标准品建立的标准曲线换算检测样品中 LTB4的含量。 According to the kit instructions, the cell extract was diluted with the buffer of the commercial EIA kit, and then added to the 96-well microtiter plate. Two replicate wells were set for each sample, and the test was repeated twice, and incubated at 4 ° C overnight. The force was applied to the developer, and the absorbance was measured at 412 nm after 90 minutes in the dark, and the content of LTB 4 in the sample was measured according to the standard curve established by the standard.
4 统计学分析  4 statistical analysis
各处理样品中 LTB4的浓度以 mean土 SEM表示， 化合物对中性粒细 胞产生 1^¾4的抑制率的计算公式为： The concentration of LTB 4 in each treated sample is represented by mean SEM. The formula for calculating the inhibition rate of neutrophils to 1^ 3⁄4 4 is:
抑制率 = (溶媒管浓度 -样品管浓度 )/溶媒管浓度 xlOO%  Inhibition rate = (solvent tube concentration - sample tube concentration) / solvent tube concentration xlOO%
根据该公式， 得出不同浓度化合物对中性粒细胞产生 LTB4的抑制 率。 According to this formula, the inhibition rate of LTB 4 produced by neutrophils by different concentrations of compounds was obtained.
5 结果  5 results
5.1标准曲线的建立  5.1 Establishment of standard curve
根据标准品 的 浓度梯度建立的对数回 归 方程为 ： Y=-1.00641n(x)+3.6998 , R2=0.9823。 5.2化合物对中性粒细胞产生 LTB4的抑制 The logarithmic regression equation established from the concentration gradient of the standard is: Y = -1.00641n(x) + 3.6998, R 2 = 0.9823. 5.2 Compound inhibition of LTB 4 production by neutrophils
在中性粒细胞孵育液中加入不同浓度的化合物后， 对钙离子载体 A23187刺激下的 LTB4生成产生不同程度的抑制作用 (表 2)。 The addition of different concentrations of the compound to the neutrophil incubation solution resulted in different degrees of inhibition of LTB 4 production stimulated by the calcium ionophore A23187 (Table 2).
表 2: 钙离子载体 A23187刺激下离体大鼠中性粒细胞（5xl06/niL)的 LTB4释放量以及化合物在不同浓度的的抑制作用 （ mean士 SEM ) 化合物 LTB4浓度 ( ng/mL ) 抑制率（％) 溶剂 362.24士 87.49 Table 2: LTB 4 release from isolated rat neutrophils (5× 10 6 /niL) stimulated by calcium ionophore A23187 and inhibition of compounds at different concentrations ( mean SEM) Compound LTB 4 concentration (ng/mL) Inhibition rate (%) Solvent 362.24士87.49
B 0.5μΜ 278.83 ±34.74 1.56  B 0.5μΜ 278.83 ±34.74 1.56
5μΜ 201.36 ±37.91 43.94 5μΜ 201.36 ±37.91 43.94
50μΜ 97.41 ±21.74 72.8850μΜ 97.41 ±21.74 72.88
B62 0.5μΜ 248.07士 44.06 30.95 B62 0.5μΜ 248.07士 44.06 30.95
5μΜ 54.45 ±35.63 84.84 5μΜ 54.45 ±35.63 84.84
50μΜ 33.04 ±28.31 90.8050μΜ 33.04 ±28.31 90.80
B55 0·5μΜ 359.78 ±56.58 0.00 B55 0·5μΜ 359.78 ±56.58 0.00
5μΜ 310.90 ±71.63 13.46 5μΜ 310.90 ±71.63 13.46
50μΜ 301.82 ±0.00 15.9950μΜ 301.82 ±0.00 15.99
B68 0.5μΜ 305.40 ±80.31 14.99 B68 0.5μΜ 305.40 ±80.31 14.99
5μΜ 239.32 ± 15.42 33.38 5μΜ 239.32 ± 15.42 33.38
50μΜ 186.24 ±37.65 48.1650μΜ 186.24 ±37.65 48.16
B61 0.5μΜ 361.30 ±77.18 0.00 B61 0.5μΜ 361.30 ±77.18 0.00
5μΜ 306.35 ± 142.89 14.72 5μΜ 306.35 ± 142.89 14.72
50μΜ 286,51 ±47.24 20.25 Zileuton 0.5μΜ 170.93 ± 4.73 52.42 50μΜ 286,51 ±47.24 20.25 Zileuton 0.5μΜ 170.93 ± 4.73 52.42
5μΜ 47.25 ± 17.98 86.85 5μΜ 47.25 ± 17.98 86.85
50μΜ 40.20 ± 35.47 88.81 从表 2可见， 所测试化合物 Β, Β55, Β62, Β61，Β68, 对离体大鼠 中性粒细胞释放 LTB4有不同程度的抑制作用， 但抑制强度次于阳性对 照 Zileuton, 抑制作用较强的两个化合物为 B62, B68。 50μΜ 40.20 ± 35.47 88.81 It can be seen from Table 2 that the tested compounds Β, Β55, Β62, Β61, Β68 have different degrees of inhibition on the release of LTB 4 from neutrophils in vitro, but the inhibition intensity is inferior to the positive control Zileuton. The two compounds with strong inhibition are B62, B68.
进一步用本试险例方法测试了化合物 B62、 B68、 C72和阳性对照 Zileuton对钙离子载体 A23187刺激下离体大鼠中性粒细胞 (5 x 106/ml) 释放 LTB4的 IC5G值， 分别为 1.52μΜ, 31.12μΜ, 11.78μΜ和 0.86μΜ。 The IC 5 G value of LTB 4 released from rat neutrophils (5 x 10 6 /ml) stimulated by calcium ionophore A23187 was further tested by the test method for compounds B62, B68, C72 and the positive control Zileuton. , 1.52μΜ, 31.12μΜ, 11.78μΜ and 0.86μΜ, respectively.
试验例 3 抗炎药物筛选药效学实验 (一）  Test Example 3 Anti-inflammatory drug screening pharmacodynamics experiment (1)
实验动物：雄性健康小鼠， 体重 22-25g。  Experimental animals: male healthy mice weighing 22-25 g.
实验方法及观察指标： 实验小鼠足跖角叉菜胶致肿法  Experimental methods and observation indicators: experimental mice foot carrageenan caused by swelling
取体重 22-25g雄性健康小鼠随机分组， 每组 10只。 设阴性 (CMC 钠， 羧甲基纤维素钠水溶液)与阳性 (p引哚美辛， 5mg/kg)对照组。 受试 药物溶解于 CMC溶液中， 药品用量均为 50mg/kg。 于致炎前 30分钟 给药 (腹腔注射或灌胃）。 然后将小鼠固定在鼠架中， 拉直后肢， 用 4号 注射器向小鼠足跖注射 0.2%角叉菜胶（Can'ageenin) 20μ1。 致炎后 4小 时处死小鼠， 沿后肢关节处分别剪取左右后肢， 比较给药组、 对照組 和阳性药对照组的差异， 经统计分析分别求出平均值、 SD、 P值和抑 制百分率（见表 3 )。 Male healthy mice weighing 22-25 g were randomly divided into groups of 10 each. Negative (CMC sodium, sodium carboxymethylcellulose aqueous solution) and positive ( p -indomethacin, 5 mg/kg) control group were set. The test drug was dissolved in the CMC solution, and the amount of the drug was 50 mg/kg. Dosing (intraperitoneal injection or gavage) 30 minutes before the onset of inflammation. The mice were then fixed in a rat rack, the hind limbs were straightened, and 0.2% carrageenan (Can'ageenin) 20 μl was injected into the ankle of the mice with a 4 gauge syringe. The mice were sacrificed 4 hours after the inflammation, and the left and right hind limbs were cut along the joints of the hind limbs. The differences between the drug-administered group, the control group and the positive drug control group were compared. The mean value, SD, P value and percent inhibition were determined by statistical analysis. (See Table 3).
表 3  table 3
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B75 50 ip 35 11.65 6.13E-05 B75 50 ip 35 11.65 6.13E-05
B76 50 i 24 13.5 2.40E-03 B76 50 i 24 13.5 2.40E-03
B77 50 ip 13 13.5 6.14E-03 B77 50 ip 13 13.5 6.14E-03
B81 50 ί 35 11.4 2.00E-04 B81 50 ί 35 11.4 2.00E-04
B82 50 ip 13 9.8 17.9E-02 B82 50 ip 13 9.8 17.9E-02
B83 50 ip 0 14.7 9.80E-01 B83 50 ip 0 14.7 9.80E-01
B84 50 ip 30 10 7.00E-03 B84 50 ip 30 10 7.00E-03
B85 50 ip 27 13.6 4.50E-02 a ip:腹腔注射或灌胃； po: 口服给药。 B85 50 ip 27 13.6 4.50E-02 a ip: intraperitoneal or intragastric; po: oral administration.
从以上实验结果看出，所筛选的 28个化合物中有 25个对小鼠足 跖角叉菜胶肿胀抑制率均大于 20%, 具有较好抗炎效果； 其中化合 物 B和 B68的抑制率大于 50%, 抗炎效果显著， 因此基于该模型， 针对这两个化合物按不同剂量作了进一步的筛选， 结果见表 4。 表 4 抑制率  From the above experimental results, it was found that 25 of the 28 compounds screened had a swelling inhibition rate of more than 20% on the carrageenan of the mice, and had a good anti-inflammatory effect; wherein the inhibition rates of the compounds B and B68 were greater than 50%, the anti-inflammatory effect was significant, so based on this model, the two compounds were further screened at different doses. The results are shown in Table 4. Table 4 inhibition rate
化合物 给药量 给药途径 SD P值  Compound dosage, route of administration, SD P value
(%)  (%)
B 6.25 29 7.17 8.8E-03  B 6.25 29 7.17 8.8E-03
12.5 32 5.2 3.7E-03 ip 12.5 32 5.2 3.7E-03 ip
25 29 11.37 2.1E-02  25 29 11.37 2.1E-02
50 52 19 3.3E-05 50 52 19 3.3E-05
12.5 po 15 19.97 1.5E-01 25 19 11.72 1.4E-02 12.5 po 15 19.97 1.5E-01 25 19 11.72 1.4E-02
50 26 9.92 1E-03 50 26 9.92 1E-03
6 10 16.72 7.6E-02 6 10 16.72 7.6E-02
12.5 21 19.64 6.9E-0312.5 21 19.64 6.9E-03
B68 po B68 po
25 33 9.28 1.70E-05  25 33 9.28 1.70E-05
50 48 15.10 1.03E-06 50 48 15.10 1.03E-06
a ip:腹腔注射或灌胃； po: 口服给药。 由表 3可以看出化合物 B68的口服活性在此模型上明显优于化合物 a ip: intraperitoneal injection or intragastric administration; po: oral administration. It can be seen from Table 3 that the oral activity of Compound B68 is significantly superior to the compound in this model.
B。 试验例 4抗炎药物筛选药效学实验 (二） 实验动物：雄性 Wister大鼠，体重 150- 180g;雄性小鼠，体重 26- 30g。 实验方法及观察指标： 实验 1. 大鼠足跖角叉菜胶致肿法 取体重 150-180g雄性 Wister大鼠随机分组， 每组 10只。 设阴性 (CMC 水溶液)与阳性（吲哚美辛 3.6mg/kg)对照组。 受试药物溶解于 CMC溶液中， 15种化合物用量均为 15mg/kg。 于致炎前 60分钟灌胃 给药。 然后给大鼠左后足跖腱膜下注射 1%角叉菜胶 0.1ml, 致炎后 3 小时测量踝关节周长。 以左右关节周长之差为肿胀程度指标， 进行 t检验， 比较组间差异 的显著性。 实验 2. 小鼠耳二甲苯致炎法 取体重 26-30g雄性小鼠， 随机分组， 每组 10只。 设阴性 (CMC水 溶液)与阳性 (吲哚美辛 7.2mg/kg)对照組。 受试药物溶解于 CMC溶液 中， 3种化合物 (B61, B62, B68)用量均为 15mg/kg。 于致炎前 60分钟 灌胃给药。 然后将二曱苯 0.05ml滴于鼠右耳， 左耳作对照。 2小时后 将小鼠颈推脱臼致死， 沿耳廓基线剪下两耳， 用打孔器分别在左、 右 耳同一部位打下圆形耳片， 称重。 B. Test Example 4 Anti-inflammatory drug screening pharmacodynamics experiment (II) Experimental animals: male Wister rats, weighing 150-180 g; male mice, weighing 26-30 g. Experimental methods and observation indicators: Experiment 1. Rat foot and carrageenan-induced swelling method. Male Wister rats weighing 150-180 g were randomly divided into groups of 10 rats each. A negative (CMC aqueous solution) and a positive (indomethacin 3.6 mg/kg) control group were set. The test drug was dissolved in the CMC solution, and the amount of each of the 15 compounds was 15 mg/kg. Administered by intragastric administration 60 minutes before the onset of inflammation. Then, 0.1 ml of 1% carrageenan was injected into the left hind foot of the rat, and the circumference of the ankle joint was measured 3 hours after the inflammation. The difference between the circumference of the left and right joints was used as the index of swelling degree, and the t test was performed to compare the significance of the difference between the groups. Experiment 2. Mouse ear xylene induced inflammation Male mice weighing 26-30 g were randomly divided into groups of 10 each. A negative (CMC aqueous solution) and a positive (indomethacin 7.2 mg/kg) control group were set. The test drug was dissolved in the CMC solution, and the amounts of the three compounds (B61, B62, B68) were both 15 mg/kg. Administered by intragastric administration 60 minutes before the onset of inflammation. Then, 0.05 ml of diphenylbenzene was dropped on the right ear of the mouse, and the left ear was used as a control. After 2 hours, the mouse neck was dislocated and lethal, and the ears were cut along the baseline of the auricle. The round ears were placed in the same part of the left and right ears with a puncher and weighed.
以左右耳片重量之差为肿胀程度指标， 进行 t检验， 比较组间差异 的显著性。  Taking the difference in the weight of the left and right ears as the index of swelling degree, a t test was performed to compare the significance of the difference between the groups.
实验 3. 大鼠佐剂性关节炎 (预防原发病变）  Experiment 3. Rat adjuvant arthritis (prevention of primary lesions)
取体重 180 ± 20g雄性 SD大鼠，随机分組，每组 10只。设阴性 (CMC 水溶液)与阳性 (吲哚美辛 0.3mg/kg)对照组。受试药物溶解于 CMC溶液 中， B62大剂量 30mg/kg, 中剂量 lOmg/kg, 小剂量 3mg/kg, B68大剂 量 100mg/kg, 中剂量 50mg/kg， 小剂量 25mg/kg。 于致炎前 60分钟灌 胃给药。  Male SD rats weighing 180 ± 20 g were randomly divided into groups of 10 rats each. A negative (CMC aqueous solution) and a positive (indomethacin 0.3 mg/kg) control group were set. The test drug is dissolved in CMC solution, B62 large dose 30mg/kg, medium dose lOmg/kg, low dose 3mg/kg, B68 large dose 100mg/kg, medium dose 50mg/kg, low dose 25mg/kg. It was administered by intragastric administration 60 minutes before the onset of inflammation.
每鼠左后足跖皮内注射 Freund's完全佐剂 (FCA)O.lml致炎。 致炎 后 18小时测量左右足爪的容积。以左右足爪容积之差为肿胀程度指标， 进行 t检验， 比较组间差异的显著性。 实验结果：  Freund's complete adjuvant (FCA) O.lml was injected intradermally into the left hind paw of each rat. The volume of the left and right paws was measured 18 hours after the inflammation. The difference between the left and right paw volume was used as the index of swelling degree, and the t test was performed to compare the significance of the difference between the groups. Experimental results:
实验 1. 大鼠足跖角叉茱胶致肿法  Experiment 1. Rat foot spasm
大鼠足跖角叉菜胶致肿的肿胀程度和本发明化合物的抑制率结果 见表 5〜7。 大鼠足跖角叉菜胶致肿法实验结果 药品 肿胀程度 抑制率 阴性对照 6.10 ± 1.45 The degree of swelling of the carrageenan carrageenan and the inhibition rate of the compound of the present invention are shown in Tables 5 to 7. Rat foot carrageenan caused by swelling test results drug swelling degree inhibition rate negative control 6.10 ± 1.45
Indomethacin 3.90 ± 1.02 36.07%  Indomethacin 3.90 ± 1.02 36.07%
Celecoxib 3.90 ± 0.97 36.07%  Celecoxib 3.90 ± 0.97 36.07%
B62 4.00 ± 1.13** 34.43% B62 4.00 ± 1.13** 34.43%
B54 5.00 + 1.53 18.03%B54 5.00 + 1.53 18.03%
B53 5.70 ± 0.89 6.56%B53 5.70 ± 0.89 6.56%
B64 5.75 ± 1.80 5.74%B64 5.75 ± 1.80 5.74%
B81 6.25 ± 1.01 -2.46%B81 6.25 ± 1.01 -2.46%
B61 6.80 ± 2.14 -11.48%B61 6.80 ± 2.14 -11.48%
B68 8.35 ± 1.63 -36.89%B68 8.35 ± 1.63 -36.89%
B 4.2 ± 2.39* 31.15%B 4.2 ± 2.39* 31.15%
* p<0.05 ** p<0.01 各组与阴性对照组比较（t检验）。 以上实验结果表明阳性对照药和 B62, Celecoxib, B 均有显著的 抗炎效果。 进一步对化合物 B和化合物 B62大、 中、 小剂量組抗角叉 菜胶诱导的大鼠足跖肿胀的作用进行测定， 结果见表 5和表 6。 * p < 0.05 ** p < 0.01 Each group was compared with a negative control group (t test). The above experimental results show that the positive control drugs and B62, Celecoxib, B have significant anti-inflammatory effects. Further, the effects of compound B and compound B62 in the large, medium and low dose groups on carrageenan-induced swelling of rat ankle were measured. The results are shown in Tables 5 and 6.
表 6 化合物 B对角叉菜胶诱导的大鼠足跖肿胀的影响  Table 6 Effect of Compound B on Carrageenan-induced Ankle Swelling in Rats
药品 n 肿胀程度 抑制率 阴性对照 10 7.30 ± 2.18  Drug n swelling degree inhibition rate negative control 10 7.30 ± 2.18
阳性于照 10 3,90 ± 1.02** 46.58% lmg/kg組 10 4.20 ± 1.30** 42.47% 3mg/kg组 10 4.45 ± 1.89 39.04% lOmg/kg组 10 4.70 ± 0.95 35.62% Positive in photo 10 3,90 ± 1.02** 46.58% lmg/kg group 10 4.20 ± 1.30** 42.47% 3mg/kg group 10 4.45 ± 1.89 39.04% lOmg/kg group 10 4.70 ± 0.95 35.62%
30mg/kg组 10 4.90 ± 1.85* 32.88% 30mg/kg group 10 4.90 ± 1.85* 32.88%
* p<0.05 各组与阴性对照组比较（t检验）。 表 7 化合物 B 62对角叉菜胶诱导的大鼠足跖肿胀的影响 * p < 0.05 Each group was compared with a negative control group (t test). Table 7 Effect of compound B 62 on carrageenan-induced swelling of rat foot
Λ  Λ
药品 n A p  Drug n A p
o o 肿胀程度 抑制率  o o degree of swelling inhibition rate
o  o
阴性对照 10 7.30 ± 2.18 阳性对照 10 3.90 ± 1.02 46.58% 小剂量 (lmg/kg) 10 7.70 ± 1.27 -5.48% 小剂量 (3mg/kg) 10 4.80 ± 2.26* 34.25% 中剂量 4.05 ± 2.72** 44.52%  Negative control 10 7.30 ± 2.18 Positive control 10 3.90 ± 1.02 46.58% Small dose (lmg/kg) 10 7.70 ± 1.27 -5.48% Small dose (3mg/kg) 10 4.80 ± 2.26* 34.25% Medium dose 4.05 ± 2.72** 44.52 %
10  10
(10mg/kg) 大剂量 6.05 ± 2.19 17.12%  (10mg/kg) high dose 6.05 ± 2.19 17.12%
10  10
(30mg/kg)  (30mg/kg)
* p<0.05 各组与阴性对照组比较（t检验）。 实验 2. 小鼠耳二曱苯致炎法 小鼠耳二曱苯致炎的肿胀程度和本发明化合物的抑制率结果见表 0。 表 8 小鼠耳二甲苯致炎法实验结果 药品 肿胀程度 抑制率 阴性对照 17.80 ± 4.24 阳性对照 8.90 ± 4.09** 50.00% B62 9.40 ± 4.60** 47.19% * p < 0.05 Each group was compared with a negative control group (t test). Experiment 2. The degree of swelling of the dioxin-induced inflammation of the mouse ear diterpene-induced inflammatory method and the inhibition rate of the compound of the present invention are shown in Table 0. Table 8 Mouse ear xylene induced inflammation test results Drug swelling degree inhibition rate negative control 17.80 ± 4.24 Positive control 8.90 ± 4.09** 50.00% B62 9.40 ± 4.60** 47.19%
B61 18.80 ± 4.18 -5.62% B61 18.80 ± 4.18 -5.62%
B68 13.30 ± 5.23* 25.28% B68 13.30 ± 5.23* 25.28%
* p<0.05 ** p<0.01 各组与阴性对照组比较 ( t检验）。 以上实验结果表明阳性对照药及 B62, B68均有显著的抗炎效果。 进一步对化合物 B和化合物 B62大、 中、 小剂量组抗二曱苯诱导的小 鼠耳廓炎症的作用进行测定， 结果见表 9和表 10。 *p<0.05 ** p<0.01 Each group was compared with the negative control group (t test). The above experimental results show that the positive control drugs and B62, B68 have significant anti-inflammatory effects. Furthermore, the effects of anti-diphenylbenzene-induced auricle inflammation in the large, medium and low dose groups of Compound B and Compound B62 were determined. The results are shown in Tables 9 and 10.
化合物 B对二曱苯诱导的 ' j、鼠耳廓炎症的影响  Effect of Compound B on Diterpene-induced 'j, Auricular Inflammation of Rats
药品 n 肿胀程度 抑制率 阴性对照 10 17.80 ± 4.24 阳性对照 10 8.90 ± 4.09** 50.00% lmg/kg组 10.50 ± 41.01%  Drug n swelling degree inhibition rate negative control 10 17.80 ± 4.24 positive control 10 8.90 ± 4.09** 50.00% lmg/kg group 10.50 ± 41.01%
10  10
3.75**  3.75**
3mg/kg组 11.80 土 33.71% 3mg/kg group 11.80 soil 33.71%
10  10
4.87**  4.87**
10mg/kg组 10 12.70 ± 4.85* 28.65% 10mg/kg group 10 12.70 ± 4.85* 28.65%
30mg/kg组 10 8.40 ± 4.95** 52.81% 30mg/kg group 10 8.40 ± 4.95** 52.81%
* p<0.05 ** ρ<0.01 各组与阴性对照组比较（t检验）。 表 10 化合物 B 62对二 •甲苯诱导的小鼠耳廓炎症的影响 *p<0.05 ** ρ<0.01 Each group was compared with the negative control group (t test). Table 10 Effect of Compound B 62 on Di-Toluene-induced Auricular Inflammation in Mice
药品 η 肿胀程度 抑制率 阴性对照 10 17.80 ± 4.24 阳性对照 10 8.90 ± 4.09** 50.00% 小剂量 (lmg/kg) 10 6.40 ± 4.06 64.04% 小剂量 (3mg/kg) 10 9.50 ± 4.77** 46.63% 中剂量 5.80 ± 4.64** 67.42% Drug η swelling degree inhibition rate negative control 10 17.80 ± 4.24 positive control 10 8.90 ± 4.09** 50.00% Small dose (lmg/kg) 10 6.40 ± 4.06 64.04% small dose (3mg/kg) 10 9.50 ± 4.77** 46.63% medium dose 5.80 ± 4.64** 67.42%
10  10
(lOmg/kg) 大剂量 6.10 ± 4,41** 65.73%  (lOmg/kg) high dose 6.10 ± 4,41** 65.73%
10  10
(30mg/kg)  (30mg/kg)
* p<0.05 ** p<0.01 各组与阴性对照组比较（ t检验）。 实验 3. 大鼠佐剂性关节炎（预防原发病变） *p<0.05 ** p<0.01 Each group was compared with the negative control group (t test). Experiment 3. Rat adjuvant arthritis (prevention of primary lesions)
本发明化合物抗大鼠佐剂性关节炎的结果见表 10。  The results of the compounds of the present invention against rat adjuvant arthritis are shown in Table 10.
表 11 化合物 B 62对大鼠佐剂性关节炎原发病变的影响 药品 n 肿胀程度 抑制率 阴性对照 10 0.95 ± 0.16 阳性对照 10 0.50 ± 0.14** 47.36% 小剂量 (3mg/kg) 10 0.56 ± 0.27 40.80% 中剂量 0.45 ± 0.14** 52.96%  Table 11 Effect of Compound B 62 on primary lesions of adjuvant arthritis in rats Drug n Inhibition rate of swelling degree Negative control 10 0.95 ± 0.16 Positive control 10 0.50 ± 0.14** 47.36% Small dose (3 mg/kg) 10 0.56 ± 0.27 40.80% medium dose 0.45 ± 0.14** 52.96%
10  10
(10mg/kg) 大剂量 0.53 ± 0.16** 43.66%  (10mg/kg) high dose 0.53 ± 0.16** 43.66%
10  10
(30mg/kg)  (30mg/kg)
* p<0.05 ** p<0.01 各组与阴性对照组比较 ( t检验）。 试验例 5抗炎化合物胃肠道副作用试验 *p<0.05 ** p<0.01 Each group was compared with the negative control group (t test). Test Example 5 Anti-inflammatory compound gastrointestinal side effect test
实验目的： 用禁食大鼠口服四种化合物评价其胃损伤性质。 Experimental purposes: The properties of gastric lesions were evaluated by oral administration of four compounds in fasted rats.
实验动物： 雄性 SD大鼠 受试药物： 吲哚美辛， Celecoxib, B62, B68 实验方法及观察指标： 随机取体重 200-220g雄性 SD大鼠， 每组 10只。 设阴性与阳性对 照组。 灌胃给药， 每日一次， 连续 4天， 这期间内对食、 水都不加控 制。 最后一次给药后 24小时将动物处死， 取出胃和小肠， 沿小弯纵向 做一切口， 用流动水清洗胃和小肠， 用食指将胃翻开， 检查胃部损伤 情况并记录。 有一处或多处损伤（出血点、 糜烂、 溃 i或穿孔)即认为阳 性。 然后用福尔马林固定， 切片观察。 计算受试组动物中胃损伤动物 的百分比。 综合各结果作比较。 受试药物溶解于 0.08%CMC 溶液中， P曰性对照药吲哚美辛 3.6mg/kg, Celecoxib, B62. B68均为 30mg/kg,阴性对照组给 0.08%CMC 溶液。 胃肠道副作用实验报告各组切片情况的照片如图 3所示。 实验结果： 各受试药物引起大鼠胃损伤情况见表 1 肉眼观察大鼠胃损伤记录表 损伤情况 Experimental animals: male SD rats Test drugs: indomethacin, Celecoxib, B62, B68 Experimental methods and observation indicators: Male Sprague-Dawley rats weighing 200-220 g were randomly selected, with 10 rats in each group. Negative and positive control groups were set. Administered by gavage, once a day for 4 consecutive days, during which no control was given to food or water. The animals were sacrificed 24 hours after the last administration, and the stomach and small intestine were taken out. The mouth was made in the longitudinal direction of the small bend. The stomach and small intestine were washed with running water, and the stomach was opened with the index finger to check the stomach damage and record. One or more lesions (bleeding point, erosion, ulceration, or perforation) are considered positive. Then fixed with formalin and sliced. The percentage of animals with gastric lesions in the animals in the test group was calculated. Combine the results for comparison. The test drug was dissolved in 0.08% CMC solution, the P曰 control drug indomethacin 3.6 mg/kg, Celecoxib, B62. B68 were both 30 mg/kg, and the negative control group was given 0.08% CMC solution. A photo of the gastrointestinal side effects test report of each group of slices is shown in Figure 3. Experimental results: The gastric damage caused by the test drugs in rats is shown in Table 1. The damage of the gastric injury record in rats was observed by naked eyes.
受试药物 - 阳性率 出血点 糜烂 清病 穿孔 阴性对照组 无. 无 无 无 0% 吲哚美辛 有， 严重 无 无 无 100% Test drug - Positive rate Bleeding point Erosion Clear disease Perforation Negative control group None. None None None 0% Indomethacin Yes, Serious No No No 100%
Celecoxib 无 无 有 无 20%Celecoxib No No Yes No 20%
B62 有， 轻微 无 无 无 20%,B62 Yes, Minor No No No 20%,
B68 无 无 无 无 0% 从上表可见， Celecoxib、 B62、 B68胃肠道副作用症状比吲哚美辛 轻， 其中 B68的显示无胃肠道副作用。 B68 No no no no 0% As can be seen from the above table, Celecoxib, B62, B68 have more gastrointestinal side effects than indomethacin Light, where B68 showed no gastrointestinal side effects.
试验例 6 化合物 B和 B62细菌回复突变试驺 Test Example 6 Compound B and B62 bacterial back mutation test
实验目的： 观察 B和 B62对鼠沙门氏菌体外试验有否诱发基因突变。 配制方法： Objectives: To observe whether B and B62 induced genetic mutations in the in vitro test of Salmonella in mice. Preparation method:
实验前用 DMSO配成不同浓度的 B和 B62, 使各剂量加入相同体 积的药液。  Different concentrations of B and B62 were prepared in DMSO before the experiment, and each dose was added to the same volume of the drug solution.
对照品： Control:
阴性对照： DMSO Negative control: DMSO
阳性对照： （分无 S9代谢系统和经 S9代谢系统 ） Positive control: (no S 9 metabolic system and S 9 metabolic system)
-S9 系统： -S 9 system:
TA97: 9-aminoacridine 由 Sigma Chemical Company lnc 生产 TA98: 2-Nitroflucrene 由 Aldrich Chemical Company lnc 生产 TA100: Methyl methanesulfonate 由 Sigma Chemical Company lnc生产 TA102: Mitomycin C 由 KYOWAHAKKO KOGYO CO.LTD.生产 TA1535: Sodium azide 由 Merck 生产  TA97: 9-aminoacridine TA98 manufactured by Sigma Chemical Company lnc: 2-Nitroflucrene TA100 manufactured by Aldrich Chemical Company lnc: Methyl methanesulfonate TA102 manufactured by Sigma Chemical Company lnc: Mitomycin C TA1535 manufactured by KYOWAHAKKO KOGYO CO.LTD.: Sodium azide by Merck produce
+S9 系统： +S 9 system:
TA97, TA98， TA100: 2-aminofluorene 由 Sigma Chemical Company lnc 生产  TA97, TA98, TA100: 2-aminofluorene produced by Sigma Chemical Company lnc
TA102: 1 ,8-dihydroxyanthraquinone 由 Aldrich Chemical Company lnc 生产  TA102: 1 ,8-dihydroxyanthraquinone produced by Aldrich Chemical Company lnc
TA1535: 注射用环磷酰胺 由上海华联制药有限公司生产 试验菌株： Salmonella typhimurium 组氨酸营养缺陷突变株。 TA1535: Cyclophosphamide for injection is produced by Shanghai Hualian Pharmaceutical Co., Ltd.: Salmonella typhimurium histidine auxotrophic mutant.
TA97 TA98 TA100 TA102和 TA1535 (市售可得）。 液氮保存菌种。 遗传特性鉴定：  TA97 TA98 TA100 TA102 and TA1535 (commercially available). Liquid nitrogen preserves the strain. Genetic characterization:
鉴定内容包括： 组氨酸营养缺陷型， 脂多糖屏障缺陷 (rfa)， 紫外线 修复缺损 O uvrB, TA102 除外），以及 R -因子。 TA97 TA98、和 TA100 带有 ρΚΜΙΟΙ 质粒， 有抗氨苄青霉素作用， TA102 带有 ρΚΜΙΟΙ 和 pAQl 质粒， 有抗氨苄青霉素和四环素作用。 上述鉴定合格者， 自发 突变数符合要求的菌株， 增菌， 作为诱变实验菌株。  The identification includes: histidine auxotrophy, lipopolysaccharide barrier defect (rfa), UV repair defect O uvrB, except TA102), and R-factor. TA97 TA98, and TA100 have a ρΚΜΙΟΙ plasmid with ampicillin resistance, TA102 with ρΚΜΙΟΙ and pAQl plasmids, and ampicillin and tetracycline. Those who have passed the above-mentioned identification, the spontaneous mutation number meets the required strain, and the bacteria are added as a mutagenized experimental strain.
剂量选择： Dose selection:
在加 S9实验系统中选用 5000 1000 500 50 5 测化合物Use 5000 1000 500 50 5 to test compounds in the S 9 experimental system
Β对 5个菌株进行毒性预测。 毒性评价标准： 第一， 观察细菌生长背 景与阴性对照组相比若变稀或消失则为毒性表现。 第二， 与阴性对照 相比计数平均每 的回变数， 若回变数明显下降或呈有剂量依赖性则 为毒性表现。 毒性 Toxicity prediction of 5 strains. Toxicity evaluation criteria: First, it was observed that the bacterial growth background was toxic if it became thinner or disappeared than the negative control group. Second, the average number of regressions per count compared to the negative control is toxic if the return variable is significantly reduced or dose dependent.
代谢活化剂： Metabolic activator:
用 Aroclor 1254 诱导制备大鼠肝脏 S9 用体重约 200 克的 Sprague -Dawley 大鼠， 腹腔注射 Aroclor 1254 ( 日本制药株式会社） 500 mg/kg, 第五天处死，无菌条件下冲洗并取出肝脏， 立即用 4 C 0.15M KCl 灌洗，再按 3 ml/g 湿重的比例加入 0.15M KC1 4 C 匀浆， 9000xg 离心， 取其上清液即为 s9,液氮中保存。 在实验使用前将冷冻的 s9緩 慢融化， 每次均用新制备的 S9Mix With Aroclor 1254-induced rat liver S 9 was prepared with about 200 grams of body weight Sprague -Dawley rats, intraperitoneal injection of Aroclor 1254 (Dainippon Pharmaceutical Co., Ltd.) 500 mg / kg, the fifth day of sacrifice, the liver was removed and rinsed under sterile conditions Immediately irrigate with 4 C 0.15M KCl, then add 0.15M KC1 4 C homogenate at a ratio of 3 ml/g wet weight, centrifuge at 9000 xg, and take the supernatant as s 9 and store in liquid nitrogen. The frozen s 9 was slowly melted before the experiment, using the newly prepared S 9 Mix each time.
实验方法： 观察时间： 37。C培养 72 小时后， 进行计数。 experimental method: Observation time: 37. After C culture for 72 hours, the count was performed.
实验： 用 DMSO配制不同浓度的药液。 + S9系统剂量为 5000、 1000、 500、 50、 5 g/亚。 -S9系统剂量为 500、 50、 5、 0.5、 0.05 g/ 。 标准平板渗入法用来测药物不经代谢活化的直接作用， 其测试顶层为： Experiment: Different concentrations of the drug solution were prepared in DMSO. + S 9 system dose is 5000, 1000, 500, 50, 5 g / sub. The -S 9 system dose is 500, 50, 5, 0.5, 0.05 g / . The standard plate infiltration method is used to measure the direct effect of the drug without metabolic activation. The top of the test is:
2.0 ml 顶层  2.0 ml top layer
0.1 ml 药液  0.1 ml liquid
0.1ml 菌液  0.1ml bacterial solution
0.5 ml 磷酸緩冲液  0.5 ml phosphate buffer
预培养则用于测药物代谢活化作用的诱变作用， 其测试顶层的組成为： Pre-culture is used to measure the mutagenic effect of drug metabolism activation. The composition of the test top layer is:
2.0 ml 顶层  2.0 ml top layer
0.1 ml 药液  0.1 ml liquid
0.1 ml 菌液  0.1 ml bacterial solution
0.5 ml S9混合液 0.5 ml S 9 mixture
所测的药液、 菌液、 S9 混合液先经 25分 35。C振摇温孵后， 再按标准 平板渗入法进行实验。 每个剂量组设 3 i, 计数每个菌株在不经药物 代谢活化或经药物代 "射活化系统（- S9 or +S9 ) 的回变菌落数 X士 SD。 有效实验接受标准： The measured drug solution, bacterial solution, and S 9 mixture were subjected to 25 minutes and 35 minutes. After shaking and incubating, the experiment was carried out according to the standard plate infiltration method. Each dose group was set to 3 i, and each strain was counted in the absence of drug metabolism or by the drug-based activation system (-S 9 or +S 9 ). The number of colonies was X-SD. Effective experiment acceptance criteria:
1. 高浓度必须达到符合指导原则的标准， 或达毒性允许的浓度。  1. High concentrations must meet standards that meet the guidelines, or concentrations that are acceptable for toxicity.
2. 阳性（阴性）对照必须落在或者接近本实验室的历史背景资料的范 围之内或与文献资料相符。  2. A positive (negative) control must fall within or close to the historical background data of the laboratory or be consistent with the literature.
3. 不应混杂技术问题的污染， 过大毒性。  3. It should not be contaminated with technical problems and is too toxic.
结果评价标准： 1. 所有测试组的回复突变值小于阴性对照组 2倍， 判为阴性。 . 任何测试组的回复突变值大于阴性对照組 4倍， 且预试验和主试验 的结论相符， 则判为阳性。 Results evaluation criteria: 1. The return mutation value of all test groups was 2 times lower than that of the negative control group and was negative. The recovery mutation value of any test group was 4 times greater than that of the negative control group, and the pretest and the conclusion of the main test were consistent, and it was judged as positive.
3. 若测试组最大效应组为阴性对照 2~4倍之间， 则作进一步分析。 a)数据转换的单侧 Dunnett's检验和多重比较的 Bonterron校正后， 仍无显箸意义 (p≤ 0.05) 则可判为阴性。 b) 若统计差别显著， 应与历史阴性对照资料 98% 上限值比较， 若 小于仍可判为阴性。 大于时则可参照剂量关系和生物学意义可判为 阳性。 难于确定时则需重复。 结果和评价 3. If the maximum effect group of the test group is between 2 and 4 times the negative control, further analysis is performed. a) One-sided Dunnett's test of data conversion and Bonterron correction of multiple comparisons, which still have no significant significance (p ≤ 0.05), can be judged as negative. b) If the statistical difference is significant, it should be compared with the historical negative control data 98% upper limit, if it is less than still can be judged as negative. When it is greater than the dose, the biological relationship can be judged as positive. It is necessary to repeat when it is difficult to determine. Results and evaluation
1. 试验化合物 B和 B62最高浓度符合指导原则要求， 阴性、 阳性回复 突变率均符合本实验室的背景资料， 实验中无污染。 本实验用来评 价是有效的。 1. The highest concentrations of test compounds B and B62 meet the guidelines. The negative and positive recovery mutation rates are consistent with the background data of the laboratory, and there is no pollution in the experiment. This experiment is valid for evaluation.
2. 用标准平板渗入法测沙门氏菌回复突变结果表明：  2. Using the standard plate infiltration method to measure Salmonella back mutation results indicate:
① 化合物 B在- S9 实验系统中浓度为 50(^g/i时，对 TA97、 TA98、 TA102菌株有抑菌作用。 而当剂量为 50、 5 、 0.5、 0.05μβ/皿时 无抑菌作用， 也无致突变作用。 结果见表 13。 ① Compound B is - S 9 test system a concentration of 50 (^ g / i, of the TA97, TA98, TA102 strain inhibitory effect when a dose of 50, 5, 0.5, when 0.05μ β / dish without suppression. There was no mutagenic effect and the results are shown in Table 13.
② 化合物 Β在 + S9 实验系统中 5000、 1000 g/Jni时，对 TA97、 TA98、 TA100、 TA102、 TA1535, 5个菌株有抑菌作用。 当剂量为 500μβ/ 时， 对 ΤΑ97、 ΤΑ98、 ΤΑ102、 3个菌株有抑菌作用。 50、 5μ^ 无抑菌也无致突变作用。 结果见表 14。 2 The compound Β has a bacteriostatic effect on TA97, TA98, TA100, TA102, TA1535 and 5 strains in 5000 and 1000 g/Jni in the +S 9 experimental system. When the dose is 500μ β /, it has a bacteriostatic effect on ΤΑ97, ΤΑ98, ΤΑ102, and 3 strains. 50, 5μ^ no bacteriostatic or mutagenic effect. The results are shown in Table 14.
③ 化合物 B62在- S9与 + S9 实验系统中浓度为 500(^g/皿时， 对 TA97、 TA98、 TA 100、 TA102、 4个菌株有抑菌作用。 而当剂量 为 1000、500、 50、5 g/J^无抑菌作用。 TA1535 菌株剂量为 5000、 1000、 500、 50、 5 g/ 时无抑制细菌菌落数的生长， 也无出现致 突变作用。 结果见表 15和表 16。 3 Compound B62 has a bacteriostatic effect on TA97, TA98, TA 100, TA102, and 4 strains in the -S 9 and + S 9 experimental systems at a concentration of 500 (^g / dish). When the dose is 1000, 500, 50, 5 g / J ^ no antibacterial effect. TA1535 strain dose of 5000, 1000, 500, 50, 5 g / no inhibition of the growth of bacterial colonies, no mutagenic effects. See Table 15 and Table 16 .
综上： B和 B62在本实验条件下， 无诱变无致突变作用。 表 13. B未经 S9代谢系统作用后 对 Salmonella typhimurium 的 i秀变试驗 In summary: B and B62 have no mutagenicity and no mutagenicity under the conditions of this experiment. Table 13. B without the action of the S 9 metabolic system i show change test for Salmonella typhimurium
剂 量 菌 落和 回 变 菌 落数 Dosage and return bacteria
TA97 TA98 TA100 TA102 TA1535 TA97 TA98 TA100 TA102 TA1535
DMSO 111+10 22+2.6 132土 17 251+26 10+2.1 DMSO 111+10 22+2.6 132 soil 17 251+26 10+2.1
0.05 98+6 20+3.2 121±5 249+25 13±1.2 0.05 98+6 20+3.2 121±5 249+25 13±1.2
0.5 93±14 18+3.2 115±5 240+25 8 ± 1.2 0.5 93±14 18+3.2 115±5 240+25 8 ± 1.2
5 97+7 20±0.6 121±11 259±8 12+3.6 5 97+7 20±0.6 121±11 259±8 12+3.6
50 103±8 20+3.1 120±13 252+21 13+2.9 50 103±8 20+3.1 120±13 252+21 13+2.9
500 抑菌 抑菌 112+7 抑菌 10±1.2 阳 性 * 1141+86 1200±205 2123±19( 1971±13( 1079+ 72 500 bacteriostatic bacteriostatic 112+7 bacteriostatic 10±1.2 positive * 1141+86 1200±205 2123±19 ( 1971±13 ( 1079+ 72
* TA97, TA98, TA100: 2-aminofluorene (50 g/i) TA102: 1 ,8-dihydroxyanthraquinone (50 g/^111) TA 1535 : cyclophosphamide 200 μg/m■ 表 14.B经 S9代谢系统作用 * TA97, TA98, TA100: 2-aminofluorene (50 g/i) TA102: 1 ,8-dihydroxyanthraquinone (50 g/^ 111 ) TA 1535 : cyclophosphamide 200 μg/ m ■ Table 14.B via the S 9 metabolic system
对 Salmonella typhimurium 的豫变作用 剂 量 菌 落和 回 变 菌 落数 μβ/^ ΤΑ97 ΤΑ98 TA100 TA102 TA1535 The dosage of colonies and reverting colonies of Salmonella typhimurium is μ β /^ ΤΑ97 ΤΑ98 TA100 TA102 TA1535
DMSO 123+12 35±3.0 147+18 301+6 19土 5.0 T N2006/003428 DMSO 123+12 35±3.0 147+18 301+6 19 soil 5.0 T N2006/003428
5 135+23 31+4.7 134+9 269+20 14±4.0 5 135+23 31+4.7 134+9 269+20 14±4.0
50 130±7 31±1.2 137±9 295±9 17+3.5 50 130±7 31±1.2 137±9 295±9 17+3.5
500 抑菌 抑菌 166+40 抑菌 17± 4.0 500 antibacterial bacteriostatic 166+40 antibacterial 17± 4.0
1000 抑菌 抑菌 抑菌 抑菌 抑菌 1000 antibacterial, antibacterial, antibacterial, antibacterial, antibacterial
5000 抑菌 抑菌 抑菌 抑菌 抑菌 阳 性 * 1341±163 2052±178 1413± 161 1158±156 319± 19 5000 bacteriostatic bacteriostasis bacteriostasis bacteriostasis bacteriostasis positive * 1341±163 2052±178 1413± 161 1158±156 319± 19
* TA97: 9-aminoacridine (50 / ) * TA97: 9-aminoacridine (50 / )
TA98: 2-Nitroflucrene (20 μ^)  TA98: 2-Nitroflucrene (20 μ^)
ΤΑ100: Methyl methanesulfonate (1 μΐ/皿)  ΤΑ100: Methyl methanesulfonate (1 μΐ/dish)
TA102: Mitomycin C (0.5 μ^)  TA102: Mitomycin C (0.5 μ^)
TA1535: Sodium azide (4 μ^) 表 15.B62未经 S9代谢系统作用 TA1535: Sodium azide (4 μ^) Table 15.B62 without the action of the S 9 metabolic system
对 Salmonella typhimurium 的豫变作用 剂 量 囷 洛 和 回 变 菌 落数  The inhibitory effect of Salmonella typhimurium on the amount of sputum and the number of bacteria
TA97 TA98 TA100 TA102 TA1535TA97 TA98 TA100 TA102 TA1535
DMSO 135+7 30+8.5 140±8 307± 8 19+2.0DMSO 135+7 30+8.5 140±8 307± 8 19+2.0
5 ' 112±13 31+7.3 122+ 9 227+32 24± 3.65 ' 112±13 31+7.3 122+ 9 227+32 24± 3.6
50 127土 15 31+6.2 135+25 235士 10 20±1.050 127 soil 15 31+6.2 135+25 235 members 10 20±1.0
500 135+16 29±3.0 132土 14 214+4 18士 1.0 1000 99±11 31±3.8 135+18 248+35 16+2.0500 135+16 29±3.0 132 soil 14 214+4 18 士 1.0 1000 99±11 31±3.8 135+18 248+35 16+2.0
5000 抑菌 抑菌 抑菌 抑菌 10±4.5 阳 性 * 1141+86 1200+ 208 2123± 190 1971± 130 1079+ 725000 Antibacterial Antibacterial Antibacterial Antibacterial 10±4.5 Positive * 1141+86 1200+ 208 2123± 190 1971± 130 1079+ 72
* TA97: 9-arainoacridine (50 g/jni) * TA97: 9-arainoacridine (50 g/jni)
TA98: 2-Nitroflucrene (20 g/ )  TA98: 2-Nitroflucrene (20 g/ )
TAIOO: Methyl methanesulfonate (1 μΐ/i)  TAIOO: Methyl methanesulfonate (1 μΐ/i)
TA102: Muitomycin C (0.5 g/亚）  TA102: Muitomycin C (0.5 g/亚)
TA1535: Sodium azide (4 g/i)  TA1535: Sodium azide (4 g/i)
表 16. B62经 S9代谢系统作用后 Table 16. B62 after S 9 metabolic system
对 Salmonella typhimurium 的豫变试验  Susceptibility test of Salmonella typhimurium
剂 量 菌 落 和 回 变 菌 落数 Dosage and return bacteria
ΤΑ97 ΤΑ98 TA100 TA102 TA1535ΤΑ97 ΤΑ98 TA100 TA102 TA1535
DMSO 118+21 35+6.6 135土 14 237+ 57 7士 1.5DMSO 118+21 35+6.6 135 soil 14 237+ 57 7 people 1.5
5 124±21 29+5.3 116+ 10 239+12 7士 1.05 124±21 29+5.3 116+ 10 239+12 7士 1.0
50 119±12 35±8，7 120±14 231± 7 10± 3.250 119±12 35±8,7 120±14 231± 7 10± 3.2
500 108±19 36± 3.6 124± 9 218土 24 17+ 4.4500 108±19 36± 3.6 124± 9 218 soil 24 17+ 4.4
1000 117+11 40± 3.6 132土 14 222+15 15± 3.51000 117+11 40± 3.6 132 soil 14 222+15 15± 3.5
5000 抑菌 抑菌 抑菌 抑菌 10± 3.5 阳 性 * 1341+16： 2052±17： 1413+16 1158±15ι 319土 19 5000 Antibacterial Antibacterial Antibacterial Antibacterial 10± 3.5 Positive * 1341+16: 2052±17: 1413+16 1158±15ι 319 soil 19
* ΤΑ97, ΤΑ98, TA100: 2-aminofluorene (50 μ^) TA102: 1 ,8-dihydroxyanthraquinone (50 g/皿) TA1535: Cyclophosphamide 200 * ΤΑ97, ΤΑ98, TA100: 2-aminofluorene (50 μ^) TA102: 1 ,8-dihydroxyanthraquinone (50 g/dish) TA1535: Cyclophosphamide 200
试验例 7 化合物 B62和 Β68小鼠骨髓微核试验 Test Example 7 Bone marrow micronucleus test of compound B62 and Β68 mice
试验目的： Test purposes:
测试 Β62和 Β68对小鼠整体给药是否导致小鼠骨髓嗜多染红细胞 染色体的损伤。  It was tested whether the overall administration of Β62 and Β68 to mice resulted in damage to the chromosome of the mouse bone marrow polychromatic erythrocytes.
对照品 Reference substance
溶剂对照： 0.5%羧曱基纤维素钠。  Solvent control: 0.5% sodium carboxymethyl cellulose.
阳性对照品： 环磷酰胺（上海华联制药有限公司产品）。  Positive control: cyclophosphamide (product of Shanghai Hualian Pharmaceutical Co., Ltd.).
动物 Animal
ICR种小鼠 90只 （？45 , $ 45 )由中国科学院上海实 -臉动物中心 提供， 合格证： 实验动物质量合格证许可证号 SCXK (沪) 2002-0010。 小鼠经三天在中科院上海药物研究所动物房适应性饲养， 给药时体重 为 18〜22克， 按体重随机分组， 供试品 14只 （ ？ 7只， δ 7只）为一 剂量组， 对照组每组 10只 （ ？ 5只， $ 5只）。 饲料购自中英合资西普 尔- 必凯实验动物有限公司。 自由取水， 饲养温度为 23±2。C, 湿度为 60±10%。  90 ICR mice (?45, $45) were provided by the Shanghai Real-face Animal Center of the Chinese Academy of Sciences, and the certificate of conformity: Laboratory Animal Quality Certificate No. SCXK (Shanghai) 2002-0010. The mice were adaptively reared in the animal room of Shanghai Institute of Materia Medica, Chinese Academy of Sciences for three days. The body weight was 18~22 grams, and they were randomly divided into groups according to their body weight. 14 samples (?7, δ7) were used as one dose group. The control group consisted of 10 rats (? 5, $ 5). The feed was purchased from Sino-British joint venture Sipper - Bikai Experimental Animals Co., Ltd. Free water intake, feeding temperature is 23 ± 2. C, humidity is 60±10%.
剂量 Dose
1. B62剂量选择试验  1. B62 dose selection test
选剂量为 2000、 1000、 500、 250、 125 mg/kg 5个剂量組， 每組 14只， 雌雄各半， 连续 2天， 每天 1次灌胃给药， 记录观察动物死亡 情况， 结果高剂量 2000 mg/kg组给药后小鼠未出现死亡 (表 1)。 The selected doses are 2000, 1000, 500, 250, 125 mg/kg 5 dose groups, each group Fourteen, male and female, were administered intragastrically once a day for two consecutive days, and the death of the animals was recorded. As a result, the mice did not die after administration of the high dose of 2000 mg/kg (Table 1).
由表可见， 小鼠 LD50大于 2000 mg/kg。  As can be seen from the table, the mouse LD50 is greater than 2000 mg/kg.
B62剂量选择试验表  B62 dose selection test table
剂量 动物数 动物死亡数 Dosage number of animals
( mg/kg ) (n) (n) ( mg/kg ) (n) (n)
125 14 0 125 14 0
250 14 0250 14 0
500 14 0500 14 0
1000 14 01000 14 0
2000 14 0 2000 14 0
2. B68剂量选择试验 2. B68 dose selection test
选剂量为 2000、 1000、 500、 250、 125 mg/kg 5个剂量组， 每組 The selected doses are 2000, 1000, 500, 250, 125 mg/kg 5 dose groups, each group
14只， 雌雄各半， 连续 2天， 每天 1次灌胃给药， 记录观察动物死亡 情况， 实验结果见下表 1。 Fourteen, male and female, were administered intragastrically once a day for 2 consecutive days, and the death of the animals was recorded. The results are shown in Table 1 below.
由表可见， 小鼠 LD50约为 1000 mg/kg。  As can be seen from the table, the mouse LD50 is approximately 1000 mg/kg.
B68剂量选择试验表  B68 dose selection test table
剂量 动物数 动物死亡数 Dosage number of animals
( mg/kg ) (n) (n) ( mg/kg ) (n) (n)
125 14 0 125 14 0
250 14 0 500 14 3 250 14 0 500 14 3
1000 14 7 1000 14 7
2000 14 8 实验剂量 2000 14 8 Experimental dose
本实验小鼠灌胃 B62最高剂量选为 2000 mg/kg, 另设 1000、 500 mg/kg 3个剂量組和 1个溶剂对照组、 1个阳性对照组。  In this experiment, the highest dose of B62 was selected as 2000 mg/kg, and another 1000, 500 mg/kg dose group, one solvent control group and one positive control group.
本实验小鼠灌胃 B68最高剂量选为 500 mg/kg, 另设 250、 125 mg/kg共 3个剂量  In this experiment, the highest dose of B68 was selected as 500 mg/kg, and another 250 doses of 250 and 125 mg/kg were administered.
剂距： 以最高剂量 0.5 倍递减。 Agent distance: 0.5 times the highest dose.
给药次数： 每天一次， 连续 2天。 Number of doses: once a day for 2 consecutive days.
给药体积： 0.2 ml/10 g。 . Dosing volume: 0.2 ml/10 g. .
给药途径： 灌胃。 Route of administration: gavage.
实验方法 experimental method
① 给药方法：  1 Method of administration:
按 ICH 的技术要求， 两次或多次给受试物可在末次给药后 12~24h间选一个时间点采样分析。 小鼠灌胃 B62： 2000、 1000、 500 mg/kg/day和阴性对照组连续给药 2天； B68: 500、 250、 125 mg/kg/day和阴性对照组连续给药 2天。 阳性对照组一次 腹腔注射（60mg/kg )， 于末次给药后 24h取样。  According to the technical requirements of ICH, the test substance can be sampled two or more times at a time point between 12 and 24 hours after the last administration. Mice were intragastrically administered B62: 2000, 1000, 500 mg/kg/day and the negative control group for 2 days; B68: 500, 250, 125 mg/kg/day and the negative control group were administered continuously for 2 days. The positive control group was intraperitoneally injected (60 mg/kg) and sampled 24 hours after the last administration.
② 不同剂量对微核形成的影响：  2 The effect of different doses on micronucleus formation:
B62: 2000、 1000、 500 mg/kg 3个剂量灌胃后 24h, 取样镜 检； B62: 2000, 1000, 500 mg/kg 3 doses 24 hours after gavage, sampling mirror Inspection
B68: 500、 250、 125 mg/kg 3个剂量灌胃后 24h,取样镜检。 标本制作  B68: 500, 250, 125 mg/kg 3 doses 24 hours after gavage, sampling microscopy. Specimen production
动物脱臼处死后， 取出双侧股骨， 用灭活小牛血清冲洗、 离心、 分散细胞涂片， 晾干并经曱醇固定 Giemsa染色、 镜检。  After the animal was dislocated, the bilateral femurs were removed, washed with inactivated calf serum, centrifuged, dispersed cell smears, air-dried and fixed by Giemsa staining and microscopic examination.
镜检方法 Microscopic examination method
每张涂片至少观察记录 2000 个分散良好， 形态完整的嗜多染红 细胞（ PCE )及带有微核的 PCE ( MNPCE ), 同时记录 PCE和正染的 红细胞 (NCE)，两者之和为 1000 个以上， 并求出 PCE/NCE 的比率， 以 观察药物是否有抑制骨髓细胞作用。  At least 2000 well-distributed, well-formed polychromatic red blood cells (PCE) and PCE (MNPCE) with micronuclei were recorded for each smear, and PCE and positively stained red blood cells (NCE) were recorded. The sum of the two was 1000. More than one, and the ratio of PCE/NCE was determined to see if the drug inhibited the action of bone marrow cells.
数据分析 data analysis
有效试验接受标准  Effective test acceptance criteria
1. 小鼠所用的剂量必须达到符合指导原则的标准。 最高剂量若无 严重的体症或严重骨髓毒性， 最高剂量必须大于 1/2 LD50。1. The dose used in mice must meet the criteria in accordance with the guidelines. The highest dose must be greater than 1/2 LD 50 if there is no serious physical illness or severe bone marrow toxicity.
2. 阳性和阴性对照品所引起的小鼠骨髓嗜多染红细胞的微核率必 须落在或者接近本试验室的历史背景资料的范围之内或与文献 资料相符。 2. The micronucleus rate of mouse bone marrow polychromatic erythrocytes caused by positive and negative controls must fall within or close to the historical background data of this laboratory or be consistent with the literature.
3. 给药组 PCE/NCE 比率在合适的范围， 无明显的骨髓细胞毒性 作用。  3. The PCE/NCE ratio in the drug-administered group was in the appropriate range and there was no obvious bone marrow cytotoxicity.
评价标准 evaluation standard
1. 所有剂量组受试物的 核率与阴性对照组微核率相似， 或不超 过 2倍， 则可判为阴性。 2. 受试物所诱发的任何一组鼓核率的增加超过阴性对照组的 4倍 则判为阳性。 1. The nuclear rate of the test substance in all dose groups is similar to the micronucleus rate of the negative control group, or not more than 2 times, it can be judged as negative. 2. Any increase in the nucleus rate of the nucleus induced by the test substance was 4 times higher than that of the negative control group.
3. 若受试物最大效应組为阴性对照 2~4倍之间， 则作进一步的统 计分析。  3. If the maximum effect group of the test substance is between 2 and 4 times the negative control, further statistical analysis is performed.
a. 数据转换的单侧 Dunnett's检验和多重比较的 Bonferrom校 正后， 仍无显著意义（p < 0.05 ), 则可判为阴性。  a. One-sided Dunnett's test of data conversion and Bonferrom correction for multiple comparisons were still not significant (p < 0.05) and were considered negative.
b. 若统计差别显著， 应与历史阴性对照资料 95 %上限值比较， 若小于仍可判为阴性。 大于时则要参照剂量关系， 微核率随剂 量增加， 统计差别显箸则判为阳性。 b. If the statistical difference is significant, it should be compared with the historical negative control data 95% upper limit, if it is less than still can be judged as negative. When it is greater than the dose relationship, the micronucleus rate increases with the dose, and the statistical difference is judged to be positive.
结果  Result
1.本实验所用剂量， 符合指导原则要求。 给药组与对照組 PCE/NCE 比率， 无明显差异， 表明灌胃 B62和 B68: 24h对骨髓细胞未见抑制作用。 阴性对照结果在本实验 室的历史背景资料的范围内。 阳性对照品环磷酰胺引起 微核率明显增加。 故本实验用于诱变微核率评价是合适 的。  1. The dosage used in this experiment meets the guidelines. There was no significant difference in the ratio of PCE/NCE between the drug-administered group and the control group, indicating that B62 and B68: 24h were not inhibited by bone marrow cells. Negative control results are within the historical background data of this laboratory. The positive control cyclophosphamide caused a significant increase in the micronucleus rate. Therefore, this experiment is suitable for the evaluation of mutagenic micronucleus rate.
2.小鼠连续 2天灌胃 B62, 在末次给药后 24h 时间点上取 样测 2000、 1000、 500mg/kg/day 3 个剂量组微核率与 阴性对照组相似， 无明显差异， 结果列于表 17。  2. The mice were intragastrically administered with B62 for 2 consecutive days. The micronucleus rate of the 2000, 1000, and 500 mg/kg/day dose groups was similar to the negative control group at 24 h after the last administration. There was no significant difference. In Table 17.
3.小鼠连续 2次灌胃 B68, 在末次给药后 24h 时间点上取 样测 125、 250、 500 mg/kg/day 3个剂量组微核率与阴 性对照組相似， 无明显差异， 结果列于表 18。 3. The mice were intragastrically administered B68 twice, at the time point of 24 h after the last administration. The micronucleus rate of the three dose groups of 125, 250, and 500 mg/kg/day was similar to that of the negative control group, and there was no significant difference. The results are shown in Table 18.
表 17. 灌胃 B62 24h对 ICR小鼠骨髓嗜多染  Table 17. B62 24h on ICR mice bone marrow polychromatic
红细胞（PCE)微核形成的影响  The effect of red blood cell (PCE) micronucleus formation
药物 剂量 动物数 镜检 PCE数 MNPCE 副 PCE/PCE PCE/ NCE  Drug Dose Number of animals Microscopic examination PCE number MNPCE Sub PCE/PCE PCE/ NCE
(mg/kg) (只） x+SD %o x+SD (mg/kg) (only) x+SD %o x+SD
CMC 10 20271 33 1.63±0.84 1.18±0.24 CMC 10 20271 33 1.63±0.84 1.18±0.24
B62 500 10 20238 40 1.98±1.06 1.01±0.20 B62 500 10 20238 40 1.98±1.06 1.01±0.20
1000 10 20171 54 2.68±0.84 0.95±0.12 1000 10 20171 54 2.68±0.84 0.95±0.12
2000 10 20216 61 3.02±0.96 1.04±0.13 2000 10 20216 61 3.02±0.96 1.04±0.13
环磷酰胺 60 10 20278 1073 52.96土 19.87 + 1.07±0.19 Cyclophosphamide 60 10 20278 1073 52.96 soil 19.87 + 1.07±0.19
表 18. 灌胃 B68 24h对 ICR小鼠骨髓嗜多染 Table 18. B68 24h to ICR mice bone marrow polychromatic
红细胞（PCE)微核形成的影响  The effect of red blood cell (PCE) micronucleus formation
药物 剂量 动物数 镜检 PCE数 M PCE MNPCE/PCE PCE/ NCE  Drug Dose Number of animals Microscopic examination PCE number M PCE MNPCE/PCE PCE/ NCE
(mg/kg) (只） x±SD %o x±SD (mg/kg) (only) x±SD %o x±SD
CMC 10 20271 33 1.63±0.84 1.18±0·24 CMC 10 20271 33 1.63±0.84 1.18±0·24
B68 125 10 20213 46 2.28±0.94 1.08士 0.25 B68 125 10 20213 46 2.28±0.94 1.08 士 0.25
250 10 20258 48 2.37±1.70 1.03±0.18 250 10 20258 48 2.37±1.70 1.03±0.18
500 10 20213 46 2.27±1.09 1.13±0.52 环磷酰胺 60 10 20278 1073 52.96±19.87 1.07±0.19 500 10 20213 46 2.27±1.09 1.13±0.52 Cyclophosphamide 60 10 20278 1073 52.96±19.87 1.07±0.19
综上可得结论： Β62和 Β68在本实验条件下在小鼠骨髓微 核实验上不增加微核形成率。 试验例 8 化合物 Β诱发培养哺乳动物细胞染色体畸变试验 实验目的 以染色体畸变为指标， 观察化合物 Β 体外试验有否引起 CHL 细胞染色体的损伤。 配制方法： In summary, Β62 and Β68 did not increase micronuclei formation rate in mouse bone marrow micronucleus experiments under the experimental conditions. Test Example 8 Compound Β Inducing Chromosomal Aberration in Cultured Mammalian Cells The purpose of the experiment was to observe the chromosomal aberration and to observe whether the compound Β caused damage to the chromosome of CHL cells in vitro. Preparation method:
受试物加少量 DMSO,再加 1640培养液。 使各剂量組培养 液体积相同。  Add a small amount of DMSO to the test substance and add 1640 medium. The culture medium was the same volume for each dose group.
对照品： Control:
阳性对照： 丝裂酶素0 (日本 Kyowa公司产品）作为（ -S9 ) 实验对照品。 Positive control: mitogenin 0 (product of Kyowa Co., Japan) as (-S 9 ) experimental reference.
环磷酰胺（上海第十二制药产品）作为代谢活化系统对照 口  Cyclophosphamide (Shanghai Twelfth Pharmaceutical Product) as a metabolic activation system
阴性对照： 1640培养液  Negative control: 1640 medium
细胞 Cell
CHL 细胞作为试验 B对染色体影响的耙细胞。 CHL 细胞 由上海药品检验所引进， 支原体检查阴性。  CHL cells serve as sputum cells for the effect of B on chromosomes. CHL cells were introduced by the Shanghai Institute of Drug Control and the mycoplasma test was negative.
培养基 Medium
RPMI1640( GIBCO产品）细胞加 15% 小牛血清置于 37。C, 5% C02培养箱作单层细胞培养。 RPMI1640 (GIBCO product) cells plus 15% calf serum were placed at 37. C, 5% C0 2 incubator for monolayer cell culture.
剂量 Dose
测出 IC5Q值为 1.82 μδ/ΐΏΐ , 作为最高剂量依次对倍稀释， 最终浓度为 1.82、 0.91、 0.455 g/ml三个剂量组。 The IC 5Q value was measured to be 1.82 μ δ /ΐΏΐ, which was diluted as the highest dose, and the final concentration was 1.82, 0.91, 0.455 g/ml.
代谢活化剂 Metabolic activator
用 Aroclor 1254诱导制备大鼠肝脏 S9 。 体重约 200克的 Sprague-Dawley 大鼠， ip Aroclor 1254 (日本制药株式会社） 500 mg/kg , 第 5天处死， 无菌条件下冲洗并取出肝脏， 立 即用 4。C 0.15M KC1灌洗， 再按 3 ml/g 湿重比例加入 4。C 0.15M KC1 匀浆， 9000xg 离心， 取其上清液既为 S9。 另在 沙门氏菌 TA97上检查 S9生物活性。 Preparation of rat liver S 9 1254 induced by Aroclor. Sprague-Dawley rats weighing approximately 200 g, ip Aroclor 1254 (Nippon Pharmaceutical Co., Ltd.) 500 mg/kg, sacrificed on day 5, rinsed under sterile conditions, and the liver was removed. Use 4 immediately. C 0.15M KC1 was irrigated, and then added to the ratio of 3 ml/g wet weight. C 0.15M KC1 homogenate, centrifuged at 9000 xg, and the supernatant was taken as S 9 . S 9 biological activity was also examined on Salmonella TA97.
药物作用时间 Drug action time
非代谢活化实验药物与细胞直接作用 24h。  Non-metabolic activation of the experimental drug directly with the cells for 24h.
代谢活化实验为 6h后换新鲜培养液继续培养至 24h。  The metabolic activation experiment was continued for 6 h after changing to fresh medium for 24 h.
标本制作时间 Specimen production time
非代谢活化组及代谢活化组 24h 收获细胞， 制作标本。 实验  The non-metabolic activation group and the metabolic activation group were harvested for 24 hours to prepare specimens. Experiment
1. IC50 测定 IC 50 determination
在 25 ml培养瓶中接种约 lxlO5 细胞， 经 24 h培养， 加入 测试品，使最终浓度为 31.25、 15.6、 7.8、 3.9、 1.95、 0.98 g/ml 6个浓度。 继续培养至 48h。 弃去培养液， 经消化后， 打均 匀细胞，并计数，用 Logit法测得受试物 B的 IC5Q值为 1.82 g/ml。 About 1× 10 5 cells were inoculated in a 25 ml culture flask, cultured for 24 hours, and the test articles were added to give final concentrations of 31.25, 15.6, 7.8, 3.9, 1.95, and 0.98 g/ml. Continue to culture for 48 hours. The culture solution was discarded, and after digestion, the cells were evenly counted and counted, and the IC 5Q value of the test substance B was measured by Logit method to be 1.82 g/ml.
2. 染色体畔变试脸  2. Chromosome test face
接种 CHL 细胞， 每瓶约含细胞 lxlO5 37 。C培养 24h后加 入受试物溶液，使在培养液中最终浓度：为 1.82、 0.91、 0.455 g/ml。 各三个剂量组和阴性对照组， 阳性对照組。 非代谢 活化於 24h 收集细胞。代谢活化组除了加药液外， 再加 0.1 ml S9混合液， 同样亦测 3个剂量组和阴性、 阳性对照组。 培养 6h后换新鲜培养液， 继续培养至 24h 收集细胞。 色体制备 Inoculate CHL cells, each containing approximately 1xlO 5 37 cells. After the culture for 24 hours, the test substance solution was added so that the final concentration in the culture solution was 1.82, 0.91, and 0.455 g/ml. Each of the three dose groups and the negative control group, the positive control group. Non-metabolic activation was performed at 24 h to collect cells. In the metabolic activation group, in addition to the drug solution, 0.1 ml of S 9 mixture was added, and three dose groups and a negative and positive control group were also measured. After 6 hours of culture, the fresh medium was changed, and the cells were further cultured until 24 hours to collect the cells. Color body preparation
收集细胞前 3h加秋水仙碱 ( Colchicine ) 0.2 g/ml , 再经 胰蛋白酶处理， 离心、 倾去上清液。 以 0.075M KC1低渗液 作用后， 在曱醇:水醋酸（3:1 ) 固定液中固定。 取数滴悬滴 于清洁玻璃片上， Giemsa染色， 镜检。 Colchicine 0.2 g/ml was added 3 h before the cells were collected, then trypsinized, centrifuged, and the supernatant was decanted. After being treated with 0.075M KC1 hypotonic solution, it was fixed in sterol: water acetic acid (3:1) fixative. Take a few drops of the drop on the clean glass, Giemsa staining, microscopic examination.
检  Check
100倍油镜下镜检。 每个剂量组观察 100个中期相细胞。 按 Ishidate MJr * 标准判断实验结果。  100 times oil mirror microscopic examination. 100 metaphase cells were observed in each dose group. The experimental results were judged according to the Ishidate MJr* standard.
验有效性的检验  Test of validity
1. 最高浓度应符合我国指导原则的要求。 即能达到溶解度 或毒性所允许的最高浓度。  1. The highest concentration should meet the requirements of China's guiding principles. This will achieve the highest concentration allowed by solubility or toxicity.
2. 阴性对照值应在本实验室以往阴性对照背景资料 99% 可信限的范围之内。  2. The negative control value should be within the 99% confidence limit of the previous negative control background data in this laboratory.
3. 必须无任何技术问题的影响。 如污染、 细胞毒性太高， 或不适合 pH等。  3. There must be no technical problems. Such as pollution, cytotoxicity is too high, or not suitable for pH.
价标准  Price standard
按 Ishidate 所提出得标准对结果进行评价，其中裂隙和多倍 体包括在内。 The results were evaluated according to the criteria proposed by Ishidate, in which fissures and polyploids were included.
阴性（一）： 畸变率 < 4.9% 可疑 ( + ): 畸变率 5〜9.9% 阳性 ( + ): 畸变率 10-19.9% 较强阳性++): 畸变率 20~49.9%
Figure imgf000084_0001
Negative (1): Distortion rate < 4.9% Suspicious ( + ): Distortion rate 5~9.9% Positive ( + ): Distortion rate 10-19.9% Strong positive ++): Distortion rate 20~49.9%
Figure imgf000084_0001
阴性： 若所有测试组的畸变率均在 4.9% 以下则可判为阴性。 阳性： 若测试组至少有一組达阳性标准， 且有剂量的依赖性或 可重复者则可判为阳性结果。 结果不肯定者则应重复试验。 实验结果 Negative: Negative if all the test groups have a distortion rate below 4.9%. Positive: If the test group has at least one group that meets the positive criteria and is dose dependent or repeatable, it can be judged as a positive result. If the result is not certain, the test should be repeated. Experimental result
(+S9)组： 化合物 B最终浓度为 1.82、 0.91、 0.455 g/ml和 阴性对照组染色体畸变率分别为： 2%、 4%和 3% 。 实验中， 高、 中、 低剂量组染色体畸变率 < 5%, 判为阴性。 阳性药物环磷酰 胺 24h诱发畸变率是 13% 为阳性 (见表 19)。 表 19化合物 B对 CHL 细胞染色体畸变率 (+S9组) (+S 9 ) group: The final concentration of compound B was 1.82, 0.91, 0.455 g/ml and the chromosome aberration rates of the negative control group were: 2%, 4% and 3%, respectively. In the experiment, the chromosomal aberration rate of the high, medium and low dose groups was < 5%, which was negative. The positive drug cyclophosphamide 24h induced distortion rate was 13% positive (see Table 19). Table 19 Chromosomal aberration rate of Compound B in CHL cells (+S 9 group)
药物 剂量 时间 畸变类型 * ' 畸变率 评定 Drug dose time distortion type * 'distortion rate assessment
(： g/ml) (h) b f t P q e d r ； 1 tr (%) 培养液 24 2 2 3 一  (: g/ml) (h) b f t P q e d r ; 1 tr (%) culture solution 24 2 2 3
B 1.82 24 2 2 一 B 1.82 24 2 2 one
0.91 24 3 1 4 一 0.91 24 3 1 4 one
0.455 24 1 2 3 一 环 酰胺 50 24 2 2 5 4 13 -1- 注： 阳性对照： 环磷酰胺用作 +s9 系统实验 0.455 24 1 2 3 Monocyclic amide 50 24 2 2 5 4 13 -1- Note: Positive control: Cyclophosphamide as a +s 9 system experiment
* 畸变类型： b-断裂； p- 多倍体； t- 三幅体； q -四幅体； a-缺损； e- 交换； f-破碎； d- 双着丝点； g- 裂隙； r-环状； 1-丟失； tr-易位  * Distortion type: b-fracture; p-polyploid; t-triple body; q-four-body; a-deficient; e-exchange; f-fragmentation; d-double centromere; g-crack; r- Ring; 1-lost; tr-translocation
评价标准： （一)： < 5%; (±)： 5—9%; (+): 10—19%；  Evaluation criteria: (1): < 5%; (±): 5-9%; (+): 10-19%;
(++): 20 9%; (+++): > 50%;  (++): 20 9%; (+++): > 50%;
一个细胞染色体畸变出现 n种类形， 畸变率计算为 1 次  A cell chromosome aberration occurs in the n-type, and the distortion rate is calculated as 1 time.
试验例 9 小鼠灌胃 B68急性毒性试验 实验目的 Test Example 9 Acute toxicity test of B68 in mice Purpose
观察受试物一次灌胃后对小鼠所产生的急性毒性反应和死 亡情况。  The acute toxicity and death of the test article in mice after one-time gavage were observed.
配制方法： Preparation method:
将受试物用 0.5% CMC-Na配制成相应浓度， 使各剂量组给药体积 相等， 现配现用。  The test substance was formulated into a corresponding concentration with 0.5% CMC-Na, so that the dose groups of each dose group were equal in volume and were ready for use.
动 物  Animal
昆明种小鼠 60 只（$ 30， δ 30 ),由中国科学院上海实验动 物中心提供，合格证： 中科动管第 005号。经一周适应性饲养。 饲料购自由上海仕林科技有限公司。 自由取水， 饲养温度 23土 2。C 。体重： 给药时体重为 18-22克。性别： 雌雄各半。 每 组动物数： 按体重随机分组， 实验时以每 10 只为一剂量组。 剂 量  60 Kunming mice ($30, δ30) were provided by the Shanghai Experimental Animal Center of the Chinese Academy of Sciences, and the certificate of compliance was: No. 005 of the Chinese Medicine. Adapted to feeding in a week. Feed purchase free Shanghai Shilin Technology Co., Ltd. Free water intake, feeding temperature 23 soil 2 . C. Body weight: The body weight is 18-22 grams when administered. Gender: Male and female. Number of animals per group: Randomly grouped by body weight, one dose per 10 groups during the experiment. Dosage
剂量设置：按预初实验结果，最高剂量定为 4082 mg/kg, 以 0.7 的比列递减， 即为 686、 980、 1400、 2000、 2857、 4082 mg/kg 共 6个剂量组； 剂距： 0.7; 每只动物接受容量： 灌胃体积： 0.2 ml / g体重，  Dose setting: According to the preliminary experimental results, the highest dose was determined to be 4082 mg/kg, which was decreased by 0.7, which was 6 dose groups of 686, 980, 1400, 2000, 2857, 4082 mg/kg; 0.7; each animal receives volume: gavage volume: 0.2 ml / g body weight,
给药途径  Route of administration
小鼠一次灌胃给药。  The mice were administered intragastrically.
方 法  Method
小鼠各按体重随机分 6组， 每组 10只， 每组小鼠体重分布 相似。 给药后即观察动物各方面反应情况， 死亡动物进行解剖， 检查内脏， 记录每天动物的死亡数。 The mice were randomly divided into 6 groups according to body weight, with 10 mice in each group. The body weight distribution of each group was similar. After the administration, all aspects of the animal's reaction were observed, and the dead animals were dissected. Check the internal organs and record the number of deaths per day.
观察指标 Observation index
观察期： 14天 Observation period: 14 days
毒性反应： 观察检查小鼠外观、 行为、 进食、 粪便等情况， 死 亡动物进行尸解。 第 15天实验结束时， 存活小鼠解剖， 肉眼检 查心、 肺、 肝、 脾、 肾等脏器病变。 Toxic reaction: Observe the appearance, behavior, eating, feces, etc. of the mice, and the dead animals are subjected to autopsy. At the end of the experiment on the 15th day, the surviving mice were dissected, and the lesions of the heart, lung, liver, spleen, kidney and other organs were examined visually.
结果 Result
1毒性反应及死亡原因  1 Toxic reaction and cause of death
小鼠灌胃后 30分钟左右出现活动减少、 阵发性震颤， 步态 蹒跚， 药后 1小时左右开始死亡。 大部分死亡发生在 4小时内。 毒性反应与剂量呈正比。 尸解小鼠脏器肉眼检查未见明显异常。 存活小鼠第 15天全部解剖， 肉眼检查内脏未见明显病变。 死亡 情况列于下表。  After 30 minutes of oral administration, the mice showed decreased activity, paroxysmal tremor, gait, and began to die about 1 hour after the drug. Most deaths occur within 4 hours. The toxicity is proportional to the dose. There was no obvious abnormality in the visual examination of the organs of the mice. Surviving mice were dissected on the 15th day, and no obvious lesions were seen in the internal organs. The deaths are listed in the table below.
灌胃 B68小鼠死亡情况列表 List of deaths of B68 mice
受试物 动物数 死亡情况 合计 剂量 (n) 4h ■ _ ' D3 D4 D5 D6 D7" DI4 01)Total number of animal deaths of test substance (n) 4h ■ _ ' D3 D4 D5 D6 D7" DI4 0 1 )
(mg/kg) ？ ί ？ ί ？ ？ S ？ S ？ δ ？ S ¥ ί ？ (mg/kg)? ί ? ί ? ? S ? S ? δ ? S ¥ ί ?
2  2
686 5 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 686 5 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
980 5 5 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1980 5 5 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1
1400 5 5 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 31400 5 5 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3
2000 5 5 0 1 2 1 0 0 0 0 0 0 0 0 0 0 0 0 42000 5 5 0 1 2 1 0 0 0 0 0 0 0 0 0 0 0 0 4
2857 5 5 1 1 2 1 , 0 1 0 0 0 0 0 0 0 0 0 0 62857 5 5 1 1 2 1 , 0 1 0 0 0 0 0 0 0 0 0 0 6
4082 5 5 4 2 0 2 0 0 0 0 0 0 0 0 0 0 0 0 84082 5 5 4 2 0 2 0 0 0 0 0 0 0 0 0 0 0 0 8
2 小鼠剂量 -反应数值表 2 mouse dose - response value table
受试物 对数 动物 死亡动物 死亡 机率单 LD50及 剂量 数 数 率 位 95%可信限 (mg/kg) (x) (只） (只） (%) (Y) (mg/kg)Test object logarithm animal death animal mortality probability single LD50 and dose number rate 95% confidence limit (mg/kg) (x) (only) (only) (%) (Y) (mg/kg)
686 2.84 10 0 0 0 686 2.84 10 0 0 0
980 2.99 10 1 10 3.72  980 2.99 10 1 10 3.72
1400 3.15 10 3 30 4.48 2315 1400 3.15 10 3 30 4.48 2315
2000 3.30 10 4 40 4.75 (1790-2993)2000 3.30 10 4 40 4.75 (1790-2993)
2857 3.46 10 6 60 5.25 2857 3.46 10 6 60 5.25
4082 3.61 10 8 80 5.84  4082 3.61 10 8 80 5.84
12.3 LD50值及统计方法 12.3 LD 50 values and statistical methods
用 Bliss法计算得到 LD5Q如下： The LD 5Q is calculated by the Bliss method as follows:
小鼠0)5。 = 2315 11¾/1 ； 95%可信限为 1790〜2993 mg/kg。 Mouse 0) 5 . = 2315 113⁄4/1 ; 95% confidence limit is 1790~2993 mg/kg.
小 结 Summary
小鼠灌胃后 30分钟左右出现活动减少、 阵发性震颤， 步态 蹒跚， 药后 1小时左右开始死亡。 大部分死亡发生在 4小时内。  After 30 minutes of oral administration, the mice showed decreased activity, paroxysmal tremor, gait, and began to die about 1 hour after the drug. Most deaths occur within 4 hours.
毒性反应与剂量呈正比。 存活者第 15天全部解剖， 肉眼检查内 脏未见明显病变。 死亡率用 Bliss 法求得 LD5Q为： 2315 mg/kg; The toxicity is proportional to the dose. The survivors were all dissected on the 15th day, and no obvious lesions were seen in the viscera. Mortality was determined by Bliss method to obtain LD 5 Q: 2315 mg/kg;
95%可信限为 1790〜2993 mg/kg。 The 95% confidence limit is 1790~2993 mg/kg.
试验例 10 细胞水平测试化合物 EGFR抑制活性 Test Example 10 Cell level test compound EGFR inhibitory activity
实验目的： Purpose:
从新合成的 27种酪氨酸激酶抑制剂新型药物中筛选出一种 抑制细胞生长效率高（有效浓度低）、 特异性针对 EGFR酪氨酸 激酶途径、 作用稳定的治疗多嚢肾新药， 准备动物试验。  From the newly synthesized 27 tyrosine kinase inhibitors, a new drug that inhibits cell growth efficiency (low effective concentration), specifically targets the EGFR tyrosine kinase pathway, and stabilizes the action, prepares animals. test.
实验材料： 细胞： SPCA1 人肺癌细胞； 刺激因子： hEGF: 人表皮生长 因子 (R and D Catalog:236-EG); 培养基： DMEM F12 1 : l(GIBCO);小牛血清 (杭州四季青)； DMSO; MTT ( 5g/l ) 实^ r方法： MTT Experimental Materials: Cells: SPCA1 human lung cancer cells; stimulating factor: hEGF: human epidermal growth factor (R and D Catalog: 236-EG); medium: DMEM F12 1 : l (GIBCO); calf serum (Hangzhou Sijiqing); DMSO; MTT ( 5g / l ) Real ^ r method: MTT
实验步骤： Experimental steps:
一、 新药配置 First, the new drug configuration
才艮据分子量配成 10mM/L的 DMSO溶液； -20度保存； 二、 在细胞水平对药物进行粗筛选， 找出抑制细胞增殖作用 最强、 有效浓度最低的药。  According to the molecular weight, 10 mM / L of DMSO solution; -20 degrees of preservation; Second, the crude screening of drugs at the cellular level, to find the drug that inhibits cell proliferation, the strongest, the lowest effective concentration.
1、 第一天， 用含 10%血清的 DMEM/F12培养液接种细胞 于 96孔板中， 细胞密度为 1 X 104个 /孔； 1. On the first day, inoculate the cells in a 96-well plate with DMEM/F12 medium containing 10% serum, and the cell density is 1×10 4 cells/well;
2、 第二天， 用无血清的 DMEM/F12同步化 24小时； 2. The next day, synchronized with serum-free DMEM/F12 for 24 hours;
3、 第三天， 弃原来培养液， 加药； 各浓度各设 3个复孔； 每孔加 lOOul; 药物干预 48小时； 取 10mM/L的母液做 1 : 1000 稀释（用无血清的 DMEM/F12作为溶剂）， 作为最高浓度， 作 倍比稀释，共设 7个药物浓度；即： 10um、 5um、 2.5um、 1.25um、 0.625um、 0.3125um、 0.156um、 Oum (阴性对照）； 3. On the third day, discard the original culture solution and add the drug; set up 3 duplicate wells for each concentration; add lOOul per well; drug intervention for 48 hours; take 10 mM/L mother liquor for 1: 1000 dilution (with serum-free DMEM) /F12 as solvent), as the highest concentration, for dilution, a total of 7 drug concentrations; namely: 10um, 5um, 2.5um, 1.25um, 0.625um, 0.3125um, 0.156um, Oum (negative control);
4、 第五天， 每孔加 lOul MTT, 4小时后于 492nm处测 OD 值；  4. On the fifth day, lOul MTT was added to each well, and the OD value was measured at 492 nm after 4 hours;
5、 结果分析；  5. Analysis of results;
以阴性对照组的增殖抑制率为 0, 其余各浓度与它相比， 得 出抑制率； 计算抑制率公式为： (对照組 OD值 -实验组 OD值) /对照组 OD值 X 100% 三、 为了筛选出特异性针对 EGFR酪氨酸激酶途径的新药， 本实验设立了加 hEGF刺激組， 对粗筛后药物进行细筛选， 找出抑制细胞增殖作用最强、 作用浓度最低的、 特异性强新 型酪氨酸激酶抑制剂。 The inhibition rate of proliferation in the negative control group was 0, and the other concentrations were compared with it, and the inhibition rate was calculated as follows: (Control group OD value - experimental group OD value) / control group OD value X 100% III. In order to screen out a new drug specific for the EGFR tyrosine kinase pathway, this experiment established a hEGF stimulation group for the crude screening drug. Fine screening was performed to identify new and strong tyrosine kinase inhibitors that inhibited cell proliferation and had the lowest concentration.
1、 第一天， 用含 10%血清的 DMEM/F12培养液接种细胞 于 96孔板中， 细胞密度为 1 104个/孔； 1. On the first day, the cells were seeded in a 96-well plate with DMEM/F12 medium containing 10% serum, and the cell density was 1 10 4 /well;
2、 第二天， 用无血清的 DMEM/F12同步化 24小时； 2. The next day, synchronized with serum-free DMEM/F12 for 24 hours;
3、 第三天， 弃原来培养液， 加药； 各浓度各设 3个复孔； 每孔加 lOOul; 药物干预 48小时； 分为 hEGF刺激组和无 hEGF 刺激组； 3. On the third day, discard the original culture solution and add the drug; set up 3 duplicate wells for each concentration; add lOOul per well; drug intervention for 48 hours; divide into hEGF stimulation group and no hEGF stimulation group;
无 hEGF刺激组：  No hEGF stimulation group:
取 10mM/L的母液做 1 : 1000稀释 (用无血清的 DMEM/F12作为溶 剂）， 作为最高浓度， 作倍比稀释， 共设 7个药物浓度； 即： 10um、 5um、 2.5um、 1.25um、 0.625觀、 0.3125醒、 0.156um、 0腿（阴性 对照 ); Take 10 mM / L mother liquor for 1: 1000 dilution (with serum-free DMEM / F12 as solvent), as the highest concentration, for dilution, a total of 7 drug concentrations; namely: 10um, 5um, 2.5um, 1.25um , 0.625 view, 0.3125 awake, 0.156 um, 0 leg (negative control);
加 hEGF刺激组：  Add hEGF stimulation group:
同上， 用无血清的 DMEM/F 12含 10ng/ml hEGF的作为溶剂， 对药 物做如上稀释， 阴性对照为含 10ng/ml hEGF 的无血清的 DMEM/F12, As above, the drug was diluted as above with serum-free DMEM/F 12 containing 10 ng/ml hEGF as a solvent, and the negative control was serum-free DMEM/F12 containing 10 ng/ml hEGF.
4、 第五天， 每孔加 lOul MTT, 4小时后于 490nm处测 OD 值； 5、 结果分析； 以阴性对照组的增殖抑制率为 0, 其余各浓度与它相比，得出 抑制率； 计算抑制率公式为： 4. On the fifth day, lOul MTT was added to each well, and the OD value was measured at 490 nm after 4 hours; 5. Analysis of results; The inhibition rate of proliferation in the negative control group was 0, and the other concentrations were compared with it, and the inhibition rate was calculated:
(对照组 OD值 -实验组 OD值） /对照组 OD值 X 100% 实险结果： 见表 20和表 21 表 20化合物 C151〜C154细胞水平测试 EGFR抑制活性结果 浓度 (M) (Control group OD value - experimental group OD value) / control group OD value X 100% Risk results: See Table 20 and Table 21 Table 20 Compound C151~C154 Cell level test EGFR inhibitory activity result Concentration (M)
Ομπι 0.01 μιη Ο.Οόμηι 0.32μηι Ι.όμιη 8μηι 40μιη 200μΐΉ Ομπι 0.01 μιη Ο.Οόμηι 0.32μηι Ι.όμιη 8μηι 40μιη 200μΐΉ
Compd. Compd.
C151 0 -10.9% -5.83% -16.7% -3.57% 9.62% 37.9% 61.3% C152 0 -15.5% -14.6% -18.5% -9.63% 4.25% 17.2% 57.4% C153 0 -14.6% -21.5% -20.7% -0.26% 5.87% 58.9% 79.1% C154 0 -0.15% -12.0% -19.1% 0.45% 36.1% 76.1% 69.5% C151 0 -10.9% -5.83% -16.7% -3.57% 9.62% 37.9% 61.3% C152 0 -15.5% -14.6% -18.5% -9.63% 4.25% 17.2% 57.4% C153 0 -14.6% -21.5% -20.7 % -0.26% 5.87% 58.9% 79.1% C154 0 -0.15% -12.0% -19.1% 0.45% 36.1% 76.1% 69.5%
表 21化合物 C151、 C153&C154二次细胞水平测试 EGFR抑制 活性结果 浓度 Table 21 compounds C151, C153 & C154 secondary cell level test EGFR inhibition activity results concentration
(M) Ομιη 0.75μηι 1.5μπι 3μιη 6μπι 12μπι 25μιτι 50μιτι Compd. (M) Ομιη 0.75μηι 1.5μπι 3μιη 6μπι 12μπι 25μιτι 50μιτι Compd.
C151 0 -5.77% 7.49% 18.2% 19.7% 26.9% 46.6 59.4% C151 0 -5.77% 7.49% 18.2% 19.7% 26.9% 46.6 59.4%
C153 0 9.63% 21.0% 30.8% 32.9% 48.0% 46.3% 56.8% C153 0 9.63% 21.0% 30.8% 32.9% 48.0% 46.3% 56.8%
C154 0 13.4% 21.9% 24.7% 33.7% 64.5% 77.0% 81.4% 试验例 11 抗肿瘤生物活性体外筛选试验 实验 1 : C154 0 13.4% 21.9% 24.7% 33.7% 64.5% 77.0% 81.4% Test Example 11 In vitro screening test for antitumor biological activity Experiment 1:
筛选方法： 磺酰罗丹明 B(sulfoiiiodamine B, SRB)蛋白染色 法  Screening method: Sulfonhodamine B (SRB) protein staining
细 胞株： HCT-116人肠癌  Cell line: HCT-116 human colon cancer
作用时间： 72*  Duration: 72*
结果评定： 无效： l(T5mol/L<85%; Evaluation of results: Invalid: l (T 5 mol / L <85%;
弱效： l(T5mol/L≥85%或 l(T6mol/L>50%; Weakness: l (T 5 mol / L ≥ 85% or l (T 6 mol / L >50%;
强效： l(T6mol/L≥85%或 l(T7mol/L>50%。 Potent: l (T 6 mol / L ≥ 85% or l (T 7 mol / L > 50%.
表 22 HCT-116人肠癌体外筛选试验结果 (部分）  Table 22 Results of in vitro screening test of HCT-116 human intestinal cancer (part)
对肿瘤细胞生长的抑制率(％)  Inhibition rate of tumor cell growth (%)
浓度 (M) HCT-116 评价 Concentration (M) HCT-116 evaluation
Compd. 10-4 10'5 106 10-7 10-8 Compd. 10- 4 10' 5 10 6 10- 7 10-8
B 97.8 98.8 23.2 0 0 弱效 B 97.8 98.8 23.2 0 0 Weakness
B51 96.7 48.7 0 0 0 无效B51 96.7 48.7 0 0 0 Invalid
B53 77.6 97.9 82.7 0 0 弱效B53 77.6 97.9 82.7 0 0 Weakness
B54 92.2 98.8 42.2 6.6 3.5 弱效B54 92.2 98.8 42.2 6.6 3.5 Weakness
B55 94.0 98.2 30.3 3.6 2.9 弱效B55 94.0 98.2 30.3 3.6 2.9 Weakness
B56 94.1 98.6 54.0 10.0 10.6 弱效B56 94.1 98.6 54.0 10.0 10.6 Weakness
B57 95.6 98.4 40.2 0 0 弱效 06 B57 95.6 98.4 40.2 0 0 Weakness 06
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筛选方法 磺酰罗丹明 B(sulforhodamine B, SRB)蛋白染色 法  Screening method Sulfonhodamine B (SRB) protein staining
细 胞株 HT-29人肠  Cell line HT-29 human intestine
作用时间 72*  Action time 72*
结果评定 无效： l(T5mol/L<85%; The results were not valid: l (T 5 mol / L <85%;
弱效： 10-5mol/L≥85%或 l(T6mol/L>50%; Weakening: 10- 5 mol / L ≥ 85% or l (T 6 mol / L >50%;
强效： l(T6mol L≥85%或 l(T7mol/L>50%c 表 23 HT-29人肠癌体外筛选试验结果 (部分） Potent: l (T 6 mol L ≥ 85% or l (T 7 mol / L > 50% c Table 23 HT-29 human intestinal cancer in vitro screening test results (part)
对肿瘤细胞生长的抑制率 (％)  Inhibition rate of tumor cell growth (%)
浓度 (M) HT-29 评价 Concentration (M) HT-29 Evaluation
Compd. 10-4 105 106 1(Γ7 10 s Compd. 10- 4 10 5 10 6 1(Γ 7 10 s
B53 59.7 86.5 42.7 0 0 弱效 B53 59.7 86.5 42.7 0 0 Weakness
B54 77.9 88.4 0 0 0 弱效B54 77.9 88.4 0 0 0 Weakness
B56 81.0 91.8 14.9 0 0.9 弱效B56 81.0 91.8 14.9 0 0.9 Weakness
B59 68.1 88.7 42.8 2.1 9.6 弱效B59 68.1 88.7 42.8 2.1 9.6 Weakness
B60 85.5 88.9 0 0 0 弱效B60 85.5 88.9 0 0 0 Weakness
B65 78.1 91.8 76.6 0 0 弱效B65 78.1 91.8 76.6 0 0 Weakness
B67 98.8 100 55.6 0 0 弱效B67 98.8 100 55.6 0 0 Weakness
B70 98.2 100 70.8 5.5 0 弱效B70 98.2 100 70.8 5.5 0 Weakness
B75 93.9 46.8 39.0 4.4 弱效 26 B75 93.9 46.8 39.0 4.4 Weakness 26
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~"产业上利用的可能性 ~ "The possibility of industrial use
本发明的取代 [1,3,5]三嗪类化合物的制备方法具有反应条 件温和、 原料丰富易得、 操作及后处理简单等优点。  The preparation method of the substituted [1,3,5]triazine compound of the present invention has the advantages of mild reaction conditions, abundant raw materials, easy handling and post-treatment.
本发明的取代 [1,3,5]三嗪类化合物在计算机虚拟筛选以及环氧合 酶和 5-脂氧酶 (COX-1, COX-2和 5-LOX)结合实验和动物体内药理试 验均证实该类化合物为环氧合酶和 5-脂氧酶 (COX-2和 5-LOX)的双重 抑制剂， 对实验性炎症有较好的预防和治疗作用， 并对 Ames实验和 小鼠微核实验有较好的安全性， 对胃肠道的副作用明显减弱。 在生物传感技术 Biacore 3000研究本发明的取代 [1,3,5]三嗪类化 合物与环氧合酶和 5-脂氧酶 (COX-1, COX-2和 5-LOX)的相互作用的 模型上， 观察到不少化合物在 10-7-1(Τ5Μ浓度范围内对此模型均有作 用。 本发明的化合物对小鼠角叉菜胶性足肿胀模型， 大鼠足跖角叉菜 胶致肿模型， 小鼠耳二曱苯致炎模型， 大鼠佐剂性关节炎（预防原发 病变）模型， 大鼠佐剂性关节炎（预防继发病变）模型有很好的抗炎 作用。 本发明的化合物毒性很低。 对 Ames实验和小鼠微核实验有较好 的安全性， 对胃肠道无毒副作用。 本发明的取代 [1,3,5]三嗪类化合物在抗肿瘤细胞株 HCT-116人肠 癌和 HT-29人肠癌的体外筛选试验中显示出了较好的抑制活性， 不少 化合物表现为强效抑制剂。 本发明的化合物在 EGFR细胞测试实验中也显示了 μΜ级的抑制 活性 t 因 jtb, 本发明的 、物—。 J m
Figure imgf000096_0001
Substituted [1,3,5]triazine compounds of the present invention in computer virtual screening and binding experiments of cyclooxygenase and 5-lipoxygenase (COX-1, COX-2 and 5-LOX) and pharmacological tests in animals These compounds were confirmed to be dual inhibitors of cyclooxygenase and 5-lipoxygenase (COX-2 and 5-LOX), which have good preventive and therapeutic effects on experimental inflammation, and Ames experiments and mice. The micronucleus test has better safety and the side effects on the gastrointestinal tract are significantly weakened. Study on the interaction of substituted [1,3,5]triazines with cyclooxygenase and 5-lipoxygenase (COX-1, COX-2 and 5-LOX) in biosensing technology Biacore 3000 On the model, a large number of compounds were observed to have an effect on this model in the range of 10 - 7 -1 (the concentration of Τ 5 。. The compound of the present invention on the mouse carrageenan foot swelling model, rat ankle angle A model of agglomerate-induced swelling, a model of dioxin-induced inflammation in a mouse ear, a model of adjuvant arthritis in rats (prevention of primary lesions), a model of adjuvant arthritis in rats (preventing secondary lesions) Anti-inflammatory effect. The compound of the present invention has low toxicity. It has good safety to Ames test and mouse micronucleus test, and has no toxic side effect on gastrointestinal tract. The substituted [1,3,5]triazine of the present invention The compound showed good inhibitory activity in an in vitro screening test of anti-tumor cell line HCT-116 human intestinal cancer and HT-29 human intestinal cancer, and many compounds appeared as potent inhibitors. The compound of the present invention is in EGFR cells. μΜ-level inhibition was also shown in the test. Activity t due to jtb, the present invention. J m
Figure imgf000096_0001
病的药物； 本发明的化合物也可用于预防和 /或治疗和 /或辅助治 疗肿瘤疾病的药物。  Diseased drugs; The compounds of the invention are also useful in the prevention and/or treatment and/or adjuvant treatment of neoplastic diseases.

Claims

权 利 要 求 一种具有式（I)所示结构的取代 [1,3,5]三嗪类化合物、 其药学 上可接受的盐及溶剂合物或水合物： (I) 、 R2、 R3和 R4各自独立地为氢、 d-C8直链或支链烃基、 取代 或未取代的芳基、 芳垸基、 CrC4烷芳基、 芳酰基， 其中芳基选自苯基、 萘基和联苯基，取代基为 1-4个选自包括卤素、 d- 直链或支链烃基、 氰基、 硝基、 氨基、 羟基、 羟甲基、 三氟甲基、 三氟曱氧基、 羧基、 C】- C4烷氧基、 巯基、 -C4烷硫基、 -C4烷羰基、 C C4烷氧羰基、 磺酰基的组的基团； 并且 R5的结构式为 其中 和 R7各自独立地为选自 包括氢、 卤素、 - 直链或支链烃基、 氰基、 硝基、 氨基、 羟基、 羟 甲基、 三氟曱基、 三氟曱氧基、 羧基、 d-C4烷氧基、 巯基、 -C4烷 硫基、 C4酰基、 和磺酰基的组的基团； Y为 CH2 、 0、 S、 或 RN, 其中 R为氢、 CrC4直链或支链烃基、羟基、 CrC4羟烷基、羧基、 CrC4 烷叛基、 -Cj烷氧炭基、 磺酰基的基团； m, n各自独立地为 0, 1 , 2 或 3, 或者， R5选自羟基、 氨基、 取代氨基、 CrC6烷基、 CrC6烷羟基、 -C(0)R8、 -(CH2)XR8、 -CH2CH=CHR8、 -C(0)OR8或 -S(0)2R8, 其中， x 为 0、 1、 2或 3; R8为氢、 羟基、 芳基、 杂芳环基、 杂脂环基或 C2-C6 烯基。 2、 根据权利要求 1的取代 [1,3,5]三嗪类化合物、 其药学上可接受 的盐及溶剂合物或水合物，其特征在于，所述取代 [1，3,5]三嗪类化合物：Ν,Ν'-二苯基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4-二胺； 6-氯 -Ν-对曱 磺酰基苯基 -Ν，-苯基 -[1，3，5]-三嗪 -2,4-二胺； Ν-对曱磺酰基苯基 -Ν，-苯基 -6- (哌嗪 -1-取代) - [1,3，5]-三嗪 -2,4-二胺； Ν-邻曱磺酰基苯基 -Ν，-苯基 - 6- (哌嗪 -1-取代) -[1,3，5]-三嗪 -2,4-二胺； Ν-间甲磺酰基苯基 -Ν，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺； 4-(6-氯 -4-苯胺基 -[1,3，5]-三嗪 -2-氨基)苯磺酰胺； 4-(4-苯胺基 -6- (哌嗪 -1-取代) -[1,3，5]-三嗪 -2-氨基)苯 磺酰胺； 2-(4-苯胺基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2-氨基)苯磺酰胺； 3_(4-苯胺基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2-氨基)苯磺酰胺； Ν-萘基 -Ν，- 苯基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4-二胺； Ν， 1^-二萘基-6-(哌嗪-1-取 代) -[1,3，5]-三嗪 -2,4-二胺； Ν-联苯基 -Ν，-苯基 -6- (哌嗪 -1-取代) -[1,3,5]- 三嗪 -2,4-二胺； Ν, Ν，-二联苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺； Ν-苯基 -6- (哌嗪 -1-取代) -Ν，-对三氟曱氧基苯基 -[1，3,5]-三嗪 -2,4-二胺; Ν- 苯基 -6- (哌嗪小取代) -Ν，-邻三氟甲氧基苯基 -[1，3,5]-三嗪 -2,4-二胺; Ν-苯 基- 6- (哌嗪 -1-取代) -Ν，-间三氟曱氧基苯基 -[1,3，5]-三嗪 -2,4-二胺; 6- (哌 嗪 -1-取代) Ν，-对三氟曱氧基苯基 -[1,3,5]-三嗪 -2,4-二胺; 6- (哌嗪 -1-取 代) -N， N，-邻三氟甲氧基苯基 -[1，3,5]-三嗪 -2，4-二胺; 6- (哌嗪 -1-取代) -N, N，-间三氟.曱氧基苯基 -[1,3,5]-三嗪 -2，4-二胺; N-对溴苯基 -N，-苯基 -6- (哌 嗪 -1-取代) -[1，3,5]-三嗪 -2，4-二胺； N-邻溴苯基 -N，-苯基 -6- (哌嗪 - 1-取 代 )-[1,3，5]-三嗪 -2,4-二胺； N-间溴苯基 -N，-苯基- 6- (哌嗪 -1-取代) -[1,3,5]- 三嗪 -2，4-二胺； N， N，-二间溴苯基 -6- (哌嗪 -1-取代) -[1，3，5]-三嗪 -2,4-二 胺； Ν, Ν'-二间溴苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺； Ν，Ν，-二 间溴苯基 -6- (哌嗪 -1-取代 )-[1，3,5]-三嗪 -2，4-二胺； Ν-苯基 -6- (哌嗪 -1-取 代) -Ν，-对曱苯基- [1,3，5]-三嗪 -2，4-二胺; Ν-苯基 -6- (哌嗪 -1-取代) -Ν，-邻 曱苯基- [1,3,5]-三嗪 -2，4-二胺; Ν-苯基 -6- (哌嗪小取代) -Ν，-间曱苯基- [1,3,5]-三嗪- 2，4-二胺; Ν, Ν，-二间曱基苯基 -6- (哌嗪 -1-取代) -[1，3,5]-三嗪 -2,4-二胺； Ν, Ν，-二邻曱基苯基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4-二胺； Ν, Ν，-二对甲基苯基 -6- (哌嗪 -1-取代) -[1，3，5]-三嗪 -2,4-二胺； Ν-对氯苯 基 -Ν，-苯基 -6- (哌嗪 -1-取代 H ,5]-三嗪 -2,4-二胺； Ν-邻氯苯基 -Ν，-苯基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4-二胺； Ν-间氯苯基 -Ν，-苯基 -6- (哌嗪 - 取代 )-[1,3,5]-三嗪 -2，4-二胺； Ν, Ν，-二间氯苯基 -6- (哌 #-1-取代 )-[1,3,5]- 三嗪 -2,4-二胺； Ν， Ν，-二邻氯苯基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4-二 胺； Ν, Ν，-二对氯苯基- 6- (哌嗪 - 取代 )-[1,3,5]-三嗪- 2,4-二胺； Ν-间氟 苯基 -Ν，-苯基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4-二； Ν-邻氟苯基 -Ν，-苯基 -6- (哌嗪 -1-取代) - [1，3,5]-三嗪 -2,4-二胺； Ν, 1^，-二对氟苯基-6-(派嗪-1- 取代) -[1,3,5]-三嗪 -2,4-二胺； Ν, Ν，-二邻氟苯基- 6- (哌嗪 -1-取代 )-[1,3，5]- 三嗪 -2,4-二胺； Ν, Ν'-二间氟苯基 -6- (哌嗪 -1-取代) - [1，3，5]-三嗪 -2,4-二 胺； Ν-对曱氧基苯基 -Ν，-苯基 -6- (哌嗪小取代 )-[1,3,5]-三嗪- 2,4-二胺； Ν-邻曱氧基苯基 -Ν，-苯基 -6- (哌。秦小取代 )-[1,3，5]-三嗪 -2,4-二胺； Ν-间 甲氧基苯基 -Ν，-苯基 -6- (哌嗪小取代) -[1，3,5]-三嗪- 2,4-二胺； Ν, Ν，-二对 曱氧基苯基 -6- (哌嗪小取代 )-[1,3，5]-三嗪 -2,4-二胺; Ν, Ν，-二邻曱氧基苯 基 -6- (哌嗪 -1-取代 )-[1，3,5]-三嗪 -2,4-二胺； Ν， Ν，-二间曱氧基苯基- 6- (哌 嗪- 1-取代) -[1,3,5]-三嗪 -2，4-二胺； Ν-对硝基苯基 -Ν，-苯基 -6- (哌嗪 - 1-取 代）-[1，3,5]-三嗪 -2，4-二胺; Ν-邻硝基苯基 -Ν，-苯基 - 6-(哌嗪 -1-取 代）-[1，3,5]-三嗪 -2,4-二胺； N-间硝基苯基 -N，-苯基 -6-(哌嗪 - 1 -取 代 )-[1,3,5]-三嗪 -2,4-二胺； N， N，-二间硝基苯基 -6- (哌嗪 -1-取代 )-[1，3,5]- 三嗪 -2，4-二胺； N， N，-二邻硝基苯基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4- 二胺； N, N，-二对硝'基苯基 -6- (哌嗪 -1-取代 )-[1,3，5]-三嗪- 2，4-二胺； N-(3,4-二曱氧基)苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2，4-二胺； N-(2,3-二甲氧基)苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2，4-二胺； N-(2，4-二曱氧基)苯基 -N，-苯基 -6- ('哌嗪 -1-取代 )-[1，3,5]-三嗪 -2，4-二胺； N-(2,5-二曱氧基)苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2，4-二胺； N-(2,6-二曱氧基)苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺； N-(3,5-二曱氧基)苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2，4-二胺； N, N，-二 (3,4-二甲氧基)苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2，4-二胺； N, N，-二 (2,3-二甲氧基)笨基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2，4-二胺； N, Ν'- 二 (2,4-二曱氧基)苯基 -6- (哌嗪小取代 )-[1，3,5]-三嗪 -2，4-二胺； Ν， Ν，-二 (2，5-二曱氧基)苯基 -6- (哌嗪 -1-取代 )-[1,3，5]-三嗪 -2，4-二胺； Ν， Ν，-二 (2,6-二曱氧基)苯基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4-二胺； Ν, Ν，-二 (3，5-二甲氧基)苯基 -6- (哌嗪 -1-取代) -[1，3,5]-三嗪 -2,4-二胺； Ν-(2,3-二氢 苯并 [1,4]二恶 -6-取代) -Ν，-苯基 -6- (哌嗪 -1-取代) -[1,3，5]-三嗪- 2,4-二胺； Ν, Ν，- (2,3-二氢苯并 [1,4]二恶 -6-取代) -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4- 二胺； 4-(4-对曱氧基苯胺基 -6- (哌嗪小取代 )-[1,3,5]-三嗪 -2-氨基)苯磺酰 胺； 4-(4- 曱氧基苯胺基 -6- (哌嗪小取代 )-[1,3,5]-三喚 -2-氨基)苯磺酰 胺； 4-(4-间曱氧基苯胺基 -6- (哌嗪 -1-取代 )-[1，3,5]-三嗪 -2-氨基)苯磺酰 胺； 3-(4-间曱氧基苯胺基 -6- (哌嗪小取代 )-[1，3，5]-三嗪 -2-氨基)苯磺酰 胺； 3-(4-邻曱氧基苯胺基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪- 2-氨基)苯磺酰 胺； 3-(4-对甲氧基苯胺基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2-氨基)苯磺酰 胺； 2-(4-对甲氧基苯胺基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2-氨基)苯磺酰 胺； 2-(4-邻曱氧基苯胺基 -6- (哌嗪 -1-取代) -[1，3,5]-三嗪 -2-氨基)苯磺酰 胺； 2-(4-间甲氧基苯胺基 -6- (哌秦 -1-取代) -[1,3,5]-三嗪 -2-氨基)苯磺酰 胺； Ν-对乙氧基苯基 -Ν，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺； N-邻乙氧基苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[l,3,5]-三嗪 -2,4-二胺； N-间 乙氧基苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺;， N-(3,4-二 曱基)苯基 -N，-苯基 -6- (哌嗪 -1-取代) -[1，3，5]-三嗪 -2,4-二胺； N-(2，3-二曱 基)苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1，3,5]-三嗪 -2,4-二胺； N-(2，4-二曱基） 苯基 N，-苯基 -6- (哌嗪 -1-取代 )-[1，3,5]-三嗪 -2,4-二胺； N-(2,5-二曱基)苯 基 -Ν'-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺； Ν-(2,6-二曱基)苯基 -Ν，-苯基 -6- (哌嗪 -1-取代) -[1,3，5]-三嗪 -2,4-二胺； Ν-(3,5-二曱基)苯基 -Ν，-苯基 -6- (哌嗪 -1-取代) -[1,3，5]-三嗪 -2,4-二胺； Ν， Ν，-二 (3,4-二曱基） 苯基 -6- (哌嗪 -1-取代 )-[1,3，5]-三嗪 -2,4-二胺； Ν, Ν，-二 (2,3-二曱基)苯基 -6- (哌 51秦 -1-取代 )-[1,3,5]-三嗪- 2，4-二胺； Ν, Ν，-二 (2,4-二曱基)苯基- 6- (哌 嗪小取代) -[1,3，5]-三嗪 -2,4-二胺； Ν， Ν，-二 (2，5-二曱基)苯基 -6- (哌嗪小 取代 )-[1,3,5]-三嗪 -2,4-二胺； Ν, Ν，-二 (2,6-二曱基)苯基- 6- (哌嗪 -1-取 代 )-[1,3,5]-三嗪 -2,4-二胺； Ν, Ν，-二 (3,5-二甲基）苯基 -6- (哌嗪小取 代) -[1,3，5]-三嗪 -2,4-二胺； Ν-对曱硫基苯基 -Ν，-苯基 -6- (哌嗪 -1-取 代) -[1,3,5]-三嗪 -2,4-二胺； Ν-邻曱硫基苯基 -Ν，-苯基 -6- (哌嗪 -1-取 代) -[1,3,5]-三嗪 -2,4-二胺； Ν-间曱硫基苯基 -Ν，-苯基- 6- (哌嗪 -1-取 代) -[1,3,5]-三嗪 -2,4-二胺； 4-(4-苯胺基 -6- (哌，秦 -1-取代) - [1,3,5]-三嗪 -2- 取代氨基)苯硫酚； 3-(4-苯胺基 -6- (哌嗪 -1-取代 H ,5]-三嗪- 2-取代氨基) 苯硫酚； 2-(4-苯胺基 -6- (哌嗪- 1 -取代 )-[1 ,3 ,5〗-三嗪 -2-取代氨基)苯石 酚； 4— (4-苯胺基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2-取代氨基)苯酚； 3-(4-苯胺基 -6- (哌嗪 -1-取代) -[1,3，5]-三嗪 -2-取代氨基)苯酚； 2-(4-苯胺基 - 6- (哌嗪小 取代) -[1,3,5]-三嗪 -2-取代氨基)苯酚； Ν-对甲苯基 -Ν，-对甲硫基苯基 -6- (哌 -1-取代 )-[1,3,5]-三嗪 -2，4-二胺； Ν-邻甲苯基 -Ν，-对曱硫基苯基 -6- (哌嗪小取代) -[1,3,5]-三嗪 -2,4-二胺； Ν-间曱苯基 -Ν，-对曱硫基苯基 -6- (哌嗪小取代 )-[1,3,5]-三嗪 -2,4-二胺； Ν-苄基 -Ν，-苯基 -6- (哌嗪 -1-取 代) -[1,3,5]-三嗪 -2,4-二胺; Ν, Ν，-二苄基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4-二胺； Ν-(3,4-二氯)苯基 -Ν，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪- 2,4- 二胺； Ν-(2，3-二氯)苯基 -Ν，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺； N-(2,4-二氯）苯基 -N，-苯基 -6- (哌嗪 -1-取代) -[1，3,5]-三嗪 -2,4-二胺； N-(2,5-二氯）苯基 -N，-苯基 -6- (哌嗪 -1-取代 )-[1,3,5]-三嗪 -2，4-二胺； N-(2，6-二氯）苯基 -N，-苯基 -6- (哌嗪 -1-取代) -[1,3，5]-三嗪- 2,4-二胺； N-(3,5-二氯)苯基 -N，-苯基 -6- (哌嗪 -1-取代) -[1,3,5]-三嗪 -2,4-二胺； Ν,Ν，- 二苯基 -6-(4-对曱苯磺酰基哌嗪 -1-取代 )-[1,3，5]-三嗪 -2,4-二胺； Ν,Ν，-二 苯基 _6— (4-甲磺酰基哌嗪小取代 )-[1，3，5]-三嗪 -2,4-二胺； Ν,Ν，-二苯基 -6- (4-乙酰基哌嗪 -1-取代 )-[1,3,5]-三嗪 -2,4-二胺； Ν,Ν'-二苯基 - 6-(4-乙氧 羰基哌嗪 -1-取代 )-[1，3，5]-三嗪 -2,4-二胺; Ν-对曱氧基苯基 -Ν，-苯基- 6-(4- 对曱苯磺酰基哌嗪小取代 )-[1，3，5]-三嗪 -2，4-二胺； Ν-对甲氧基苯基 - Ν，- 苯基— 6— (4_甲磺酰基哌。秦小取代 )_[1,3，5]_三嗪 _2,4-二胺； Ν-对曱氧基苯 基— Ν，-苯基 -6- (4-乙酰基哌嗪 -1-取代 )-[1,3，5]-三嗪 _2,4-二胺; Ν-对曱氧基 苯基 -Ν，-苯基 -6-(4-乙氧羰基哌。秦 -1-取代 )-[1,3，5]-三嗪 -2，4-二胺； 4-[4- 苯胺 _6-(4-曱磺酰基哌嗪 -1-取代) -[1,3，5]-三嗪 -2-氨基]苯磺酰胺； 4-[4- 苯胺 -6-(4-对曱苯磺酰基哌嗪 -1-取代) -[1,3,5]-三嗪 -2-氨基]苯磺酰胺； 4- [4-苯胺 -6-(4-乙酰基哌嗪 -1-取代 )-[1,3，5]-三嗪 -2-氨基]苯磺酰胺； 4-[4- 苯胺— 6-(4-乙氧羰基哌嗪 -1-取代) -[1，3,5]-三嗪 -2-氨基]苯磺酰胺； 6- (吗啉 -4 -取代) -Ν,Ν'-二苯基 -[1,3,5]-三嗪 -2,4-二胺； Ν-对氯苯基 -6- (吗啉 -4-取 代) -Ν，-苯基- [1,3,5]-三嗪- 2,4-二胺； Ν-邻氯苯基 -6- (吗啉 -4-取代) -Ν，-苯 基- [1,3，5]-三嗪 -2,4-二胺； Ν-间氯苯基 -6- (吗啉 -4-取代) -Ν'-苯基 -[1，3,5]- 三嗪 -2，4-二胺； Ν, Ν，-二间氯苯基 -6- (吗啉 -4-取代) -[1,3，5]-三嗪 -2,4-二 胺； Ν，Ν'-二邻氯苯基 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪 -2，4-二胺； Ν，Ν，-二 对氯苯基- 6- (吗啉 -4-取代) -[1,3,5]-三嗪 -2,4-二胺； Ν-邻曱氧基苯基 -6- (吗 啉 _4-取代) -Ν，-苯基 -[1,3,5]-三嗪 -2,4-二 Ν-间曱氧基苯基 -6- (吗啉 -4- 取代) - Ν，-苯基 -[1,3,5]-三嗪 -2，4-二胺； Ν-对曱氧墓苯基 -6- (吗啉 -4-取 代) -Ν，-苯基- [1,3，5]-三嗪 -2,4-二胺； Ν，Ν，-二对曱氧基苯基- 6- (吗啉 -4-取 代）-[1，3,5]-三嗪 -2，4-二胺； Ν,Ν'-二邻甲氧基苯基 -6-(吗啉 -4-取 代）-[1,3,5]-三嗪 -2,4-二胺； Ν，Ν，-二间曱氧基苯基 -6-(吗啉 -4-取 代) -[1 ,3，5]-三嗪 -2，4-二胺； 6- (吗啉 -4-取代) 苯基 -Ν，-对三氟曱氧基苯 基- [1，3，5]-三嗪-2，4-二胺； 6- (吗啉 -4-取代) -N-苯基 -N，-邻三氟甲氧基苯 基- [1，3，5]-三嗪 -2，4-二胺； 6- (吗啉 -4-取代) -N-苯基 -N，-间三氟曱氧基苯 基- [1，3,5]-三嗪 -2,4-二胺； N-对溴苯基 -6- (吗啉 -4-取代) -N，-苯基 -[1，3，5]- 三嗪 -2,4-二胺； N-邻溴苯基 -6- (吗啉 -4-取代) -N，-苯基 -[1，3,5]-三嗪 -2，4- 二胺； N-间溴苯基 -6- (吗啉 - 4-取代) -N，-苯基 -[1,3，5]-三嗪 -2,4-二胺； N- 对乙氧基苯基 -6- (吗啉 -4-取代) -N，-苯基 -[1,3,5]-三嗪 -2,4-二胺； 4-(6- (吗 啉 _4-取代) -4-苯胺基 -[1，3,5]-三嗪 -2-氨基)苯曱酰胺； 3-(6- (吗啉 -4-取 代) -4-苯胺基 - [1,3，5]-三嗪 -2-氨基)苯曱酰胺； 2-(6- (吗啉 - 4-取代) -4-苯胺 基 -[1,3，5]-三嗪 -2-氨基)苯曱酰胺； N-对氟苯基 -N，-对甲氧基苯基 -6- (吗 啉 -4-取代) -[1，3，5]-三嗪 -2，4-二胺； N-对氟苯基 -6- (吗啉 -4-取代) -N，-对三 氟曱氧基苯基 -[1,3，5]-三嗪 -2,4-二胺； N-对氟苯基 -6- (吗啉 -4-取代) -Ν'- 苯基 -[1,3,5]-三嗪 -2，4-二胺； Ν-(3,4-二曱氧基)苯基 -6- (吗啉 - 4-取代) -Ν，- 苯基— [1,3,5]-三嗪 -2，4-二胺； Ν-(2,3-二曱氧基)苯基 -6- (吗啉 -4-取代) - Ν，- 苯基— [1,3,5]-三嗪 -2,4-二胺； Ν-(2，4-二曱氧基)苯基 -6- (吗啉 -4-取代) -Ν，- 苯基— [1,3，5]-三嗪 -2，4-二胺； Ν-(2,5-二甲氧基)苯基 -6- (吗啉 -4-取代) -Ν，- 苯基— [1,3,5]-三嗪 -2,4-二胺； Ν-(2,6-二曱氧基)苯基- 6- (吗啉 -4-取代) -Ν，- 苯基— [1,3,5]-三嗪 -2,4-二胺； Ν-(3，5-二曱氧基)苯基 -6- (吗啉 -4-取代) - Ν'- 苯基 [1,3，5]-三嗪 -2,4-二胺； 4-(4-苯胺基 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪 -2-氨基)苯磺酰胺； 3-(4-苯胺基 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪 -2-氨基)苯 磺酰胺； 2-(4-苯胺基 -6- (吗啉 -4-取代) -[1，3,5]-三嗪- 2-氨基)苯磺酰胺； 4-(4-对甲氧基苯胺基 -6- (吗啉 -4-取代) -[1，3,5]-三嗪 -2-氨基)苯磺酰胺； Ν-对曱氧基苯基 -Ν，-(2- (吗啉 -4-取代)乙基) -Ν"-苯基 -[1,3,5]-三嗪 -2,4,6- 三胺； Ν-(2- (吗淋 -4-取代）乙基) -Ν，,Ν，，-二苯基 -[1,3,5]-三嗪 -2,4,6-三胺； Ν-苄基 -Ν，- (2- (吗啉 -4-取代）乙基) -Ν，，-苯基 -[1，3,5]-三嗪- 2,4,6-三胺； Ν- 苄基 _6- (吗啉 -4-取代) -Ν，-苯基 -[1，3,5]-三嗪- 2,4-二胺； Ν-对曱氧基苄基 一 6- (吗啉 -4-取代) -Ν，-苯基 -[1,3,5]-三嗪 -2,4-二胺； Ν-邻曱氧基苄基 -6- (吗 啉 _4-取代) -Ν，-苯基 -[1,3,5]-三嗪 -2,4-二胺； Ν-间曱氧基苄基 -6- (吗啉 -4- 取代) - Ν，-苯基 -[1，3，5]-三嗪 -2,4-二胺； ' Ν-苄基 -6- (吗啉 -4-取代) -Ν，-对甲 苯基 -[1,3，5]-三嗪 -2，4-二胺； 4-(4-苄胺基 -6- (吗啉 -4-取代) -[1，3，5]-三嗪 -2- 氨基)苯磺酰胺； N-苄基 -N，-对甲氧基苯基 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪 -2,4-二胺； N-苄基 -N，-对氟苯基 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪 -2,4-二胺； N-苄基- N，-邻氟苯基 -6- (吗淋 -4-取代 )-[1，3,5]-三嗪 -2,4-二胺； N-苄基 -N，- 间氟苯基 -6- (吗啉 -4-取代 )-[1，3,5]-三嗪 -2,4-二胺； Ν,Ν'-二苄基 -6- (吗啉 一 4-取代) -[1,3,5]-三嗪 -2，4-二胺； 2-[4,6-二苯胺基 -[1,3,5]-三嗪- 2-氨基]乙 醇； 3- [4，6-二苯胺基 -[1,3,5]-三嗪 -2-氨基]丙醇； 2-[4，6-二苯胺基- [1,3,5]- 三嗪- 2-氨基]乙胺； 2-[4-对曱氧基苯胺基 -6-苯胺基 -[1,3,5]-三嗪 -2-氨基] 乙醇； 3- [4-对甲氧基苯胺基 -6-苯胺基 -[1,3,5]-三嗪 -2-氨基]丙醇； 2-[4- 对曱氧基苯胺基 -6-苯胺基 -[1,3,5]-三嗪 -2-氨基]乙胺； 2-[4-苄胺基 -6-苯 胺基 -[1,3，5]-三嗪 -2-氨基]乙醇； 3-[4-苄胺基 -6-苯胺基 -[1,3,5]-三嗪 -2-氨 基]丙醇； 2-[4-苄胺基 -6-苯胺基 -[1,3,5]-三嗪 -2-氨基]乙胺； 4,6-二 (吗啉 -4-取代) -Ν-苯基- [1,3,5]-三嗪 -2-胺； 4-[4,6-二 (吗啉 -4-取代) -[1,3,5]-三嗪 -2-氨基]苯磧酰胺； Ν-对甲氧基苯基 -4,6-二 (吗啉 -4-取代 )-[1,3，5]-三嗪 -2- 胺； Ν-对氟苯基 -4，6-二 (吗啉 -4-取代) -[1,3,5]-三嗪 -2-胺； Ν-苄基- 4,6-二 (吗啉 _4-取代) -[1,3,5]-三嗪 -2-胺； 4-氯- 6- (吗啉 -4-取代) -Ν-苯基 -[1,3,5]- 三嗪 -2-胺； 4-[4-氯 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪 _2-氨基]苯 酰胺； 4- 氯 -Ν-对曱氧基苯基 -6- (吗啉 -4-取代 )-[1,3，5]-三嗪 -2-胺； 4-氯 -Ν-邻曱氧 基苯基 -6- (吗啉 -4-取代) -[1,3,5]-三嗪 -2-胺； 4-氯 -Ν-间甲氧基苯基- 6- (吗 啉—4-取代 )-[1,3，5]-三嗪 -2-胺； 4-氯- Ν-对氟苯基 -6- (吗淋 -4-取代 )-[1,3,5]- 三嗪 -2-胺； Ν-苄基 -4-氯 -6- (吗啉 -4-取代 )-[1，3,5]-三嗪 -2-胺； 2-氯 -4，6- 二 (吗啉— 4-取代) -[1,3，5]-三嗪； 2-甲氧基 -4,6-二 (吗啉 -4-取代 )-[1,3,5]-三 嗪； Ν-苄基 -4-甲氧基 -6- (吗啉 -4-取代) -[1,3,5]-三嗪 -2-胺； Ν-苄基 -4-乙 氧基—6- (吗啉 -4-取代 )-[1,3，5]-三嗪 -2-胺； 2, 4, 6-三 (吗啉 -4-取代 )-[1,3,5]- 三嗪； 4-曱氧基 对甲氧基苯基 -6- (吗啉 -4-取代 )-[1,3,5]-三嗪- 2-胺； 2_[4-(4,6-二对曱氧基苯胺基 -[1,3，5]-三嗪 -2-取代)哌嗪 -1-取代]乙醇； 2_[4— (4—对曱氧基苯胺基 -6-苯胺基 -[1,3,5]-三嗪 -2-取代)哌嗪 -1-取代]乙 醇； 2-[4-(4,6-二苯胺基 -[1,3，5]-三嗪 -2-取代)哌嗪 -1-取代]乙醇； Ν-对曱 硫基苯基 -6- (吗啉 -4-取代) -N，-对曱苯基 -[1,3，5]-三嗪 -2,4-二胺； N-对曱 硫基苯基 -6- (吗啉 -4-取代) -N，-对甲氧基苯基 -[1，3,5]-三嗪 -2，4-二胺； N- 对曱硫基苯基 -6- (吗啉 -4-取代) -N，-苯基 -[1,3，5]-三嗪 -2，4-二胺； N-邻甲 硫基苯基 -6- (吗啉 - 4-取代) -N，-苯基- [1，3，5]-三嗪 -2，4-二胺； N-间甲硫基 苯基 -6- (吗啉 -4-取代) -N，-苯基 -[1,3，5]-三嗪 -2，4-二胺； 6- (吗啉 -4-取 代）-N-苯基 -N，-(吡啶 -4-取代）-[1 ,3,5]-三嗪 -2,4-二胺； 6-(吗啉 -4-取 代) (吡啶 -4-取代) -Ν'-对甲苯基 -[1,3,5]-三嗪 -2，4-二胺； 6- (吗啉 -4-取 代) -Ν- (吡啶 -4-取代) -Ν'-邻甲苯基 -[1,3，5]-三嗪 -2,4-二胺； 6- (吗啉 -4-取 代)- Ν- (吡啶 -4-取代) -Ν'-间曱苯基 -[1,3，5]-三嗪 -2,4-二胺； Ν-对甲氧基苯 基 -6- (吗啉 -4-取代) -Ν，- (吡啶 -4-取代) -[1，3,5]-三嗪 -2，4-二胺； Ν-邻曱氧基 苯基 -6- (吗啉 -4-取代) -Ν，- (吡啶 -4-取代 )-[1,3,5]-三嗪- 2,4-二胺; Ν-间曱氧 基苯基 -6- (吗啉 -4-取代) -Ν，- (吡啶 -4-取代 )-[1,3,5]-三嗪 -2,4-二胺。 3、 权利要求 1所述通式 (I)所示取代 [1,3,5]三嗪类化合物或其药学 上可接受的盐或它们的溶剂合物或水合物的制备方法， 其特征在于包 括以下步骤： Claims: A substituted [1,3,5]triazine compound having the structure of the formula (I), a pharmaceutically acceptable salt thereof and a solvate or hydrate thereof: (I), R2, R3 and R4 Each independently is hydrogen, d-C8 straight or branched chain alkyl, substituted or unsubstituted aryl, aryl fluorenyl, CrC4 alkaryl, aroyl, wherein the aryl group is selected from the group consisting of phenyl, naphthyl and biphenyl The substituents are from 1 to 4 selected from the group consisting of halogen, d-linear or branched hydrocarbon, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C. a group of a group of a C4 alkoxy group, a decyl group, a -C4 alkylthio group, a -C4 alkylcarbonyl group, a C4 alkoxycarbonyl group, a sulfonyl group; and a structural formula of R5 wherein the R7 is independently selected from the group consisting of hydrogen , halogen, - linear or branched hydrocarbon, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, d-C4 alkoxy, decyl, -C4 alkane a group of a group of a thio group, a C4 acyl group, and a sulfonyl group; Y is CH2, 0, S, or RN, wherein R is hydrogen, a CrC4 linear or branched hydrocarbon group, a hydroxyl group, a CrC4 hydroxy group a group of a carboxyl group, a carboxyl group, a CrC4 alkyl group, a -Cj alkoxycarbonyl group, a sulfonyl group; m, n are each independently 0, 1, 2 or 3, or R5 is selected from a hydroxyl group, an amino group, a substituted amino group, and a CrC6 Alkyl, CrC6 alkylhydroxy, -C(0)R8, -(CH2)XR8, -CH2CH=CHR8, -C(0)OR8 or -S(0)2R8, wherein x is 0, 1, 2 or 3 R8 is hydrogen, hydroxy, aryl, heteroaryl ring, heteroalicyclic or C2-C6 alkenyl. The substituted [1,3,5]triazine compound, a pharmaceutically acceptable salt thereof, and a solvate or hydrate thereof according to claim 1, wherein the substitution [1, 3, 5] Pyrazines: hydrazine, Ν'-diphenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; 6-chloro-indole-pair Sulfonylphenyl-indole, -phenyl-[1,3,5]-triazine-2,4-diamine; Ν-p-sulfonylphenyl-indole, -phenyl-6- (piperazine- 1-substituted) - [1,3,5]-triazine-2,4-diamine; Ν-o-sulfonylphenyl-hydrazine, -phenyl-6-(piperazin-1-substituted)-[ 1,3,5]-triazine-2,4-diamine; Ν-m-methylsulfonylphenyl-indole, -phenyl-6-(piperazin-1-substituted)-[1,3,5] -triazine-2,4-diamine; 4-(6-chloro-4-anilino-[1,3,5]-triazin-2-amino)benzenesulfonamide; 4-(4-anilino- 6-(piperazin-1-substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide; 2-(4-anilino-6-(piperazin-1-substituted)-[ 1,3,5]-triazin-2-amino)benzenesulfonamide; 3-(4-anilino-6-(piperazin-1-substituted)-[1,3,5]-triazine-2-amino Benzenesulfonamide; Ν-naphthyl-anthracene, -phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; oxime, 1^- Dinaphthyl-6-(piperazine-1-take )) -[1,3,5]-triazine-2,4-diamine; Ν-biphenyl-hydrazine, -phenyl-6-(piperazin-1-substituted)-[1,3,5 ]-triazine-2,4-diamine; hydrazine, hydrazine, -diphenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine Ν-Phenyl-6-(piperazin-1-substituted)-indole,-p-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine; Ν-benzene -6-(piperazine substituted)-indole,-o-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine; fluorenyl-phenyl-6- (piperider Pyrazin-1-substituted)-Ν,-m-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine; 6-(piperazin-1-substituted) oxime,- p-Trifluorodecyloxyphenyl-[1,3,5]-triazine-2,4-diamine; 6-(piperazin-1-substituted)-N,N,-o-trifluoromethoxybenzene -[1,3,5]-triazine-2,4-diamine; 6-(piperazin-1-substituted)-N, N,-m-trifluoro-decyloxyphenyl-[1,3 ,5]-triazine-2,4-diamine; N-p-bromophenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2 , 4-diamine; N-o-bromophenyl-N,-phenyl-6-(piperazine-1-substituted)-[1,3,5]-triazine-2,4-diamine; N- m-bromophenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N, N,-di-bromophenyl -6- (piperazine-1 -substituted) -[1,3,5]-triazine-2,4-diamine; Ν, Ν'-di-bromophenyl-6-(piperazin-1-substituted)-[1,3,5 ]-Triazine-2,4-diamine; Ν,Ν,-di-bromophenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-di Amine; phenyl-phenyl-6-(piperazin-1-substituted)-indole, p-p-phenyl-[1,3,5]-triazine-2,4-diamine; - (piperazin-1-substituted)-indole,-o-phenylene-[1,3,5]-triazine-2,4-diamine; Ν-phenyl-6-(piperazine small substitution) - Ν,-M-phenyl-[1,3,5]-triazine- 2,4-diamine; Ν, Ν,-di-m-decylphenyl-6-(piperazin-1-substituted)-[ 1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine, -di-nonylphenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine -2,4-diamine; hydrazine, hydrazine, -di-p-methylphenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; -p-chlorophenyl-indole, -phenyl-6-(piperazin-1-substituted H,5]-triazine-2,4-diamine; Ν-o-chlorophenyl-indole, -phenyl-6 - (piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-m-chlorophenyl-indole,-phenyl-6-(piperazine-substituted)- [1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine,-di-chlorophenyl-6-(pipe#-1-substituted)-[1,3,5]-triazine -2,4-diamine; Ν, Ν,-di-o-chlorophenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine,-di-p-chlorophenyl - 6- (piperazine-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-m-fluorophenyl-indole, -phenyl-6- (piperazine-1-substituted -[1,3,5]-triazine-2,4-di; fluorenyl-o-fluorophenyl-indole,-phenyl-6-(piperazin-1-substituted)-[1,3,5] -triazine-2,4-diamine; hydrazine, 1^,-di-p-fluorophenyl-6-(pyrazine-1-substituted)-[1,3,5]-triazine-2,4-di Amine, hydrazine, bis-fluorophenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, Ν'-di-difluoro Phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-p-nonyloxyphenyl-indole,-phenyl-6- ( Piperazine small substituted)-[1,3,5]-triazine-2,4-diamine; Ν-o-nonyloxyphenyl-indole, -phenyl-6- (piper. Qin Xiao substituted)-[1,3,5]-triazine-2,4-diamine; Ν-m-methoxyphenyl-oxime,-phenyl-6-(piperazine small substitution)-[1, 3,5]-triazine-2,4-diamine; hydrazine, hydrazine, -di-p-methoxyphenyl-6-(piperazine small substituted)-[1,3,5]-triazine-2, 4-diamine; hydrazine, hydrazine, -di-o-hydroxyphenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine ,-di-methoxyphenyl-6-(piperazine-1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-p-nitrophenyl-hydrazine,- Phenyl-6-(piperazine-1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-o-nitrophenyl-indole,-phenyl-6-(piperidin Pyrazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-m-nitrophenyl-N,-phenyl-6-(piperazine- 1 -substituted)- [1,3,5]-triazine-2,4-diamine; N, N,-di-nitrophenyl-6-(piperazin-1-substituted)-[1,3,5]- Pyrazine-2,4-diamine; N,N,-di-o-nitrophenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N, N,-di-p-nitrophenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(3,4-di曱oxy)phenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(2,3-di Methoxy Phenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(2,4-didecyloxy) phenyl-N,-phenyl-6-('piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(2,5-dioxine Phenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(2,6-dioxyloxy) Phenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(3,5-dioxyloxy) Phenyl-N,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N, N,-di (3,4 -dimethoxy)phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N, N,-di(2,3-di Methoxy) phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N, Ν'-bis(2,4-dioxyloxy) Phenyl-6-(piperazine small substituted)-[1,3,5]-triazine-2,4-diamine; oxime, fluorene,-bis(2,5-dimethoxy)phenyl -6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine,-bis(2,6-dimethoxy)phenyl-6 - (piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine,-bis(3,5-dimethoxy)phenyl-6- ( Piperazine-1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-(2,3-dihydrogen Benzo[1,4]dioxin-6-substituted)-indole,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν, Ν,-(2,3-dihydrobenzo[1,4]dioxin-6-substituted)-6-(piperazin-1-substituted)-[1,3,5]-triazine-2 , 4-diamine; 4-(4-p-methoxyanilino-6-(piperazine small substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide; 4-(4 - methoxyanilino-6-(piperazine small substituted)-[1,3,5]-tripa-2-amino)benzenesulfonamide; 4-(4-m-decyloxyanilin-6- ( Piperazine-1-substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide; 3-(4-metamethoxyanilino-6-(piperazine small substituted)-[1 ,3,5]-triazin-2-amino)benzenesulfonamide; 3-(4-o-methoxyanilino-6-(piperazin-1-substituted)-[1,3,5]-triazine 2-(2-amino)benzenesulfonamide; 3-(4-p-methoxyanilino-6-(piperazin-1-substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide 2-(4-p-methoxyanilino-6-(piperazin-1-substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide; 2-(4-o-guanidine Oxyanilino-6-(piperazin-1-substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide; 2-(4-m-methoxyanilino-6- ( Piperazine-1-substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide; Ν-p-ethoxyphenyl-fluorene,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-o-ethoxyl phenyl-N,-phenyl-6-(piperazin-1-substituted)-[l,3,5]-triazine-2,4-diamine; N-m-ethoxyphenyl-N,- Phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine;, N-(3,4-diindenyl)phenyl-N,- Phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(2,3-diindenyl)phenyl-N,-benzene -6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(2,4-dimercapto)phenyl N,-phenyl- 6-(Piperazine-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(2,5-dimercapto)phenyl-fluorene-phenyl--6 - (piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-(2,6-dimercapto)phenyl-indole, -phenyl-6- (piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-(3,5-dimercapto)phenyl-indole, -phenyl-6- ( Piperazine-1-substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine,-bis(3,4-dimercapto)phenyl-6- (piperazine- 1-substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine,-bis(2,3-dimercapto)phenyl-6- (piperidin-5-methyl-1- Substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine, -di(2,4-difluorene) Phenyl-6-(piperazine small substituted)-[1,3,5]-triazine-2,4-diamine; oxime, fluorene,-bis(2,5-diindenyl)phenyl-6 - (piperazine small substitution)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine, -bis(2,6-dimercapto)phenyl-6-(piperazine- 1-substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine,-bis(3,5-dimethyl)phenyl-6-(piperazine small substitution) - [1,3,5]-triazine-2,4-diamine; Ν-p-thiophenyl-anthracene, -phenyl-6-(piperazin-1-substituted)-[1,3,5 ]-triazine-2,4-diamine; Ν-o-nonylthiophenyl-indole,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2 , 4-diamine; Ν-meta-thiophenyl-hydrazine, -phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; 4-(4-anilino-6-(piperidin, hen-1-substituted)-[1,3,5]-triazine-2-substituted amino)thiophenol; 3-(4-anilino-6- (piperazin-1-substituted H,5]-triazine-2-substituted amino) thiophenol; 2-(4-anilino-6-(piperazine- 1 -substituted)-[1,3,5 - triazine-2-substituted amino) fenpropenol; 4-(4-anilino-6-(piperazin-1-substituted)-[1,3,5]-triazine-2-substituted amino)phenol; 3-(4-anilino-6-(piperazin-1-substituted)-[1,3,5]-triazine-2-substituted amino)phenol; 2-(4- Amino-6-(piperazine small substituted)-[1,3,5]-triazine-2-substituted amino)phenol; Ν-p-tolyl-indole, p-methylthiophenyl-6- (perphenemate -1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-o-tolyl-indole,-p-nonylthiophenyl-6-(piperazine small substitution)-[ 1,3,5]-triazine-2,4-diamine; Ν-meta-phenyl-indole,-p-nonylthiophenyl-6-(piperazine small substitution)-[1,3,5] -triazine-2,4-diamine; Ν-benzyl-hydrazine, -phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine Ν, Ν,-dibenzyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-(3,4-dichloro)benzene Base-oxime, -phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-(2,3-dichloro)phenyl- Ν,-phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(2,4-dichloro)phenyl-N, -phenyl-6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(2,5-dichloro)phenyl-N,-benzene -6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(2,6-dichloro)phenyl-N,-phenyl- 6-(piperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; N-(3,5-dichloro)phenyl-N,-phenyl-6- (piperazin-1-substituted) -[1,3,5]-triazine-2,4 -diamine; hydrazine, hydrazine, - diphenyl-6-(4-p-nonylbenzenesulfonylpiperazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; , hydrazine, -diphenyl-6-(4-methanesulfonylpiperazine small substitution)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine, -diphenyl-6 - (4-Acetylpiperazine-1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν,Ν'-diphenyl-6-(4-ethoxycarbonylpiperidine Pyrazin-1-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-p-methoxyphenyl-indole,-phenyl-6-(4-p-phenylenesulfonyl) Piperazine small substituted)-[1,3,5]-triazine-2,4-diamine; Ν-p-methoxyphenyl- hydrazine, -phenyl-6-(4-methanesulfonylpiperone. Qin Xiao substituted) _[1,3,5]_triazine_2,4-diamine; Ν-p-methoxyphenyl- hydrazine,-phenyl-6- (4-acetylpiperazine-1- Substituted)-[1,3,5]-triazine_2,4-diamine; Ν-p-methoxyphenyl-indole,-phenyl-6-(4-ethoxycarbonylpiped. Qin-1- Substituted)-[1,3,5]-triazine-2,4-diamine; 4-[4-aniline_6-(4-oxasulfonylpiperazin-1-substituted)-[1,3,5 ]-Triazine-2-amino]benzenesulfonamide; 4-[4-aniline-6-(4-p-nonylbenzenesulfonylpiperazin-1-substituted)-[1,3,5]-triazine-2 -amino]benzenesulfonamide; 4-[4-aniline-6-(4-acetylpiperazine-1-substituted)-[1,3,5]-triazin-2-amino]benzenesulfonamide; 4- [4-aniline-6-(4-ethoxycarbonylpiperazine-1-substituted)-[1,3,5]-triazin-2-amino]benzenesulfonamide; 6-(morpholine-4 -substituted) -Ν,Ν'-diphenyl-[1,3,5]-triazine-2,4-diamine; Ν-p-chlorophenyl-6-(morpholin-4-substituted)-indole,-benzene -[1,3,5]-triazine-2,4-diamine; Ν-o-chlorophenyl-6-(morpholin-4-substituted)-indole,-phenyl-[1,3,5 ]-triazine-2,4-diamine; Ν-m-chlorophenyl-6-(morpholin-4-substituted)-Ν'-phenyl-[1,3,5]-triazine-2,4 -diamine; hydrazine, hydrazine, -dichlorophenyl-6-(morpholin-4-substituted)-[1,3,5]-triazine-2,4- Amine; Ν'-di-o-chlorophenyl-6-(morpholin-4-substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine, -di-p-chloro Phenyl-6-(morpholin-4-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-o-methoxyphenyl-6- (morpholine-4-substituted) - Ν,-phenyl-[1,3,5]-triazine-2,4-diindole-m-decyloxyphenyl-6-(morpholin-4-substituted)-indole,-phenyl- [1,3,5]-triazine-2,4-diamine; Ν-p-oxo tomb phenyl-6-(morpholin-4-substituted)-indole,-phenyl-[1,3,5 ]-Triazine-2,4-diamine; Ν,Ν,-di-p-methoxyphenyl-6-(morpholine-4-substituted)-[1,3,5]-triazine-2,4 -diamine; hydrazine, Ν'-di-o-methoxyphenyl-6-(morpholin-4-substituted)-[1,3,5]-triazine-2,4-diamine; hydrazine, hydrazine, - bis-methoxyphenyl-6-(morpholin-4-substituted)-[1 ,3,5]-triazine-2,4-diamine; 6-(morpholine-4-substituted) phenyl -Ν,-p-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine; 6-(morpholin-4-substituted)-N-phenyl-N,- O-trifluoromethoxyphenyl-[1,3,5]-triazine-2,4-diamine; 6-(morpholin-4-substituted)-N-phenyl-N,-m-trifluoroanthracene Oxyphenyl-[1,3,5]-triazine-2,4-diamine; N-p-bromophenyl-6-(morpholin-4-substituted) -N,-phenyl-[1,3,5]-triazine-2,4-diamine; N-o-bromophenyl-6-(morpholin-4-substituted)-N,-phenyl-[ 1,3,5]-triazine-2,4-diamine; N-m-bromophenyl-6-(morpholine-4-substituted)-N,-phenyl-[1,3,5]-three Alkyl-2,4-diamine; N-p-ethoxyphenyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5]-triazine-2,4- Diamine; 4-(6-(morpholine-4-substituted)-4-anilino-[1,3,5]-triazin-2-amino)benzamide; 3-(6-(morpholine- 4-substituted)-4-anilino-[1,3,5]-triazin-2-amino)benzamide; 2-(6-(morpholine-4-substituted)-4-anilino-[1 ,3,5]-triazin-2-amino)benzamide; N-p-fluorophenyl-N,-p-methoxyphenyl-6-(morpholin-4-substituted)-[1,3, 5]-triazine-2,4-diamine; N-p-fluorophenyl-6-(morpholin-4-substituted)-N,-p-trifluoromethoxyphenyl-[1,3,5] -triazine-2,4-diamine; N-p-fluorophenyl-6-(morpholin-4-substituted)-Ν'-phenyl-[1,3,5]-triazine-2,4- Diamine; Ν-(3,4-dimethoxy)phenyl-6-(morpholine-4-substituted)-indole,-phenyl-[1,3,5]-triazine-2,4- Diamine; Ν-(2,3-dimethoxy)phenyl-6-(morpholin-4-substituted)-indole,-phenyl-[1,3,5]-triazine-2,4- two Ν-(2,4-Dimethoxy)phenyl-6-(morpholin-4-substituted)-indole,-phenyl-[1,3,5]-triazine-2,4-diamine Ν-(2,5-Dimethoxy)phenyl-6-(morpholin-4-substituted)-indole,-phenyl-[1,3,5]-triazine-2,4-diamine Ν-(2,6-dimethoxy)phenyl-6-(morpholin-4-substituted)-indole,-phenyl-[1,3,5]-triazine-2,4-diamine Ν-(3,5-dimethoxy)phenyl-6-(morpholin-4-substituted)-Ν'-phenyl[1,3,5]-triazine-2,4-diamine;4-(4-anilino-6-(morpholin-4-substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide; 3-(4-anilino-6- (? Phenyl-4-substituted)-[1,3,5]-triazin-2-amino)benzenesulfonamide; 2-(4-anilino-6-(morpholin-4-substituted)-[1,3, 5]-triazine-2-amino)benzenesulfonamide; 4-(4-p-methoxyanilino-6-(morpholin-4-substituted)-[1,3,5]-triazine-2- Amino)benzenesulfonamide; Ν-p-methoxyphenyl-indole,-(2-(morpholin-4-substituted)ethyl)-indole-phenyl-[1,3,5]-triazine- 2,4,6-triamine; Ν-(2-(N-butyl-4-substituted)ethyl)-indole, hydrazine,,-diphenyl-[1,3,5]-triazine-2, 4,6-triamine; Ν-benzyl-hydrazine, -(2-(morpholin-4-substituted)ethyl)-indole,-phenyl-[1,3,5]-triazine-2, 4,6- Triamine; Ν-benzyl_6-(morpholin-4-substituted)-indole,-phenyl-[1,3,5]-triazine-2,4-diamine; Ν-p-methoxybenzyl Base 6-(morpholin-4-substituted)-oxime,-phenyl-[1,3,5]-triazine-2,4-diamine; Ν-o-methoxybenzyl-6- (?啉_4-substituted)-Ν,-phenyl-[1,3,5]-triazine-2,4-diamine; Ν-metamethoxybenzyl-6-(morpholin-4-substituted) - Ν,-phenyl-[1,3,5]-triazine-2,4-diamine; 'Ν-benzyl-6-(morpholin-4-substituted)-Ν,-p-tolyl-[ 1,3,5]-triazine-2,4-diamine; 4-(4-benzylamino-6-(morpholin-4-substituted)-[1,3,5]-triazine-2- Amino)benzenesulfonamide; N-benzyl-N,-p-methoxyphenyl-6-(morpholin-4-substituted)-[1,3,5]-triazine-2,4-diamine; N-benzyl-N,-p-fluorophenyl-6-(morpholin-4-substituted)-[1,3,5]-triazine-2,4-diamine; N-benzyl-N,- o-Fluorophenyl-6-(norpo--4-substituted)-[1,3,5]-triazine-2,4-diamine; N-benzyl-N,-m-fluorophenyl-6- ( Morpholine-4-substituted)-[1,3,5]-triazine-2,4-diamine; Ν,Ν'-dibenzyl-6-(morpholine-4-substituted)-[1,3 ,5]-triazine-2,4-diamine; 2-[4,6-diphenylamino-[1,3,5]-triazine-2-amino]ethanol; 3-[4,6-di Anilino-[1,3,5]- Triazin-2-amino]propanol; 2-[4,6-diphenylamino-[1,3,5]-triazine-2-amino]ethylamine; 2-[4-p-methoxyanilide -6-anilino-[1,3,5]-triazine-2-amino]ethanol; 3-[4-p-methoxyanilino-6-anilino-[1,3,5]-triazine 2-amino]propanol; 2-[4-p-methoxyanilino-6-anilino-[1,3,5]-triazin-2-amino]ethylamine; 2-[4-benzylamine -6-anilino-[1,3,5]-triazine-2-amino]ethanol; 3-[4-benzylamino-6-anilino-[1,3,5]-triazine-2 -amino]propanol; 2-[4-benzylamino-6-anilino-[1,3,5]-triazin-2-amino]ethylamine; 4,6-di(morpholine-4-substituted - Ν-phenyl-[1,3,5]-triazin-2-amine; 4-[4,6-di(morpholine-4-substituted)-[1,3,5]-triazine- 2-amino]benzamide; Ν-p-methoxyphenyl-4,6-di(morpholine-4-substituted)-[1,3,5]-triazin-2-amine; Ν-p-fluoro Phenyl-4,6-di(morpholine-4-substituted)-[1,3,5]-triazin-2-amine; Ν-benzyl- 4,6-di(morpholine-4-substituted) -[1,3,5]-triazin-2-amine; 4-chloro-6-(morpholin-4-substituted)-fluorenyl-phenyl-[1,3,5]-triazin-2-amine ; 4-[4-chloro-6-(morpholin-4-substituted)-[1,3,5]-triazine-2-amino]benzamide; 4-chloro-indole-p-methoxyphenyl- 6- (morpholin-4- ))-[1,3,5]-triazin-2-amine; 4-chloro-indole-o-methoxyphenyl-6-(morpholin-4-substituted)-[1,3,5]- Triazin-2-amine; 4-chloro-indole-m-methoxyphenyl-6-(morpholine-4-substituted)-[1,3,5]-triazin-2-amine; 4-chloro- Ν-p-fluorophenyl-6-(L-butyl-4-substituted)-[1,3,5]-triazin-2-amine; Ν-benzyl-4-chloro-6- (morpholin-4- Substituted)-[1,3,5]-triazin-2-amine; 2-chloro-4,6-di(morpholine-4-substituted)-[1,3,5]-triazine; 2-A Oxy-4,6-di(morpholine-4-substituted)-[1,3,5]-triazine; Ν-benzyl-4-methoxy-6-(morpholin-4-substituted) [1,3,5]-triazin-2-amine; Ν-benzyl-4-ethoxy-6-(morpholin-4-substituted)-[1,3,5]-triazine-2- Amine; 2,4,6-tris(morpholin-4-substituted)-[1,3,5]-triazine; 4-decyloxyp-methoxyphenyl-6-(morpholin-4-substituted )-[1,3,5]-triazine-2-amine; 2_[4-(4,6-di-p-methoxyanilino-[1,3,5]-triazine-2-substituted) piperidine Alkyl-1-substituted]ethanol; 2_[4-(4-p-methoxyanilino-6-anilino-[1,3,5]-triazine-2-substituted) piperazin-1-substituted]ethanol ; 2-[4-(4,6-diphenylamino-[1,3,5]-triazine-2-substituted) piperazin-1-substituted]ethanol; Ν-p-thiophenyl-6- (morpholin-4-substituted) -N,- P-phenyl-[1,3,5]-triazine-2,4-diamine; N-p-thiophenyl-6-(morpholin-4-substituted)-N,-p-methoxy Phenyl-[1,3,5]-triazine-2,4-diamine; N-p-thiophenyl-6-(morpholin-4-substituted)-N,-phenyl-[1, 3,5]-triazine-2,4-diamine; N-o-methylthiophenyl-6-(morpholine-4-substituted)-N,-phenyl-[1,3,5]-three Azin-2,4-diamine; N-m-methylthiophenyl-6-(morpholin-4-substituted)-N,-phenyl-[1,3,5]-triazine-2,4- Diamine; 6-(morpholin-4-substituted)-N-phenyl-N,-(pyridin-4-substituted)-[1 ,3,5]-triazine-2,4-diamine; 6- (morpholin-4-substituted) (pyridine-4-substituted)-Ν'-p-tolyl-[1,3,5]-triazine-2,4-diamine; 6-(morpholin-4-substituted -Ν-(pyridyl-4-substituted)-Ν'-o-tolyl-[1,3,5]-triazine-2,4-diamine; 6-(morpholin-4-substituted)-Ν- (pyridyl-4-substituted)-Ν'-m-phenyl-[1,3,5]-triazine-2,4-diamine; Ν-p-methoxyphenyl-6-(morpholine-4 -substituted) -Ν,-(pyridyl-4-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-o-methoxyphenyl-6-(morpholin-4- Substituted) -Ν,-(pyridyl-4-substituted)-[1,3,5]-triazine-2,4-diamine; Ν-metamethoxyphenyl-6- ( 4-substituted) -Ν, - (pyridin-4-substituted) - [1,3,5] - triazine-2,4-diamine. A process for producing a substituted [1,3,5]triazine compound of the formula (I) according to Claim 1 or a pharmaceutically acceptable salt thereof or a solvate or hydrate thereof, characterized in that Includes the following steps:
(1)将通式 (II)所示化合物在碱性溶剂中于 0-50。C温度下与取代胺 反应，  (1) The compound of the formula (II) is used in an alkaline solvent at 0-50. Reacts with a substituted amine at C temperature,
Figure imgf000105_0001
Figure imgf000105_0001
其中， Rx为氢、 卤素、 羟基、 琉基、 -C4烃基胺、 或(^ 4氨烷基; 和 分别为氢、 （¾素、 CrC4氨烷基、 或 (^-(^ 代烃基， 从而得到 通式 (III)所示化合物：
Figure imgf000106_0001
Wherein R x is hydrogen, halogen, hydroxy, decyl, -C 4 hydrocarbylamine, or (^ 4 aminoalkyl; and respectively hydrogen, ( 3⁄4 , C r C 4 aminoalkyl, or (^-( ^ Hydrocarbyl group, thereby obtaining a compound of the formula (III):
Figure imgf000106_0001
(III)  (III)
其中， 、 R2、 Rx和 Ry与通式 (1)、 （II)中定义相同； Wherein, R 2 , R x and R y are the same as defined in the formulae (1) and (II);
(2)将通式 (III)所示化合物在碱性溶剂中于 20-100。C 温度下与取 代胺、 取代芳胺、 取代芳基烷胺、 醇或硫醇等反应， 得到通式 (IV)所示 化合物：  (2) The compound of the formula (III) is used in an alkaline solvent at 20-100. The compound represented by the formula (IV) is obtained by reacting with a substituted amine, a substituted arylamine, a substituted arylalkylamine, an alcohol or a thiol at a C temperature:
Figure imgf000106_0002
Figure imgf000106_0002
(IV)  (IV)
其中， R!、 R2、 R3、 R4与通式 (I)中定义相同， Rx与通式（Π ) 中定 义相同； Wherein R!, R 2 , R 3 and R4 are the same as defined in the formula (I), and R x is the same as defined in the formula (Π);
(3)在 0-120°C下、 在碱性溶剂中， 将通式 (IV)所示化合物与取代 脂环胺、 取代芳基胺、 取代芳基烷胺、 醇或硫醇进行反应， 得到式 (I) 所示化合物；  (3) reacting a compound of the formula (IV) with a substituted alicyclic amine, a substituted arylamine, a substituted arylalkylamine, an alcohol or a thiol at 0-120 ° C in an alkaline solvent. Obtaining a compound of formula (I);
(4)根据需要， 通过本领域常规方法进行成盐反应， 或形成溶剂合 物或水合物。 4、如权利要求 3所述的制备方法，其中步骤 (1)和步骤 (2)中所述的 碱性溶剂是用惰性溶剂配制的碱溶液， 所述碱选自包括吡啶、 三乙胺、 4-二曱胺基吡啶、二异丙基乙胺的有机碱和包括碳酸钠、碳酸钾、 氢氧 化钠、 氢氧化钾的无机碱的组。 (4) A salt formation reaction or a solvate or a hydrate is formed by a conventional method in the art as needed. The method according to claim 3, wherein the alkaline solvent described in the step (1) and the step (2) is an alkali solution prepared by using an inert solvent selected from the group consisting of pyridine, triethylamine, An organic base of 4-diguanylidenepyridine, diisopropylethylamine, and a group of inorganic bases including sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.
5、 如权利要求 4所述的制备方法， 其中所述惰性溶剂为一种或多 种选自包括四氢呋喃、 乙醚、 二曱基曱酰胺、 乙二醇二甲醚、 乙二醇 二乙醚、 二氧六环的组的溶剂。 ' The method according to claim 4, wherein the inert solvent is one or more selected from the group consisting of tetrahydrofuran, diethyl ether, dimercaptoamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, and two Solvent for the group of oxyhexacyclohexane. '
6、 如权利要求 3所述的制备方法， 其中步骤 (3)中所述的碱性溶剂 是用极性有机溶剂配制的碱溶液， 所述极性有机溶剂为一种或多种选 自包括二曱基甲酰胺、 二甲基亚砜、 二氧六环、 乙醇、 甲醇、 丙酮、 乙酸乙酯和四氢呋喃的组的溶剂； 所述碱为一种或多种选自包括吡啶、 三乙胺、 4-二甲胺基吡啶 (DMAP)、 二异丙基乙胺的有机碱和包括碳酸 钠、 碳酸钾、 氢氧化钠、 氢氧化钾的无机碱的组的碱。 The preparation method according to claim 3, wherein the alkaline solvent described in the step (3) is an alkali solution prepared by using a polar organic solvent, and the polar organic solvent is one or more selected from the group consisting of a solvent of the group of dimercaptocarboxamide, dimethyl sulfoxide, dioxane, ethanol, methanol, acetone, ethyl acetate and tetrahydrofuran; the base is one or more selected from the group consisting of pyridine and triethylamine a base of 4-dimethylaminopyridine (DMAP), an organic base of diisopropylethylamine, and a group of inorganic bases including sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide.
7、 权利要求 1所述的取代 [1,3，5]三嗪类化合物或其药学上可接受 的盐或它们的溶剂合物或水合物作为环氧合酶抑制剂的应用。 Use of the substituted [1,3,5]triazine compound according to Claim 1 or a pharmaceutically acceptable salt thereof or a solvate or hydrate thereof as a cyclooxygenase inhibitor.
8、 权利要求 1所述取代 [1,3，5]三嗪类化合物或其药学上可接受的 盐或它们的溶剂合物或水合物作为 5-脂氧酵抑制剂的应用。 The use of the substituted [1,3,5]triazine compound or a pharmaceutically acceptable salt thereof or a solvate or hydrate thereof as claimed in claim 1 as a 5-lipoxygenase inhibitor.
9、 权利要求 1所述取代 [1，3,5]三嗪类化合物或其药学上可接受的 盐或它们的溶剂合物或水合物作为环氧合酶和 5-脂氧酶双重抑制剂的 应用。 A substituted [1,3,5]triazine compound or a pharmaceutically acceptable salt thereof or a solvate or hydrate thereof as claimed in claim 1 as a double inhibitor of cyclooxygenase and 5-lipoxygenase Applications.
10、权利要求 1所述取代 [1,3,5]三嗪类化合物或其药学上可接受的 盐或它们的溶剂合物或水合物在制备预防和 /或治疗炎症疾病的药物上 的应用。 The use of the substituted [1,3,5]triazine compound of claim 1, or a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof, for the preparation of a medicament for preventing and/or treating an inflammatory disease .
11、权利要求 1所述取代 [1,3,5]三嗪类化合物或其药学上可接受的 盐或它们的溶剂合物或水合物作为 EGFR酶抑制剂的应用。 The use of the substituted [1,3,5]triazine compound or a pharmaceutically acceptable salt thereof or a solvate or hydrate thereof as claimed in claim 1 as an EGFR enzyme inhibitor.
12、权利要求 1所述取代 [1,3,5]三嗪类化合物或其药学上可接受的 盐或它们的溶剂合物或水合物用于预防和 /或治疗和 /或辅助治疗癌症 的应用。 The substituted [1,3,5]triazine compound according to Claim 1, or a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof, for use in the prevention and/or treatment and/or adjuvant treatment of cancer. application.
13、 一种药物组合物， 其特征在于， 所述药物组合物包含治疗有 效量的如式 (I)所示的取代 [1,3,5]三嗪类化合物或其药学上可接受的盐 或它们的溶剂合物或水合物和至少一种药学上可接受的载体。 A pharmaceutical composition comprising a therapeutically effective amount of a substituted [1,3,5]triazine compound represented by formula (I) or a pharmaceutically acceptable salt thereof. Or their solvates or hydrates and at least one pharmaceutically acceptable carrier.
14、 如权利要求 13所述的药物组合物， 其特征在于， 所述药学上 可接受的载体包括离子交换剂、 氧化铝、 硬脂酸铝、 卵磷脂、 血清蛋 白、 緩冲物质如磷酸盐、 甘油、 山梨酸、 山梨酸钾、 饱和植物脂肪酸 的部分甘油酯混合物、 水， 盐或电解质、 磷酸氢二钠、 磷酸氢钾、 氯 化钠、 锌盐、 胶态氧化硅、 三硅酸镁、 聚乙烯吡咯烷酮、 纤维素物质、 聚乙二醇、 羧曱基纤维素钠、 聚丙烯酸酯、 蜂蜡和羊毛脂。 The pharmaceutical composition according to claim 13, wherein the pharmaceutically acceptable carrier comprises an ion exchanger, alumina, aluminum stearate, lecithin, serum protein, a buffer substance such as phosphate. , glycerin, sorbic acid, potassium sorbate, partial glyceride mixture of saturated plant fatty acids, water, salt or electrolyte, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate , polyvinylpyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax and lanolin.
15、如权利要求 13所述的药物组合物用于预防和 /或治疗炎症性疾 病的应用。 15. Use of a pharmaceutical composition according to claim 13 for the prevention and/or treatment of an inflammatory disease.
16、 如权利要求 13所述的药物组合物用于预防和 /或治疗和 /或辅 助治疗肿瘤疾病的应用。 16. Use of a pharmaceutical composition according to claim 13 for the prevention and/or treatment and/or adjuvant treatment of a neoplastic disease.
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