CN110003176B - Amide-containing benzimidazole compound and application thereof - Google Patents

Abstract

The invention belongs to the technical field of medicine, and relates to 2-[(pyridin-2-ylmethyl)thio]-1H-benzimidazole compounds and a preparation method and application thereof. The general formula of the described 2-[(pyridin-2-ylmethyl)thio]-1H-benzimidazole compounds and pharmaceutically acceptable salts is as follows: R ₁ , R ₂ are the same or different, select From hydrogen, C1-C8 alkyl, C3-C6 cycloalkyl, phenyl, halogen-substituted phenyl, C1-C4 alkyl substituted phenyl, C1-C4 alkoxy substituted phenyl, halogen and C1- C4 alkoxy co-substituted phenyl, halogen and C1-C4 alkoxy co-substituted phenyl, halogen substituted C1-C4 alkyl substituted phenyl, benzyl, 4-benzyloxyphenyl; or R ₁ , R ₂ and the nitrogen atom that they are connected together form substituted or unsubstituted morpholinyl, phenylpiperazine or benzhydryl piperazine; Described substituent is C1-C4 alkoxyl group, C1-C4 alkyl group , halogen; R ₃ , R ₅ can be selected from H, C1-C4 alkyl. The compound of the present invention has a simple synthesis method, is suitable for industrial production, and has obvious antitumor activity.

Description

Amide-containing benzimidazole compounds and their applications

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 stromal cells through a variety of effects, Promote blood vessel formation; (3) Insulin receptor (IR) family, including insulin receptor, insulin-like growth factor receptor (IGFR) and insulin related 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 factor is affected by The fibroblast growth factor receptor (FGFR) family, including FGFR-1, FGFR-2, FGFR-3 and FGFR-4, is a pleiotropic growth factor that regulates cell division, proliferation, migration and differentiation. 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-LAKcells). A kinase PBK (PDZ-bindingkinase, PBK) that can bind to the PDZ2 region of hDig was found to be the same molecule as TOPK in the HeLa cell cDNA library, 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

R ₁ and R ₂ are the same or different, and are selected from hydrogen, C1-C8 alkyl, C3-C6 cycloalkyl, phenyl, halogen-substituted phenyl, C1-C4 alkyl-substituted phenyl, and C1-C4 alkoxy phenyl substituted by halogen, phenyl substituted by halogen and C1-C4 alkoxy, phenyl substituted by halogen and C1-C4 alkoxy, phenyl substituted by halogen, C1-C4 alkyl, benzyl, 4-benzyloxyphenyl;

Or R ₁ , R ₂ and their connected nitrogen atoms together form a substituted or unsubstituted morpholinyl, phenylpiperazine or benzhydrylpiperazine; the substituents are C1-C4 alkoxy, C1-C4 Alkyl, halogen;

R ₃ and R ₅ can be selected from H, C1-C4 alkyl.

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

in,

R ₁ and R ₂ are the same or different, and are selected from hydrogen, C1-C8 alkyl, C3-C6 cycloalkyl, phenyl, halogen-substituted phenyl, C1-C4 alkyl-substituted phenyl, and C1-C4 alkoxy phenyl substituted by halogen, phenyl substituted by halogen and C1-C4 alkoxy, phenyl substituted by halogen and C1-C4 alkoxy, phenyl substituted by halogen, C1-C4 alkyl, benzyl, 4-benzyloxyphenyl;

Or R ₁ , R ₂ together with the nitrogen atom they are attached to form morpholin-1-yl, C1-C4 alkoxy substituted phenylpiperazin-1-yl, 4-benzylpiperazin-1-yl , halogen-substituted phenylpiperazin-1-yl;

R ₃ and R ₅ can be selected from H, C1-C4 alkyl.

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

R ₁ and R ₂ are the same or different, and are selected from hydrogen, ethyl, isopropyl, n-butyl, cyclopentyl, cyclohexyl, 4-chlorophenyl, 2-methylphenyl, 5-bromo-2- Methoxyphenyl, 2,4-dimethoxyphenyl, 3-(trifluoromethyl)phenyl, 4-(benzyloxy)phenyl, 3-chloro-4-(trifluoromethyl) phenyl, 4-methoxyphenyl, benzyl;

Or R ₁ , R ₂ and the nitrogen atom to which they are attached together form 4-(2,3-dichlorophenyl)piperazin-1-yl, (4-benzyl)piperazin-1-yl, 4- (4-Methoxyphenyl)piperazin-1-yl, morpholin-1-yl, (4-benzyloxyphenyl)piperazin-1-yl.

R ₃ and R ₅ can be selected from hydrogen and methyl.

Further, the present invention preferably the following compounds:

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-N-ring Hexylacetamide;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-N-iso Propylacetamide;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-N-ethyl acetamide;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-N-ring Amylacetamide;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-N-[ 3-Chloro-4-(trifluoromethyl)phenyl]acetamide;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-N-( 2-methylphenyl)acetamide;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-N,N - diethylacetamide;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-N-( 4-methoxyphenyl)acetamide;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-N-( 2,4-dimethoxyphenyl)acetamide;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-N-( 4-chlorophenyl)acetamide;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-N-butyl acetamide;

2-{3-{{2-{[(1H-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-N-benzyl acetamide;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-N-( 4-trifluoromethylphenyl)acetamide;

2-{3-{{2-{[(1H-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-1- olinoethyl-1-one;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-N,N - Dicyclohexylacetamide;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-N-( 4-Bromo-2-methoxyphenyl)acetamide;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methyl-pyridin-4-yl}oxy}propoxy}-1- [4-(4-Methoxyphenyl)piperazin-1-yl]ethanone;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methyl-pyridin-4-yl}oxy}propoxy}-1- [4-(2,3-Dichlorophenyl)piperazin-1-yl]ethanone;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methyl-pyridin-4-yl}oxy}propoxy}-1- [(4-Diphenylmethyl)piperazin-1-yl]ethanone;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methyl-pyridin-4-yl}oxy}propoxy}-N- (3,5-difluorophenyl)acetamide;

2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methyl-pyridin-4-yl}oxy}propoxy}-N- [4-(benzyloxy)phenyl)]acetamide.

"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 inhibition of BRaf kinase, Vascular endothelial growth factor receptor-2 (VEGFR-2), Platelet-derived growth factor receptors-β (PDGFR-β) and a pharmaceutical composition of T-LAK cell-derived protein kinase, the composition contains a compound of formula I or a derivative 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, It has good application value and development and application prospects.

Detailed ways

The schemes outline the preparative steps for the preparation of compounds of the present invention.

process

Among them, R ₁ , R ₂ , R ₃ 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: 2-{3-{{2-{[(1H-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy} Preparation of -N-cyclohexylacetamide (compound X01)

Step A: Preparation of 2-{[4-(3-Methoxypropoxy)-3-methylpyridin-2-yl]methylthio}-1H-benzimidazole

2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine hydrochloride (0.50 g, 1.88 mmol) was placed in a 125 ml eggplant-shaped flask, and 11 ml of ethanol was added to dissolve it, 1H-benzimidazole-2-thiophenol (0.28 g, 1.88 mmol) and 4 ml NaOH (80 g/L) were added, and the mixture was refluxed at 68° C. for 4 h, and the reaction was completed by TLC monitoring. The reaction solution was poured into a 100-ml beaker, cooled to room temperature naturally, and a white solid was precipitated, which was recrystallized from ethyl acetate and petroleum ether (2:1) to obtain 0.58 g of white needle-like crystals with a yield of 89.3%. m.p.: 115-118°C (literature value: 116-118°C).

Step B: Preparation of 3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propan-1-ol

2-{[4-(3-Methoxypropoxy)-3-methylpyridin-2-yl]methylthio}-1H-benzimidazole (3.00 g, 9.12 mmol) was placed in 100 ml eggplant Into the bottle, add 30 ml of dichloromethane to dissolve it, slowly add boron tribromide (6.80 g, 27.2 mmol) dropwise in an ice-water bath, naturally return to room temperature, react for 5 hours, and monitor the completion of the reaction by TLC. 20 ml of ice water was added to quench the reaction, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and 2.56 g of white solid was obtained by suction filtration, with a yield of 85.3%. m.p.: 97.0～99.2℃. It was used directly in the next reaction without purification.

Step C: 2-{3-{{2-{[(1H-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy}- Preparation of N-cyclohexylacetamide (compound X01)

3-{{2-{[(1H-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propan-1-ol (0.5 g, 1.52 mmol) and 2-chloro-N-cyclohexylacetamide (0.27g, 1.52mmol) were placed in a 100ml eggplant-shaped flask, 30ml of acetone was added to dissolve it, then potassium carbonate (1.05g, 7.56mmol) and potassium iodide (0.1 g), the reaction temperature of TBAB (0.1 g) was raised to 65° C., the reaction was carried out for 9 h, and the reaction was completed by TLC detection. The remaining solvent was distilled off under reduced pressure, 50ml of water was added, stirred for 3min, extracted with dichloromethane (30ml×3), the organic layers were combined, dried over magnesium sulfate, filtered with suction, and the filtrate was concentrated and the residue was purified by column chromatography (dichloromethane). : methanol=60:1) to obtain the target compound. White solid 0.34 g, yield 48.3%. mp: 192.0-194.1°C;; IR: (KBr, cm ^-1 )3442, 3286, 2929, 2853, 1654, 1611, 1581, 1492, 1447, 1397, 743; ¹ H-NMR (400MHz, DMSO): δ8 .28(d,J＝7.7 Hz,1H,Pyridine-6-H),8.22(d,J＝5.6 Hz,1H,Ar-H),7.58(dd,J＝6.1,2.9 Hz,1H,Ar- H), 7.40 (dd, J=6.3, 2.8Hz, 1H, Ar-H), 7.21～7.12 (m, 2H, Pyridine-5-H, NH), 6.96 (d, 1H, J=5.7Hz, Ar -H), 4.79(s, 2H, SCH ₂ ), 4.69(s, 2H, OCH ₂ ), 3.63～3.47(m, 3H, CH ₂ , NCH), 2.20(s, 3H, CH ₃ ), 1.89( p, J＝6.1 Hz, 2H, CH ₂ ), 1.77～1.6 (m, 4H, 2×CH ₂ ), 1.53 (d, J＝11.8 Hz, 1H), 1.32～1.05 (m, 6H, 3×CH2 ); ESI-MS (m/z): 469.3 ([M+H] ⁺ ).

Example 2: 2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy} - Preparation of N-isopropylacetamide (compound X02)

Referring to the preparation method of Example 1, 0.57 g of white solid was obtained with a yield of 87.2%. mp: 162.9-164.7°C; IR: (KBr, cm ^-1 ) 3278, 3086, 2924, 1656, 1584, 1464, 1442, 1369, 732; ¹ H-NMR (400MHz, DMSO): δ8.36(d, 1H, J＝7.4Hz, Pyridine-6-H), 8.22(d, 1H, J＝5.6Hz, Ar-H), 7.63～7.45(m, 1H, Ar-H), 7.44～7.37(m, 1H , Ar-H), 7.21～7.13 (m, 2H, Pyridine-5-H, NH), 6.96 (d, 1H, J=5.7Hz, Ar-H), 4.78 (s, 2H, SCH ₂ ), 4.69 (s, 2H, OCH ₂ ), 4.12 (t, J=6.2 Hz, 2H, CH ₂ ), 3.82 (dq, J=13.5, 6.7 Hz, 1H, NCH), 3.57 (dd, J=10.5, 5.7 Hz ESI _- MS (m/z): 429.3 ([M+H] ⁺ ).

Example 3: 2-{3-{{2-{[(1H-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy} - Preparation of N-ethylacetamide (compound X03)

Referring to the preparation method of Example 1, 0.59 g of white solid was obtained with a yield of 85.3%. mp: 258-260℃; IR: (KBr,cm ^-1 )3441(s), 2924(s), 2853(s), 1637(s), 1456(m), 1384(s), 736(s) , 620(s); ¹ HNMR(400MHz, DMSO): δ3.09(s, 3H, CH ₃ ), 7.32-7.36(m, 1H, Ar-H), 7.41-7.45(m, 1H, Ar-H ),7.69(t,1H,Ar-H,J=8.2Hz),7.75(d,1H,Ar-H,J=8.1Hz),8.01(dd,1H,Ar-H,J=8.1,1.8Hz ), 8.11 (dd, 2H, Ar-H, J=8.1, 2.4Hz), 8.68 (t, 1H, Ar-H, J=2.1Hz), 10.74 (s, 1H, NH); ESI-MS (m /z): 350.7 ([MH] ^- ). mp: 158.7-160.2°C; IR: (KBr, cm ^-1 ) 3415, 3293, 2983, 2926, 2831, 1661, 1611, 1492, 1462, 1441, 1397, 738; ¹ H-NMR (400MHz, DMSO): δ8.31(t,1H,J＝5.3Hz,acetamide-NH),δ8.22(d,1H,J＝5.5Hz,Pyridine-6-H),7.58(dd,1H,J＝6.2,2.6Hz , Ar-H), 7.41 (dd, 1H, J=6.4, 2.7Hz, Ar-H), 7.21–7.13 (m, 2H, Ar-H), 6.97 (d, 1H, J=5.6Hz, Pyridine- 5-H), 4.79 (s, 2H, SCH ₂ ), 4.70 (s, 2H, OCH ₂ ), 4.12 (t, J=6.2 Hz, 2H, CH ₂ ), 3.58 (q, J=7.2 Hz, 2H , CH ₂ ), 3.10 (t, J=6.2 Hz, 2H, CH ₂ ), 1.89 (p, J=6.0 Hz, 2H, CH ₂ ), 2.20 (s, 3H, Ar-CH ₃ ), 1.89 (p , J=6.0 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H); ESI-MS (m/z): 415.3 ([M+H] ⁺ ).

Example 4: 2-{3-{{2-{[(1H-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy} - Preparation of N-cyclopentylacetamide (compound X04)

Referring to the preparation method of Example 1, 0.56 g of white solid was obtained with a yield of 80.5%. mp: 178.2-180.1°C;; IR: (KBr, cm ^-1 )3283, 3062, 2954, 2870, 1657, 1580, 1479, 1462, 1442, 1369, 740; ¹ H-NMR (400MHz, DMSO): δ8 .34(d,J=7.3Hz,1H,Pyridine-6-H),8.22(d,J=5.6Hz,1H,Ar-H),7.58(dd,J=6.2,2.6Hz,1H,Ar- H), 7.40 (dd, J=6.3, 2.8Hz, 1H, Ar-H), 7.21～7.13 (m, 2H, Pyridine-5-H, NH), 6.97 (d, 1H, J=5.7Hz, Ar -H), 4.78 (s, 2H, SCH ₂ ), 4.69 (s, 2H, OCH ₂ ), 4.12 (t, 2H, J=6.2 Hz, OCH ₂ ), 3.98 (dq, J=12.6, 6.4 Hz, 1H, N-CH), 2.20 (s, 3H, CH ₃ ), 1.99 (m, 2H, CH ₂ ), 1.79 (dt, J=13.0, 5.9 Hz, 2H, CH ₂ ), 1.53 (m, 2H, _CH2 ), 1.50 (m, 2H, _CH2 ), 1.40 (dt, J=12.1, 5.7 Hz, 2H, _CH2 ); ESI-MS (m/z): 455.3 ([M+H] ⁺ ).

Example 5: 2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy} - Preparation of N-[3-Chloro-4-(trifluoromethyl)phenyl]acetamide (Compound X05)

Referring to the preparation method of Example 1, 0.69 g of white solid was obtained with a yield of 79.8%. mp: 148.9-150.4°C; IR: (KBr, cm ^-1 )3424, 3262, 3239, 3066, 2938, 2831, 1704, 1614, 1549, 1484, 1461, 1443, 1420, 1368, 742; ¹ H-NMR (400MHz, DMSO): δ10.95(s,1H,amide-NH),8.20(d,J=5.6Hz,1H,Pyridine-6-H),8.16(d,J=2.3Hz,1H,Ar- B-5-H),7.80(dd,J=8.8,2.3Hz,1H,Ar-B-6-H),7.69(d,J=8.8Hz,1H,Ar-B-2-H),7.62 (m,1H,Ar-AH),7.51(m,1H,,Ar-AH),7.20(m,2H,Ar-AH),6.95(d,J＝5.7Hz,1H,Pyridine-5-H) , 5.12 (s, 2H, SCH ₂ ), 4.72 (s, 2H, OCH ₂ ), 4.10 (t, J=6.2 Hz, 2H, CH ₂ ), 3.57 (dd, J=11.2, 5.9 Hz, 2H), 2.19 (s, 3H, _CH3 ), 1.88 (p, J=6.0 Hz, 2H); ESI-MS (m/z): 565.4 ([M+H] ⁺ ).

Example 6: 2-{3-{{2-{[(lH-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy} - Preparation of N-(2-methylphenyl)acetamide (compound X06)

Referring to the preparation method of Example 1, 0.59 g of white solid was obtained with a yield of 82.1%. mp: 177.9-180.6℃; IR: (KBr,cm ^-1 )3424,3254,2984,2924,2831,1667,1611,1542,1492,1441,1397,736; δ9.85(s,1H,amide- NH), 8.22(d, J=5.6Hz, 1H, Pyridine-6-H), 7.60(m, 1H, Ar-AH), 7.52(m, 1H, Ar-AH), 7.39(d, J=7.4 Hz, 1H, Ar-B-2-H), 7.20(m, 3H, 2×Ar-AH, Ar-B-5-H), 7.14(t, 1H, Ar-BH), 7.08(t, 1H ,, Ar-BH), 6.96(d, J=5.6Hz, 1H, Pyridine-5-H), 5.12(s, 2H, SCH ₂ ), 4.73(s, 2H, OCH ₂ ), 4.12(t, J =6.2Hz, 2H, CH ₂ ), 3.57 (t, J=5.9 Hz, 2H), 2.23 (s, 3H, CH ₃ ), 2.20 (s, 3H), 1.89 (m, 2H); ESI-MS ( m/z): 477.3 ([M+H] ⁺ ).

Example 7: 2-{3-{{2-{[(1H-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy} Preparation of -N,N-diethylacetamide (compound X07)

Referring to the preparation method of Example 1, 0.57 g of yellow-brown solid was obtained with a yield of 84.9%. mp: 57.7-60.3°C IR: (KBr, cm ^-1 ) 3422, 2925, 2872, 2854, 1617, 1584, 1491, 1441, 1368, 741; ¹ H-NMR (400MHz, DMSO): δ8.23(d , J=4.3Hz, 1H, Pyridine-6-H), 7.59(s, 1H, Ar-H), 7.39(s, 1H, Ar-H), 6.97(d, J=4.8Hz, 1H, Pyridine- 5-H), 7.17(s, 2H, 2×Ar-H), 5.08(s, 2H, SCH ₂ ), 4.67(s, 2H, OCH ₂ ), 4.12(t, J=6.2Hz, 2H, CH ) ₂ ), 3.45 (t, J＝6.1Hz, 2H, CH ₂ ), 2.19 (s, 3H, CH ₃ ), 1.98～1.80 (m, 2H, CH ₂ ), 1.22 (m, 5H, CH ₂ CH ₃ ), 1.01 (m, 5H, _{CH2CH3 )} ; ESI-MS (m/z): 443.4 ([M+H] ⁺ ).

Example 8: 2-{3-{{2-{[(1H-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy} - Preparation of N-(4-methoxyphenyl)acetamide (compound X08)

Referring to the preparation method of Example 1, 0.66 g of white solid was obtained with a yield of 87.7%. mp: 138.5-141.2°C IR: (KBr, cm ^-1 ) 3383, 3252, 3062, 2955, 2926, 2853, 1668, 1584, 1548, 1461, 1441, 1374, 743; ¹ H-NMR (400MHz, DMSO) :δ10.35(s,1H,acetamide-NH),8.21(d,J=5.6Hz,1H,Pyridine-6-H),7.61(dd,J=6.2,2.6Hz,1H,Ar-H), 7.49(m,3H,A-Ar-H,2×B-Ar-H),6.95(d,J=5.6Hz,1H,Pyridine-5-H),7.19(m,2H,A-Ar-H ), 6.90(s, 1H, B-Ar-H), 6.88(s, 1H, B-Ar-H), 5.04(s, 2H, SCH ₂ ), 4.72(s, 2H, OCH ₂ ), 4.11( t, J=6.1 Hz, 2H, CH ₂ ), 3.71 (s, 3H, OCH ₃ ), 3.57 (dd, J=11.4, 5.9 Hz, 2H, CH ₂ ), 2.20 (s, 3H, CH ₃ ), 1.96-1.80 (m, 2H, _CH2 ); ESI-MS (m/z): 493.5 ([M+H] ⁺ ).

Example 9: 2-{3-{{2-{[(lH-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy} - Preparation of N-(2,4-dimethoxyphenyl)acetamide (compound X09)

Referring to the preparation method of Example 1, 0.69 g of white solid was obtained with a yield of 86.5%. mp: 96.5-98.4°C; IR: (KBr, cm ^-1 ) 3424, 2984, 2925, 2831, 1679, 1602, 1543, 1492, 1463, 1441, 1397, 740; ¹ H-NMR (400MHz, DMSO): δ9.70(s,1H,acetamide-NH),8.21(d,J=5.6Hz,1H,Pyridine-6-H),7.60(dd,J=5.4,3.6Hz,1H,A-Ar-H) ,7.50(dd,J＝5.9,2.8Hz,1HA-Ar-H),7.23～7.15(m,2H,A-Ar-H,B-Ar-6-H),6.99(d,J＝9.0Hz ,1H,B-Ar-7-H),6.95(d,J=5.6Hz,1H,Pyridine-5-H),6.63(dd,J=8.8,2.7Hz,1HB-Ar-3-H), 5.22 (s, 2H, SCH ₂ ), 4.73 (s, 2H, OCH ₂ ), 4.11 (t, J=6.1 Hz, 2H, CH ₂ ), 3.82 (s, 3H, B-Ar-2-OCH ₃ ) , 3.63(s, 3H, B-Ar-4-OCH3), 3.57(dd, J=11.4, 5.9Hz, 2H, CH ₂ ), 2.20(s, 3H, CH ₃ ), 1.88(p, J=6.0 Hz, 2H, CH ₂ ); ESI-MS (m/z): 523.5 ([M+H] ⁺ ).

Example 10: 2-{3-{{2-{[(lH-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy} - Preparation of N-(4-chlorophenyl)acetamide (compound X10)

Referring to the preparation method of Example 1, 0.64 g of white solid was obtained with a yield of 84.4%. mp: 125.1-128.9°C; IR: (KBr, cm ^-1 ) 3396, 3253, 2053, 2927, 1671, 1585, 1543, 1492, 1462, 1442, 1401, 741; ¹ H-NMR (400MHz, DMSO): δ8.15(d,J＝5.6Hz,1H,Pyridine-6-H),7.74(m,3H,Ar-AH,Ar-BH×2),7.63(m,3H,Ar-AH,Ar-BH ×2),7.32(m,3H,Ar-AH×2,aceta-mide-NH),6.92(d,J＝5.8Hz,1H,Pyridine-5-H),5.11(s,2H,SCH ₂ ) , 4.64 (s, 2H, OCH ₂ ), 4.18 (t, J=6.2 Hz, 2H, CH ₂ ), 3.76 (t, J=6.2 Hz, 2H, CH ₂ ), 2.20 (s, 3H, CH ₃ ) , 2.03 (m, 2H, CH ₂ ); ESI-MS (m/z): 497.4 ([M+H] ⁺ ).

Example 11: 2-{3-{{2-{[(lH-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy} - Preparation of N-butylacetamide (compound X11)

Referring to the preparation method of Example 1, 0.59 g of white solid was obtained with a yield of 87.0%. mp: 161.1-162.6°C; IR: (KBr, cm ^-1 ) 3291, 3088, 2956, 2928, 2872, 1660, 1581, 1462, 1442, 1370, 738; ¹ H-NMR (400MHz, DMSO): δ8. 29(t,J=5.6Hz,1H,acetamide-NH),8.22(d,J=5.6Hz,1H,Pyridine-6-H),7.58(dd,J=6.2,2.7Hz,1H,Ar-4 -H),7.41(dd,J＝6.3,2.7Hz,1H,Ar-7-H),7.21～7.13(m,2H,Ar-5-H,Ar-6-H),6.97(d,J =5.7Hz,1H,Pyridine-5-H),4.80(s,2H,SCH ₂ ),4.70(s,2H,OCH ₂ ),4.12(t,J=6.2Hz,2H,CH ₂ ),3.57( q, J=5.9Hz, 2H, CH ₂ ), 3.08 (dd, J=12.6, 6.6 Hz, 2H, CH ₂ ), 2.20 (s, 3H, CH ₃ ), 1.89 (p, J=6.1 Hz, 2H , CH ₂ ), 1.45～1.33 (m, 2H, CH ₂ ), 1.33～1.25 (m, 2H, CH ₂ ), 0.84 (t, J=7.3Hz, 3H); ESI-MS (m/z): 443.5 ([M+H] ⁺ ).

Example 12: 2-{3-{{2-{[(1H-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy} - Preparation of N-benzylacetamide (compound X12)

Referring to the preparation method of Example 1, 0.75 g of white solid was obtained with a yield of 86.3%. mp: 176.6-177.7°C; IR: (KBr, cm ^-1 ) 3423, 3288, 2923, 1655, 1610, 1586, 1492, 1462, 1441, 1397, 737; ¹ H-NMR (400MHz, DMSO): δ8. 83(t,J=5.7Hz,1H,acetamide-NH),8.23(d,J=5.6Hz,1H,Pyridine-6-H),7.59(dd,J=6.2,2.7Hz,1H,Ar-4 -H),7.45(dd,J＝6.3,2.7Hz,1H,Ar-7-H),7.34～7.21(m,5H,B-Ar-4-H),7.21～7.15(m,2H,A -Ar-4-H, A-Ar-7-H), 6.98(d, J=5.7Hz, 1H, Pyridine-5-H), 4.91(s, 2H, SCH ₂ ), 4.71(s, 2H, OCH ₂ ), 4.32 (d, J=5.8 Hz, 2H, B-Ar-CH ₂ ), 4.13 (t, J=6.1 Hz, 2H, CH ₂ ), 3.58 (q, J=5.9 Hz, 2H, CH ) ₂ ), 2.20 (s, 3H, CH ₃ ), 1.90 (p, J=6.1Hz, 2H, CH ₂ ), 1.45～1.33 (m, 2H, CH ₂ ), 1.33～1.25 (m, 2H, CH ₂ ), 0.84 (t, J=7.3 Hz, 3H); ESI-MS (m/z): 571.4 ([M+H] ⁺ ).

Example 13: 2-{3-{{2-{[(lH-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy} - Preparation of N-(4-trifluoromethylphenyl)acetamide (compound X13)

Referring to the preparation method of Example 1, 0.68 g of a white solid was obtained with a yield of 83.7%. mp: 144.6-146.9°C; IR: (KBr, cm ^-1 ) 3416, 3266, 2925, 1675, 1583, 1546, 1491, 1446, 1372, 745; ¹ H-NMR (400MHz, DMSO): δ10.86( s,1H,Imidazole-NH),8.20(d,J=5.6Hz,1H,Pyridine-6-H),8.07(s,1H,acetamide-NH),7.75(d,J=8.3Hz,1H,B -Ar-2-H),7.61(dd,J=7.8,4.4Hz,1H,A-Ar-4-H),7.57(d,J=8.1Hz,1H,B-Ar-3-H), 7.52(dd,J=7.8,4.4Hz,1H,A-Ar-5-H),7.44(d,J=7.8Hz,1H,B-Ar-5-H),7.21～7.19(m,2H, A-Ar-4-H, A-Ar-7-H), 6.95(d, J=5.7Hz, 1H, Pyridine-5-H), 5.12(s, 2H, SCH ₂ ), 4.73(s, 2H , OCH ₂ ), 4.10 (t, J=6.2 Hz, 2H, CH ₂ ), 3.57 (q, J=5.9 Hz, 2H, CH ₂ ), 2.19 (s, 3H, CH ₃ ), 1.88 (p, J =6.1 Hz, 2H, CH ₂ ); ESI-MS (m/z): 530.9 ([M+H] ⁺ ).

Example 14: 2-{3-{{2-{[(lH-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy} - Preparation of 1-morpholinoethan-1-one (compound X14)

Referring to the preparation method of Example 1, 0.60 g of white solid was obtained with a yield of 85.9%. mp: 97.7-99.6°C; IR: (KBr, cm ^-1 ) 3416, 3266, 2925, 1675, 1583, 1546, 1491, 1446, 1372, 745; ¹ H-NMR (400MHz, DMSO): δ8.23( d, J=5.6Hz, 1H, Pyridine-6-H), 7.59 (dd, J=6.0, 3.1Hz, 1H, A-Ar-4-H), 7.43 (dd, J=6.0, 3.1Hz, 1H ,A-Ar-4-H),7.20～7.13(m,1H,2H,Ar-4-H,Ar-7-H),7.52(dd,J=7.8,4.4Hz,1H,A-Ar- 5-H), 6.97(d, J=5.7Hz, 1H, Pyridine-5-H), 5.12(s, 2H, SCH ₂ ), 4.69(s, 2H, OCH ₂ ), 4.12(t, J=6.2 Hz, 2H, CH ₂ ), 3.58 (q, J=5.9 Hz, 2H, CH ₂ ), 3.68 (t, J=4.1 Hz, 1H, CH ₂ ), 3.64～3.51 (m, 4H, 2×CH ₂ ), 3.44 (d, J=4.4 Hz, 1H, CH ₂ ), 2.20 (s, 3H, CH ₃ ), 1.89 (p, J=6.1 Hz, 2H, CH ₂ ); ESI-MS (m/z) : 456.9 ([M+H] ⁺ ).

Example 15: 2-{3-{{2-{[(lH-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy} Preparation of -N,N-dicyclohexylacetamide (compound X15)

Referring to the preparation method of Example 1, 0.71 g of a brown-red solid was obtained with a yield of 84.7%. mp: 104.9-106.5°C; IR: (KBr, cm ^-1 ) 3423, 2929, 2853, 1648, 1681, 1492, 1443, 1497, 1368, 740; δ8.21 (d, J=5.6Hz, 1H, Pyridine -6-H),7.58(dd,J=6.3,2.7Hz,1H,Ar-H),7.38(dd,J=6.2,2.8Hz,1H,Ar-H),7.24～7.12(m,2H, Pyridine-5-H, NH), 6.95 (d, J=5.7 Hz, 1H, Ar-H), 5.04 (s, 2H, SCH ₂ ), 4.65 (s, 2H, OCH ₂ ), 4.11 (t, J = 6.2 Hz, 2H, CH ₂ ), 3.56 (t, J=6.1 Hz, 2H, CH ₂ ), 2.28–2.08 (m, 5H, CH ₃ , 2×CH ₂ ), 1.88 (p, J=6.1 Hz , 2H, CH ₂ ), 1.72 (t, J=12.2Hz, 5H), 1.64–1.46 (m, 6H, 2×CH ₂ ), 1.77～1.62 (m, 4H, 2×CH ₂ ), 1.40～1.27 (m, 4H, 2×CH ₂ ), 1.22 (t, J=13.3 Hz, 5H); ESI-MS (m/z): 551.4 ([M+H] ⁺ ).

Example 16: 2-{3-{{2-{[(lH-benzimidazol-2-yl)sulfanyl]methyl}-3-methylpyridin-4-yl}oxy}propoxy} - Preparation of N-(4-bromo-2-methoxyphenyl)acetamide (compound X16)

Referring to the preparation method of Example 1, 0.60 g of white solid was obtained with a yield of 82.8%. mp: 103.0-105.5°C; IR: (KBr, cm ^-1 ) 3428, 2922, 2850, 1674, 1608, 1530, 1492, 1462, 1440, 1306, 780; ¹ H-NMR (400MHz, DMSO): δ9. 92(s,1H,acetamide-NH),8.23(s,1H,Pyridine-6-H),8.18(s,1H,Ar-B-6-H),7.60(s,1H,Ar-B-4 -H), 7.50(s, 1H, Ar-B-3-H), 7.25(dd, J=8.3Hz, 1H, Ar-A-4-H), 7.19(s, 2H, Ar-A-5 -H, Ar-A-6-H), 7.24(dd, J=8.3Hz, 1H, Ar-A-4-H), 6.99(s, 1H, Pyridine-5-H), 5.23(s, 2H , SCH ₂ ), 4.73(s, 2H, OCH ₂ ), 4.13(d, 2H, CH ₂ ), 3.88(s, 3H, CH ₃ ), 3.57(s, 2H, CH ₂ ), 2.20(s, 3H , CH ₃ ), 1.91 (m, 2H, CH ₂ ); ESI-MS (m/z): 476.9 ([M+H] ⁺ ).

Example 17: 2-{3-{{2-{[(lH-benzimidazol-2-yl)sulfanyl]methyl}-3-methyl-pyridin-4-yl}oxy}propoxy Preparation of }-1-[4-(4-methoxyphenyl)piperazin-1-yl]ethanone (Compound X17)

Referring to the preparation method of Example 1, 0.26 g of white solid was obtained, with a yield of 52.8%; mp: 127.4-129.1°C; ESI-MS: m/z 562.6[M+H] ⁺ , 584.2[M+Na] ⁺ ; ¹ HNMR (400MHz, DMSO-d ₆ )δ8.22(d,J=5.6Hz,1H),7.64-7.55(m,1H),7.49-7.40(m,1H),7.22-7.14(m,2H) ,6.99-6.90(m,3H),6.89-6.81(m,2H),5.21(s,2H),4.69(s,2H),4.59(t,J＝5.1Hz,1H),4.12(t,J ＝6.2Hz, 2H), 3.74(t, J＝4.9Hz, 2H), 3.70(s, 3H), 3.57(q, J＝5.6Hz, 4H), 3.12(t, J＝4.9Hz, 2H), 2.99(d, J=5.2Hz, 2H), 2.20(s, 3H), 1.89(p, J=6.2Hz, 2H).

Example 18: 2-{3-{{2-{[(lH-benzimidazol-2-yl)sulfanyl]methyl}-3-methyl-pyridin-4-yl}oxy}propoxy For the preparation of }-1-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethanone (Compound X18), referring to the preparation method of Example 1, 0.18 g of white solid was obtained, with a yield of 49.1% ; mp: 165.8-167.3°C; ESI-MS: m/z 600.7, 602.0, [M+H] ⁺ ; ¹ HNMR (400MHz, DMSO-d ₆ ) δ 8.23 (d, J=5.6Hz, 1H), 7.59 (dt, J=7.2, 3.5Hz, 1H), 7.45 (dd, J=6.1, 3.1Hz, 1H), 7.39–7.32 (m, 2H), 7.23–7.12 (m, 3H), 6.97 (d, J =5.7Hz,1H),5.23(s,2H),4.70(s,2H),4.59(t,J=5.1Hz,1H),4.12(t,J=6.2Hz,2H),3.77(d,J ＝5.0Hz, 2H), 3.62(t, J＝4.9Hz, 2H), 3.57(q, J＝5.9Hz, 2H), 3.11(d, J＝4.9Hz, 2H), 2.98(t, J＝5.0 Hz, 2H), 2.20(s, 3H), 1.89(p, J=6.2Hz, 2H).

Example 19: 2-{3-{{2-{[(lH-benzimidazol-2-yl)sulfanyl]methyl}-3-methyl-pyridin-4-yl}oxy}propoxy Preparation of }-1-[(4-Diphenylmethyl)piperazin-1-yl]ethanone (Compound X19)

Referring to the preparation method of Example 1, 0.26 g of white solid was obtained, the yield was 51.3%; mp: 156.6-158.3°C; ESI-MS: m/z 622.6 [M+H] ⁺ ; ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.23(d, J＝5.7Hz, 1H), 7.58(dd, J＝6.0, 3.1Hz, 1H), 7.45(d, J＝7.6Hz, 5H), 7.32(t, J＝7.6Hz ,5H),7.25–7.11(m,5H),6.98(d,J＝5.7Hz,1H),5.12(s,2H),4.67(s,2H),4.60(t,J＝5.2Hz,1H) ,4.36(s,1H),4.12(t,J＝6.2Hz,2H),3.58(dt,J＝11.6,6.4Hz,4H),3.47(s,2H),2.39(s,2H),2.28( d, J=8.3Hz, 2H), 2.19 (s, 3H), 1.89 (p, J=6.4Hz, 2H).

Example 20: 2-{3-{{2-{[(lH-benzimidazol-2-yl)sulfanyl]methyl}-3-methyl-pyridin-4-yl}oxy}propoxy Preparation of }-N-(3,5-difluorophenyl)acetamide (Compound X20)

Referring to the preparation method of Example 1, 0.21 g of white solid was obtained, with a yield of 48.4%; mp: 169.6-170.8°C; ESI-MS: m/z 499.3 [M+H] ⁺ ; ¹ HNMR (400MHz, DMSO-d ₆ ) δ10.92(s, 1H), 8.21(d, J=5.6Hz, 1H), 7.61(dt, J=7.4, 3.5Hz, 1H), 7.51(dd, J=6.2, 3.1Hz, 1H) ,7.29(h,J＝5.1Hz,2H),7.21(dt,J＝6.0,3.6Hz,2H),7.01–6.91(m,2H),5.11(s,2H),4.73(s,2H), 4.59(t,J＝5.3Hz,1H),4.11(t,J＝6.2Hz,2H),3.57(q,J＝5.8Hz,2H),2.20(s,4H),1.88(p,J＝6.2 Hz, 2H).

Example 21: 2-{3-{{2-{[(lH-benzimidazol-2-yl)sulfanyl]methyl}-3-methyl-pyridin-4-yl}oxy}propoxy Preparation of }-N-[4-(benzyloxy)phenyl)]acetamide (Compound X21)

Referring to the preparation method of Example 1, 0.19 g of white solid was obtained, with a yield of 44.3%; mp: 154.3-155.8°C; ESI-MS: m/z 569.4[M+H] ⁺ , 591.1[M+Na] ⁺ ; ¹ HNMR (400MHz, DMSO-d ₆ ) δ 10.36 (s, 1H), 8.21 (d, J=5.6Hz, 1H), 7.65-7.56 (m, 1H), 7.49 (dd, J=7.2, 4.0Hz ,3H),7.43(d,J=7.0Hz,2H),7.38(t,J=7.3Hz,2H),7.35–7.28(m,1H),7.24–7.15(m,2H),6.96(dd, J＝7.5, 5.8Hz, 3H), 5.06(s, 2H), 5.04(s, 2H), 4.73(s, 2H), 4.59(t, J＝5.2Hz, 1H), 4.11(t, J＝6.2 Hz, 2H), 3.57(q, J=5.9Hz, 2H), 2.20(s, 3H), 1.89(p, J=6.2Hz, 2H).

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 22: Inhibitory activity of test compounds on the proliferation of A549, HCT-116 and PC3 cells

(1) Experimental materials

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 X01 to X21: 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 23: 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.

Target compounds numbered X01 to X21: 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 MgCl2, 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 24: Gelatin Capsules

Hard gelatin capsules were prepared using:

The above formulations can be modified with reasonable variations provided.

Example 25: Tablets

Tablets were prepared using:

The above components are mixed and compressed into tablets.

Example 26: Tablets

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

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 US 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 27: 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 US 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 compound of formula I, and pharmaceutically acceptable salts of the foregoing compounds:

in, R ₁ and R ₂ are the same or different, and are selected from hydrogen, C1-C8 alkyl, C3-C6 cycloalkyl, phenyl, halogen-substituted phenyl, C1-C4 alkyl-substituted phenyl, and C1-C4 alkoxy Alkyl-substituted phenyl, phenyl substituted with both halogen and C1-C4 alkoxy, halogen substituted C1-C4 alkyl substituted phenyl, benzyl, 4-benzyloxyphenyl, 3-chloro-4- (trifluoromethyl)phenyl; Or R ₁ , R ₂ and their connected nitrogen atoms together form a substituted or unsubstituted morpholinyl, phenylpiperazine or benzhydrylpiperazine; the substituents are C1-C4 alkoxy, C1-C4 Alkyl, halogen; R ₃ and R ₅ are selected from H, C1-C4 alkyl. 2. Compounds of formula I according to claim 1, and pharmaceutically acceptable salts of said compounds: R ₁ and R ₂ are the same or different, and are selected from hydrogen, C1-C8 alkyl, C3-C6 cycloalkyl, phenyl, halogen-substituted phenyl, C1-C4 alkyl-substituted phenyl, and C1-C4 alkoxy Alkyl-substituted phenyl, phenyl substituted with both halogen and C1-C4 alkoxy, halogen substituted C1-C4 alkyl substituted phenyl, benzyl, 4-benzyloxyphenyl, 3-chloro-4- (trifluoromethyl)phenyl; Or R ₁ , R ₂ together with the nitrogen atom they are attached to form morpholin-1-yl, C1-C4 alkoxy substituted phenylpiperazin-1-yl, 4-benzylpiperazin-1-yl , halogen-substituted phenylpiperazin-1-yl. 3. A compound of formula I according to claim 1 or 2, and a pharmaceutically acceptable salt of said compound: in, R ₁ and R ₂ are the same or different, and are selected from hydrogen, ethyl, isopropyl, n-butyl, cyclopentyl, cyclohexyl, 4-chlorophenyl, 2-methylphenyl, 5-bromo-2- Methoxyphenyl, 2,4-dimethoxyphenyl, 3-(trifluoromethyl)phenyl, 4-(benzyloxy)phenyl, 3-chloro-4-(trifluoromethyl) phenyl, 4-methoxyphenyl, benzyl; Or R ₁ , R ₂ and the nitrogen atom to which they are attached together form 4-(2,3-dichlorophenyl)piperazin-1-yl, (4-benzyl)piperazin-1-yl, 4- (4-Methoxyphenyl)piperazin-1-yl, morpholin-1-yl, (4-benzyloxyphenyl)piperazin-1-yl; R ₃ and R ₅ are selected from hydrogen and methyl. 4. The compound of claim 1, and a pharmaceutically acceptable salt, selected from the group consisting of: 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methylpyridin - 4-yl}oxy}propoxy}-N- Cyclohexylacetamide; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methylpyridin - 4-yl}oxy}propoxy}-N- Isopropylacetamide; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methylpyridin - 4-yl}oxy}propoxy}-N- Ethylacetamide; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methylpyridin - 4-yl}oxy}propoxy}-N- Cyclopentylacetamide; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methylpyridin - 4-yl}oxy}propoxy}-N- [3-Chloro-4-(trifluoromethyl)phenyl]acetamide; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methylpyridin - 4-yl}oxy}propoxy}-N- (2-methylphenyl)acetamide; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy} -N, N -diethylacetamide; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methylpyridin - 4-yl}oxy}propoxy}-N- (4-methoxyphenyl)acetamide; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methylpyridin - 4-yl}oxy}propoxy}-N- (2,4-dimethoxyphenyl)acetamide; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methylpyridin - 4-yl}oxy}propoxy}-N- (4-chlorophenyl)acetamide; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methylpyridin - 4-yl}oxy}propoxy}-N- Butylacetamide; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methylpyridin - 4-yl}oxy}propoxy}-N- benzylacetamide; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methylpyridin - 4-yl}oxy}propoxy}-N- (4-trifluoromethylphenyl)acetamide; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy}-1- Morpholin-1-one; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy} -N, N -dicyclohexylacetamide; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methylpyridin - 4-yl}oxy}propoxy}-N- (4-Bromo-2-methoxyphenyl)acetamide; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methyl-pyridin-4-yl}oxy}propoxy}-1 -[4-(4-Methoxyphenyl)piperazin-1-yl]ethanone; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methyl-pyridin-4-yl}oxy}propoxy}-1 -[4-(2,3-Dichlorophenyl)piperazin-1-yl]ethanone; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)thio]methyl}-3-methyl-pyridin-4-yl}oxy}propoxy}-1 -[(4-Diphenylmethyl)piperazin-1-yl]ethanone; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)sulfanyl]methyl}-3-methyl-pyridin-4-yl}oxy}propoxy} -N -(3,5-Difluorophenyl)acetamide; 2-{3-{{2-{[( 1H -benzimidazol-2-yl)sulfanyl]methyl}-3-methyl-pyridin-4-yl}oxy}propoxy} -N -[4-(benzyloxy)phenyl)]acetamide. 5. A pharmaceutical composition comprising, as an active ingredient, the compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 6. the preparation method of the compound of claim 1, its flow process is as follows:

Wherein, R ₁ , R ₂ , R ₃ and R ₅ are as described in claim 1 . 7. Use of the compound according to any one of claims 1 to 4, and a pharmaceutically acceptable salt or the pharmaceutical composition according to claim 5, in the preparation of a medicament for treating tumors. 8. The compound of any one of claims 1-4, and a pharmaceutically acceptable salt or pharmaceutical composition in the preparation of BRaf kinase, vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor-beta or T - Application of LAK cell-derived protein kinase inhibitors. 9. The compound of any one of claims 1-4, and a pharmaceutically acceptable salt or pharmaceutical composition prepared with BRaf kinase, vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor-beta or Application of T-LAK cell-derived protein kinase dysregulation-related disease drugs. 10. The use according to claim 9, wherein the diseases related to the deregulation of BRaf kinase, vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor-beta or T-LAK cell-derived protein kinase are lung cancer, liver cancer , melanoma, colon cancer, rectal cancer, breast cancer, ovarian cancer, kidney cancer.