CN110054584A - 1- aryl -3- { 4- [(pyridine -2- ylmethyl) sulfenyl] phenyl } carbamide compounds and application - Google Patents

Abstract

The invention belongs to the technical field of medicine, and relates to 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea compounds and a preparation method thereof and in the preparation of medicines for anti-tumor diseases application. Described 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea compounds, their prodrugs and pharmaceutically active metabolites and pharmaceutically acceptable salts The general structural formula is as follows: X can independently select CH, N; R can be hydrogen, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkane Oxy group, halogen; R can be single or multiple; R ₃ , R ₄ , R ₅ can be independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkoxy , C1-C4 alkoxy substituted by C1-C4 alkoxy. The compound of the present invention has a simple synthesis method and is suitable for industrial production. The biological activity test shows that the compound has anti-tumor activity and is a new type of anti-tumor drug.

Description

1-Aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea compounds and application

technical field

The invention belongs to the technical field of medicine, and relates to 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea compounds and a preparation method thereof, as well as a BRaf kinase, vascular Vascularendothelial growth factor receptor-2 (VEGFR-2), Platelet-derived growth factor receptors-β (PDGFR-β) and T-LAK cell-derived protein kinase (T-LAK cell-originated protein kinase, TOPK) inhibitors.

Background technique

In recent years, with the continuous elucidation of tumor pathogenesis and the continuous discovery of anti-tumor targets, multi-target inhibition of tumor signal transduction has become an important direction for tumor drug development. Compared with single-target drugs and the combination of multiple single-target drugs, multi-target drugs have more advantages: it can avoid drug interactions, reduce adverse reactions, and have comprehensive therapeutic effects. Among various molecular targets, protein tyrosine kinase (PTK) is one of the most effective and promising antitumor drug targets.

PTKs can be divided into receptor PTKs and non-receptor PTKs according to their structures. Receptor PTKs typically have an extracellular domain that can bind to specific ligands, a transmembrane domain, and an intracellular kinase domain that can selectively bind to and phosphorylate substrates. When the corresponding specific ligand binds to the extracellular domain of the receptor PTK, the cellular structure of the receptor PTK changes to form a dimer, and then the intracellular kinase domain binds to ATP for phosphorylation, resulting in a series of enzymatic catalysis. . Common receptor PTKs are: (1) epidermal growth factor receptor (EGFR; ErbB-1; HER1) family, including ErbB-1 (EGFR), ErbB-2 (HER-2), ErbB- 3 (HER-3) and ErbB-4 (HER-4), these receptors are highly expressed in epithelial cell tumors; (2) Platelet derived growth factor receptor (PDGFR) family, including PDGFRα, PDGFRβ , colony-stimulating factor-1 receptor (CSF-1R) and stem cell growth factor receptor (SCFR; C-Kit), PDGF can act on endothelial cells and stroma through a variety of effects (3) insulin receptor (IR) family, including insulin receptor, insulin-like growth factor receptor (IGFR) and insulin related receptor (insulinrelated receptor, IRR), such receptors are often highly expressed in hematological tumors; (4) the vascular endothelial growth factor receptor (VEGFR) family, including VEGFR-1 (FLT-1), VEGFR-2 ( FLK-1) and VEGFR-3 (FLT-4), VEGF is overexpressed in many tumor tissues, such as liver cancer, lung cancer, breast cancer, etc., and plays a key role in tumor angiogenesis; (5) Fibroblast growth The fibroblast growth factor receptor (FGFR) family includes FGFR-1, FGFR-2, FGFR-3 and FGFR-4. FGFR is a pleiotropic growth factor that can regulate cell division, proliferation, migration and differentiation. Such receptors play an important role in angiogenesis. In addition to the above common receptors PTK, there are also the orginal myosinreceptor kinase (TRK) family, the hepatocyte growth factor receptor (HGFR) family and the leukocyte tyrosine kinase (1eukocyte tyrosine kinase) family. tyrosine kinase, LTK) family, etc., they also play an important role in tumor cell signaling, metastasis and angiogenesis.

Non-receptor PTKs generally have no extracellular structure. They are usually located in the cytoplasm continuously or temporarily, or bind to transmembrane receptors on the inside of the cell membrane, so they are also called cytoplasmic PTKs. And other signaling pathways perform signal transduction functions, mainly including families such as SRC, ABL, JAK, ACK, CSK, FAK, FRK, TEC and SYK.

At present, the listed multi-target tyrosine kinase inhibitors mainly include:

Imatinib mesylate (Gleevec): Imatinib mesylate belongs to the class of 2-phenylaminopyrimidine compounds and is a highly specific tyrosine kinase inhibitor. It can selectively inhibit tyrosine kinases such as bcr-abl, C-kit and platelet-derived growth factor receptor (PDGFR), and its anti-tumor mechanism is as an ATP competitive inhibitor. It blocks the phosphorylation of tyrosine kinases , inhibit bcr-abl expression. Thereby preventing cell proliferation and tumor formation.

Sorafenib (sorafenib, Nexavar): Sorafenib is the first oral multi-target tyrosine kinase inhibitor, the structure is a biaryl urea compound. The tosylate salt of sorafenib is used clinically. It has dual anti-tumor effects. On the one hand, it directly inhibits tumor growth by inhibiting the RAF/MEK/ERK signal transduction pathway, and on the other hand, it blocks the formation of tumor angiogenesis by inhibiting vascular endothelial growth factor and platelet-derived growth factor receptors, and cuts off the nutrient supply to tumor cells. achieve the purpose of suppressing tumors.

Sunitinib (sunitinib, Sutent): Sunitinib is one of the targeted anti-tumor drugs with the most known targets and has broad-spectrum anti-tumor activity. It is an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, stem cell factor receptor, tyrosine kinase, etc.

Lapatinib (Tykerb): Lapatinib is a dual-target tyrosine kinase inhibitor against EGFR/ErbB-2. Lapatinib is a 4-anilinoquinazoline kinase inhibitor in the form of tosylate salt hydrate. It is a reversible multi-targeted tyrosine kinase inhibitor. Its mechanism of action is to inhibit the ATP site of EGFR(ErbB-1)/HERE(ErbB-2) in cells, preventing tumor cell phosphorylation and activation, and through the synergy of EGFR(ErbB-1)/HERE(ErbB-2). Plasma and heterodimers block down-regulating signals, thereby inhibiting the proliferation of breast cancer cells and inducing apoptosis to achieve the purpose of anti-tumor.

Nilotinib (Tasigna): Nilotinib is an anilidine derivative, and its mechanism of action is to selectively inhibit the tyrosine kinase Bcr-Abl and inhibit the stem cell factor receptor Kit and platelet-derived growth factor receptors. Antibody (PDGFR) kinase has an antagonistic effect.

Dasatinib (Sprycel): Dasatinib is a dual inhibitor of tinib ABL and SRC kinases.

Pazopanib (pazopanib, votrient): Pazopanib is a selective multi-target TKI developed by GlaxoSmithKline, UK. All kinds of PTK have inhibitory effect.

The research and development of multi-target tyrosine kinase inhibitor drugs is one of the main research hotspots of anti-tumor drugs. The discovery of such drugs has brought new options and light to the treatment of tumor patients, thus opening up a new field of anti-tumor drug research. Multi-targeted tyrosine kinase inhibitors are specific and effective compared to traditional antitumor drugs. At the same time, it has the advantages of less gastrointestinal reactions and hematological adverse reactions, so it has a broader development prospect.

In addition, recent studies have shown that TOPK is a novel serine-threonine protein kinase identified from the cDNA library of lymphokine-activated killer T cells (T-LAK cells), Scientists found a kinase PBK (PDZ-bindingkinase, PBK) that can bind to the PDZ2 region of hDig in the HeLa cell cDNA library is the same molecule as TOPK, so it is also called PBK/TOPK. T-cell-originatedprotein kinase (TOPK) is highly expressed in many malignant tumors, such as lung cancer, breast cancer, lymphoma, bladder cancer, colon cancer, gastric cancer, liver cancer, pancreatic cancer, prostate cancer, ovarian cancer, etc., and TOPK The degree of expression is related to tumor prognosis, especially in breast cancer and lung cancer. The higher the TOPK expression, the worse the prognosis, but the TOPK expression level in normal tissues is very low, and it is only expressed in the testis and thymus. Therefore, TOPK has become a new target for tumor treatment, and there is currently no drug specifically targeting this target. Therefore, inhibitors that can specifically bind to TOPK have become a research hotspot for new anti-tumor drugs.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide a compound as shown in formula I, its prodrugs and pharmaceutically active metabolites and pharmaceutically acceptable salts thereof, and provide its preparation for prevention and treatment and BRaf kinase, Vascular endothelial growth factor receptor-2 (VEGFR-2), Platelet-derived growth factor receptors-β (PDGFR-β) and T-LAK cell source Application of drugs in diseases related to T-LAK cell-originated protein kinase (TOPK) dysregulation.

in

X can be selected from CH, N;

R can be hydrogen, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkoxy, halogen; R can be single or multiple;

R ₃ , R ₄ , R ₅ can be independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkoxy, C1-C4 alkoxy substituted C1-C4 alkoxy Oxygen.

Further, the present invention preferably has the following compounds of formula I, their prodrugs and pharmaceutically active metabolites and their pharmaceutically acceptable salts:

X can independently choose CH, N;

R can be hydrogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy, 4-chloro-3-trifluoromethyl, 3,5-difluoro, fluorine, chlorine, bromine; R can be single or multiple;

R ₃ , R ₄ , R ₅ can be selected from hydrogen, methyl, 2,2,2-trifluoroethoxy, methoxy, 3-methoxypropoxy.

Further, the present invention preferably the following compounds:

1-4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio}phenyl}-3-phenylurea;

1-{4-Chlorophenyl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio}phenyl} Urea;

1-(4-Bromophenyl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio}phenyl} Urea;

1-[4-Chloro-3-(trifluoromethyl)phenyl]-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl] methyl}thio}phenyl}urea;

1-(3,5-Difluorophenyl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio} phenyl}urea;

1-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}sulfanyl}phenyl}-3-[4-(trifluoromethyl oxy)phenyl]urea;

1-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}sulfanyl}phenyl}-3-[3-(trifluoromethyl base) phenyl] urea;

1-(4-Fluorophenyl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio}phenyl} Urea;

1-(4-Methoxyphenyl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio}benzene base}urea;

1-{4-{{[4-(3-Methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio}phenyl}-3-(4-methylpyridine- 2-yl) urea;

1-(6-Bromopyridin-2-yl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio} phenyl}urea;

1-(5-Chloropyridin-2-yl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio} phenyl}urea;

1-(2-Chloro-4-methylpyridin-3-yl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl group}thio}phenyl}urea;

1-{4-{[(3,4-Dimethoxypyridin-2-yl)methyl]thio}phenyl}-3-phenylurea;

1-(4-Chlorophenyl)-3-{4-{[(3,4-dimethoxypyridin-2-yl)methyl]thio}phenyl}urea;

1-(4-Bromophenyl)-3-{4-{[(3,4-dimethoxypyridin-2-yl)methyl]thio}phenyl}urea;

1-[4-Chloro-3-(trifluoromethyl)phenyl]-3-{4-{[(3,4-dimethoxypyridin-2-yl)methyl]sulfanyl}phenyl} Urea;

1-(3,5-Difluorophenyl)-3-{4-{[(3,4-dimethoxypyridin-2-yl)methyl]thio}phenyl}urea;

1-{4-{[(3,4-Dimethoxypyridin-2-yl)methyl]thio}phenyl}-3-[4-(trifluoromethoxy)phenyl]urea;

1-{4-{[(3,4-Dimethoxypyridin-2-yl)methyl]thio}phenyl}-3-[3-(trifluoromethyl)phenyl]urea;

1-{4-{[(3,4-Dimethoxypyridin-2-yl)methyl]thio}phenyl}-3-(4-fluorophenyl)urea;

1-{4-{[(3,4-Dimethoxypyridin-2-yl)methyl]thio}phenyl}-3-(4-methoxyphenyl)urea;

1-[4-Chloro-3-(trifluoromethyl)phenyl]-3-{4-{[(4-methoxy-3,5-lutidine-2-yl)methyl]sulfur base}phenyl}urea;

1-{4-{[(4-Methoxy-3,5-lutidine-2-yl)methyl]sulfanyl}phenyl}-3-[4-(trifluoromethoxy)benzene base]urea;

1-{4-{[(4-methoxy-3,5-lutidine-2-yl)methyl]sulfanyl}phenyl}-3-phenylurea;

1-(4-Chlorophenyl)-3-{4-{[(4-methoxy-3,5-lutidine-2-yl)methyl]thio}phenyl}urea;

1-{4-{[(4-Methoxy-3,5-lutidine-2-yl)methyl]sulfanyl}phenyl}3-[3-(trifluoromethyl)phenyl] Urea;

1-(4-Fluorophenyl)-3-{4-{[(4-methoxy-3,5-lutidine-2-yl)methyl]thio}phenyl}urea;

1-{4-{[(4-methoxy-3,5-lutidine-2-yl)methyl]sulfanyl}phenyl}-3-(4-methoxyphenyl)urea;

1-[4-Chloro-3-(trifluoromethyl)phenyl]-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridine-2 -yl]methyl}thio}phenyl}urea;

1-{4-{{[3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}sulfanyl}phenyl}-3-[4-( trifluoromethoxy)phenyl]urea;

1-(3,5-Difluorophenyl)-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl} thio}phenyl}urea;

1-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}thio}phenyl}-3-phenylurea; 1-(4-Chlorophenyl)-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}sulfanyl} phenyl}urea;

1-{4-{{[3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}sulfanyl}phenyl}-3-[3-( trifluoromethyl)phenyl]urea;

1-(4-Fluorophenyl)-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}sulfanyl} phenyl}urea;

1-(4-Methoxyphenyl)-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}thio base}phenyl}urea;

1-(4-Bromophenyl)-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}sulfanyl} Phenyl}urea.

"Pharmaceutically acceptable salt" refers to conventional acid or base addition salts formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases that retain the biological potency and properties of the compounds of formula I. Examples of acid addition salts include malate, maleate, sulfamate, hydrochloride, acetate, adipate, alginate, aspartate, benzyl acid salt, benzenesulfonate, p-toluenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cypionate, digluconate, dodecyl Sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochlorate, hydrobromide, hydroiodate, 2-Hydroxyethanesulfonate, Lactate, Maleate, Mesylate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Oxalate, Pamoate, Pectinate, Persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate, etc. . Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts of organic bases such as dicyclohexylamine salts, N-methyl-D-glucosamine salts, and salts of amino acids such as arginine, lysine, etc. Also, basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl halides such as methyl, ethyl, propyl and butyl chlorine, bromine and iodide groups; dialkyl sulfates such as dimethyl, diethyl, dibutyl and dipentyl sulfate; long chain halides such as decyl, lauryl, myristyl and hard Chlorine, bromine and iodide of fatty acyl groups; halides of aralkyl groups, such as benzyl and phenethyl bromides, etc. Preferred acids for forming acid addition salts include hydrochloric acid and acetic acid.

"Pharmaceutically acceptable" such as pharmaceutically acceptable carriers, excipients, prodrugs, etc., means pharmacologically acceptable and substantially non-toxic to the patient to whom the particular compound is administered.

"Pharmaceutically active metabolite" refers to a metabolite of a compound of Formula I that is pharmaceutically acceptable and effective.

The present invention also relates to a pharmaceutical composition for inhibiting tyrosine kinase and T-LAK cell-derived protein kinase, the composition comprising a compound or derivative of formula I or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.

The term "halogen" as used herein includes fluorine, chlorine, bromine or iodine.

The compounds of the present invention can be administered to a patient by a variety of methods, such as orally in capsules or tablets, as sterile solutions or suspensions, and in some cases intravenously as solutions. The free base compounds of the present invention can be formulated and administered in the form of their pharmaceutically acceptable acid addition salts.

The compounds described in the present invention serve as novel structural types of BRaf kinases, Vascular endothelial growth factor receptor-2 (VEGFR-2) and Platelet-derived growth factor receptors (Platelet-derived growth factor receptors). -β, PDGFR-β) and T-LAK cell-originated protein kinase (TOPK) inhibitors, with novel structural types and the ability to act on multiple targets, can be used for treatment or Prevention and BRaf kinase, vascular endothelial growth factor receptor-2 (Vascularendothelial growth factor receptor-2, VEGFR-2) and platelet-derived growth factor receptor-β (Platelet-derived growth factor receptors-β, PDGFR-β) and T -LAK cell-originated protein kinase (TOPK)-related tumor diseases such as small cell lung cancer, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, colorectal cancer, breast cancer, ovarian cancer, renal cell carcinoma , has good application value and development and application prospects.

Detailed ways

Taking X as CH as an example, the following scheme summarizes the preparation steps for preparing the compounds of the present invention.

process

Among them, R, R ₃ , R ₄ and R ₅ are as described above.

The present invention is described in detail by the following examples. It should be understood, however, that the present invention is not limited to the specifically recited examples below.

Example 1: 1-4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio}phenyl}-3-phenylurea ( Preparation of compound Z01)

Step A: Preparation of 4-(3-Methoxypropoxy)-3-methyl-2-{[(4-nitrophenyl)thio]methyl}pyridine

In a 500mL eggplant-shaped flask, add 4-nitrothiophenol (15.52g, 0.10mol), 2-chloromethyl-3-methyl-4-(methoxypropoxy)pyridine hydrochloride (26.62g, 0.10 mol) and absolute ethanol (200 mL). A 3 mol/L aqueous sodium hydroxide solution (100 mL) was added dropwise at room temperature. After the dropwise addition, the reaction was carried out at room temperature for 6 h. After the reaction, part of the ethanol was evaporated under reduced pressure, and 200 mL of water was added to the residue to precipitate a large amount of white solid, which was filtered with suction, and the filter cake was washed with water and dried in the air to obtain 31.81 g of white solid with a yield of 91.3%. The product was used directly in the next step without further purification.

Step B: Preparation of 4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio}aniline

4-(3-Methoxypropoxy)-3-methyl-2-{[(4-nitrophenyl)thio]methyl}pyridine (19.22 g, 0.05 mol), 10% palladium on carbon (1.00g) and anhydrous methanol (100mL) were placed in a 250mL eggplant-shaped flask, and hydrogen was introduced into the system. After gas replacement, the reaction was stirred at room temperature and normal pressure for 5h. After the reaction was completed, pad diatomaceous earth for suction filtration , the filtrate was concentrated to obtain 15.14g of pale yellow oil, the yield was 95.1%. The product was used directly in the next step without purification.

Step C: 1-4-{{[4-(3-Methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio}phenyl}-3-phenylurea (compound Preparation of Z01)

Phenyl isocyanate (0.12 g, 1 mmol) and dichloromethane (10 mL) were added to a 100 mL eggplant flask, and the 4-{{[4-(3-methoxypropoxyl group obtained in the previous step was added at room temperature. )-3-methylpyridin-2-yl]methyl}sulfanyl}aniline (0.32 g, 1 mmol) in dichloromethane solution (10 mL) was added dropwise to the above solution, after the dropwise addition was completed, continued stirring at room temperature for 2 h, After the reaction was complete, 50 mL of water was added, stirred for 5 min, the organic layer was separated, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered with suction, evaporated to remove the solvent, and the residue was purified by column chromatography (dichloromethane: methanol =60:1), to obtain a white solid 0.24g, yield 54.5%, mp: 105.2-106.8°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.74(s, 1H), 8.69(s, 1H) ,8.17(d,J＝5.6Hz,1H),7.42(dd,J＝17.9,8.1Hz,4H),7.29(dd,J＝17.7,8.2Hz,4H),6.97(t,J＝7.4Hz, 1H), 6.90(d, J＝5.7Hz, 1H), 4.09(t, J＝6.2Hz, 2H), 3.48(t, J＝6.2Hz, 2H), 3.25(s, 3H), 2.12(s, 3H), 1.97 (p, J=6.3 Hz, 2H). ESI-MS: m/z 438.4 [M+H] ⁺ ; 460.2 [M+Na] ⁺ .

Example 2: 1-{4-Chlorophenyl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio Preparation of }phenyl}urea (compound Z02)

Referring to the preparation method of Example 1, 0.16g of white solid was obtained, yield 49%, mp: 191.7-192.5°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.83(s, 1H), 8.77(s, 1H), 8.17(d, J＝5.6Hz, 1H), 7.52-7.44(m, 2H), 7.44-7.37(m, 2H), 7.37-7.28(m, 4H), 6.90(d, J＝5.7Hz ,1H),4.22(s,2H),4.08(t,J＝6.2Hz,2H),3.48(t,J＝6.2Hz,2H),3.25(s,3H),2.12(s,3H),1.97 (p, J=6.3 Hz, 2H). ESI-MS: m/z 472.4, 474.0, 475.1, 476.0 [M+H] ⁺ .

Example 3: 1-(4-Bromophenyl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio Preparation of }phenyl}urea (compound Z03)

Referring to the preparation method of Example 1, 0.07g of white solid was obtained, yield 20%, mp: 177.9-178.5°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.83(s, 1H), 8.77(s, 1H), 8.17(d, J＝5.6Hz, 1H), 7.49-7.36(m, 6H), 7.32(d, J＝8.7Hz, 2H), 6.90(d, J＝5.7Hz, 1H), 4.22( s, 2H), 4.08(t, J=6.2Hz, 2H), 3.48(t, J=6.2Hz, 2H), 3.25(s, 3H), 2.12(s, 3H), 1.97(p, J=6.3 Hz, 3H). ESI-MS: m/z 516.0, 518.0 [M+H] ⁺ .

Example 4: 1-[4-Chloro-3-(trifluoromethyl)phenyl]-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridine- Preparation of 2-yl]methyl}thio}phenyl}urea (compound Z04)

Referring to the preparation method of Example 1, 0.11 g of white solid was obtained, yield 30%, mp: 136.0-137.0°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ9.16(s, 1H), 8.89(s, 1H), 8.16(d, J=5.6Hz, 1H), 8.10(d, J=2.2Hz, 1H), 7.64-7.60(m, 2H), 7.45-7.37(m, 2H), 7.36-7.29(m ,2H),6.89(d,J＝5.7Hz,1H),4.23(s,2H),4.09(t,J＝6.2Hz,2H),3.48(t,J＝6.2Hz,2H),3.25(s , 3H), 2.13 (s, 3H), 1.97 (p, J=6.3 Hz, 2H). ESI-MS: m/z 540.2 [M+H] ⁺ , 562.0 [M+Na] ⁺ .

Example 5: 1-(3,5-Difluorophenyl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl Preparation of }thio}phenyl}urea (Compound Z05)

Referring to the preparation method of Example 1, 0.17g of white solid was obtained, yield 41%, mp: 138.9-140.0°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ9.09(s, 1H), 8.89(s, 1H), 8.17(d, J＝5.6Hz, 1H), 7.40(d, J＝8.7Hz, 2H), 7.33(d, J＝8.7Hz, 2H), 7.22-7.14(m, 2H), 6.90( d, J＝5.7Hz, 1H), 6.79(tt, J＝9.5, 2.4Hz, 1H), 4.23(s, 2H), 4.09(t, J＝6.2Hz, 2H), 3.48(t, J＝6.2 Hz,2H),3.25(s,3H),2.13(s,3H),1.97(p,J=6.3Hz,2H).ESI-MS: m/z 474.2[M+H] ⁺ ,496.3[M+ Na] ⁺ .

Example 6: 1-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}sulfanyl}phenyl}-3-[4- Preparation of (trifluoromethoxy)phenyl]urea (compound Z06)

Referring to the preparation method of Example 1, 0.25g of white solid was obtained, yield 61.0%, mp: 132.0-133.7°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.94(s, 1H), 8.83(s, 1H), 8.16(d, J＝5.6Hz, 1H), 7.59-7.51(m, 2H), 7.40(d, J＝8.7Hz, 2H), 7.30(dd, J＝14.1, 8.6Hz, 4H), 6.89(d,J＝5.7Hz,1H),4.22(s,2H),4.09(t,J＝6.3Hz,2H),3.48(t,J＝6.2Hz,2H),3.25(s,3H), 2.13 (s, 3H), 1.97 (p, J=6.3 Hz, 2H). ESI-MS: m/z 522.3 [M+H] ⁺ .

Example 7: 1-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}sulfanyl}phenyl}-3-[3- Preparation of (trifluoromethyl)phenyl]urea (compound Z07)

Referring to the preparation method of Example 1, 0.20 g of white solid was obtained, yield 52%, mp: 136.1-137.9°C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 8.84 (s, 1H), 8.17(d, J＝5.6Hz, 1H), 8.00(d, J＝2.3Hz, 1H), 7.60-7.47(m, 2H), 7.41(d, J＝8.7Hz, 2H), 7.32( dd,J＝8.0,5.8Hz,3H),6.90(d,J＝5.7Hz,1H),4.23(s,2H),4.09(t,J＝6.2Hz,2H),3.48(t,J＝6.2 Hz, 2H), 3.25 (s, 3H), 2.13 (s, 3H), 1.97 (p, J=6.3 Hz, 2H). ESI-MS: m/z 506.3 [M+H] ⁺ .

Example 8: 1-(4-Fluorophenyl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio Preparation of }phenyl}urea (Compound Z08)

Referring to the preparation method of Example 1, 0.14g of white solid was obtained, yield 39%, mp: 131.6-132.8°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.73 (d, J=6.6Hz, 2H) ,8.18(d,J＝5.7Hz,1H),7.49-7.35(m,4H),7.34-7.27(m,2H),7.16-7.07(m,2H),6.92(d,J＝5.7Hz,1H ), 4.22(s, 2H), 4.10(t, J=6.2Hz, 2H), 3.48(t, J=6.2Hz, 2H), 3.25(s, 3H), 2.12(s, 3H), 1.98(p , J=6.2 Hz, 2H). ESI-MS: m/z 456.3 [M+H] ⁺ .

Example 9: 1-(4-Methoxyphenyl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl} Preparation of thio}phenyl}urea (compound Z09)

Referring to the preparation method of Example 1, 0.27g of white solid was obtained, yield 64%, mp: 144.8-146.6°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.64(s, 1H), 8.47(s, 1H), 8.16(d, J=5.6Hz, 1H), 7.43-7.26(m, 6H), 6.92-6.82(m, 3H), 4.21(s, 2H), 4.08(t, J=6.2Hz, 2H ), 3.71(s, 3H), 3.48(t, J=6.2Hz, 2H), 2.12(s, 3H), 1.97(p, J=6.3Hz, 2H). ESI-MS: m/z 468.4[M +H] ⁺ ,460.2[M+Na] ⁺ .

Example 10: 1-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}sulfanyl}phenyl}-3-(4- Preparation of methylpyridin-2-yl)urea (compound Z10)

Referring to the preparation method of Example 1, 0.21 g of white solid was obtained, yield 58%, mp: 125.0-126.0°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.72(s, 1H), 9.40(s, 1H), 8.15(dd, J＝12.2, 5.4Hz, 2H), 7.51-7.43(m, 2H), 7.37-7.30(m, 2H), 7.27(s, 1H), 6.89(d, J＝5.7Hz ,1H),6.87-6.83(m,1H),4.23(s,2H),4.09(t,J=6.2Hz,2H),3.48(t,J=6.3Hz,2H),3.24(s,3H) , 2.29 (s, 3H), 2.13 (s, 3H), 1.97 (p, J=6.3 Hz, 2H). ESI-MS: m/z 453.2 [M+H] ⁺ .

Example 11: 1-(6-Bromopyridin-2-yl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl Preparation of }thio}phenyl}urea (Compound Z11)

Referring to the preparation method of Example 1, 0.07g of white solid was obtained, yield 43%, mp: 146.0-147.3°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ9.59(s, 1H), 9.37(s, 1H), 8.17(d, J＝5.6Hz, 1H), 7.80-7.65(m, 2H), 7.44-7.31(m, 4H), 7.24(d, J＝7.5Hz, 1H), 6.90(d, J ＝5.7Hz, 1H), 4.24(s, 2H), 4.09(t, J＝6.2Hz, 2H), 3.48(t, J＝6.2Hz, 2H), 3.25(s, 3H), 2.13(s, 3H ), 1.97 (p, J=6.0 Hz, 2H). ESI-MS: m/z 517.3, 519.0 [M+H] ⁺ , 539.0, 541.0 [M+Na] ⁺ .

Example 12: 1-(5-Chloropyridin-2-yl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl Preparation of }thio}phenyl}urea (Compound Z12)

Referring to the preparation method of Example 1, 0.22 g of white solid was obtained, yield 53%, mp: 155.6-156.9°C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.86 (s, 1H), 9.49 (s, 1H), 8.32(d, J＝2.6Hz, 1H), 8.17(d, J＝5.6Hz, 1H), 7.86(dd, J＝9.0, 2.7Hz, 1H), 7.70(d, J＝8.9Hz, 1H), 7.48-7.40(m, 2H), 7.38-7.31(m, 2H), 6.90(d, J=5.7Hz, 1H), 4.24(s, 2H), 4.09(t, J=6.2Hz, 2H) ), 3.48(t, J＝6.2Hz, 2H), 3.24(s, 3H), 2.13(s, 3H), 1.97(p, J＝6.2Hz, 2H). ESI-MS: m/z 473.3[M +H] ⁺ ,495.2[M+Na] ⁺ .

Example 13: Preparation of 1-{4-{[(3,4-dimethoxypyridin-2-yl)methyl]thio}phenyl}-3-phenylurea (Compound Z13)

Referring to the preparation method of Example 1, 0.15g of white solid was obtained, yield 37%, mp: 127.7-128.5°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.70 (d, J=17.0Hz, 2H) ,8.12(d,J＝5.5Hz,1H),7.42(ddd,J＝15.5,7.7,1.8Hz,4H),7.36-7.23(m,4H),7.07-6.93(m,2H),4.17(s , 2H), 3.87(s, 3H), 3.74(s, 3H). ESI-MS: m/z 396.3[M+H] ⁺ ; 418.2[M+Na] ⁺ .

Example 14: 1-(4-Chlorophenyl)-3-{4-{[(3,4-dimethoxypyridin-2-yl)methyl]thio}phenyl}urea (Compound Z14) preparation

Referring to the preparation method of Example 1, 0.11 g of white solid was obtained, yield 34%, mp: 141.7-142.0°C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (s, 1H), 8.76 (s, 1H), 8.11(d, J＝5.5Hz, 1H), 7.48(d, J＝8.5Hz, 2H), 7.40(d, J＝8.4Hz, 2H), 7.32(d, J＝8.5Hz, 4H) , 7.03(d, J=5.5Hz, 1H), 4.17(s, 2H), 3.87(s, 3H), 3.74(s, 3H). ESI-MS: m/z430.6[M+H] ⁺ ; 452.1[M+Na] ⁺ .

Example 15: 1-(4-Bromophenyl)-3-{4-{[(3,4-dimethoxypyridin-2-yl)methyl]thio}phenyl}urea (Compound Z15) preparation

Referring to the preparation method of Example 1, 0.12 g of white solid was obtained, yield 36%, mp: 179.2-180.11 °C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (s, 1H), 8.76 (s, 1H), 8.11(d, J＝5.5Hz, 1H), 7.49-7.37(m, 6H), 7.37-7.29(m, 2H), 7.03(d, J＝5.6Hz, 1H), 4.17(s, 2H) ), 3.87(s, 3H), 3.74(s, 3H). ESI-MS: m/z 476.0, 478.1[M+H] ⁺ , 496.2, 498.1[M+Na] ⁺ .

Example 16: 1-[4-Chloro-3-(trifluoromethyl)phenyl]-3-{4-{[(3,4-dimethoxypyridin-2-yl)methyl]sulfanyl Preparation of }phenyl}urea (Compound Z16)

Referring to the preparation method of Example 1, 0.14g of white solid was obtained, yield 43%, mp: 188.1-189.2°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ9.15(s, 1H), 8.88(s, 1H), 8.14-8.07(m, 2H), 7.67-7.57(m, 2H), 7.46-7.38(m, 2H), 7.38-7.30(m, 2H), 7.03(d, J=5.5Hz, 1H) , 4.17(s, 2H), 3.88(s, 3H), 3.74(s, 3H). ESI-MS: m/z 498.2, 500.2 [M+H] ⁺ .

Example 17: 1-(3,5-Difluorophenyl)-3-{4-{[(3,4-dimethoxypyridin-2-yl)methyl]thio}phenyl}urea ( Preparation of compound Z17)

Referring to the preparation method of Example 1, white solid 0.12g was obtained, yield 34%, mp: 55.6-157.0°C; ¹ HNMR (400MHz, DMSO-d ₆ )δ9.09(s,1H),8.88(s,1H) ),8.11(d,J＝5.5Hz,1H),7.44-7.30(m,4H),7.24-7.13(m,2H),7.03(d,J＝5.6Hz,1H),6.79(tt,J＝ 9.4, 2.4Hz, 1H), 4.17(s, 2H), 3.87(s, 3H), 3.74(s, 3H). ESI-MS: m/z 432.2[M+H] ⁺ .

Example 18: 1-{4-{[(3,4-Dimethoxypyridin-2-yl)methyl]sulfanyl}phenyl}-3-[4-(trifluoromethoxy)phenyl ] Preparation of urea (compound Z18)

Referring to the preparation method of Example 1, 0.11g of white solid was obtained, yield 32%, mp: 162.0-163.6°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.91(s, 1H), 8.79(s, 1H), 8.11(d, J＝5.5Hz, 1H), 7.59-7.50(m, 2H), 7.44-7.37(m, 2H), 7.37-7.25(m, 4H), 7.03(d, J＝5.5Hz , 1H), 4.17(s, 2H), 3.87(s, 3H), 3.74(s, 3H). ESI-MS: m/z 480.2[M+H] ⁺ , 502.2[M+Na] ⁺ .

Example 19: 1-{4-{[(3,4-Dimethoxypyridin-2-yl)methyl]sulfanyl}phenyl}-3-[3-(trifluoromethyl)phenyl] Preparation of Urea (Compound Z19)

Referring to the preparation method of Example 1, 0.15g of white solid was obtained, yield 43%, mp: 198.4-199.8°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ 9.04(s, 1H), 8.83(s, 1H), 8.11(d, J＝5.5Hz, 1H), 8.01(d, J＝1.9Hz, 1H), 7.60-7.46(m, 2H), 7.43(d, J＝2.0Hz, 1H), 7.41- 7.28(m, 4H), 7.03(d, J=5.6Hz, 1H), 4.17(s, 2H), 3.88(s, 3H), 3.75(s, 3H). ESI-MS: m/z 464.2[M +H] ⁺ .

Example 20: 1-{4-{[(3,4-Dimethoxypyridin-2-yl)methyl]thio}phenyl}-3-(4-fluorophenyl)urea (Compound Z20) preparation

Referring to the preparation method of Example 1, 0.14g of white solid was obtained, yield 37%, mp: 143.2-144.9°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.69 (d, J=1.5Hz, 2H) ,8.11(d,J＝5.5Hz,1H),7.50-7.35(m,4H),7.35-7.28(m,2H),7.12(t,J＝8.9Hz,2H),7.03(d,J＝5.5 Hz, 1H), 4.16(s, 2H), 3.87(s, 3H), 3.74(s, 3H). ESI-MS: m/z 414.3[M+H] ⁺ , 436.2[M+Na] ⁺ .

Example 21: 1-{4-{[(3,4-Dimethoxypyridin-2-yl)methyl]thio}phenyl}-3-(4-methoxyphenyl)urea (compound Preparation of Z21)

Referring to the preparation method of Example 1, 0.08g of white solid was obtained, yield 25%, mp: 179.0-180.6°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.62(s, 1H), 8.46(s, 1H), 8.11(d, J=5.5Hz, 1H), 7.43-7.26(m, 6H), 7.03(d, J=5.5Hz, 1H), 6.91-6.82(m, 2H), 4.15(s, 2H) ), 3.87(s, 3H), 3.74(s, 3H), 3.71(s, 3H). ESI-MS: m/z 426.3[M+H] ⁺ .

Example 22: 1-[4-Chloro-3-(trifluoromethyl)phenyl]-3-{4-{[(4-methoxy-3,5-lutidine-2-yl) Preparation of methyl]thio}phenyl}urea (compound Z22)

Referring to the preparation method of Example 1, 0.36g of white solid was obtained, yield 72%, mp: 152.3-153.1°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ 9.18(s, 1H), 8.91(s, 1H), 8.14-8.07(m, 2H), 7.63(d, J=2.9Hz, 2H), 7.41(d, J=8.7Hz, 2H), 7.36-7.28(m, 2H), 4.22(s, 2H) ), 3.70(s, 3H), 2.19(s, 3H), 2.18(s, 3H). ESI-MS: m/z 496.1, 497.1, 498.1, 499.1 [M+H] ⁺ .

Example 23: 1-{4-{[(4-Methoxy-3,5-lutidine-2-yl)methyl]sulfanyl}phenyl}-3-[4-(trifluoromethyl Preparation of oxy)phenyl]urea (compound Z23)

Referring to the preparation method of Example 1, 0.24g of white solid was obtained, yield 54%, mp: 181.1-182.8°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.89(s, 1H), 8.79(s, 1H), 8.11(s, 1H), 7.59-7.50(m, 2H), 7.44-7.36(m, 2H), 7.30(dd, J=10.3, 8.4Hz, 4H), 4.21(s, 2H), 3.70 (s, 3H), 2.18 (d, J=1.9 Hz, 6H). ESI-MS: m/z 478.3 [M+H] ⁺ .

Example 24: 1-{4-{[(4-Methoxy-3,5-lutidine-2-yl)methyl]thio}phenyl}-3-phenylurea (Compound Z24) preparation

Referring to the preparation method of Example 1, 0.31 g of white solid was obtained, yield 78%, mp: 188.1-188.9°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.72(s, 1H), 8.67(s, 1H),8.12(s,1H),7.42(ddd,J=17.9,7.6,1.7Hz,4H),7.34-7.23(m,4H),6.97(t,J=7.4Hz,1H),4.21(s , 2H), 3.70(s, 3H), 2.18(s, 6H). ESI-MS: m/z 394.6[M+H] ⁺ , 416.3[M+Na] ⁺ .

Example 25: 1-(4-Chlorophenyl)-3-{4-{[(4-methoxy-3,5-lutidine-2-yl)methyl]sulfanyl}phenyl} Preparation of Urea (Compound Z25)

Referring to the preparation method of Example 1, 0.31 g of white solid was obtained, yield 78%, mp: 206.8-208.2°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.81(s, 1H), 8.75(s, 1H), 8.11(s, 1H), 7.52-7.43(m, 2H), 7.43-7.37(m, 2H), 7.37-7.27(m, 4H), 4.21(s, 2H), 3.70(s, 3H) , 2.18 (d, J=1.5 Hz, 6H). ESI-MS: m/z 428.7 [M+H] ⁺ .

Example 26: 1-{4-{[(4-Methoxy-3,5-lutidine-2-yl)methyl]sulfanyl}phenyl}3-[3-(trifluoromethyl ) Phenyl]urea (Compound Z26) Preparation

Referring to the preparation method of Example 1, 0.26 g of white solid was obtained, yield 64%, mp: 156.9-159.1 °C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 1H), 8.84 (s, 1H), 8.12(s, 1H), 8.00(d, J=2.0Hz, 1H), 7.61-7.47(m, 2H), 7.46-7.37(m, 2H), 7.31(dd, J=8.8, 2.4Hz) , 3H), 4.22(s, 2H), 3.70(s, 3H), 2.19(s, 3H), 2.18(s, 3H). ESI-MS: m/z 462.3[M+H] ⁺ .

Example 27: 1-(4-Fluorophenyl)-3-{4-{[(4-methoxy-3,5-lutidine-2-yl)methyl]sulfanyl}phenyl} Preparation of Urea (Compound Z27)

Referring to the preparation method of Example 1, 0.22g of white solid was obtained, yield 47%, mp: 186.3-187.9°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.71 (d, J=5.9Hz, 2H) ,8.11(s,1H),7.47-7.43(m,2H),7.41-7.37(m,2H),7.33-7.26(m,2H),7.12(t,J＝8.9Hz,2H),4.20(s , 2H), 3.70 (s, 3H), 2.18 (s, 6H). ESI-MS: m/z 412.3 [M+H] ⁺ .

Example 28: 1-{4-{[(4-Methoxy-3,5-lutidine-2-yl)methyl]sulfanyl}phenyl}-3-(4-methoxybenzene Preparation of urea (compound Z28)

Referring to the preparation method of Example 1, 0.19g of white solid was obtained, yield 48%, mp: 171.4-172.6°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.68(s, 1H), 8.50(s, 1H), 8.15(s, 1H), 7.40-7.24(m, 6H), 6.87(dq, J=10.2, 3.5, 2.8Hz, 2H), 4.21(s, 2H), 3.73(s, 3H), 3.71 (s,3H), 2.20(s,3H), 2.17(s,3H). ESI-MS: m/z 424.3[M+H] ⁺ .

Example 29: 1-[4-Chloro-3-(trifluoromethyl)phenyl]-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy ) Preparation of pyridin-2-yl]methyl}thio}phenyl}urea (compound Z29)

Referring to the preparation method of Example 1, white solid 0.34g was obtained, yield 77%, mp: 142.0-143.0°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ9.17(s, 1H), 8.90(s, 1H), 8.24(d, J=5.7Hz, 1H), 8.10(d, J=2.2Hz, 1H), 7.68-7.57(m, 2H), 7.45-7.37(m, 2H), 7.36-7.29(m ,2H),7.04(d,J＝5.7Hz,1H),4.89(q,J＝8.8Hz,2H),4.26(s,2H),2.16(s,3H).ESI-MS:m/z 550.1 ,552.1,553.1[M+H] ⁺ .

Example 30: 1-{4-{{[3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}thio}phenyl}-3- Preparation of [4-(trifluoromethoxy)phenyl]urea (Compound Z30)

Referring to the preparation method of Example 1, 0.10 g of white solid was obtained, yield 37%, mp: 173.2-174.9°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.95(s, 1H), 8.84(s, 1H), 8.24(d, J=5.6Hz, 1H), 7.60-7.50(m, 2H), 7.44-7.36(m, 2H), 7.30(dd, J=12.7, 8.6Hz, 4H), 7.03(d , J=5.7Hz, 1H), 4.88(q, J=8.7Hz, 2H), 4.25(s, 2H), 2.16(s, 3H). ESI-MS: m/z 532.2[M+H] ⁺ , 554.2[M+Na] ⁺ .

Example 31: 1-(3,5-Difluorophenyl)-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl Preparation of ]methyl}thio}phenyl}urea (compound Z31)

Referring to the preparation method of Example 1, white solid 0.13g was obtained, yield 47%, mp: 181.2-182.7°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ9.14(s, 1H), 8.95(s, 1H), 8.24(d, J＝5.7Hz, 1H), 7.43-7.36(m, 2H), 7.36-7.29(m, 2H), 7.24-7.13(m, 2H), 7.03(d, J＝5.7Hz ,1H),6.79(tt,J＝9.4,2.4Hz,1H),4.88(q,J＝8.7Hz,2H),4.26(s,2H),2.16(s,3H).ESI-MS:m/ z 484.2[M+H] ⁺ , 506.2[M+Na] ⁺ .

Example 32: 1-{4-{{[3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}thio}phenyl}-3- Preparation of Phenylurea (Compound Z32)

Referring to the preparation method of Example 1, 0.06 g of white solid was obtained, yield 21%, mp: 143.3-145.1 °C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (s, 1H), 8.67 (s, 1H),8.24(d,J=5.7Hz,1H),7.42(dd,J=18.1,8.3Hz,4H),7.29(dd,J=16.8,8.3Hz,4H),7.03(d,J=5.7 Hz,1H),6.97(t,J=7.3Hz,1H),4.89(q,J=8.7Hz,2H),4.25(s,2H),2.16(s,3H).ESI-MS:m/z 448.4[M+H] ⁺ , 470.2[M+Na] ⁺ .

Example 33: 1-(4-Chlorophenyl)-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl Preparation of }thio}phenyl}urea (Compound Z33)

Referring to the preparation method of Example 1, 0.14g of white solid was obtained, yield 43%, mp: 203.6-205.2°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.81(s, 1H), 8.75(s, 1H),8.23(d,J=5.7Hz,1H),7.52-7.43(m,2H),7.39(d,J=8.7Hz,2H),7.37-7.27(m,4H),7.03(d,J =5.7Hz,1H),4.88(q,J=8.7Hz,2H),4.25(s,2H),2.16(s,3H).ESI-MS:m/z 482.6[M+H] ⁺ ,504.3[ M+Na] ⁺ .

Example 34: 1-{4-{{[3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}thio}phenyl}-3- Preparation of [3-(trifluoromethyl)phenyl]urea (Compound Z34)

Referring to the preparation method of Example 1, 0.09 g of white solid was obtained, yield 27%, mp: 174.7-176.4°C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.07 (s, 1H), 8.87 (s, 1H), 8.24(d, J＝5.7Hz, 1H), 8.01(s, 1H), 7.61-7.47(m, 2H), 7.46-7.37(m, 2H), 7.37-7.28(m, 3H), 7.04 (d, J=5.7Hz, 1H), 4.89(q, J=8.7Hz, 2H), 4.26(s, 2H), 2.16(s, 3H). ESI-MS: m/z 516.2[M+H] ⁺ .

Example 35: 1-(4-Fluorophenyl)-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl Preparation of }thio}phenyl}urea (Compound Z35)

Referring to the preparation method of Example 1, 0.21 g of white solid was obtained, yield 56%, mp: 163.4-165.1°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.70 (d, J=6.7Hz, 2H) ,8.23(d,J＝5.6Hz,1H),7.48-7.42(m,2H),7.42-7.36(m,2H),7.35-7.26(m,2H),7.17-7.06(m,2H),7.03 (d, J=5.7Hz, 1H), 4.88 (q, J=8.8Hz, 2H), 2.16 (s, 3H). ESI-MS: m/z 466.3[M+H] ⁺ , 488.2[M+Na ] ⁺ .

Example 36: 1-(4-Methoxyphenyl)-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl] Preparation of methyl}thio}phenyl}urea (compound Z36)

Referring to the preparation method of Example 1, 0.17g of white solid was obtained, yield 55%, mp: 171.3-172.1°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ 9.33(s, 1H), 9.13(s, 0H),8.88(d,J＝22.7Hz,1H),8.60(t,J＝5.8Hz,1H),7.62(d,J＝8.8Hz,1H),7.52-7.43(m,2H),7.37( dt,J＝11.9,9.0Hz,3H),7.28-7.20(m,1H),6.87(ddd,J＝8.9,6.0,2.8Hz,2H),5.11(dq,J＝25.3,8.6Hz,2H) , 3.72(s, 2H), 3.71(s, 3H), 1.24(s, 3H). ESI-MS: m/z 478.3[M+H] ⁺ .

Example 37: 1-(4-Bromophenyl)-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl Preparation of }thio}phenyl}urea (Compound Z37)

Referring to the preparation method of Example 1, 0.17g of white solid was obtained, yield 55%, mp: 153.4-154.2°C; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.70 (d, J=6.7Hz, 2H) ,8.23(d,J＝5.6Hz,1H),7.48-7.42(m,2H),7.42-7.36(m,2H),7.35-7.26(m,2H),7.17-7.06(m,2H),7.03 (d, J=5.7Hz, 1H), 4.88 (q, J=8.8Hz, 2H), 2.16 (s, 3H). ESI-MS: m/z 526.2[M+H] ⁺ , 528.1[M+Na ] ⁺ .

The above are only preferred embodiments of the present invention, and are not intended to limit the present invention in other forms. Any person skilled in the art may use the technical content disclosed above to make changes or modifications to equivalent changes. Example. However, any simple modifications, equivalent changes and modifications made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solutions of the present invention still belong to the protection scope of the technical solutions of the present invention.

Pharmacological Example

Example 38: Inhibitory activity of test compound on A549, HCT-116, PC3 cell proliferation (1) Experimental material

Cell lines: A549, HCT-116, PC3 cells, plated in 96-well plates at a density of 3000/well, 100ul per well, used after 24h.

Target compounds numbered Z01 to Z37: dissolved in DMSO, diluted with culture medium to prepare five different concentrations of 50 μM, 20 μM, 10 μM, 5 μM, 2 μM and stored at -20°C for use. The final concentration of DMSO in culture medium is less than 0.1% .

Positive control drug: sorafenib.

MTT: dissolve in PBS to 5 mg/mL and store at -20°C.

(2) Experimental method

Using MTT method, A549, HCT-116 and PC3 cells were selected to evaluate the anti-tumor proliferation activity of the test samples. Cell lines were grown on RPMI 1640 medium containing 10% fetal bovine serum (FBS). Cells were pooled when they had proliferated to 80-90% and then subcultured for no more than 20 passages, then they were acclimated for 24 h before further treatment. The cells were plated in 96-well plates (8 x 104/mL) and then cultured overnight in a humidified environment containing 5% _CO2 and temperature-controlled at 37°C. After 24 h, various concentrations of representative compounds of the invention were added. After another 24 h of cultivation, MTT (5 mg/mL) was added thereto and the cultivation was continued for 4 h. The culture substrate was removed, the crystals were dissolved in DMSO, and the absorbance was measured at a wavelength of 490 nm using a microplate reader (TECANSPECTRA, WetDar, Germany). According to the formula: cell growth inhibition rate=(1-OD value of drug group/OD value of control group)×100%, calculate the cell growth inhibition rate at the corresponding concentration, and take the different concentrations of the test compound and the inhibition rate to cells as the logarithm Curve, calculate the corresponding _IC50 value of the test compound. Representative compounds of the present invention were determined according to the methods described above, and the results are shown in Table 1:

Table 1

Example 39: Inhibitory activity of test compounds against BRaf, VEGFR-2, PDGFR-β and TOPK kinases

(1) Experimental materials

Kinases: BRaf kinase (wild type), VEGFR-2, PDGFR-beta and TOPK kinases.

No. Z01 to Z37 target compounds: dissolve in DMSO, and do the same treatment for the reference substance.

Positive control drug: sorafenib.

Kinase Buffer: Contains 50 mM HEPES, pH 7.5, 10 mM MgCl 2, 0.0015% Brij-35 and 2 mM DTT.

Stop Buffer: Contains 100 mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3 and 50 mM ethylenediaminetetraacetic acid (EDTA).

(2) Experimental method

All kinase assays were performed in 50 μL reaction volumes in 96-well plates. Compounds were diluted to 500 [mu]M with DMSO, then 10 [mu]L of compounds were transferred to a new 96-well plate as an intermediate plate, and 90 [mu]L of kinase buffer was added to each well. Transfer 5 µl of each well of the intermediate plate to a 384-well plate. Each well contains the following enzymes and substrates: kinase base buffer, FAM-labeled peptide, ATP and enzyme solution. DMSO wells with substrate, enzyme and no compound served as DMSO controls. Wells containing only substrate without enzyme were used as low controls. Compounds were incubated at room temperature for 10 minutes. Add 10 μL of peptide solution to each well and incubate at 28 °C for the indicated period of time and stop the reaction with 25 μL of stop buffer. Finally, data were collected using the Caliper program, which converts measured data values into inhibition rates.

Inhibition rate (%)=(max-conversion)/(max-min)×100, where “max” represents DMSO control; “min” represents low control.

Representative compounds of the present invention were determined according to the methods described above, and the results are shown in Table 2:

Table 2

Formulation Example

The following formulation examples merely illustrate the scope of protection of the present invention and are not intended to be limiting in any way.

Example 40: Gelatin Capsules

Hard gelatin capsules were prepared using:

The above formulations can be modified with reasonable variations provided.

Example 41: Tablets

Tablets were prepared using:

The above components are mixed and compressed into tablets.

Example 42: Tablets

Tablets containing 2.5-1000 mg of active ingredient per tablet are prepared as follows:

Pass the active ingredient, starch and cellulose through a No. 45 mesh U.S. sieve and mix thoroughly. The polyvinylpyrrolidone solution was mixed with the resulting powder and passed through a No. 14 mesh US sieve. The resulting granules were dried at 50-60°C and passed through a No. 18 mesh U.S. sieve. Sodium carboxymethylcellulose, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, were added to the granules, followed by mixing and compression on a tablet machine to obtain tablets.

Example 43: Combination Tablets

The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The polyvinylpyrrolidone solution was mixed with the resulting powder and passed through a No. 14 mesh US sieve. The resulting granules were dried at 50-60°C and passed through a No. 18 mesh U.S. sieve. Sodium carboxymethylcellulose, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, were added to the granules, followed by mixing and compression on a tablet machine to obtain tablets.

From the above description, those skilled in the art can easily understand the essential features of the present invention, and without departing from the spirit and scope of the present invention, various changes and modifications can be made to the present invention to adapt to different applications and conditions.

Claims (10)

1. a kind of compound of formula I, pro-drug and pharmaceutical active metabolite and above compound is pharmaceutically acceptable Salt:

Wherein

X can be selected from CH, N；

R can be selected from hydrogen, C1-C4 alkyl, the C1-C4 alkyl that halogen replaces, C1-C4 alkoxy, the C1-C4 alcoxyl that halogen replaces Base, halogen；R can be single or multiple；

R₃、R₄、R₅The C1-C4 alkoxy that can replace independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 The C1-C4 alkoxy that alkoxy replaces.

2. 1 compound of formula of claim 1, pro-drug and pharmaceutical active metabolite and above compound are pharmaceutically Acceptable salt:

R be selected from hydrogen, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy, the chloro- 3- trifluoromethyl of 4-, 3,5- difluoros, fluorine, chlorine, Bromine；R can be single or multiple.

3. 1 compound of formula of claims 1 or 2, the pharmacy of pro-drug and pharmaceutical active metabolite and above compound Upper acceptable salt:

R₃、R₄、R₅Hydrogen, methyl, 2,2,2- trifluoro ethoxies, methoxyl group, 3- methoxy propoxy can be selected from.

4. compound as described below, pro-drug and pharmaceutical active metabolite and pharmaceutically acceptable salt, are selected from:

1-4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -3- phenylurea；

1- 4- chlorphenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } Urea；

1- (4- bromophenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } Urea；

1- [4- chloro- 3- (trifluoromethyl) phenyl] -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] first Base } sulfenyl } phenyl } urea；

1- (3,5- difluorophenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } benzene Base } urea；

1- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -3- [4- (trifluoro methoxy Base) phenyl] urea；

1- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -3- [3- (fluoroform Base) phenyl] urea；

1- (4- fluorophenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } Urea；

1- (4- methoxyphenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } benzene Base } urea；

1- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -3- (4- picoline - 2- yl) urea；

1- (6- bromopyridine -2- base) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } benzene Base } urea；

1- (5- chloropyridine -2- base) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } benzene Base } urea；

1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- phenylurea；

1- (4- chlorphenyl) -3- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } urea；

1- (4- bromophenyl) -3- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } urea；

1- [4- chloro- 3- (trifluoromethyl) phenyl] -3- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } Urea；

1- (3,5- difluorophenyl) -3- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } urea；

1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- [4- (trifluoromethoxy) phenyl] urea；

1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- [3- (trifluoromethyl) phenyl] urea；

1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- (4- fluorophenyl) urea；

1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- (4- methoxyphenyl) urea；

1- [4- chloro- 3- (trifluoromethyl) phenyl] -3- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } Phenyl } urea；

1- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } -3- [4- (trifluoromethoxy) benzene Base] urea；

1- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } -3- phenylurea；

1- (4- chlorphenyl) -3- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } urea；

1- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } 3- [3- (trifluoromethyl) phenyl] Urea；

1- (4- fluorophenyl) -3- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } urea；

1- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } -3- (4- methoxyphenyl) urea；

1- [4- chloro- 3- (trifluoromethyl) phenyl] -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] first Base } sulfenyl } phenyl } urea；

1- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } phenyl } -3- [4- (fluoroform Oxygroup) phenyl] urea；

1- (3,5- difluorophenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } Phenyl } urea；

1- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } phenyl } -3- phenylurea；

1- (4- chlorphenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } phenyl } Urea；

1- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } phenyl } -3- [3- (fluoroform Base) phenyl] urea；

1- (4- fluorophenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } phenyl } Urea；

1- (4- methoxyphenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } Phenyl } urea；

1- (4- bromophenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } phenyl } Urea.

5. a kind of pharmaceutical composition, including compound described in the claim 1-4 any one as active constituent, precursor Drug and pharmaceutical active metabolite and above compound pharmaceutically any one compound and drug in acceptable salt Acceptable carrier or diluent.

6. the preparation method of compound of formula I as described in claim 1, which is characterized in that

Wherein, R, R₃、R₄、R₅As described in claim 1.

7. compound described in claim 1-4 any one, its pro-drug and pharmaceutical active metabolite, and can pharmaceutically connect Application of the pharmaceutical composition described in the salt or claim 5 received in preparation tumor.

8. compound described in claim 1-4 any one, its pro-drug and pharmaceutical active metabolite, and can pharmaceutically connect The salt received or pharmaceutical composition are in preparation BRaf kinases, vascular endothelial growth factor receptor -2, platelet derived growth factor by Application in body-β or T-LAK cell source kinases inhibitor.

9. compound described in claim 1-4 any one, its pro-drug and pharmaceutical active metabolite, and can pharmaceutically connect The salt or pharmaceutical composition received are in preparation and BRaf kinases, vascular endothelial growth factor receptor -2, platelet derived growth factor Application in the related disease drug of receptor-beta or T-LAK cell source disregulated protein kinases.

10. application as claimed in claim 9, wherein with BRaf kinases, vascular endothelial growth factor receptor -2, blood platelet spreads out The related disease of raw growth factor receptors-β or T-LAK cell source disregulated protein kinases is lung cancer, liver cancer, melanoma, colon Cancer, the carcinoma of the rectum, breast cancer, oophoroma, kidney.