Abstract:
This present invention discloses a heterocyclic substituted acardite derivate and application thereof, namely compounds in the general formula (1) or the general formula (2) or pharmaceutically acceptable salts thereof, wherein A is monosubstituted or polysubstituted quinoline, isoquinoline, quinazoline, pyrrole or pyrimidine, and the substituent is halogen, C 1-5 alkyl, C 1-5 haloalkyl, C 1-5 alkoxy, C 1-5 haloalkoxy, C 1-5 alkylamino, C 1-5 haloalkylamino, amino or nitryl; R 1  is C 1-5 alkyl; R 2  is one or more selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy; and R 3  is one or more selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy. The compound of the present invention and the pharmaceutically acceptable salt thereof can be used for treating tumor or leukemia.

Description:
Cross Reference to Related Patent Application 
     The present application is the US national stage of PCT/CN2010/072417 filed on May 4, 2010, which claims the priority of the Chinese patent application No. 200910026748.8 filed on May 5, 2009, which application is incorporated herein by reference. 
     FIELD OF THE INVENTION 
     This present invention relates to an aromatic heterocyclic substituted acardite derivate and application thereof In addition, the present invention relates to application of aromatic heterocyclic substituted acardite derivate and pharmaceutically acceptable salts thereof in the treatment of tumor or leukemia. 
     BACKGROUND OF THE INVENTION 
     With better understanding of the tumor molecular mechanisms, the research on the targeted therapy of the tumor moleculars has achieved important advance. Protein kinase inhibitor is one of newly developed targeted therapy drugs, which affects the survival, proliferation and disease progression of tumor cells through blocking the intra-cellular molecular transduction pathway. Raf kinases play a crucial role in the signal transduction pathway of Raf/MEK/ERK. Although the function of the Raf kinase in normal tissues is not yet understood, but the existing basic and clinical research results have shown that the upregulation of Raf gene and overexpression of its protein are present in various solid tumors, including renal cell carcinoma, hepatocellular carcinoma, melanoma and non-small cell lung cancer. Currently, more and more single target point and multi-target point therapy drugs for Raf kinases are successfully developed and applied clinically, for example, sorafenib and erlotinib have achieved good clinical results, and the anti-tumor therapy has came into the “molecular targeted therapy” era. CN200810129360.6 disclosed that a kind of aromatic heterocyclic substituted acardite derivates with no substituent or only carbamyl in the A ring have prospect of inhibiting specific tumors, and the preliminary pharmacological experiments found that the effects of some compouns are better than sorafenib. 
     SUMMARY OF THE INVENTION 
     The objective of the present invention is to provide an aromatic heterocyclic substituted acardite derivate having more medicinal value through structural modification based on the existing technology. After the present invention adds specific substituents in the A ring, especially adding substituents in the quinazoline, pyrrole or pyrimidine rings, the inhibitory activity and selectivity of the compounds to specific tumors are greatly increased, and the absorptivity and utilization rate of the compounds are increased and the toxic side effects are reduced. The objective of the present invention is further to provide application of the compound or pharmaceutically acceptable salts thereof in the treatment of tumor or leukemia. The heterocyclic substituted acardite derivate of the present invention can be represented by the following formulas [1] and [2]: 
     
       
                 
         
             
             
         
      
         
         
           
             wherein, 
           
         
       
    
     A is monosubstituted or polysubstituted quinoline, isoquinoline, quinazoline, pyrrole or pyrimidine, preferably monosubstituted or polysubstituted quinazoline, pyrrole or pyrimidine, further preferably monosubstituted or polysubstituted quinazoline; the substituent is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, haloalkylamino, amino or nitryl, preferably halogen, C 1-5 alkyl, C 1-5 haloalkyl, C 1-5 alkoxy, C 1-5 haloalkoxy, C 1-5 alkylamino, C 1-5 haloalkylamino, amino or nitryl, more preferably halogen, C 1-5 alkyl, C 1-5 haloalkyl, C 1-5 alkoxy, C 1-5 haloalkoxy, amino or nitryl; still more preferably halogen, amino, C 1-5 alkyl or C 1-3 alkoxy, particularly preferably Cl, Br, F, amino, methoxy, methyl, ethyl, propyl, isopropyl, butyl or t-butyl in the present invention. 
     R 1  is alkyl, more preferably C 1-5 alkyl, most preferably methyl, ethyl, propyl and isopropyl. 
     R 2  is one or more selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy; preferably one or more selected from hydrogen, halogen, C 1-5 alkyl, C 1-5 alkoxy, C 1-5 haloalkyl or C 1-5 haloalkoxy, most preferably one or more selected from H, Cl, Br, F, methoxy, ethoxy, propoxy, methyl, ethyl, propyl, isopropyl, butyl, t-butyl or trifluoromethyl. 
     R 3  is one or more selected from hydrogen, halogen, alkyl, alkoxy, C 1-5  haloalkyl or C 1-5 haloalkoxy, preferably one or more selected from hydrogen, halogen, C 1-5 alkyl, C 1-5 alkoxy, C 1-5 haloalkyl or C 1-5 haloalkoxy, most preferably one or more selected from H, Cl, Br, F, methoxy, ethoxy, propoxy, methyl, ethyl, propyl, isopropyl, butyl, t-butyl or trifluoromethyl. 
     The pharmaceutically acceptable salts of the compound in the present invention are selected from:
     a) basic salts of inorganic acids and organic acids, the described acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, mesylate, trifluoromethanesulfonic acid, benzene sulfonic acid, paratoluenesulfonic acid, 1-naphthalene sulfonic acid, 2-naphthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid or almonds acid;   b) acid salts of organic and inorganic base, the described cation is selected from alkali metal cation, alkaline earth metal cation, ammonium cation, aliphatic-substituted ammonium cation or aromatic-substituted ammonium cation.   

     Preparation of the Compound of Formula 1 
     Method 1: the target compound is obtained from substituted heterocyclic 2-carboxylate as starting materials through acyl chlorination, aminoalkylation, two-step condensation and salt forming reaction and the route is as follows: 
     
       
                 
         
             
             
         
      
     
     Method 2: the target compound is obtained from substituted heterocyclic 2-carboxylate as starting materials through acyl chlorination, aminoalkylation, condensation and salt forming reaction and the route is as follows: 
     
       
                 
         
             
             
         
      
     
     Preparation of the Compound of Formula 2 
     The target compound is obtained from halogen substituted heterocyclic as starting materials through two-step condensation and salt forming reaction and the route is as follows: 
     
       
                 
         
             
             
         
      
     
     The substituents A, R 1 , R 2  and R 3  in the above menthioned reaction routes have the above described meanings. 
     The beneficial effects of the present invention are as follows: 
     The derivatives of the present invention have raf kinase inhibitory activity. The action mechanism of this compound is that this compound affects the survival, proliferation and disease progression of tumor cells through inhibiting raf kinase and blocking the ras protein signal transduction connection, thereby inhibiting the growth of achiblastomas, such as malignant tumors (for example, bladder cancer, lung cancer, pancreatic cancer), myelopathy (for example, myelogenous leukemia) or adenoma (for example, villous adenoma of colon). 
     The experiment results have shown that the compound with special substituents added in A ring in the present invention has stronger antitumor activity compared with the previously disclosed compound with no substituent or only carbamyl in A ring, which is obviously stronger than Sorafenib in the effects of tumor cell metastasis and tumor angiogenesis. The test on normal human umbilical vein endothelial cells found that this part of the compounds have lower toxicity to normal human cells, such as endothelial cell, which are safe and reliable, but which can inhibit the tumor angiogenesis to achieve anti-tumor activity. In vivo nude mice transplanted model experiment proved that the compound of the present invention has inhibitory effects to human liver and kidney cancer and the effects are stronger than Sorafenib, which has more obvious effects on lung cancer and the effects are significantly better than the positive control drug Sorafenib. The results show that the compound of the present invention or pharmaceutically acceptable salts thereof can be used in the drugs for the treatment of cancer or leukemia, particularly drugs used for treating lung cancer. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The melting point was measured by the electric melting point instrument and the thermometer was not corrected; the elemental analyzer was Foss-Heraeus type; and the mass spectrograph was electrospray ionization mass spectrometry. 
     A: preparing the aromatic heterocyclic substituted acardite derivate having the general formula 1 accroding to method 1 
     
       
                 
         
             
             
         
      
     
     Embodiment 1: Preparation of 4-chloro-6-methoxyquinolinyl-2-carbonyl chloride 50g of 4-hydroxy-6-methoxy-2-quinolinecarboxylic acid and 100 m1 of thionyl chloride were added into a three-necked flask, heated and refluxed for 17 hours until the reaction finished. The filtrate was added with toluene and concentrated under vacuum to obtain yellow solid, namely 4-chloro-6-methoxyquinolinyl-2-carbonyl chloride, with dry weight of 50g. 
     Embodiment 2: Preparation of 4-chloro-7-fluoroquinazolinyl-2-carbonyl chloride Prepared from 4-hydroxy-7-fluoro-2-quinazolinecarboxylic acid with reference to the method of embodiment 1. 
     Embodiment 3: Preparation of 4-methoxy-5-chloropyrimidine-2-carbonyl chloride Prepared from 4-methoxy-5-hydroxy-2-pyrimidinecarboxylic acid with reference to the method of embodiment 1. 
     Embodiment 4: Preparation of 4-chloro-7-amino-isoquinolyl-2-carbonyl chloride Prepared from 4-hydroxy-7-amino-2-quinazolinecarboxylic acid with reference to the method of embodiment 1. 
     Embodiment 5: Preparation of 5-methyl-4-chloropyrrolyl-2-carbonyl chloride Prepared from 5-methyl-4-hydroxy-2-pyrrolecarboxylic acid with reference to the method of embodiment 1. 
     Embodiment 6: Preparation of 4-chloro-6-methoxyl-N-methyl-2-quinolinyl formamide 10 g of 4-chloro-6-methoxyquinolinyl-2-carbonyl chloride (obtained from embodiment 1) was reacted with 200 ml of 2M methylamine ethanol solution under 0° C. for 36 hours until the reaction finished. The solvent was evaporated under vacuum and the residues were added with water followed by stirring evenly. Ethyl acetate was added for extracting and the ethyl acetate layer was dried with anhydrous sodium sulfate. The ethyl acetate layer was removed under vacuum to obtain 9 g of 4-chloro-6-methoxy-N-methyl-2-quinoline carboxamide. 
     Embodiment 7: Preparation of 4-chloro-7-fluoro-N-methyl-2-quinazoline methanamide Prepared from 4-chloro-7-fluoroquinazolinyl-2-carbonyl chloride with reference to the method of embodiment 6. 
     Embodiment 8: Preparation of 4-methoxyl-5-chloro-N-methyl-2-pyrimidinecarboxamide Prepared from 4-methoxyl-5-chloropyrimidinyl-2-carbonyl chloride with reference to the method of Embodiment 6. 
     Embodiment 9: Preparation of 4-chloro-7-amino-N-methyl-2-isoquinolinecarboxamide Prepared from 4-chloro-7-aminoisoquinolyl-2-carbonyl chloride with reference to the method of embodiment 6. 
     Embodiment 10: Preparation of 5-methyl-4-chloro-N-methyl-2-pyrrole carboxamide Prepared from 5-methyl-4-chloropyrryl-2-carbonyl chloride with reference to the method of embodiment 6. 
     Embodiment 11: Preparation of 4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquinolinyl) oxy))aniline 10 g of 4-chloro-6-methoxyl-N-methyl-2-quinoline carboxamide (obtained from embodiment 6) was dissolved in DMF, added with 20 g of potassium tert-butylate and 10 g of 4-aminophenol and kept at 70° C. under the protection of nitrogen for 8 hours. After the reaction finished, the reaction solution was poured into 250 ml of ethyl acetate and 250 ml of saturated saline solution and stirred evenly for separation. The water solution was extracted with ethyl acetate again. The ethyl acetate layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The solvent was evaporated and removed under vacuum to obtain 6 g of 4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquinolinyl)oxy))aniline. 
     Embodiment 12: Preparation of 4-(2-(N-Methylaminoformoxyl)-4-(7Fluoroquinazolinyl) Oxy)Aniline 
     Prepared from 4-chloro-7-fluoro-N-methyl-2-quinazoline methanamide with reference to the method of embodiment 11. 
     Embodiment 13: Preparation of 4-(2-(N-methylaminoformoxyl)-5-(4-methoxypyrimidinyl) oxy)aniline Prepared from 4-methoxyl-5-chloro-N-methyl-2-pyrimidinecarboxamide with reference to the method of embodiment 11. 
     Embodiment 14: Preparation of 4-(2-(N-Methylaminoformoxyl)-4-(7-Amino-Isoquinolyl) Oxy)Aniline Prepared from 4-chloro-7-amino-N-methyl-2-isoquinolinecarboxamide with reference to the method of embodiment 11. 
     Embodiment 15: Preparation of 4-(2-(N-methylaminoformoxyl)-4-(5-methyl-pyrryl)oxy) Aniline Prepared from 5-methyl-4-chloro-N-methyl-2-pyrrole carboxamide with reference to the method of embodiment 11. 
     Embodiment 16: Synthesis of 4-chloro-3-(trifluoromethyl)phenyl isocyanate 20 g of 4-chloro-3-(trifluoromethyl)aniline was mixed with 100 ml benzene, added with 20g of diphosgene and refluxed for 12 hours. The reaction solution was added with toluene, and the solvent was evaporated and removed under vacuum to obtain the product 4-chloro-3-(trifluoromethyl)phenyl isocyanate. 
     Embodiment 17: Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate Prepared from 4-bromo-3-(trifluoromethyl)aniline with reference to the method of embodiment 16. 
     Embodiment 18: Synthesis of 4-fluoro-3-(trifluoromethyl)phenyl isocyanate Prepared from 4-fluoro-3-(trifluoromethyl)aniline with reference to the method of embodiment 16. 
     Embodiment 19: Synthesis of compound 17 g of 4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquinolinyl)oxy))aniline (obtained from embodiment 11), 5 g of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (obtained from embodiment 16) and 50 ml of methylene dichloride were stirred at room temperature for 24 hours, and the crystals were separated out followed by air pump filtration and collection to obtain N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquino linyl)oxy))phenyl)urea. 
     Embodiment 20: Synthesis of compound 2N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquino linyl)oxy))phenyl)urea was prepared from 4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquinolinyl) oxy))anilineaniline and 4-fluoro-3-(trifluoromethyl)phenyl isocyanate according to the method of Embodiment 19. 
     Embodiment 21: Synthesis of compound 3N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquin olinyl)oxy))phenyl)urea was prepared from 4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquinolinyl)oxy))aniline and 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to the method of Embodiment 19. 
     Embodiment 22: Synthesis of compound 4N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(7fluoroquinazol inyl)oxy) phenyl)urea was prepared from 4-(2-(N-methylaminoformoxyl)-4-(7fluoroquinazolinyl)oxy)aniline (obtained from embodiment 12) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to the method of Embodiment 19. 
     Embodiment 23: Synthesis of compound 5N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(7fluoroquinazoli nyl)oxy) phenyl)urea was prepared from 4-(2-(N-methylaminoformoxyl)-4-(7fluoroquinazolinyl)oxy)aniline and 4-fluoro-3-(trifluoromethyl)phenyl isocyanate according to the method of Embodiment 19. 
     Embodiment 24: Synthesis of compound 6N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(7fluoroquinazol inyl)oxy) phenyl)urea was prepared from 4-(2-(N-methylaminoformoxyl)-4-(7fluoroquinazolinyl)oxy)aniline and 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to the method of Embodiment 19. 
     Embodiment 25: Synthesis of compound 7N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-5-(4-methoxypyri midinyl)oxy) phenyl)urea was prepared from 4-(2-(N-methylaminoformoxyl)-5-(4-methoxypyrimidinyl)oxy)aniline (obtained from embodiment 13) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to the method of Embodiment 19. 
     Embodiment 26: Synthesis of compound 8N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-5-(4-methoxypyrim idinyl)oxy) phenyl)urea was prepared from 4-(2-(N-methylaminoformoxyl)-5-(4-methoxypyrimidinyl)oxy)aniline and 4-fluoro-3-(trifluoromethyl)phenyl isocyanate according to the method of Embodiment 19. 
     Embodiment 27: Synthesis of compound 9N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-5-(4-methoxypyri midinyl)oxy) phenyl)urea was prepared from 4-(2-(N-methylaminoformoxyl)-5-(4-methoxypyrimidinyl)oxy)aniline and 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to the method of Embodiment 19. 
     Embodiment 28: Synthesis of compound 10N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(7-amino-isoquin olyl)oxy)phenyl)urea was prepared from 4-(2-(N-methylaminoformoxyl)-4-(7-amino-isoquinolyl)oxy)aniline (obtained from embodiment 14) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to the method of Embodiment 19. 
     Embodiment 29: Synthesis of compound 11N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(7-amino-isoquin olyl)oxy)phenyl)urea was prepared from 4-(2-(N-methylaminoformoxyl)-4-isoquinolyl)oxy)aniline and 4-fluoro-3-(trifluoromethyl)phenyl isocyanate according to the method of Embodiment 19. 
     Embodiment 30: Synthesis of compound 12N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(7-amino-isoqui nolyl)oxy)phenyl)urea was prepared from 4-(2-(N-methylaminoformoxyl)-4-isoquinolyl)oxy)aniline and 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to the method of Embodiment 19. 
     Embodiment 31: Synthesis of compound 13N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(5-methyl-pyrryl) oxy)phenyl)urea was prepared from 4-(2-(N-methylaminoformoxyl)-4-(5-methyl-pyrryl)oxy)aniline (obtained from embodiment 15) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to the method of Embodiment 19. 
     Embodiment 32: Synthesis of compound 14N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(5-methyl-pyrryl) oxy)phenyl)urea was prepared from 4-(2-(N-methylaminoformoxyl)-4-(5-methyl-pyrryl)oxy)aniline and 4-fluoro-3-(trifluoromethyl)phenyl isocyanate according to the method of Embodiment 19. 
     Embodiment 33: Synthesis of compound 15N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(5-methyl-pyrryl) oxy)phenyl)urea was prepared from 4-(2-(N-methylaminoformoxyl)-4-(5-methyl-pyrryl)oxy)aniline and 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to the method of Embodiment 19. 
     Embodiment 34: Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquino linyl)oxy))phenyl)urea mesylate 10 g of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquino linyl)oxy))phenyl)urea free base was dissolved in 300 ml of ether and added with methanesulfonic acid/ethanol solution in drops at room temperature until pH=2, and white crystal was precipitated followed by air pump filtration and collection to obtain N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquino linyl)oxy))phenyl)urea mesylate. 
     Embodiment 35: Synthesis of pharmaceutically acceptable salts of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquin olinyl)oxy))phenyl)urea With reference to the method of embodiment 34, fluoromethanesulfonic acid/ethanol solution, benzene sulfonic acid/ethanol solution, p-toluenesulfonic acid/ethanol solution, 1-naphthalenesulfonic acid/ethanol solution, 2-naphthalenesulfonic acid/ethanol solution, acetic acid/ethanol solution, trifluoroacetic acid/ethanol solution, malic acid/ethanol solution, tartaric acid/ethanol solution, citric acid/ethanol solution, lactic acid/ethanol solution, oxalic acid/ethanol solution, succinic acid/ethanol solution, fumaric acid/ethanol solution, maleic acid/ethanol solution, benzoic acid/ethanol solution, salicylic acid/ethanol solution, phenylacetic acid/ethanol solution or mandelic acid/ethanol solution were added in drops to synthesize trifluoromethylsulfonate, benzene sulfonate, tosilate, 1-naphthalenesulfenesulfonate, 2-naphthalenesulfenesulfonate, acetate, trifluoroactate, malate, tartrate, citrate, lactate, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate or mandelate of N-(4-chloro-3 -(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquino linyl)oxy))phenyl)urea. 
     The pharmaceutically acceptable salts of compounds 2-15 can be also synthesized according to the above mentioned method. 
     B: preparing the aromatic heterocyclic substituted acardite derivate having the general formula 1 accroding to method 2 
     
       
                 
         
             
             
         
      
     
     Embodiment 36: Synthesis of N-(4-chloro-3 -(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea 20 g of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (obtained from embodiment 16), 15 g of 4-aminophenol and 500 ml of dichloromethane were stirred at room temperature for 2 h, and the crystal was precipitated, followed by air pump filtration and collection, washing with dichloromethane and vacuum drying to obtain N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea. 
     Embodiment 37: Synthesis of N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea Prepared from 4-bromo-3-(trifluoromethyl)phenyl isocyanate (obtained from embodiment 17) with reference to embodiment 36. 
     Embodiment 38: Synthesis of N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea Prepared from 4-fluoro-3-(trifluoromethyl)phenyl isocyanate (obtained from embodiment 18) with reference to embodiment 36. 
     Embodiment 39: Synthesis of N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquino linyl)oxy))phenyl)urea (compound 1) 10 g of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea (obtained from embodiment 36), 8.2 g of 4-chloro-6-methoxyl-N-methyl-2-quinoline carboxamide (obtained from embodiment 6) and 50 ml dichloromethane were stirred at room temperature for 24 h, and the crystal was precipitated, followed by air pump filtration and collection to obtain 12 g of N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquino linyl)oxy))phenyl)urea. 
     Embodiment 40: Synthesis of compound 2N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquino linyl)oxy))phenyl)urea was prepared from N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea and 4-chloro-6-methoxyl-N-methyl-2-quinoline carboxamide according to the method of Embodiment 39. 
     Embodiment 41: Synthesis of compound 3N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(6-methoxyquin olinyl)oxy))phenyl)urea was prepared from N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea and 4-chloro-6-methoxyl-N-methyl-2-quinoline carboxamide according to the method of Embodiment 39. 
     Embodiment 42: Synthesis of compound 4N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(7fluoroquinazol inyl)oxy) phenyl)urea was prepared from N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea and 4-chloro-7-fluoro-N-methyl-2-quinazoline methanamide (obtained from embodiment 7) according to the method of Embodiment 39. 
     Embodiment 43: Synthesis of compound 5N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(7fluoroquinazoli nyl)oxy)phenyl)urea was prepared from N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea and 4-chloro-7-fluoro-N-methyl-2-quinazoline methanamide according to the method of Embodiment 39. 
     Embodiment 44: Synthesis of compound 6N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(7fluoroquinazol inyl)oxy)phenyl)urea was prepared from N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea and 4-chloro-7-fluoro-N-methyl-2-quinazoline methanamide according to the method of Embodiment 39. 
     Embodiment 45: Synthesis of compound 7N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-5-(4-methoxypyri midinyl)oxy) phenyl)urea was prepared from N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea and 4-methoxyl-5-chloro-N-methyl-2-pyrimidinecarboxamide (obtained from embodiment 8) according to the method of Embodiment 39. 
     Embodiment 46: Synthesis of compound 8N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-5-(4-methoxypyrim idinyl)oxy)phenyl)urea was prepared from N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea and 4-methoxyl-5-chloro-N-methyl-2-pyrimidinecarboxamide according to the method of Embodiment 39. 
     Embodiment 47: Synthesis of compound 9N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-5-(4-methoxypyri midinyl)oxy)phenyl)urea was prepared from N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea and 4-chloro-N-methyl-2-pyrimidinecarboxamide according to the method of Embodiment 39. 
     Embodiment 48: Synthesis of compound 10N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(7-amino-isoquin olyl)oxy)phenyl)urea was prepared from N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea and 4-chloro-7-amino-N-methyl-2-isoquinolinecarboxamide (obtained from embodiment 9) according to the method of Embodiment 39. 
     Embodiment 49: Synthesis of compound 11N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(7-amino-isoquin olyl)oxy)phenyl)urea was prepared from N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea and 4-chloro-7-amino-N-methyl-2-isoquinolinecarboxamide according to the method of Embodiment 39. 
     Embodiment 50: Synthesis of compound 12N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(7-amino-isoqui nolyl)oxy)phenyl)urea was prepared from N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea and 4-chloro-7-amino-N-methyl-2-isoquinolinecarboxamide according to the method of Embodiment 39. 
     Embodiment 51: Synthesis of compound 13N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(2-methyl-pyrryl) oxy)phenyl)urea was prepared from N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea and 2-methyl-4-chloro-N-methyl-2-pyrrole carboxamide (prepared from embodiment 10) according to the method of Embodiment 39. 
     Embodiment 52: Synthesis of compound 14N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(2-methyl-pyrryl) oxy)phenyl)urea was prepared from N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea and 2-methyl-4-chloro-N-methyl-2-pyrrole carboxamide according to the method of Embodiment 39. 
     Embodiment 53: Synthesis of compound 15N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylaminoformoxyl)-4-(2-methyl-pyrryl) oxy)phenyl)urea was prepared from N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-hydroxylphenyl)urea and 2-methyl-4-chloro-N-methyl-2-pyrrole carboxamide according to the method of Embodiment 39. 
     C: preparing the aromatic heterocyclic substituted acardite derivate having the general formula 2 accroding to method 3 
     
       
                 
         
             
             
         
      
     
     Embodiment 54: Preparation of 4-(4-(6-methoxyquinolinyl)oxy))aniline 8 g of 4-chloro-6-methoxyquinoline was dissolved in DMF, added with 20 g of potassium tert-butylate and 10 g of 4-aminophenol and reacted under the protection of nitrogen at 70° C. for 8 hours. After the end of the reaction, the reaction liquid was poured into 250 ml of ethyl acetate and 250 ml of saturated salt water and mixed evenly followed by liquid separation. The water solution was extracted with ethyl acetate. 
     The ethyl acetate layer was added with saturated salt water for washing and dried by anhydrous sodium sulfate. The solvent was evaporated under vacuum to obtain 6 g of 4-(4-(6-methoxyquinolinyl)oxy))aniline. 
     Embodiment 55: Preparation of 4-(4-(7fluoroquinazolinyl)oxy)aniline 
     Prepared from 4-chloroquinazoline with reference to the method of embodiment 54. 
     Embodiment 56: Preparation of 4-(5-(4-methoxypyrimidinyl)oxy)aniline 
     Prepared from 5-chloro-4-methoxypyrimidine with reference to the method of embodiment 54. 
     Embodiment 57: Preparation of 4-(4-(7-amino-isoquinolyl)oxy)aniline 
     Prepared from 4-chloro-7-aminoisoquinoline with reference to the method of embodiment 54. 
     Embodiment 58: Preparation of 4-(4-(2-methyl-pyrryl)oxy)aniline 
     Prepared from 4-chloro-2-methylpyrrol with reference to the method of embodiment 54. 
     Embodiment: 59: Preparation of 4-(4-(6-methoxyl-7-fluoro-quinolinyl)oxy)aniline 
     Prepared from 4-chloro-6-methoxyl-7-fluoro-quinoline with reference to the method of embodiment 54. 
     Embodiment: 60: Preparation of 4-(4-(6-methyl-7-fluoro-quinolinyl)oxy))aniline 
     Prepared from 4-chloro-6-methyl-7-fluoro-quinazoline with reference to the method of embodiment 54. 
     Embodiment 61: Synthesis of 4-chloro-3-(trifluoromethyl)phenyl isocyanate 100 ml of diphosgene is mixed with 20 g of 4-chloro-3-(trifluoromethyl)aniline and refluxed for 12 hours. The reaction liquid was added into toluene, and the solvent was evaporated under vacuum to obtain the product 4-chloro-3-(trifluoromethyl)phenyl isocyanate. 
     Embodiment 62: Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate 
     Prepared from 4-bromo-3-(trifluoromethyl)aniline with reference to the method of embodiment 61. 
     Embodiment 63: Synthesis of 4-fluoro-3-(trifluoromethyl)phenyl isocyanate 
     Prepared from 4-fluoro-3-(trifluoromethyl)aniline with reference to the method of embodiment 61. 
     Embodiment 64: Synthesis of 4-chloro-3-ethylphenyl isocyanate 
     Prepared from 4-chloro-3-ethylaniline with reference to the method of embodiment 61. 
     Embodiment 65: Synthesis of 4-ethyl-3-trifluoromethyl 
     Prepared from 4-ethyl3-trifluoromethylaniline with reference to the method of embodiment 61. 
     Embodiment 66: Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(4-quinolinyl)oxyphenyl)urea (compound 16) 7 g of 4-(4-(6-methoxyquinolinyl)oxy))aniline4-(4-quinolinyl)oxyaniline (prepared from embodiment 54), 5 g of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (prepared from embodiment 61) and 50 ml of methylene dichloride were mixed and reacted at room temperature for 24 hours, and the crystal was precipitated, followed by air pump filtration and collection to obtain N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(4-(6-methoxyquinolinyl)oxy))phenyl)urea. 
     Embodiment 67: Synthesis of compound 17N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(4-(6-methoxyquinolinyl)oxy))phenyl)urea was prepared from 4-(4-(6-methoxyquinolinyl)oxy))aniline and 4-fluoro-3-(trifluoromethyl)phenyl isocyanate according to the method of Embodiment 66. 
     Embodiment 68: Synthesis of compound 18N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(4-(6-methoxyquinolinyl)oxy))phenyl)urea was prepared from 4-(4-(6-methoxyquinolinyl)oxy))aniline and 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to the methd of Embodiment 66. 
     Embodiment 69: Synthesis of compound 19N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(4-(7fluoroquinazolinyl)oxy)phenyl)urea was prepared from 4-(4-(7fluoroquinazolinyl)oxy)aniline (prepared from embodiment 55) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to the methd of Embodiment 66. 
     Embodiment 70: Synthesis of compound 20N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(4-(7fluoroquinazolinyl)oxy)phenyl)urea was prepared from 4-(4-(7fluoroquinazolinyl)oxy)aniline and 4-fluoro-3-(trifluoromethyl)phenyl isocyanate according to the methd of Embodiment 66. 
     Embodiment 71: Synthesis of compound 21N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(4-(7fluoroquinazolinyl)oxy)phenyl)urea was prepared from 4-(4-(7fluoroquinazolinyl)oxy)aniline and 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to the methd of Embodiment 66. 
     Embodiment 72: Synthesis of compound 22N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(5-(4-methoxypyrimidinyl)oxy)phenyl)urea was prepared from 4-(5-(4-methoxypyrimidinyl)oxy)aniline (prepared from embodiment 56) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to the methd of Embodiment 66. 
     Embodiment 73: Synthesis of compound 23N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(5-(4-methoxypyrimidinyl)oxy)phenyl)urea was prepared from 4-(5-(4-methoxypyrimidinyl)oxy)aniline and 4-fluoro-3-(trifluoromethyl)phenyl isocyanate according to the methd of Embodiment 66. 
     Embodiment 74: Synthesis of compound 24N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(5-(4-methoxypyrimidinyl)oxy)phenyl)urea was prepared from 4-(5-(4-methoxypyrimidinyl)oxy)aniline and 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to the methd of Embodiment 66. 
     Embodiment 75: Synthesis of compound 25N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(4-(7-amino-isoquinolyl)oxy)phenyl)urea was prepared from 4-(4-(7-amino-isoquinolyl)oxy)aniline (prepared from embodiment 57) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to the methd of Embodiment 66. 
     Embodiment 76: Synthesis of compound 26N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(4-(7-amino-isoquinolyl)oxy)phenyl)urea was prepared from 4-(4-(7-amino-isoquinolyl)oxy)aniline and 4-fluoro-3-(trifluoromethyl)phenyl isocyanate according to the methd of Embodiment 66. 
     Embodiment 77: Synthesis of compound 27N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(4-(7-amino-isoquinolyl)oxy)phenyl)urea was prepared from 4-(4-(7-amino-isoquinolyl)oxy)aniline and 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to the methd of Embodiment 66. 
     Embodiment 78: Synthesis of compound 28N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(4-(2-methyl-pyrryl)oxy)phenyl)urea was prepared from 4-(4-(2-methyl-pyrryl)oxy)aniline (prepared from embodiment 58) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to the methd of Embodiment 66. 
     Embodiment 79: Synthesis of compound 29N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(4-(2-methyl-pyrryl)oxy)phenyl)urea was prepared from 4-(4-(5-methyl-pyrryl)oxy)aniline and 4-fluoro-3-(trifluoromethyl)phenyl isocyanate according to the methd of Embodiment 66. 
     Embodiment 80: Synthesis of compound 30N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(4-(2-methyl-pyrryl)oxy)phenyl)urea was prepared from 4-(4-(5-methyl-pyrryl)oxy)aniline and 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to the methd of Embodiment 66. 
     Embodiment 81: Synthesis of compound 31N-(4-chloro-3-ethylphenyl)-N′-(4-(4-(6-methoxyl-7-fluoro-quinolinyl)oxy)phenyl)urea was prepared from 4-(4-(6-methoxyl-7-fluoro-quinolinyl)oxy)aniline (prepared from embodiment 59) and 4-chloro-3-ethylphenyl isocyanate (prepared from embodiment 64) according to the methd of Embodiment 66. 
     Embodiment 82: Synthesis of compound 32N-(4-ethyl-3-(trifluoromethyl)phenyl)-N′-(4-(4-(6-methoxyl-7-fluoro-quinolinyl)oxy)phenyl)urea was prepared from 4-(4-(6-methoxyl-7-fluoro-quinolinyl)oxy)aniline (prepared from embodiment 59) and 4-ethyl-3-trifluoromethyl isocyanate (prepared from embodiment 65) according to the methd of Embodiment 66. 
     Embodiment 83: Synthesis of compound 33N-(4-chloro-3-ethylphenyl)-N′-(4-(4-(6-methyl-7-fluoro-quinolinyl)oxy))phenyl)urea was prepared from 4-(4-(6-methyl-7-fluoro-quinolinyl)oxy))aniline (prepared from embodiment 60) and 4-chloro-3-ethylphenyl isocyanate (prepared from embodiment 64) according to the methd of Embodiment 66. 
     Embodiment 84: Synthesis of compound 34N-(4-ethyl-3-(trifluoromethyl)phenyl)-N′-(4-(4-(6-methyl-7-fluoro-quinolinyl)oxy))phenyl)urea was prepared from 4-(4-(6-methyl-7-fluoro-quinolinyl)oxy))aniline (prepared from embodiment 60) and 4-ethyl-3-trifluoromethyl isocyanate (prepared from embodiment 65) according to the methd of Embodiment 66. 
     Embodiment 85: Preparation of 4-chloro-7-nitrylquinoline-2-carbonyl chloride Prepared from 4-hydroxyl-7-nitryl-2-quinoline carboxylic acid with reference to the method of embodiment 1. 
     Embodiment 86: Preparation of 4-chloro-7-trifluoromethylquinazoline-2-carbonyl chloride Prepared from 4-hydroxyl-7-trifluoromethyl-2-quinazoline carboxylic acid with reference to the method of embodiment 1. 
     Embodiment 87: Preparation of 4-chloro-7-nitryl-N-ethyl-2-quinoline carboxamide Prepared from 4-chloro-7-nitrylquinoline-2-carbonyl chloride (prepared from embodiment 58) and 2M ethylamine ethanol solution with reference to the method of embodiment 6. 
     Embodiment 88: Preparation of 4-chloro-7-trifluoromethyl-N-propyl-2-quinazoline methanamide Prepared from 4-chloro-7-trifluoromethylquinazoline-2-carbonyl chloride (prepared from embodiment 86) and 2M propylamine ethanol solution with reference to the method of embodiment 6. 
     Embodiment 89: Preparation of 2-methyl-4-(2-(N-ethylcarbamyl)-4-(7-nitrylquinolinyl)oxy))aniline Prepared from 4-chloro-7-nitryl-N-ethyl-2-quinoline carboxamide (prepared from embodiment 87) and 3-methyl-4-aminophenol with reference to the method of embodiment 11. 
     Embodiment 90: Preparation of 2-methoxyl-4-(2-(N-ethylcarbamyl)-4-(7-nitrylquinolinyl)oxy))aniline Prepared from 4-chloro-7-nitryl-N-ethyl-2-quinoline carboxamide (prepared from embodiment 87) and 3-methoxyl-4-aminophenol with reference to the method of embodiment 11. 
     Embodiment 91: Preparation of 2-fluoro-4-(2-(N-propylcarbamyl)-4-(7-trifluoromethylquinolinyl)oxy)) aniline Prepared from 4-chloro-7-trifluoromethyl-N-propyl-2-quinazoline methanamide (prepared from embodiment 88) and 3-fluoro-4-aminophenol with reference to the method of embodiment 11. 
     Embodiment 92: Preparation of 2-trifluoromethyl-4-(2-(N-propylcarbamyl)-4-(7-trifluoromethylquinolinyl)oxy))aniline Prepared from 4-chloro-7-trifluoromethyl-N-propyl-2-quinazoline methanamide (prepared from embodiment 88) and 4-amino-3-trifluoromethyl phenol with reference to the method of embodiment 11. 
     Embodiment 93: Synthesis of 4-chloro-3-methoxyphenyl isocyanate Prepared from 4-chloro-3-methoxyaniline with reference to the method of embodiment 61. 
     Embodiment 94: Preparation of compound 35N-(4-chloro-3-methoxyphenyl)-N′-(2-methyl-4-(2-(N-ethylcarbamyl)-4-(7-nitryl-quinolinyl)ox y)phenyl)urea was sythesized from 2-methyl-4-(2-(N-ethylcarbamyl)-4-(7-nitrylquinolinyl)oxy))aniline (prepared from embodiment 89) and 4-chloro-3-methoxyphenyl isocyanate (prepared from embodiment 93) according to the method of Embodiment 19. 
     Embodiment 95: Preparation of compound 36N-(4-chloro-3-methoxyphenyl)-N′-(2-methoxyl-4-(2-(N-ethylcarbamyl)-4-(7-nitryl-quinolinyl) oxy)phenyl)urea was sythesized from 2-methoxyl-4-(2-(N-ethylcarbamyl)-4-(7-nitrylquinolinyl)oxy))aniline (prepared from embodiment 90) and 4-chloro-3-methoxyphenyl isocyanate (prepared from embodiment 93) according to the method of Embodiment 19. 
     Embodiment 96: Preparation of compound 37N-(4-chloro-3-methoxyphenyl)-N′-(2-fluoro-4-(2-(N-propylcarbamyl)-4-(7-trifluoromethylqui nolinyl)oxy))phenyl)urea was sythesized from 2-fluoro-4-(2-(N-propylcarbamyl)-4-(7-trifluoromethylquinolinyl)oxy))aniline (prepared from embodiment 91) and 4-chloro-3-methoxyphenyl isocyanate (prepared from embodiment 93) according to the method of Embodiment 19. 
     Embodiment 97: Preparation of compound 38N-(4-chloro-3-methoxyphenyl)-N′-(2-trifluoromethyl-4-(2-(N-propylcarbamyl)-4-(7-trifluorom ethylquinolinyl)oxy))phenyl)urea was sythesized from 2-trifluoromethyl-4-(2-(N-propylcarbamyl)-4-(7-trifluoromethylquinolinyl)oxy))aniline (prepared from embodiment 92) and 4-chloro-3-methoxyphenyl isocyanate (prepared from embodiment 93) according to the method of Embodiment 19. 
     Embodiment 98: Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(4-(6-methoxyquinolinyl)oxy))phenyl)urea mesylate 10 g of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(4-(6-methoxyquinolinyl)oxy))phenyl)urea free base was dissolved in 300 ml of ether and added with methanesulfonic acid/ethanol solution in drops at room temperature until pH=2, and white crystal was precipitated followed by air pump filtration and collection to obtain N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(4-(6-methoxyquinolinyl)oxy))phenyl)urea mesylate. 
     Embodiment 99: Synthesis of pharmaceutically acceptable salts of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(4-(6-methoxyquinolinyl)oxy))phenyl)urea With reference to the method of embodiment 85, fluoromethanesulfonic acid/ethanol solution, benzene sulfonic acid/ethanol solution, p-toluenesulfonic acid/ethanol solution, 1-naphthalenesulfonic acid/ethanol solution, 2-naphthalenesulfonic acid/ethanol solution, acetic acid/ethanol solution, trifluoroacetic acid/ethanol solution, malic acid/ethanol solution, tartaric acid/ethanol solution, citric acid/ethanol solution, lactic acid/ethanol solution, oxalic acid/ethanol solution, succinic acid/ethanol solution, fumaric acid/ethanol solution, maleic acid/ethanol solution, benzoic acid/ethanol solution, salicylic acid/ethanol solution, phenylacetic acid/ethanol solution or mandelic acid/ethanol solution were added in drops to synthesize trifluoromethylsulfonate, benzene sulfonate, tosilate, 1-naphthalenesulfenesulfonate, 2-naphthalenesulfenesulfonate, acetate, trifluoroactate, malate, tartrate, citrate, lactate, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate or mandelate of N-(4-chloro-3 -(trifluoromethyl)phenyl)-N′-(4-(4-quinolinyl)oxyphenyl)urea. 
     The pharmaceutically acceptable salts of compounds 17-38 can be also synthesized according to the above mentioned method. 
     The compounds in table 1 to 14 were prepared according to methods of the above mentioned embodiments, and the characteristics are shown in the following tables. 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 substituted quinoline derivatives 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Compound 
                   
                 Elementary 
                   
                 Mass spectrum 
               
               
                 No. 
                 R 3   
                 analysis 
                 Name 
                 M + 1 
               
               
                   
               
             
          
           
               
                 1 
                 4-chloro-3- 
                 C: 57.3 
                 N-(4-chloro-3-(trifluoromethyl)phenyl)-N′- 
                 545.5 
               
               
                   
                 trifluoromethyl 
                 H: 3.8 
                 (4-(2-(N-methylaminoformoxyl)-4-(6- 
                   
               
               
                   
                   
                 N: 10.3 
                 methoxyquinolinyl)oxy))phenyl)urea 
                   
               
               
                 2 
                 4-fluoro-3- 
                 C: 59.2 
                 N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′- 
                 529 
               
               
                   
                 trifluoromethyl 
                 H: 3.9 
                 (4-(2-(N-methylaminoformoxyl)-4-(6- 
                   
               
               
                   
                   
                 N: 10.5 
                 methoxyquinolinyl)oxy))phenyl)urea 
                   
               
               
                 3 
                 4-bromo-3- 
                 C: 53.0 
                 N-(4-bromo-3-(trifluoromethyl)phenyl)-N′- 
                 590 
               
               
                   
                 trifluoromethyl 
                 H: 3.31 
                 (4-(2-(N-methylaminoformoxyl)-4-(6- 
                   
               
               
                   
                   
                 N: 9.38 
                 methoxyquinolinyl)oxy))phenyl)urea 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 substituted quinazoline derivatives 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Compound 
                   
                 Elementary 
                   
                 Mass spectrum 
               
               
                 No. 
                 R 3   
                 analysis 
                 Name 
                 M + 1 
               
               
                   
               
             
          
           
               
                 4 
                 4-chloro-3- 
                 C: 54.1 
                 N-(4-chloro-3-(trifluoromethyl)phenyl)-N′- 
                 534.5 
               
               
                   
                 trifluoromethyl 
                 H: 3.11 
                 (4-(2-(N-methylaminoformoxyl)-4- 
                   
               
               
                   
                   
                 N: 13.0 
                 (7 fluoroquinazolinyl)oxy)phenyl)urea 
                   
               
               
                 5 
                 4-fluoro-3- 
                 C: 55.5 
                 N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′- 
                 518 
               
               
                   
                 trifluoromethyl 
                 H: 3.30 
                 (4-(2-(N-methylaminoformoxyl)-4- 
                   
               
               
                   
                   
                 N: 13.4 
                 (7 fluoroquinazolinyl)oxy)phenyl)urea 
                   
               
               
                 6 
                 4-bromo-3- 
                 C: 49.7 
                 N-(4-bromo-3-(trifluoromethyl)phenyl)-N′- 
                 579 
               
               
                   
                 trifluoromethyl 
                 H: 2.91 
                 (4-(2-(N-methylaminoformoxyl)-4- 
                   
               
               
                   
                   
                 N: 12.2 
                 (7 fluoroquinazolinyl)oxy)phenyl)urea 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 substituted pyrimidine derivatives 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Compound 
                   
                 Elementary 
                   
                 Mass 
               
               
                 No. 
                 R 3   
                 analysis 
                 Name 
                 spectrum m/e 
               
               
                   
               
             
          
           
               
                 7 
                 4-chloro-3- 
                 C: 50.9 
                 N-(4-chloro-3-(trifluoromethyl)phenyl)-N′- 
                 496.5 
               
               
                   
                 trifluoromethyl 
                 H: 3.48 
                 (4-(2-(N-methylaminoformoxyl)-5-(4- 
                   
               
               
                   
                   
                 N: 14.0 
                 methoxypyrimidinyl)oxy)phenyl)urea 
                   
               
               
                 8 
                 4-fluoro-3- 
                 C: 52.5 
                 N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′- 
                 480 
               
               
                   
                 trifluoromethyl 
                 H: 3.67 
                 (4-(2-(N-methylaminoformoxyl)-5-(4- 
                   
               
               
                   
                   
                 N: 14.5 
                 methoxypyrimidinyl)oxy)phenyl)urea 
                   
               
               
                 9 
                 4-bromo-3- 
                 C: 46.8 
                 N-(4-bromo-3-(trifluoromethyl)phenyl)-N′- 
                 541 
               
               
                   
                 trifluoromethyl 
                 H: 3.00 
                 (4-(2-(N-methylaminoformoxyl)-5-(4- 
                   
               
               
                   
                   
                 N: 13.1 
                 methoxypyrimidinyl)oxy)phenyl)urea 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 substituted isoquinoline derivatives 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Compound 
                   
                 Elementary 
                   
                 Mass 
               
               
                 No. 
                 R 3   
                 analysis 
                 Name 
                 spectrum m/e 
               
               
                   
               
             
          
           
               
                 10 
                 4-chloro-3- 
                 C: 56.5 
                 N-(4-chloro-3-(trifluoromethyl)phenyl)-N′- 
                 530.5 
               
               
                   
                 trifluoromethyl 
                 H: 3.70 
                 (4-(2-(N-methylaminoformoxyl)- 
                   
               
               
                   
                   
                 N: 13.2 
                 4-(7-amino-isoquinolyl)oxy)phenyl)urea 
                   
               
               
                 11 
                 4-fluoro-3- 
                 C: 58.5 
                 N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′- 
                 514 
               
               
                   
                 trifluoromethyl 
                 H: 3.81 
                 (4-(2-(N-methylaminoformoxyl)- 
                   
               
               
                   
                   
                 N: 13.8 
                 4-(7-amino-isoquinolyl)oxy)phenyl)urea 
                   
               
               
                 12 
                 4-bromo-3- 
                 C: 52.4 
                 N-(4-bromo-3-(trifluoromethyl)phenyl)-N′- 
                 574 
               
               
                   
                 trifluoromethyl  
                 H: 3.44 
                 (4-(2-(N-methylaminoformoxyl)- 
                   
               
               
                   
                   
                 N: 12.4 
                 4-(7-amino-isoquinolyl)oxy)phenyl)urea 
                   
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 substituted pyrrole derivatives 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Compound 
                   
                 Elementary 
                   
                 Mass 
               
               
                 No. 
                 R 3   
                 analysis 
                 Name 
                 spectrum m/e 
               
               
                   
               
             
          
           
               
                 13 
                 4-chloro-3- 
                 C: 54.1 
                 N-(4-chloro-3-(trifluoromethyl)phenyl)-N′- 
                 467.5 
               
               
                   
                 trifluoromethyl 
                 H: 4.01 
                 (4-(2-(N-methylaminoformoxyl)-4-(5- 
                   
               
               
                   
                   
                 N: 12.2 
                 methyl-pyrryl)oxy)phenyl)urea 
                   
               
               
                 14 
                 4-fluoro-3- 
                 C: 55.8 
                 N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′- 
                 451 
               
               
                   
                 trifluoromethyl 
                 H: 4.02 
                 (4-(2-(N-methylaminoformoxyl)-4-(5- 
                   
               
               
                   
                   
                 N: 12.6 
                 methyl-pyrryl)oxy)phenyl)urea 
                   
               
               
                 15 
                 4-bromo-3- 
                 C: 49.5 
                 N-(4-bromo-3-(trifluoromethyl)phenyl)-N′- 
                 511 
               
               
                   
                 trifluoromethyl  
                 H: 3.70 
                 (4-(2-(N-methylaminoformoxyl)-4-(5- 
                   
               
               
                   
                   
                 N: 11.0 
                 methyl-pyrryl)oxy)phenyl)urea 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 substituted quinoline derivatives 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Compound 
                   
                 Elementary 
                   
                 Mass 
               
               
                 No. 
                 R 3   
                 analysis 
                 Name 
                 spectrum m/e 
               
               
                   
               
             
          
           
               
                 16 
                 4-chloro-3- 
                 C: 59.2 
                 N-(4-chloro-3-(trifluoromethyl)phenyl)-N′- 
                 488.5 
               
               
                   
                 trifluoromethyl 
                 H: 3.70 
                 (4-(4-(6-methoxyquinolinyl)oxy))phenyl)urea 
                   
               
               
                   
                   
                 N: 8.77 
                   
                   
               
               
                 17 
                 4-fluoro-3- 
                 C: 61.3 
                 N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′- 
                 472 
               
               
                   
                 trifluoromethyl 
                 H: 3.81 
                 (4-(4-(6-methoxyquinolinyl)oxy))phenyl)urea 
                   
               
               
                   
                   
                 N: 8.80 
                   
                   
               
               
                 18 
                 4-bromo-3- 
                 C: 54.0 
                 N-(4-bromo-3-(trifluoromethyl)phenyl)-N′- 
                 532 
               
               
                   
                 trifluoromethyl  
                 H: 3.40 
                 (4-(4-(6-methoxyquinolinyl)oxy))phenyl)urea 
                   
               
               
                   
                   
                 N: 7.79 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 substituted quinazoline derivatives 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Compound 
                   
                 Elementary 
                   
                 Mass 
               
               
                 No. 
                 R 3   
                 analysis 
                 Name 
                 spectrum m/e 
               
               
                   
               
             
          
           
               
                 19 
                 4-chloro-3- 
                 C: 55.5 
                 N-(4-chloro-3-(trifluoromethyl)phenyl)-N′- 
                 477.5 
               
               
                   
                 trifluoromethyl 
                 H: 2.91 
                 (4-(4-(7 fluoroquinazolinyl)oxy)phenyl)urea 
                   
               
               
                   
                   
                 N: 11.6 
                   
                   
               
               
                 20 
                 4-fluoro-3- 
                 C: 57.7 
                 N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′- 
                 461 
               
               
                   
                 trifluoromethyl 
                 H: 2.75 
                 (4-(4-(7 fluoroquinazolinyl)oxy)phenyl)urea 
                   
               
               
                   
                   
                 N: 12.2 
                   
                   
               
               
                 21 
                 4-bromo-3- 
                 C: 50.5 
                 N-(4-bromo-3-(trifluoromethyl)phenyl)-N′- 
                 522 
               
               
                   
                 trifluoromethyl 
                 H: 2.71 
                 (4-(4-(7 fluoroquinazolinyl)oxy)phenyl)urea 
                   
               
               
                   
                   
                 N: 10.8 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 substituted pyrimidine derivatives 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Compound 
                   
                 Elementary 
                   
                 Mass 
               
               
                 No. 
                 R 3   
                 analysis 
                 Name 
                 spectrum m/e 
               
               
                   
               
             
          
           
               
                 22 
                 4-chloro-3- 
                 C: 52.1 
                 N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-  
                 439.5 
               
               
                   
                 trifluoromethyl 
                 H: 3.30 
                 (4-(5-(4-methoxypyrimidinyl)oxy)phenyl) 
                   
               
               
                   
                   
                 N: 12.8 
                   
                   
               
               
                 23 
                 4-fluoro-3- 
                 C: 54.2 
                 N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-  
                 423 
               
               
                   
                 trifluoromethyl 
                 H: 3.38 
                 (4-(5-(4-methoxypyrimidinyl)oxy)phenyl) 
                   
               
               
                   
                   
                 N: 13.3 
                   
                   
               
               
                 24 
                 4-bromo-3- 
                 C: 47.2 
                 N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-  
                 484 
               
               
                   
                 trifluoromethyl 
                 H: 2.99 
                 (4-(5-(4-methoxypyrimidinyl)oxy)phenyl) 
                   
               
               
                   
                   
                 N: 11.4 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                 substituted isoquinoline derivatives 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Compound 
                   
                 Elementary 
                   
                 Mass 
               
               
                 No. 
                 R 3   
                 analysis % 
                 Name 
                 spectrum m/e 
               
               
                   
               
             
          
           
               
                 25 
                 4-chloro-3- 
                 C: 58.4 
                 N-(4-chloro-3-(trifluoromethyl)phenyl)-N′- 
                 473.5 
               
               
                   
                 trifluoromethyl 
                 H: 3.38 
                 (4-(4-(7-amino-isoquinolyl)oxy)phenyl)urea 
                   
               
               
                   
                   
                 N: 11.81 
                   
                   
               
               
                 26 
                 4-fluoro-3- 
                 C: 60.7 
                 N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′- 
                 457 
               
               
                   
                 trifluoromethyl 
                 H: 3.70 
                 (4-(4-(7-amino-isoquinolyl)oxy)phenyl)urea 
                   
               
               
                   
                   
                 N: 13.5 
                   
                   
               
               
                 27 
                 4-bromo-3- 
                 C: 53.5 
                 N-(4-bromo-3-(trifluoromethyl)phenyl)-N′- 
                 518 
               
               
                   
                 trifluoromethyl 
                 H: 3.40 
                 (4-(4-(7-amino-isoquinolyl)oxy)phenyl)urea 
                   
               
               
                   
                   
                 N: 10.7 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 10 
               
             
             
               
                   
               
               
                 substituted pyrrole derivatives 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Compound 
                   
                 Elementary 
                   
                 Mass 
               
               
                 No. 
                 R 3   
                 analysis % 
                 Name 
                 spectrum m/e 
               
               
                   
               
             
          
           
               
                 28 
                 4-chloro-3- 
                 C: 55.7 
                 N-(4-chloro-3-(trifluoromethyl)phenyl)-N′- 
                 410.5 
               
               
                   
                 trifluoromethyl 
                 H: 3.75 
                 (4-(4-(2-methyl-pyrryl)oxy)phenyl)urea 
                   
               
               
                   
                   
                 N: 10.4 
                   
                   
               
               
                 29 
                 4-fluoro-3- 
                 C: 58.2 
                 N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′- 
                 395 
               
               
                   
                 trifluoromethyl 
                 H: 4.01 
                 (4-(4-(2-methyl-pyrryl)oxy)phenyl)urea 
                   
               
               
                   
                   
                 N %: 10.5 
                   
                   
               
               
                 30 
                 4-bromo-3- 
                 C: 50.3 
                 N-(4-bromo-3-(trifluoromethyl)phenyl)-N′- 
                 455 
               
               
                   
                 trifluoromethyl 
                 H: 3.49 
                 (4-(4-(2-methyl-pyrryl)oxy)phenyl)urea 
                   
               
               
                   
                   
                 N: 9.41 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 11 
               
             
             
               
                   
               
               
                 polysubstituted quinoline derivatives 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Compound 
                   
                 Elementary 
                   
                 Mass 
               
               
                 No. 
                 R 3   
                 analysis  
                 Name 
                 spectrum m/e 
               
               
                   
               
             
          
           
               
                 31 
                 4-chloro-3- 
                 C: 64.6 
                 N-(4-chloro-3-ethylphenyl)-N′-(4-(4-(6- 
                 466.5 
               
               
                   
                 ethyl 
                 H: 4.71 
                 methoxyl-7-fluoro-quinolinyl)oxy)phenyl)urea 
                   
               
               
                   
                   
                 N: 9.20 
                   
                   
               
               
                 32 
                 4-ethyl-3- 
                 C: 62.7 
                 N-(4-ethyl-3-(trifluoromethyl)phenyl)-N′-(4-(4-(6- 
                 501.5 
               
               
                   
                 trifluoromethyl 
                 H: 4.36 
                 methoxyl-7-fluoro-quinolinyl)oxy)phenyl)urea 
                   
               
               
                   
                   
                 N: 8.22 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 12 
               
             
             
               
                   
               
               
                 polysubstituted quinazoline derivatives 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Compound 
                   
                 Elementary 
                   
                 Mass 
               
               
                 No. 
                 R 3   
                 analysis  
                 Name 
                 spectrum m/e 
               
               
                   
               
             
          
           
               
                 33 
                 4-chloro-3- 
                 C: 64.1 
                 N-(4-chloro-3-ethylphenyl)-N′-(4-(4-(6- 
                 451.5 
               
               
                   
                 ethyl 
                 H: 4.70 
                 methyl-7-fluoro-quinolinyl)oxy)phenyl)urea 
                   
               
               
                   
                   
                 N: 12.3 
                   
                   
               
               
                 34 
                 4-ethyl-3- 
                 C: 61.8 
                 N-(4-ethyl-3-(trifluoromethyl)phenyl)-N′-(4-(4-(6- 
                 485 
               
               
                   
                 trifluoromethyl 
                 H: 4.01 
                 methyl-7-fluoro-quinolinyl)oxy)phenyl)urea 
                   
               
               
                   
                   
                 N: 11.38 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 13 
               
             
             
               
                   
               
               
                 substituted quinoline derivatives 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Compound 
                   
                 Elementary 
                   
                 Mass 
               
               
                 No. 
                 R 2   
                 analysis  
                 Name 
                 spectrum m/e 
               
               
                   
               
             
          
           
               
                 35 
                 2-methyl 
                 C: 59.1 
                 N-(4-chloro-3-methoxyphenyl)-N′- 
                 550.5 
               
               
                   
                   
                 H: 4.32 
                 (2-methyl-4-(2-(N-ethylcarbamyl)-4- 
                   
               
               
                   
                   
                 N: 12.5 
                 (7-nitryl-quinolinyl)oxy)phenyl)urea 
                   
               
               
                 36 
                 2-methoxy 
                 C: 57.2 
                 N-(4-chloro-3-methoxyphenyl)-N′- 
                 566.5 
               
               
                   
                   
                 H: 4.36 
                 (2-methoxyl-4-(2-(N-ethylcarbamyl)-4- 
                   
               
               
                   
                   
                 N: 12.2 
                 (7-nitryl-quinolinyl)oxy)phenyl)urea 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 14 
               
             
             
               
                   
               
               
                 substituted quinazoline derivatives 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Compound 
                   
                 Elementary 
                   
                 Mass 
               
               
                 No. 
                 R 2   
                 analysis  
                 Name 
                 spectrum m/e 
               
               
                   
               
             
          
           
               
                 37 
                 2-fluoro 
                 C: 56.1 
                 N-(4-chloro-3-methoxyphenyl)-N′- 
                 579.5 
               
               
                   
                   
                 H: 4.17 
                 (2-fluoro-4-(2-(N-propylcarbamyl)-4- 
                   
               
               
                   
                   
                 N: 9.72 
                 (7-trifluoromethylquinolinyl)oxy))phenyl)urea 
                   
               
               
                 38 
                 2-trifluoro- 
                 C: 53.4 
                 N-(4-chloro-3-methoxyphenyl)-N′- 
                 629.5 
               
               
                   
                 methyl 
                 H: 3.91 
                 (2-trifluoromethyl-4-(2-(N-propylcarbamyl)-4- 
                   
               
               
                   
                   
                 N: 8.58 
                 (7-trifluoromethylquinolinyl)oxy))phenyl)urea 
               
               
                   
               
             
          
         
       
     
     Determination of Antitumor Activity 
     1. Inhibitory activity of the compound of the present invention on raf kinase 
     [Test Method] 
     Raf-1 inhibitor screening by chemoluminescence method 
     [Instruments] 
     Westernblot electrophoresis apparatus Rotaryshaker 
     [Test Materials] 
     Raf-1(truncated), Magnesium/ATP Cocktail, MEK1 unactive 
     [Tested Samples] 
     Compounds 1-38 
     [Positive Control] 
     Sorafenib 
     
       
         
           
             
               Inhibiton 
               ⁢ 
               
                   
               
               ⁢ 
               rate 
               ⁢ 
               
                   
               
               ⁢ 
               % 
             
             = 
             
               
                 
                   
                     
                       
                         
                           Gray 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           value 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           of 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           the 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           negative 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           control 
                           ⁢ 
                           
                             
                                 
                             
                             ⁢ 
                             
                                 
                             
                           
                           ⁢ 
                           group 
                         
                         - 
                       
                     
                   
                   
                     
                       
                         gray 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         value 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         of 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         the 
                         ⁢ 
                         
                           
                               
                           
                           ⁢ 
                           
                               
                           
                         
                         ⁢ 
                         drug 
                         ⁢ 
                         
                           - 
                         
                         ⁢ 
                         treated 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         group 
                       
                     
                   
                 
                 
                   Gray 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   value 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   of 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   the 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   negative 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   control 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   group 
                 
               
               × 
               100 
               ⁢ 
               % 
             
           
         
       
     
     [Results] 
     
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 13 
               
             
             
               
                   
               
               
                 Inhibition of compounds 1-16 and positive control medicine on raf kinase 
               
             
          
           
               
                 Compound 
                 Final concentration 
                 Inhibition 
                   
                 Compound 
                 Final concentration 
                 Inhibition 
                   
               
               
                 No. 
                 1.0*10 −5  mol/ml 
                 rate % 
                 Activity 
                 No. 
                 1.0*10 −5  mol/ml 
                 rate % 
                 Activity 
               
               
                   
               
             
          
           
               
                 1 
                 1 
                 75.0 
                 + 
                 9 
                 1 
                 99.2 
                 + 
               
               
                 2 
                 1 
                 61.1 
                 + 
                 10 
                 1 
                 3.5 
               
               
                 3 
                 1 
                 56.3 
                 + 
                 11 
                 1 
                 11.2 
               
               
                 4 
                 1 
                 82.2 
                 + 
                 12 
                 1 
                 12.1 
               
               
                 5 
                 1 
                 98.9 
                 + 
                 13 
                 1 
                 55.0 
                 + 
               
               
                 6 
                 1 
                 80.1 
                 + 
                 14 
                 1 
                 41.3 
               
               
                 7 
                 1 
                 99.1 
                 + 
                 15 
                 1 
                 35.5 
               
               
                 8 
                 1 
                 44..5 
                   
                 16 
                 1 
                 62.1 
                 + 
               
               
                 Positive 
                 1 
                 85.7 
                 + 
               
               
                 control 
               
               
                 medicine 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 14 
               
             
             
               
                   
               
               
                 Inhibition of compounds 17-38 and positive control medicine on raf kinase 
               
             
          
           
               
                 Compound 
                 Final concentration 
                 Inhibition 
                   
                 Compound 
                 Final concentration 
                 Inhibition 
                   
               
               
                 No. 
                 1.0*10 −5  mol/ml 
                 rate % 
                 Activity 
                 No. 
                 1.0*10 −5  mol/ml 
                 rate % 
                 Activity 
               
               
                   
               
             
          
           
               
                 17 
                 1 
                 58.2 
                 + 
                 28 
                 1 
                 33.5 
                   
               
               
                 18 
                 1 
                 34.4 
                   
                 29 
                 1 
                 85.3 
                 + 
               
               
                 19 
                 1 
                 93.5 
                 + 
                 30 
                 1 
                 16.8 
               
               
                 20 
                 1 
                 87.7 
                 + 
                 31 
                 1 
                 89.4 
                 + 
               
               
                 21 
                 1 
                 98.9 
                 + 
                 32 
                 1 
                 90.5 
                 + 
               
               
                 22 
                 1 
                 88.1 
                 + 
                 33 
                 1 
                 92.3 
                 + 
               
               
                 23 
                 1 
                 89.9 
                 + 
                 34 
                 1 
                 96.2 
                 + 
               
               
                 24 
                 1 
                 91.3 
                 + 
                 35 
                 1 
                 45.3 
               
               
                 25 
                 1 
                 11.5 
                   
                 36 
                 1 
                 81.2 
                 + 
               
               
                 26 
                 1 
                 15.3 
                   
                 37 
                 1 
                 81.5 
                 + 
               
               
                 27 
                 1 
                 8.8 
                   
                 38 
                 1 
                 88.1 
                 + 
               
               
                 Positive 
                 1 
                 85.7 
                 + 
               
               
                 control 
               
               
                 medicine 
               
               
                   
               
             
          
         
       
     
     The test results of inhibitory activity of the compound on raf kinase showed that the inhibitory activity of the compound in the present invention is better than or equivalent to positive control medicine sorafenib. The test results indicate that these compounds can affect the survival, proliferation and disease progression of tumor cells through inhibiting the raf kinase and blocking the ras protein signal transduction cascade of tumor cells. The compound of the present invention has potential of being applied to treat tumor and leukemia. 
     2. Experimental therapeutic action of the compound in the present invention on S180 sarcoma mice 
     [Test Materials]
         Test animals: ICR mice, 18-25 g   Tumor types: mice S180 sarcoma, provided by Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
           Positive control medicine: Sorafenib   Tested samples: compounds 1-38   
               

     [Test Method] 
     18-25 g female ICR mice and well grown 7-11 day old mice sarcoma S180 tumor seeds were selected, and the seeds were inoculated into the subcutaneous at the right axillary. After inoculated 24 hours, these mice were randomly divided into cages and orally administrated 60 mg/kg for 9 days. On 10 day, the animals were killed and weighed, and the tumor weights were weighed to calculate average tumor weight in each group, followed by calculating the tumor inhibition rate according to the following formula and T test. 
     
       
         
           
             
               Tumor 
               ⁢ 
               
                   
               
               ⁢ 
               growth 
               ⁢ 
               
                   
               
               ⁢ 
               inhibition 
               ⁢ 
               
                   
               
               ⁢ 
               rate 
             
             = 
             
               
                 
                   
                     
                       
                         
                           Average 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           tumor 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           weight 
                           ⁢ 
                           
                             
                                 
                             
                             ⁢ 
                             
                                 
                             
                           
                           ⁢ 
                           in 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           the 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           control 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           group 
                         
                         - 
                       
                     
                   
                   
                     
                       
                         average 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         tumor 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         weight 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         in 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         the 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         treatment 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         group 
                       
                     
                   
                 
                 
                   average 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   tumor 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   weight 
                   ⁢ 
                   
                     
                         
                     
                     ⁢ 
                     
                         
                     
                   
                   ⁢ 
                   in 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   the 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   treatment 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   group 
                 
               
               × 
               100 
               ⁢ 
               % 
             
           
         
       
     
     [Determination Results] 
     
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 15 
               
             
             
               
                   
               
               
                 Tumor growth inhibition rate of compounds 1-3 and sorafenib on mice S180 sarcoma 
               
             
          
           
               
                   
                 Administration 
                 Animal number 
                 Weight (g) 
                 Tumor weight 
                 Inhibition 
                   
               
             
          
           
               
                 Groups 
                 Dosage 
                 methods 
                 Start 
                 Final 
                 Start 
                 Final 
                 x ± SD(g) 
                 rate (%) 
                 P value 
               
               
                   
               
             
          
           
               
                 Normal 
                 0.4 
                 ml/mouse 
                 ig 
                 20 
                 20 
                 18.9 ± 1.5 
                 22.0 ± 3.4 
                 1.61 ± 0.36 
                   
                   
               
               
                 saline 
               
               
                 Sora 
                 60 
                 mg/kg 
                 ig 
                 10 
                 10 
                 18.8 ± 1.2 
                 21.7 ± 2.4 
                 0.71 ± 0.30 
                 55.9 
                 &lt;0.05 
               
               
                 Compound 1 
                 60 
                 mg/kg 
                 ig 
                 10 
                 10 
                 18.7 ± 1.9 
                 22.3 ± 1.3 
                 0.99 ± 0.20 
                 38.5 
                 &lt;0.05 
               
               
                 Compound 2 
                 60 
                 mg/kg 
                 ig 
                 10 
                 10 
                 18.9 ± 1.7 
                 20.9 ± 2.3 
                 0.87 ± 0.24 
                 46.0 
                 &lt;0.05 
               
               
                 Compound 3 
                 60 
                 mg/kg 
                 ig 
                 10 
                 10 
                 18.0 ± 1.1 
                 20.2 ± 2.5 
                 0.75 ± 0.36 
                 53.4 
                 &lt;0.05 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 16 
               
             
             
               
                   
               
               
                 Tumor growth inhibition rate of compounds 1-12 and sorafenib on mice S180 sarcoma (%) 
               
             
          
           
               
                   
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 Sorafenib 
               
               
                   
                   
               
             
          
           
               
                 Mice 
                 38.5 
                 24.1 
                 53.4 
                 50.1 
                 49.3 
                 51.2 
                 21.5 
                 58.2 
                 55.9 
                 55.2 
                 54.2 
                 45.7 
                 55.9% 
               
               
                 S180 
               
               
                 sarcoma 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 17 
               
             
             
               
                   
               
               
                 Tumor growth inhibition rate of compounds 13-26 and sorafenib on mice S180 sarcoma (%) 
               
             
          
           
               
                   
                 13 
                 14 
                 15 
                 16 
                 17 
                 18 
                 19 
                 20 
                 21 
                 22 
                 23 
                 24 
                 25 
                 26 
               
               
                   
                   
               
             
          
           
               
                 Mice 
                 21.2 
                 18.2 
                 56.7 
                 33.6 
                 44.2 
                 35.7 
                 50.8 
                 54.6 
                 59.7 
                 52.1 
                 51.5 
                 54.6 
                 55.8 
                 7.6 
               
               
                 S180 
               
               
                 sarcoma 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 18 
               
             
             
               
                   
               
               
                 Tumor growth inhibition rate of compounds 27-38 
               
               
                 and sorafenib on mice S180 sarcoma (%) 
               
             
          
           
               
                   
                 27 
                 28 
                 29 
                 30 
                 31 
                 32 
                 33 
                 34 
                 35 
                 36 
                 37 
                 38 
               
               
                   
                   
               
             
          
           
               
                 Mice 
                 55.1 
                 11.5 
                 14.2 
                 55.2 
                 50.3 
                 49.8 
                 55.3 
                 52.6 
                 55.8 
                 55.1 
                 24.1 
                 59.2 
               
               
                 S180 
               
               
                 sarcoma 
               
               
                   
               
             
          
         
       
     
     3. Experimental therapeutic action of the compound in the present invention on Human colon cancer HT-29 transplantable tumor in nude mice. 
     [Test Materials]
         Test animals: Female BALB/cA nude mice, 35-40 day old, with weight of 18-22 g.   Tumor seeds: Human colon cancer HT-29 transplantable tumor in nude mice, established by inoculating human colon cancer HT-29 cell strains subcutaneously in nude mice
           Positive control medicine: Sorafenib
               Tested samples: Compounds 1-38   
               
               

     [Test Method] 
     Take eugenic tumor tissues and cut into about 1.5 mm 3 , and then incoculate subcutaneously at the right armpit of nude mice under the sterile conditions. The diameter of the transplantable tumor in nude mice was determined with a vernier caliper, and the animals were divided into groups after the tumors were grown to 100-300 mm 3 . Using the method of measuring the tumor diameter, dynamically observe the antitumor effects of tested materials. The diameter of the tumor was determined three times every week and the mouse weight was weighed at the same time. The mice were intragastrically administrated with Sorafenib and tested drugs, 60 mg/kg, for continuous 9 times. The solvent was intragastrically administrated as the control for continuous 9 times. Equal amount of control was administrated in the negative control group. 
     Tumor volume (TV) is calculated as: TV=½×a×b 2 , wherein a and b respectively represent length and width. 
     Relative tumor volume (RTV) is calculated as: RTV=TV t /TV 0 , wherein TV 0  is the tumor volume when administrated according to different cages and TV t  is the tumor volume measured each time. 
     Relative tumor reproduction rate T/C (%) is calculated as follows: 
     
       
         
           
             
               T 
               ⁢ 
               
                 / 
               
               ⁢ 
               
                 C 
                 ⁡ 
                 
                   ( 
                   % 
                   ) 
                 
               
             
             = 
             
               
                 
                   T 
                   RTV 
                 
                 
                   C 
                   RTV 
                 
               
               × 
               100 
             
           
         
       
     
     T RTV : RTV in the treatment group; C RTV : RTV in the negative control group. 
     The test results used relative tumor reproduction rate T/C (%) as evaluating indicator of anti-tumor activity. 
     Evaluation of in vivo anti-tumor activity 
     
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                 T/C % 
                 Evaluation 
               
               
                   
                   
               
             
             
               
                   
                 ≧60 
                 (−) No activity 
               
               
                   
                 60-50 
                 (+/−) Marginal activity 
               
               
                   
                 50-40 
                 (+) Moderate-strength activity 
               
               
                   
                 40-10 
                 (++) High-strength activity 
               
               
                   
                 ≦10 
                 (+++)Extremenly high-strength activity 
               
               
                   
                   
               
             
          
         
       
     
     [Determination results] 
     
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 19 
               
             
             
               
                   
               
               
                 Experimental treatment of compounds 1-3 and Sorafenib on human 
               
               
                 colon cancer HT-29 transplantable tumor in nude mice 
               
             
          
           
               
                   
                   
                 Animal 
                   
                   
                   
                   
               
               
                   
                 Dosage 
                 number 
                 Weight (g) 
                 TV 
                   
                 T/C 
               
             
          
           
               
                 Groups 
                 mg/kg 
                 Start 
                 Final 
                 d0 
                 d13 
                 d0 
                 d13 
                 RTV 
                 (%) 
               
               
                   
               
             
          
           
               
                 Control 
                   
                 6 
                 6 
                 18.8 ± 1.1 
                 19.6 ± 0.9 
                 133 ± 60 
                 626 ± 226 
                 5.07 ± 1.39 
                   
               
               
                 Solvent control 
                   
                 6 
                 6 
                 19.7 ± 0.6 
                 20.8 ± 0.8 
                 133 ± 32 
                 547 ± 172 
                 4.15 ± 0.93 
                 81.85 
               
               
                 Sorafenib 
                 60 
                 6 
                 6 
                 19.9 ± 1.1 
                 20.4 ± 1.4 
                 133 ± 33 
                 308 ± 86  
                 2.36 ± 0.57 
                 46.48** 
               
               
                 Compound 1 
                 60 
                 6 
                 6 
                 19.5 ± 1.0 
                 20.5 ± 1.1 
                 128 ± 34 
                 359 ± 108 
                 2.81 ± 1.05 
                 55.42** 
               
               
                 Compound 2 
                 60 
                 6 
                 6 
                 19.9 ± 0.8 
                 21.0 ± 0.8 
                 133 ± 23 
                 265 ± 100 
                 2.00 ± 0.41 
                 39.45** 
               
               
                 Compound 3 
                 60 
                 6 
                 6 
                 19.1 ± 1.0 
                 19.7 ± 1.4 
                 133 ± 18 
                 322 ± 129 
                 2.40 ± 0.67 
                 47.34** 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 20 
               
             
             
               
                   
               
               
                 Relative tumor reproduction rate of compounds 1-10 and Sorafenib on 
               
               
                 Human colon cancer HT-29 transplantable tumor in nude mice T/C (%) 
               
             
          
           
               
                   
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 Sorafenib 
               
               
                   
                   
               
             
          
           
               
                 Human colon cancer 
                 55.42 
                 39.45 
                 47.34 
                 33.15 
                 38.24 
                 39.58 
                 40.1 
                 37.6 
                 35.2 
                 78.9 
                 46.48 
               
               
                 HT-29 transplantable 
               
               
                 tumor in nude mice 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 21 
               
             
             
               
                   
               
               
                 Relative tumor reproduction rate of compounds 11-20 and Sorafenib on 
               
               
                 human colon cancer HT-29 transplantable tumor in nude mice T/C (%) 
               
             
          
           
               
                   
                 11 
                 12 
                 13 
                 14 
                 15 
                 16 
                 17 
                 18 
                 19 
                 20 
               
               
                   
                   
               
             
          
           
               
                 Human colon 
                 81.2 
                 80.5 
                 81.2 
                 40.1 
                 85.2 
                 55.2 
                 54.7 
                 40.2 
                 39.4 
                 40.1 
               
               
                 cancer HT-29 
               
               
                 transplantable 
               
               
                 tumor in nude 
               
               
                 mice 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 22 
               
             
             
               
                   
               
               
                 Relative tumor reproduction rate of compounds 21-30 and Sorafenib on 
               
               
                 human colon cancer HT-29 transplantable tumor in nude mice T/C (%) 
               
             
          
           
               
                   
                 21 
                 22 
                 23 
                 24 
                 25 
                 26 
                 27 
                 28 
                 29 
                 30 
               
               
                   
                   
               
             
          
           
               
                 Human colon 
                 38.7 
                 41.2 
                 39.7 
                 37.8 
                 79.5 
                 41.1 
                 80.3 
                 39.1 
                 78.3 
                 79.5 
               
               
                 cancer HT-29 
               
               
                 transplatable 
               
               
                 tumor in nude 
               
               
                 mice 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 23 
               
             
             
               
                   
               
               
                 Relative tumor reproduction rate of compounds 
               
               
                 31-38 and Sorafenib on human colon cancer HT-29 
               
               
                 transplantable tumor in nude mice T/C (%) 
               
             
          
           
               
                   
                 31 
                 32 
                 33 
                 34 
                 35 
                 36 
                 37 
                 38 
               
               
                   
                   
               
             
          
           
               
                 Human colon 
                 50.3 
                 46.2 
                 39.9 
                 45.9 
                 51.2 
                 41.5 
                 39.5 
                 41.2 
               
               
                 cancer HT-29 
               
               
                 transplantable 
               
               
                 tumor in 
               
               
                 nude mice 
               
               
                   
               
             
          
         
       
     
     The results of the above in vivo and vitro tumor inhibition tests showed that the inhibiting effects of such derivatives on S180 sarcoma in mice and human colon cancer HT-29 transplantable tumor in nude mice were better than or equivalent to positive control medicine sorafenib.The test results showed that the compound of the present invention or the pharmaceutically acceptable salt thereof can be used for treating tumor or leukemia. The pharmacodynamic experiments of the compounds in the present invention, positive control medicine sorafenib and compounds A′, B′ and C′ with no substituent or only amino formyl in A ring on human lung cancer cell strain A549, human high-metastic lung cancer cell strain 95D, lung cancer cell A549, human umbilical vein endothelial cell HUVEC cell growth and lumen formation, human lung cancer A549 cell transplantation tumor model in nude mice, human liver cancer cell bel-7402 transplantation tumor model in nude mice, and renal carcinoma cell line GCR-1 transplantation tumor model in nude mice were carried out to verify the effect of the compounds of the present invention. 
     Sorafenib was abbreviated as Sorafenib hereafter, and the compounds A′, B′ and C′ were respectively prepared according the method of CN200810129360.6, which were compounds with no substituent in A ring, wherein A′ is N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(4-quinolinyl)oxy)phenyl)urea, B′is N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(4-pyrimidinyl)oxy)phenyl)urea, and C′           N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-(4-(4-pyrryl)oxy)phenyl)urea.
     4. Using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay (MTT) to detect the inhibition effects on the growth of human lung cancer cell strain A549 
     [Test materials] MTT working solution, F12 medium containing 10% FBS, continuous injectors 
     [Tested compound] Compounds 1-38 
     [Positive control medicine] Sorafenib, compounds A′, B′, C′ with no substituent or only amino formyl in A ring 
     The inhibition rate is calculated as follows: 
     
       
         
           
             
               Cell 
               ⁢ 
               
                   
               
               ⁢ 
               reproduction 
               ⁢ 
               
                   
               
               ⁢ 
               rate 
               ⁢ 
               
                   
               
               ⁢ 
               % 
             
             = 
             
               1 
               - 
               
                 
                   
                     ( 
                     
                       
                         
                           
                             
                               Relative 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               OD 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               value 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               of 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               conrol 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               well 
                             
                             - 
                           
                         
                       
                       
                         
                           
                             Relative 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             OD 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             value 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             of 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             drug 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             well 
                           
                         
                       
                     
                     ) 
                   
                   
                     Relative 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     OD 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     value 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     of 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     conrol 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     well 
                   
                 
                 × 
                 100 
                 ⁢ 
                 % 
               
             
           
         
       
     
     Relative OD value of conrol well=OD value of control well−OD value of blank well 
     Relative OD value of drug well=OD value of drug well−OD value of blank well 
     [Screening Results] 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 24 
               
             
             
               
                   
               
               
                 Inhibition effects of compounds 1-18 on 
               
               
                 the growth of human lung cancer cell A549 
               
             
          
           
               
                   
                 Compound 
                 Final concentration 
                 Inhibition 
                   
               
               
                   
                 No. 
                 1.0*10 (−5)  mol/L 
                 rate 
                 Activity 
               
               
                   
                   
               
             
          
           
               
                   
                 1 
                 1 
                 50.20% 
                 + 
               
               
                   
                 2 
                 1 
                 61.11% 
                 ++ 
               
               
                   
                 3 
                 1 
                 69.67% 
                 ++ 
               
               
                   
                 4 
                 1 
                 91.12% 
                 +++ 
               
               
                   
                 5 
                 1 
                 93.50% 
                 +++ 
               
               
                   
                 6 
                 1 
                 92.50% 
                 +++ 
               
               
                   
                 7 
                 1 
                 45.30% 
                 + 
               
               
                   
                 8 
                 1 
                 60.67% 
                 ++ 
               
               
                   
                 9 
                 1 
                 61.54% 
                 ++ 
               
               
                   
                 10 
                 1 
                 74.50% 
                 ++ 
               
               
                   
                 11 
                 1 
                 69.20% 
                 ++ 
               
               
                   
                 12 
                 1 
                 42.31% 
                 + 
               
               
                   
                 13 
                 1 
                 64.23% 
                 ++ 
               
               
                   
                 14 
                 1 
                 67.25% 
                 ++ 
               
               
                   
                 15 
                 1 
                 72.17% 
                 ++ 
               
               
                   
                 16 
                 1 
                 89.71% 
                 +++ 
               
               
                   
                 17 
                 1 
                 88.52% 
                 +++ 
               
               
                   
                 18 
                 1 
                 90.71% 
                 +++ 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 25 
               
             
             
               
                   
               
               
                 Inhibition effects of compounds 19-38 on 
               
               
                 the growth of human lung cancer cell A549 
               
             
          
           
               
                 Compound 
                 Final concentration 
                 Inhibition 
                   
               
               
                 No. 
                 1.0*10 (−5)  mol/ml 
                 rate 
                 Activity 
               
               
                   
               
               
                 19 
                 1 
                 91.23% 
                 +++ 
               
               
                 20 
                 1 
                 88.32% 
                 +++ 
               
               
                 21 
                 1 
                 89.21% 
                 +++ 
               
               
                 22 
                 1 
                 82.49% 
                 +++ 
               
               
                 23 
                 1 
                 55.41% 
                 + 
               
               
                 24 
                 1 
                 86.32% 
                 +++ 
               
               
                 25 
                 1 
                 63.26% 
                 + 
               
               
                 26 
                 1 
                 55.50% 
                 + 
               
               
                 27 
                 1 
                 64.71% 
                 + 
               
               
                 28 
                 1 
                 88.52% 
                 +++ 
               
               
                 29 
                 1 
                 86.42% 
                 +++ 
               
               
                 30 
                 1 
                 85.47% 
                 +++ 
               
               
                 31 
                 1 
                 46.78% 
                 + 
               
               
                 32 
                 1 
                 45.76% 
                 + 
               
               
                 33 
                 1 
                 57.53% 
                 + 
               
               
                 34 
                 1 
                 59.52% 
                 + 
               
               
                 35 
                 1 
                 55.74% 
                 + 
               
               
                 36 
                 1 
                 72.45% 
                 ++ 
               
               
                 37 
                 1 
                 71.65% 
                 ++ 
               
               
                 38 
                 1 
                 74.56% 
                 ++ 
               
               
                 Posive Sorafenib 
                 1 
                 54.60% 
                 + 
               
               
                 Compound A′ 
                 1 
                 58.51% 
                 + 
               
               
                 Compound B′ 
                 1 
                 61.62% 
                 + 
               
               
                 Compound C′ 
                 1 
                 62.25% 
                 + 
               
               
                   
               
             
          
         
       
     
     5 Inhibition effects of compounds on human high-metastic lung cancer cell 95D migration 
     [Test materials] Boyden Chamber Transwell chamber (with pore size of 8 μm), human high-metastic lung cancer cell 95D cell strain, 1640 medium containing 10% FBS, 1640 medium containing no serum 
     [Tested compound] Compounds 1-38 
     [Positive control medicine] Sorafenib, compounds A′, B′, C′ with no substituent or only amino formyl in A ring 
     The inhibition rate is calculated as follows: 
     
       
         
           
             
               Cell 
               ⁢ 
               
                   
               
               ⁢ 
               migration 
               ⁢ 
               
                   
               
               ⁢ 
               inhibition 
               ⁢ 
               
                   
               
               ⁢ 
               rate 
               ⁢ 
               
                   
               
               ⁢ 
               % 
             
             = 
             
               
                 
                   ( 
                   
                     
                       
                         
                           
                             migrated 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             cell 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             number 
                             ⁢ 
                             
                               
                                   
                               
                               ⁢ 
                               
                                   
                               
                             
                             ⁢ 
                             in 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             the 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             chamber 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             containing 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             no 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             drug 
                           
                           - 
                         
                       
                     
                     
                       
                         
                           migrated 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           cell 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           number 
                           ⁢ 
                           
                             
                                 
                             
                             ⁢ 
                             
                                 
                             
                           
                           ⁢ 
                           in 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           the 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           chamber 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           containing 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           drug 
                         
                       
                     
                   
                   ) 
                 
                 
                   migrated 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   cell 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   number 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   in 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   the 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   chamber 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   containing 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   no 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   drug 
                 
               
               × 
               100 
               ⁢ 
               % 
             
           
         
       
     
     [Screening Results] 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 26 
               
             
             
               
                   
               
               
                 Inhibition effects of compounds 1-18 on human high- 
               
               
                 metastic lung cancer 95D cell strain migration 
               
             
          
           
               
                   
                 Compound 
                 Final concentration 
                 Inhibition 
                   
               
               
                   
                 No. 
                 1.0*10 (−5)  mol/L 
                 rate 
                 Activity 
               
               
                   
                   
               
             
          
           
               
                   
                 1 
                 1 
                 80.21% 
                 ++ 
               
               
                   
                 2 
                 1 
                 85.17% 
                 +++ 
               
               
                   
                 3 
                 1 
                 96.64% 
                 +++ 
               
               
                   
                 4 
                 1 
                 96.38% 
                 +++ 
               
               
                   
                 5 
                 1 
                 97.51% 
                 +++ 
               
               
                   
                 6 
                 1 
                 93.71% 
                 +++ 
               
               
                   
                 7 
                 1 
                 89.34% 
                 +++ 
               
               
                   
                 8 
                 1 
                 89.56% 
                 +++ 
               
               
                   
                 9 
                 1 
                 91.42% 
                 +++ 
               
               
                   
                 10 
                 1 
                 61.43% 
                 + 
               
               
                   
                 11 
                 1 
                 78.66% 
                 ++ 
               
               
                   
                 12 
                 1 
                 66.79% 
                 ++ 
               
               
                   
                 13 
                 1 
                 65.45% 
                 ++ 
               
               
                   
                 14 
                 1 
                 57.57% 
                 + 
               
               
                   
                 15 
                 1 
                 63.68% 
                 + 
               
               
                   
                 16 
                 1 
                 89.31% 
                 +++ 
               
               
                   
                 17 
                 1 
                 90.52% 
                 +++ 
               
               
                   
                 18 
                 1 
                 93.73% 
                 +++ 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 27 
               
             
             
               
                   
               
               
                 Inhibition effects of compounds 19-38 on human high- 
               
               
                 metastic lung cancer 95D cell strain migration 
               
             
          
           
               
                 Compound 
                 Final concentration 
                 Inhibition 
                   
               
               
                 No. 
                 1.0*10 (−5)  mol/L 
                 rate 
                 Activity 
               
               
                   
               
               
                 19 
                 1 
                 90.21% 
                 +++ 
               
               
                 20 
                 1 
                 89.12% 
                 +++ 
               
               
                 21 
                 1 
                 88.76% 
                 +++ 
               
               
                 22 
                 1 
                 88.77% 
                 +++ 
               
               
                 23 
                 1 
                 85.53% 
                 +++ 
               
               
                 24 
                 1 
                 85.48% 
                 +++ 
               
               
                 25 
                 1 
                 59.76% 
                 + 
               
               
                 26 
                 1 
                 60.52% 
                 + 
               
               
                 27 
                 1 
                 59.77% 
                 + 
               
               
                 28 
                 1 
                 70.53% 
                 + 
               
               
                 29 
                 1 
                 61.44% 
                 + 
               
               
                 30 
                 1 
                 69.62% 
                 ++ 
               
               
                 31 
                 1 
                 76.18% 
                 ++ 
               
               
                 32 
                 1 
                 66.92% 
                 ++ 
               
               
                 33 
                 1 
                 77.52% 
                 ++ 
               
               
                 34 
                 1 
                 63.65% 
                 + 
               
               
                 35 
                 1 
                 68.47% 
                 ++ 
               
               
                 36 
                 1 
                 84.59% 
                 +++ 
               
               
                 37 
                 1 
                 79.25% 
                 + 
               
               
                 38 
                 1 
                 80.53% 
                 + 
               
               
                 Positive Sorafenib 
                 1 
                 62.32% 
                 + 
               
               
                 Compound A′ 
                 1 
                 63.51% 
                 + 
               
               
                 Compound B′ 
                 1 
                 61.60% 
                 + 
               
               
                 Compound C′ 
                 1 
                 63.20% 
                 ++ 
               
               
                   
               
             
          
         
       
     
     6. Effects of tested compounds on the adhesive ability of lung cancer cell A549 
     [Test materials] gelatin, CCK8, poly-lysine (PLL), A549 cell stains, 1640 medium containing 10% FBS 
     [Tested compound] Compounds 1-38 to be tested 
     [Positive control medicine] Sorafenib, compounds A′, B′, C′ with no substituent or only amino formyl in A ring 
     [Screening Results] 
     The inhibition rate is calculated as follows: 
     
       
         
           
             
               Inhibition 
               ⁢ 
               
                   
               
               ⁢ 
               rate 
               ⁢ 
               
                   
               
               ⁢ 
               of 
               ⁢ 
               
                   
               
               ⁢ 
               cell 
               ⁢ 
               
                   
               
               ⁢ 
               adhesion 
               ⁢ 
               
                   
               
               ⁢ 
               % 
             
             = 
             
               
                 
                   
                     
                       
                         
                           Cell 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           group 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           without 
                           ⁢ 
                           
                             
                                 
                             
                             ⁢ 
                             
                                 
                             
                           
                           ⁢ 
                           treatment 
                         
                         ⁢ 
                         
                             
                         
                       
                     
                   
                   
                     
                       
                         
                             
                         
                         ⁢ 
                         
                           
                             ( 
                             
                               glutin 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               adhesion 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               
                                 OD 
                                 / 
                                 PLL 
                               
                               ⁢ 
                               
                                 
                                     
                                 
                                 ⁢ 
                                 
                                     
                                 
                               
                               ⁢ 
                               adhesion 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               OD 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               value 
                             
                             ⁢ 
                             
                                 
                             
                             ) 
                           
                           - 
                         
                       
                     
                   
                   
                     
                       
                         dosing 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         cell 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         group 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         
                           ( 
                           
                             glutin 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             adhesion 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             
                               OD 
                               / 
                               PLL 
                             
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             adhesion 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             OD 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             value 
                           
                           ) 
                         
                       
                     
                   
                 
                 
                   
                     
                       
                         Cell 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         group 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         without 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         treatment 
                       
                     
                   
                   
                     
                       
                         ( 
                         
                           glutin 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           adhesion 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           
                             OD 
                             / 
                             PLL 
                           
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           adhesion 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           OD 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           value 
                         
                         ) 
                       
                     
                   
                 
               
               × 
               100 
               ⁢ 
               % 
             
           
         
       
     
     Dosing dosing cells without cell group (gelatin adhesive OD/PLL adhesion OD)−Dosing cell group (gelatin adhesive OD/PLL adhesion OD value) 
     Dosing dosing cells without cell group (gelatin adhesive OD/PLL adhesion OD value) 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 28 
               
             
             
               
                   
               
               
                 Inhibition effects of compounds 1-18 on the adhesion 
               
               
                 ability of human lung cancer cell A549 
               
             
          
           
               
                   
                 Compound 
                 Final concentration 
                 Inhibition 
                   
               
               
                   
                 No. 
                 1.0*10 (−5)  mol/L 
                 rate 
                 Activity 
               
               
                   
                   
               
             
          
           
               
                   
                 1 
                 1 
                 60.22% 
                 + 
               
               
                   
                 2 
                 1 
                 75.15% 
                 ++ 
               
               
                   
                 3 
                 1 
                 79.66% 
                 ++ 
               
               
                   
                 4 
                 1 
                 89.71% 
                 +++ 
               
               
                   
                 5 
                 1 
                 87.58% 
                 +++ 
               
               
                   
                 6 
                 1 
                 93.59% 
                 +++ 
               
               
                   
                 7 
                 1 
                 68.34% 
                 ++ 
               
               
                   
                 8 
                 1 
                 61.56% 
                 + 
               
               
                   
                 9 
                 1 
                 85.32% 
                 +++ 
               
               
                   
                 10 
                 1 
                 64.57% 
                 + 
               
               
                   
                 11 
                 1 
                 59.63% 
                 + 
               
               
                   
                 12 
                 1 
                 62.30% 
                 + 
               
               
                   
                 13 
                 1 
                 63.39% 
                 + 
               
               
                   
                 14 
                 1 
                 67.51% 
                 ++ 
               
               
                   
                 15 
                 1 
                 68.63% 
                 ++ 
               
               
                   
                 16 
                 1 
                 90.77% 
                 +++ 
               
               
                   
                 17 
                 1 
                 97.50% 
                 +++ 
               
               
                   
                 18 
                 1 
                 93.72% 
                 +++ 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 29 
               
             
             
               
                   
               
               
                 Inhibition effects of compounds 19-38 on the adhesion 
               
               
                 ability of human lung cancer cell A549 
               
             
          
           
               
                 Compound 
                 Final concentration 
                 Inhibition 
                   
               
               
                 No. 
                 1.0*10 (−5)  mol/L 
                 rate 
                 Activity 
               
               
                   
               
               
                 19 
                 1 
                 90.28% 
                 +++ 
               
               
                 20 
                 1 
                 95.31% 
                 +++ 
               
               
                 21 
                 1 
                 90.22% 
                 +++ 
               
               
                 22 
                 1 
                 72.44% 
                 ++ 
               
               
                 23 
                 1 
                 77.56% 
                 ++ 
               
               
                 24 
                 1 
                 73.30% 
                 ++ 
               
               
                 25 
                 1 
                 63.51% 
                 + 
               
               
                 26 
                 1 
                 68.57% 
                 ++ 
               
               
                 27 
                 1 
                 94.77% 
                 +++ 
               
               
                 28 
                 1 
                 90.53% 
                 +++ 
               
               
                 29 
                 1 
                 91.40% 
                 +++ 
               
               
                 30 
                 1 
                 92.44% 
                 +++ 
               
               
                 31 
                 1 
                 66.77% 
                 ++ 
               
               
                 32 
                 1 
                 64.73% 
                 + 
               
               
                 33 
                 1 
                 77.59% 
                 ++ 
               
               
                 34 
                 1 
                 76.54% 
                 ++ 
               
               
                 35 
                 1 
                 75.72% 
                 ++ 
               
               
                 36 
                 1 
                 74.50% 
                 ++ 
               
               
                 37 
                 1 
                 71.74% 
                 ++ 
               
               
                 38 
                 1 
                 75.53% 
                 ++ 
               
               
                 Positive medicine 
                 1 
                 72.66% 
                 ++ 
               
               
                 Sorafenib 
               
               
                 Compound A′ 
                 1 
                 71.55% 
                 ++ 
               
               
                 Compound B′ 
                 1 
                 69.26% 
                 ++ 
               
               
                 Compound C′ 
                 1 
                 68.62% 
                 ++ 
               
               
                   
               
             
          
         
       
     
     7. Effects of tested compounds on the growth of human umbilical vein endothelial cell HUVEC cell by CCK8 method 
     [Test materials] CCK8, human umbilical vein endothelial cell HUVEC cell, 1640 medium containing 10% FBS 
     [Tested compound] Compounds 1-38 to be tested 
     [Positive control medicine] Sorafenib, compounds A′, B′, C′ with no substituent or only amino formyl in A ring 
     [Screening Results] 
     
       
         
           
             
               Cell 
               ⁢ 
               
                   
               
               ⁢ 
               reproduction 
               ⁢ 
               
                   
               
               ⁢ 
               rate 
               ⁢ 
               
                   
               
               ⁢ 
               % 
             
             = 
             
               1 
               - 
               
                 
                   
                     ( 
                     
                       
                         
                           
                             
                               Relative 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               OD 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               value 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               of 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               conrol 
                               ⁢ 
                               
                                   
                               
                               ⁢ 
                               well 
                             
                             - 
                           
                         
                       
                       
                         
                           
                             Relative 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             OD 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             value 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             of 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             drug 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             well 
                           
                         
                       
                     
                     ) 
                   
                   
                     Relative 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     OD 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     value 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     of 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     conrol 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     well 
                   
                 
                 × 
                 100 
                 ⁢ 
                 % 
               
             
           
         
       
     
     Relative OD value of conrol well=OD value of control well−OD value of blank well 
     Relative OD value of drug well=OD value of drug well−OD value of blank well 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 30 
               
             
             
               
                   
               
               
                 Inhibition effects of compounds 1-18 on the growth 
               
               
                 of human umbilical vein endothelial cell HUVEC cell 
               
             
          
           
               
                   
                 Compound 
                 Final concentration 
                 Inhibition 
                   
               
               
                   
                 No. 
                 1.0*10 (−5)  mol/L 
                 rate 
                 Activity 
               
               
                   
                   
               
             
          
           
               
                   
                 1 
                 1 
                 9.20% 
                   
               
               
                   
                 2 
                 1 
                 13.11% 
               
               
                   
                 3 
                 1 
                 27.67% 
               
               
                   
                 4 
                 1 
                 5.12% 
               
               
                   
                 5 
                 1 
                 8.50% 
               
               
                   
                 6 
                 1 
                 7.50% 
               
               
                   
                 7 
                 1 
                 8.30% 
               
               
                   
                 8 
                 1 
                 13.67% 
               
               
                   
                 9 
                 1 
                 11.54% 
               
               
                   
                 10 
                 1 
                 14.50% 
               
               
                   
                 11 
                 1 
                 29.20% 
               
               
                   
                 12 
                 1 
                 12.31% 
               
               
                   
                 13 
                 1 
                 24.23% 
               
               
                   
                 14 
                 1 
                 17.25% 
               
               
                   
                 15 
                 1 
                 38.17% 
               
               
                   
                 16 
                 1 
                 10.71% 
               
               
                   
                 17 
                 1 
                 13.52% 
               
               
                   
                 18 
                 1 
                 5.71% 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 31 
               
             
             
               
                   
               
               
                 Inhibition effects of compounds 19-38 on the growth 
               
               
                 of human umbilical vein endothelial cell HUVEC cell 
               
             
          
           
               
                 Compound 
                 Final concentration 
                 Inhibition 
                   
               
               
                 No. 
                 1.0*10 (−5)  mol/L 
                 rate 
                 Activity 
               
               
                   
               
             
          
           
               
                 19 
                 1 
                 5.23% 
                   
               
               
                 20 
                 1 
                 7.32% 
               
               
                 21 
                 1 
                 11.21% 
               
               
                 22 
                 1 
                 12.49% 
               
               
                 23 
                 1 
                 17.41% 
               
               
                 24 
                 1 
                 13.32% 
               
               
                 25 
                 1 
                 23.26% 
               
               
                 26 
                 1 
                 32.50% 
               
               
                 27 
                 1 
                 24.73% 
               
               
                 28 
                 1 
                 20.55% 
               
               
                 29 
                 1 
                 21.40% 
               
               
                 30 
                 1 
                 25.46% 
               
               
                 31 
                 1 
                 26.70% 
               
               
                 32 
                 1 
                 24.77% 
               
               
                 33 
                 1 
                 17.50% 
               
               
                 34 
                 1 
                 19.52% 
               
               
                 35 
                 1 
                 5.74% 
               
               
                 36 
                 1 
                 12.45% 
               
               
                 37 
                 1 
                 19.65% 
               
               
                 38 
                 1 
                 14.56% 
               
               
                 Positive medicine 
                 1 
                 22.61% 
               
               
                 Sorafenib 
               
               
                 Compound A′ 
                 1 
                 23.11% 
               
               
                 Compound B′ 
                 1 
                 31.64% 
               
               
                 Compound C′ 
                 1 
                 22.27% 
               
               
                   
               
             
          
         
       
     
     8. Inhibition effects of compounds on the lumen formation ability of human umbilical vein endothelial cell HUVEC 
     [Experimental principles] The human umbilical vein endothelial cells have ability of spontaneously forming blood lumen on Matrigel, which can be used to simulate the process of angiogenesis in vivo. We used Matrigel method to investigate the effects of the compound on the lumen formation ability of human umbilical vein endothelial cell HUVEC. 
     [Test materials] HUVEC (taking generation 3 to 5 cells for experiments after obtained from primary separation and cultured at 37 under the conditions of 5% CO 2 ), Matrigel, cell culture medium M199. 
     [Tested compound] Compounds 1-38 
     [Positive control medicine] Sorafenib, compounds A′, B′, C′ with no substituent or only amino formyl in A ring 
     [Screening Results] 
     The inhibition rate is calculated as follows: 
     
       
         
           
             
               Lumen 
               ⁢ 
               
                   
               
               ⁢ 
               formation 
               ⁢ 
               
                   
               
               ⁢ 
               inhibition 
               ⁢ 
               
                   
               
               ⁢ 
               rate 
               ⁢ 
               
                   
               
               ⁢ 
               % 
             
             = 
             
               
                 
                   ( 
                   
                     
                       
                         
                           
                             length 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             sum 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             of 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             lumen 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             without 
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             dosing 
                           
                           - 
                         
                       
                     
                     
                       
                         
                           length 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           sum 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           of 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           lumen 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           after 
                           ⁢ 
                           
                             
                                 
                             
                             ⁢ 
                             
                                 
                             
                           
                           ⁢ 
                           dosing 
                         
                       
                     
                   
                   ) 
                 
                 
                   length 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   sum 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   of 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   lumen 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   without 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   dosing 
                 
               
               × 
               100 
               ⁢ 
               % 
             
           
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 32 
               
             
             
               
                   
               
               
                 Inhibition effects of compounds 1-18 on the lumen formation 
               
               
                 ability of human umbilical vein endothelial cell HUVEC 
               
             
          
           
               
                   
                 Compound 
                 Final concentration 
                 Inhibition 
                   
               
               
                   
                 No. 
                 1.0*10 (−5)  mol/L 
                 rate 
                 Activity 
               
               
                   
                   
               
             
          
           
               
                   
                 1 
                 1 
                 72.22% 
                 ++ 
               
               
                   
                 2 
                 1 
                 75.14% 
                 ++ 
               
               
                   
                 3 
                 1 
                 76.61% 
                 ++ 
               
               
                   
                 4 
                 1 
                 86.77% 
                 +++ 
               
               
                   
                 5 
                 1 
                 87.50% 
                 +++ 
               
               
                   
                 6 
                 1 
                 90.55% 
                 +++ 
               
               
                   
                 7 
                 1 
                 60.34% 
                 + 
               
               
                   
                 8 
                 1 
                 78.59% 
                 ++ 
               
               
                   
                 9 
                 1 
                 91.45% 
                 +++ 
               
               
                   
                 10 
                 1 
                 50.34% 
                 + 
               
               
                   
                 11 
                 1 
                 79.63% 
                 ++ 
               
               
                   
                 12 
                 1 
                 52.37% 
                 + 
               
               
                   
                 13 
                 1 
                 53.36% 
                 + 
               
               
                   
                 14 
                 1 
                 67.53% 
                 ++ 
               
               
                   
                 15 
                 1 
                 68.64% 
                 ++ 
               
               
                   
                 16 
                 1 
                 80.79% 
                 ++ 
               
               
                   
                 17 
                 1 
                 67.50% 
                 ++ 
               
               
                   
                 18 
                 1 
                 63.71% 
                 + 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 33 
               
             
             
               
                   
               
               
                 Inhibition effects of compounds 19-38 on the lumen formation 
               
               
                 ability of human umbilical vein endothelial cell HUVEC 
               
             
          
           
               
                 Compound 
                 Final concentration 
                 Inhibition 
                   
               
               
                 No. 
                 1.0*10 (−5)  mol/L 
                 rate 
                 Activity 
               
               
                   
               
               
                 19 
                 1 
                 89.22% 
                 +++ 
               
               
                 20 
                 1 
                 88.54% 
                 +++ 
               
               
                 21 
                 1 
                 89.47% 
                 +++ 
               
               
                 22 
                 1 
                 86.72% 
                 +++ 
               
               
                 23 
                 1 
                 97.56% 
                 +++ 
               
               
                 24 
                 1 
                 93.78% 
                 +++ 
               
               
                 25 
                 1 
                 79.79% 
                 ++ 
               
               
                 26 
                 1 
                 70.53% 
                 ++ 
               
               
                 27 
                 1 
                 89.75% 
                 +++ 
               
               
                 28 
                 1 
                 89.52% 
                 +++ 
               
               
                 29 
                 1 
                 86.43% 
                 +++ 
               
               
                 30 
                 1 
                 90.66% 
                 +++ 
               
               
                 31 
                 1 
                 66.77% 
                 ++ 
               
               
                 32 
                 1 
                 54.74% 
                 + 
               
               
                 33 
                 1 
                 67.51% 
                 ++ 
               
               
                 34 
                 1 
                 66.52% 
                 ++ 
               
               
                 35 
                 1 
                 65.70% 
                 ++ 
               
               
                 36 
                 1 
                 64.50% 
                 + 
               
               
                 37 
                 1 
                 71.72% 
                 ++ 
               
               
                 38 
                 1 
                 65.55% 
                 ++ 
               
               
                 Positive medicine 
                 1 
                 55.60% 
                 ++ 
               
               
                 Sorafenib 
               
               
                 Compound A′ 
                 1 
                 60.51% 
                 ++ 
               
               
                 Compound B′ 
                 1 
                 61.62% 
                 ++ 
               
               
                 Compound C′ 
                 1 
                 60.50% 
                 ++ 
               
               
                   
               
             
          
         
       
     
     9. Tumor inhibition rate of tested compounds on human lung cancer A549 cell transplantation model in nude mice 
     [Test animals] female BALB/cA nude mice, 35-40 days old, with weight of 18-22g. There were 12 mice in the negative conrol group and 6 mice in the treatment group. 
     [Test method] Take eugenic tumor tissues and cut into about 1.5 mm 3 , and then incoculate subcutaneously at the right armpit of nude mice under the sterile conditions. The diameter of the transplantable tumor in nude mice was determined with a vernier caliper, and the animals were divided into groups after the tumors were grown to 100-300 mm 3 .Using the method of measuring the tumor diameter, dynamically observe the antitumor effects of tested materials. 
     The diameter of the tumor was determined three times every week and the mouse weight was weighed at the same time. The dosage of the compound was 60 mg/kg, 6 times every week for 3 weeks. Sorafenib was oral administrated with dosage of 60 mg/kg, 6 times every week for 3 weeks. Equal amount of normal saline was administrated in the negative control group. Observe for one week after administration. 
     [Detection Indicators and Calculation Methods]
     (1) Tumor volume (TV) is calculated as:
 
TV=½×a×b 2  
   

     wherein a and b respectively represents length and width.
     (2) Relative tumor volume (RTV) is calculated as:
 
RTV=TV t /TV 0° 
   

     wherein TV 0  is the tumor volume when administrated according to different cages and TV t  is the tumor volume measured each time.
     (3) Relative tumor reproduction rate T/C (%) is calculated as follows:   

     
       
         
           
             
               T 
               ⁢ 
               
                 / 
               
               ⁢ 
               
                 C 
                 ⁡ 
                 
                   ( 
                   % 
                   ) 
                 
               
             
             = 
             
               
                 
                   T 
                   RTV 
                 
                 
                   C 
                   RTV 
                 
               
               × 
               100 
             
           
         
       
     
     T RTV : RTV in the treatment group; C RTV : RTV in the negative control group. The test results used relative tumor reproduction rate T/C (%) as evaluating indicator of anti-tumor activity. 
     [Screening results] There was no mortality for the animals in the group of compounds and Sorafenib in the experiments with less toxicity. 
     
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 34 
               
               
                   
               
               
                 Relative tumor reproduction rate of compounds and Sorafenib on human 
               
               
                 lung cancer A549 transplantation tumor in nude mice T/C (%) 
               
               
                   
               
             
             
               
                 Relative tumor reproduction rate of compounds 1-10 and Sorafenib on human lung 
               
               
                 cancer A549 transplantation tumor in nude mice T/C (%) 
               
             
          
           
               
                   
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
               
               
                   
               
               
                 human lung 
                 38.7 
                 35.3 
                 37.2 
                 12.3 
                 11.6 
                 15.9 
                 39.3 
                 30.5 
                 38.7 
                 30.1 
               
               
                 cancer A549 
               
               
                 transplantation 
               
               
                 tumor 
               
               
                   
               
             
          
           
               
                 Relative tumor reproduction rate of compounds 11-20 and Sorafenib on human lung 
               
               
                 cancer A549 transplantation tumor in nude mice T/C (%) 
               
             
          
           
               
                   
                 11 
                 12 
                 13 
                 14 
                 15 
                 16 
                 17 
                 18 
                 19 
                 20 
               
               
                   
               
               
                 human lung 
                 43.7 
                 36.3 
                 38.4 
                 32.2 
                 38.7 
                 9.9 
                 7.3 
                 12.5 
                 7.7 
                 12.1 
               
               
                 cancer A549 
               
               
                 transplantation 
               
               
                 tumor 
               
               
                   
               
             
          
           
               
                 Relative tumor reproduction rate of compounds 21-30 and Sorafenib on human lung 
               
               
                 cancer A549 transplantation tumor in nude mice T/C (%) 
               
             
          
           
               
                   
                 21 
                 22 
                 23 
                 24 
                 25 
                 26 
                 27 
                 28 
                 29 
                 30 
               
               
                   
               
               
                 human lung 
                 13.7 
                 15.3 
                 17.1 
                 15.6 
                 39.4 
                 33.1 
                 36.3 
                 13.6 
                 14.7 
                 13.1 
               
               
                 cancer A549 
               
               
                 transplantation 
               
               
                 tumor 
               
               
                   
               
             
          
           
               
                 Relative tumor reproduction rate of compounds 31-38 and Sorafenib on human lung 
               
               
                 cancer A549 transplantation tumor in nude mice T/C (%) 
               
             
          
           
               
                   
                 31 
                 32 
                 33 
                 34 
                 35 
                 36 
                 37 
                 38 
                 Sorafenib 
               
               
                   
               
               
                 human lung 
                 38.7 
                 35.3 
                 37.5 
                 22.3 
                 23.6 
                 37.9 
                 38.3 
                 36.5 
                 41.8 
               
               
                 cancer A549 
               
               
                 transplantation 
               
               
                 tumor 
               
               
                   
               
             
          
           
               
                   
                   
                 Compound A′ 
                 Compound B′ 
                 Compound C′ 
               
               
                   
                   
               
               
                   
                 human lung 
                 43.2 
                 40.4 
                 36.6 
               
               
                   
                 cancer A549 
               
               
                   
                 transplantation 
               
               
                   
                 tumor 
               
               
                   
                   
               
             
          
         
       
     
     10. Tumor inhibition rate of tested compounds on human liver cancer cell bel-7402 transplantation tumor model in nude mice 
     [Test animals] female BALB/cA nude mice, 35-40 days old, with weight of 18-22g. There were 12 mice in the negative conrol group and 6 mice in the treatment group. 
     [Test method] Take eugenic tumor tissues and cut into about 1.5 mm 3 , and then incoculate subcutaneously at the right armpit of nude mice under the sterile conditions. The diameter of the transplantable tumor in nude mice was determined with a vernier caliper, and the animals were divided into groups after the tumors were grown to 100-300 mm 3 .Using the method of measuring the tumor diameter, dynamically observe the antitumor effects of tested materials. 
     The diameter of the tumor was determined three times every week and the mouse weight was weighed at the same time. The dosage of the compound was 60 mg/kg, 6 times every week for 3 weeks. Sorafenib was oral administrated with dosage of 60 mg/kg, 6 times every week for 3 weeks. Equal amount of normal saline was administrated in the negative control group. Observe for one week after administration. 
     [Detection Indicators and Calculation Methods]
     (1) Tumor volume (TV) is calculated as:
 
TV=½×a×b 2  
   

     wherein a and b respectively represents length and width.
     (2) Relative tumor volume (RTV) is calculated as:
 
RTV=TV t /TV 0° 
   

     wherein TV 0  is the tumor volume when administrated according to different cages (d 0 ) and TV t  is the tumor volume measured each time.
     (3) Relative tumor reproduction rate T/C (%) is calculated as follows:   

     
       
         
           
             
               T 
               ⁢ 
               
                 / 
               
               ⁢ 
               
                 C 
                 ⁡ 
                 
                   ( 
                   % 
                   ) 
                 
               
             
             = 
             
               
                 
                   T 
                   RTV 
                 
                 
                   C 
                   RTV 
                 
               
               × 
               100 
             
           
         
       
     
     T RTV : RTV in the treatment group; C RTV : RTV in the negative control group. The test results used relative tumor reproduction rate T/C (%) as evaluating indicator of anti-tumor activity. 
     [Screening results] There was no mortality for the animals in the group of compounds and Sorafenib in the experiments with less toxicity. 
     
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 35 
               
               
                   
               
               
                 Relative tumor reproduction rate of compounds and Sorafenib on human liver 
               
               
                 cancer cell bel-7402 transplantation tumor model in nude mice T/C (%) 
               
               
                 Relative tumor reproduction rate of compounds 1-10 and Sorafenib on human liver 
               
               
                 cancer cell bel-7402 transplantation tumor model in nude mice T/C (%) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
               
               
                   
               
               
                 human liver 
                 33.7 
                 35.4 
                 30.1 
                 15.3 
                 15.7 
                 19.5 
                 34.2 
                 30.6 
                 36.8 
                 28.1 
               
               
                 cancer cell 
               
               
                 bel-7402 
               
               
                 transplantation 
               
               
                 tumor 
               
               
                   
               
               
                   
                 11 
                 12 
                 13 
                 14 
                 15 
                 16 
                 17 
                 18 
                 19 
                 20 
               
               
                   
               
               
                 human liver 
                 23.7 
                 31.6 
                 29.8 
                 36.1 
                 33.6 
                 14.9 
                 12.5 
                 12.7 
                 16.3 
                 17.2 
               
               
                 cancer cell 
               
               
                 bel-7402 
               
               
                 transplantation 
               
               
                 tumor 
               
               
                   
               
               
                   
                 21 
                 22 
                 23 
                 24 
                 25 
                 26 
                 27 
                 28 
                 29 
                 30 
               
               
                   
               
               
                 human liver 
                 16.4 
                 15.3 
                 17.7 
                 16.8 
                 29.1 
                 36.1 
                 29.2 
                 17.5 
                 16.2 
                 16.1 
               
               
                 cancer cell 
               
               
                 bel-7402 
               
               
                 transplantation 
               
               
                 tumor 
               
               
                   
               
             
          
           
               
                   
                 31 
                 32 
                 33 
                 34 
                 35 
                 36 
                 37 
                 38 
                 Sorafenib 
               
               
                   
               
               
                 human liver 
                 33.4 
                 31.4 
                 32.7 
                 31.5 
                 34.5 
                 37.9 
                 36.3 
                 31.5 
                 35.9 
               
               
                 cancer cell 
               
               
                 bel-7402 
               
               
                 transplantation 
               
               
                 tumor 
               
               
                   
               
             
          
           
               
                   
                   
                 Compound A′ 
                 Compound B′ 
                 Compound C′ 
               
               
                   
                   
               
               
                   
                 human liver 
                 37.2 
                 30.4 
                 32.6 
               
               
                   
                 cancer cell 
               
               
                   
                 bel-7402 
               
               
                   
                 transplantation 
               
               
                   
                 tumor 
               
               
                   
                   
               
             
          
         
       
     
     11. Tumor inhibition rate of medicines on renal carcinoma cell line GCR-1 transplanted tumor model in nude mice 
     [Test animals] female BALB/cA nude mice, 35-40 days old, with weight of 18-22g. There were 12 mice in the negative conrol group and 6 mice in the treatment group. 
     [Test method] Take eugenic tumor tissues and cut into about 1.5 mm 3 , and then incoculate subcutaneously at the right armpit of nude mice under the sterile conditions. The diameter of the transplantable tumor in nude mice was determined with a vernier caliper, and the animals were divided into groups after the tumors were grown to 100-300 mm 3 .Using the method of measuring the tumor diameter, dynamically observe the antitumor effects of tested materials. The diameter of the tumor was determined three times every week and the mouse weight was weighed at the same time. The dosage of the medicine was 60 mg/kg, 6 times every week for 3 weeks. Sorafenib was oral administrated with dosage of 60 mg/kg, 6 times every week for 3 weeks. Equal amount of normal saline was administrated in the negative control group. Observe for one week after administration. 
     [Detection Indicators and Calculation Methods]
     (1) Tumor volume (TV) is calculated as:
 
TV=½×a×b 2  
   

     wherein a and b respectively represents length and width.
     (2) Relative tumor volume (RTV) is calculated as:
 
RTV=TV t /TV 0° 
   

     wherein TV 0  is the tumor volume when administrated according to different cages (d 0 ) and TV t  is the tumor volume measured each time.
     (3) Relative tumor reproduction rate T/C (%) is calculated as follows:   

     
       
         
           
             
               T 
               ⁢ 
               
                 / 
               
               ⁢ 
               
                 C 
                 ⁡ 
                 
                   ( 
                   % 
                   ) 
                 
               
             
             = 
             
               
                 
                   T 
                   RTV 
                 
                 
                   C 
                   RTV 
                 
               
               × 
               100 
             
           
         
       
     
     T RTV : RTV in the treatment group; C RTV : RTV in the negative control group. The test results used relative tumor reproduction rate T/C (%) as evaluating indicator of anti-tumor activity. 
     [Screening results] There was no mortality for the animals in the group of compounds and Sorafenib in the experiments with less toxicity. 
     
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 36 
               
               
                   
               
               
                 Relative tumor reproduction rate of compounds and Sorafenib on human renal 
               
               
                 carcinoma GCR-1 cell transplanted tumor model in nude mice T/C (%) 
               
               
                   
               
             
             
               
                 Relative tumor reproduction rate of compounds 11-20 and Sorafenib on human renal 
               
               
                 carcinoma GCR-1 cell transplanted tumor model in nude mice T/C (%) 
               
             
          
           
               
                   
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
               
               
                   
               
               
                 human renal 
                 30.5 
                 23.2 
                 31.3 
                 9.6 
                 11.2 
                 12.5 
                 21.2 
                 29.1 
                 28.3 
                 27.1 
               
               
                 carcinoma 
               
               
                 GCR-1 cell 
               
               
                 transplanted 
               
               
                 tumor 
               
               
                   
               
             
          
           
               
                   
                 11 
                 12 
                 13 
                 14 
                 15 
                 16 
                 17 
                 18 
                 19 
                 20 
               
               
                   
               
               
                 human renal 
                 32.1 
                 20.5 
                 28.3 
                 31.1 
                 22.5 
                 9.9 
                 11.1 
                 12.3 
                 13.2 
                 13.1 
               
               
                 carcinoma 
               
               
                 GCR-1 cell 
               
               
                 transplanted 
               
               
                 tumor 
               
               
                   
               
             
          
           
               
                 Relative tumor reproduction rate of compounds 21-30 and Sorafenib on human renal 
               
               
                 carcinoma GCR-1 cell transplanted tumor model in nude mice T/C (%) 
               
             
          
           
               
                   
                 21 
                 22 
                 23 
                 24 
                 25 
                 26 
                 27 
                 28 
                 29 
                 30 
               
               
                   
               
               
                 human renal 
                 7.8 
                 8.1 
                 9.1 
                 10.8 
                 31.2 
                 24.2 
                 26.2 
                 11.4 
                 12.8 
                 10.2 
               
               
                 carcinoma 
               
               
                 GCR-1 cell 
               
               
                 transplanted 
               
               
                 tumor 
               
               
                   
               
             
          
           
               
                   
                 31 
                 32 
                 33 
                 34 
                 35 
                 36 
                 37 
                 38 
                 Sorafenib 
               
               
                   
               
               
                 human renal 
                 31.4 
                 32.5 
                 33.4 
                 36.1 
                 32.3 
                 25.9 
                 32.3 
                 20.5 
                 33.9 
               
               
                 carcinoma 
               
               
                 GCR-1 cell 
               
               
                 transplanted 
               
               
                 tumor 
               
               
                   
               
             
          
           
               
                   
                 Compound A′ 
                 Compound B′ 
                 Compound C′ 
               
               
                   
                   
               
             
          
           
               
                   
                 human renal 
                 34.2 
                 30.4 
                 35.6 
                 34.2 
                 30.4 
               
               
                   
                 carcinoma 
               
               
                   
                 GCR-1 cell 
               
               
                   
                 transplanted 
               
               
                   
                 tumor 
               
               
                   
                   
               
             
          
         
       
     
     According to the experimental results, the compound added with specific substituents in A ring have stronger anti-tumor activity than the compouns with no substituent or only amino formyl in A ring, especially the 4#-6# 16#-18# 19#-24# 28#-30# compounds have stonger anti-tumor activity which are stonger than the positive conrol Sorafenib, which have particularly evident effects on the tumor cell metastasis and tumor angiogenesis that are significantly stronger than Sorafenib. The test on normal human umbilical vein endothelial cells CCK8 found that these compounds have less toxicity to normal human cells like endothelial cells, which are relatively safe and reliable, but these compounds can achieve the antitumor activity through inhibiting the tumor angiogenesis. The in vivo transplantation experiments in nude mice showed that 4#-6# 16#-18# 19#-24# 28#-30# compounds have inhibition effects on human liver cancer and renal caner and their effects are better than Sorafenib, but these compounds have very significant effects on lung cancer and the effects obviously exceed the positive control medicine Sorafenib, which is an unexpected result. 
     The above results indicate that the compounds added with specific substituents in A-ring have more advantages than previously found compounds with no substituent or only amino formyl in A ring, and these new compounds have broader prospects in the treatment of cancer.