CN101220044A - Telomerase inhibitor and its preparation method and use - Google Patents

Abstract

The present invention relates to the field of medicinal chemistry, in particular to a class of thiazo[5,4-b]pyridine compounds (I), their preparation methods, pharmaceutical compositions containing these compounds and their medical applications, especially as terminal Use of granzyme inhibitors.

Description

Telomerase inhibitor and its preparation method and use

technical field

The present invention relates to the field of medicinal chemistry, in particular to a class of thiazo[5,4-b]pyridine compounds, their preparation methods, pharmaceutical compositions containing these compounds and their medical uses, especially as telomerase inhibitors use of the agent.

Background technique

In 1985, the Blackburn research group first discovered telomerase, which catalyzes the synthesis of telomere repeat sequence, in Tetrahymena. In 1989, Morin of Yale University also found human telomerase in human cervical cancer cells. According to the report of Kim’s research group, more than 85% of tumor tissues have telomerase expression, but there is no expression of telomerase in normal somatic cells (except germ cells, hematopoietic red blood cells) Express. This makes telomerase an ideal target for anticancer drug design.

Since the 1990s, the research on telomerase inhibitors has become a hot spot in the research and development of antitumor drugs. Especially after 1998, hundreds of related patents and articles are published every year.

Contents of the invention

The present invention studies pyridine-α-thioether compounds with telomerase inhibitory activity, benzothiazole compounds with antitumor activity and oxazolopyridine compounds with antitumor activity, and is applied to conformational constraints, bioelectronics, etc. Based on the row principle, a series of compounds with new structures were designed. The results of preliminary pharmacological experiments show that the designed compounds have high telomerase inhibitory activity.

Compound general formula I of the present invention is as follows:

Wherein R ¹ and R ² each independently represent hydrogen, hydroxyl, nitro, amino, methyl, trifluoromethyl, fluorine, chlorine, bromine, iodine or nitrile;

Where X represents N, O or S;

where M represents a bond, -(CH ₂ ) _m -O-(CH ₂ ) _n -, -(CH ₂ ) _m -(CH ₂ ) _n -, -(CH ₂ ) _m -C(O)-(CH ₂ ) _n -, -(CH ₂ ) _m -NR ³ -(CH ₂ ) _n -, -(CH ₂ ) _m -NR ³ C(O)-(CH ₂ ) _n -, -(CH ₂ ) _m -S -(CH ₂ ) _n -, -(CH ₂ ) _m -CF ₂ -(CH ₂ ) _n -or -(CH ₂ ) _m -S(O)-(CH ₂ ) _n -, m=0～4, n=0～4; R ³ is hydrogen or methyl, ethyl, propyl.

Wherein Q ¹ and Q ² each independently represent phenyl, phenyl with 1 to 3 substituents, naphthyl with 1 to 2 substituents, five-membered or A six-membered substituted heterocyclic ring, said substitution refers to being substituted by hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, amino, cyano, methoxy or ethoxy.

R ¹ , R ² preferably represent hydrogen.

Q ¹ and Q ² are preferably phenyl or substituted phenyl, said substitution refers to being substituted by hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, amino, cyano, methoxy or ethoxy; Q ¹ is further preferably phenyl, and Q ² is further preferably substituted phenyl, and the substituent refers to being substituted by chlorine, bromine, methyl, methoxy or ethoxy.

M is preferably a single bond or -CH ₂ -, more preferably a single bond.

X is preferably O or S, more preferably O.

The most preferred two compounds are: R ¹ and R ² are hydrogen, Q ¹ is phenyl, M is a single bond, Q ² is m-chlorophenyl, and X is S.

R ¹ and R ² are hydrogen, Q ¹ is phenyl, M is -CH ₂ -, Q ² is phenyl, and X is O.

The compound of above-mentioned general formula can be:

2-Phenyl-6-(4'-methylbenziminomethyl)thiazo[5,4-b]pyridine (I-1);

2-Phenyl-6-(2'-methylbenziminomethyl)thiazo[5,4-b]pyridine (I-2);

2-Phenyl-6-(3'-methylbenziminomethyl)thiazo[5,4-b]pyridine (I-3);

2-Phenyl-6-(4'-chlorophenyliminomethyl)thiazo[5,4-b]pyridine (I-4);

2-Phenyl-6-(2',3',4'-trifluorophenyliminomethyl)thiazo[5,4-b]pyridine (I-5);

2-Phenyl-6-(2',5'-dimethylbenziminomethyl)thiazo[5,4-b]pyridine (I-6);

2-Phenyl-6-(3-chlorophenyliminomethyl)thiazo[5,4-b]pyridine (I-7);

2-phenyl-6-phenyliminomethylthiazo[5,4-b]pyridine (I-8);

2-Phenyl-6-[2-(2'-benzo[1,3]cyclopentadioxane)ethyliminomethyl]thiazo[5,4-b]pyridine (I-9);

2-Phenyl-6-(4'-methoxyphenyliminomethyl)thiazo[5,4-b]pyridine (I-10);

2-phenyl-6-(2-(5'-ethoxybenzothiazole))iminomethyl)thiazo[5,4-b]pyridine (I-11);

2-Phenyl-6-(4'-fluorophenyliminomethyl)thiazo[5,4-b]pyridine (I-12);

2-Phenyl-6-(3',4'-difluorophenyliminomethyl)thiazo[5,4-b]pyridine (I-13);

2-Phenyl-6-(2',4'-dichlorobenzimidomethyl)thiazo[5,4-b]pyridine (I-14);

2-Phenyl-6-(4'-methylbenziminomethyl)oxazol[5,4-b]pyridine (II-1);

2-Phenyl-6-(2'-methylbenziminomethyl)oxazol[5,4-b]pyridine (II-2);

2-Phenyl-6-(3'-methylbenziminomethyl)oxazol[5,4-b]pyridine (II-3);

2-Phenyl-6-(4'-chlorophenyliminomethyl)oxazol[5,4-b]pyridine (II-4);

2-phenyl-6-phenyliminomethyloxazol[5,4-b]pyridine (II-5);

2-Phenyl-6-[2-(2'-benzo[1,3]cyclopentadioxane)ethyliminomethyl]oxazol[5,4-b]pyridine (II-6);

2-Phenyl-6-(2,5-dimethylbenziminomethyl)oxazol[5,4-b]pyridine (II-7);

2-Phenyl-6-(2'-phenyl)ethyliminomethyloxazol[5,4-b]pyridine (II-8);

2-Phenyl-6-(4'-bromophenyliminomethyl)oxazol[5,4-b]pyridine (II-9);

2-Phenyl-6-(4'-fluorophenyliminomethyl)oxazol[5,4-b]pyridine (II-10);

2-phenyl-6-(2',4'-dichlorobenzimidomethyl)oxazol[5,4-b]pyridine (II-11);

2-phenyl-6-(2'-methyl 5'-chlorophenyliminomethyl)oxazol[5,4-b]pyridine (II-12);

2-Phenyl-6-(3'-acetylphenyliminomethyl)oxazol[5,4-b]pyridine (II-13);

2-Phenyl-6-(3'-chlorophenyliminomethyl)oxazol[5,4-b]pyridine (II-14);

2-phenyl-6-(3',4'-difluorophenyliminomethyl)oxazol[5,4-b]pyridine (II-15);

2-phenyl-6-(2',4'-difluorophenyliminomethyl)oxazol[5,4-b]pyridine (II-16);

2-Phenyl-6-(4'-methoxyphenyliminomethyl)oxazol[5,4-b]pyridine (II-17);

2-phenyl-6-(3'-chloro4'-fluorophenyliminomethyl)oxazol[5,4-b]pyridine (II-18);

2-phenyl-6-(2',3'-dichlorobenzimidomethyl)oxazol[5,4-b]pyridine (II-19);

The preparation method of some compounds of the present invention is as follows:

The preparation method of some compounds of the present invention can be:

The compounds of the present invention can be prepared by the above-mentioned or similar preparation methods, and the corresponding raw materials can be selected according to the difference of the substituent and the position of the substituent.

Pharmacological test results show that the compound of general formula (I) and its pharmaceutically acceptable salt all have different degrees of inhibition to in vitro telomerase, therefore, the compound of formula (I) and its pharmaceutically acceptable salt can be used For the treatment of clinical conditions associated with telomerase inhibitors. The diseases related to telomerase inhibitors can be melanoma, liver cancer, kidney cancer, acute, leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, skin cancer, colorectal cancer, pancreatic cancer, ovarian cancer, breast cancer cancer, myelodysplastic syndrome, esophageal cancer, gastrointestinal cancer, or mesothelioma. The following are some pharmacological tests and results:

Reagent RPMI1640 (GIBCO)

  Trypsin (SIGMA)

  Newborn bovine serum (HYCLONE)

Taq Enzyme (Promega)

Dntp(Promega)

CHAPS(Amresco)

EGTA(Amresco)

PMSF(Amresco)

    β-Mercaptoethanol (Amresco)

      Tris base (NOVON)

  Primers (Shanghai Sangong)

Ts: 5’-AATCCGTCGAGCAGAGTT-3’

Cx: 5'-CCCTTACCCTTACCCTTACCCTAA-3'

    Telo TAGGG Telomerase PCR Elisa Kit (Roche, No.11 854

     666910) Protein Detection Kit (Nanjing Jiancheng)

Cell line Hela

[method]

1. Cell Treatment

Take cells in the logarithmic growth phase, digest with 0.25% trypsin for 2 minutes, discard the digestion solution, add new culture medium and pipette evenly to form a cell suspension. Take the cell suspension (containing 1×106 cells, counted under the microscope) and inoculate it in a culture bottle, change the medium after 24 hours, add the drug to be tested to the final concentration of 10-6M in the fresh serum-free culture medium, and equilibrate for half at room temperature After 24 hours, the cells were collected, centrifuged, washed twice with PBS buffer, and placed in an Eppendorf tube for later use (stored at -20°C); the positive control cell suspension (containing 1×106 cells) was inoculated into a culture flask , after 48 hours of culture, the cells were collected, centrifuged, washed twice with PBS buffer, and put into Eppendorf tubes for later use (stored at -20°C).

2. Preparation of cell extracts

Take 1×106 cells to be frozen at -20°C, add 150ul of cell lysate, mix well, keep in ice bath for 30 minutes, centrifuge at 14000rpm at 4°C for 30 minutes, take the supernatant for protein quantification by Brandford method, and store at -80°C pending inspection.

Protein quantification by the Brandford method was carried out according to the operation manual of the kit.

3. TRAP response

Take 1 μl of the above cell extract and add it to the TRAP reaction solution, which contains 1 μl of Ts primer (0.1 μg/ml), 2U TaqDNA polymerase, 50 mM dNTP, the reaction volume is 50 μl, the temperature is 25 ° C, and the reaction is 30 min.

4.PCR amplification

Add 1 μl of Cx B primer (0.1 μg/ml) for PCR amplification, the conditions are: 94°C for 30s; 50°C for 30s; 72°C for 90s, 30 cycles. Then add 5 μl bromophenol blue to the reaction tube.

5. ELISA detection

Take 5 μl of the above PCR amplification product, add 20 μl of denaturing solution, mix well, let stand at room temperature for 10 minutes, then add 225 μl of hybridization mixture (containing digoxin-labeled detection probe) and mix well, transfer 100 μl of the mixture to avidin On the protein-coated microwell plate, hybridize on a shaker at 37°C for 2 hours, wash the plate 3 times with washing solution, add 100 μl of anti-digoxigenin antibody conjugated with peroxidase, incubate on a shaker at room temperature for 30 minutes, and wash the plate Add 100 μl of POD-containing substrate tetramethylbenzidine for 3 times, develop color on a shaker at room temperature for 30 minutes, add 100 μl of stop solution to terminate the reaction, and measure the absorbance values at wavelengths of 450 nm and 690 nm with a microplate reader, ΔA=A450-A690, ΔA values represent relative telomerase activity.

Two, partial compound screening results (the compound number corresponds to the number of the compound in the examples)

serial number Inhibition rate(%) serial number Inhibition rate(%) serial number Inhibition rate(%) I-1 0.346 II-1 0.395 II-10 0.178 I-2 2.179 II-2 1.279 II-11 19.143 I-3 1.990 II-3 14.893 II-12 2.669 I-6 1.027 II-4 1.621 II-13 3.189 I-7 76.578 II-5 0.652 II-14 2.975 I-9 0.300 II-6 9.343 II-15 10.813 I-10 0.354 II-7 12.061 II-16 1.008 I-11 5.772 II-8 52.905 II-17 0.150 I-12 0.894 II-9 36.094 II-19 1.054

Pharmacological test results show that the compound of the present invention has telomerase inhibitory activity and can be used to prevent or treat clinical diseases related to telomerase inhibitors. These diseases can be: melanoma, liver cancer, kidney cancer, acute, leukemia, non-small Lung cancer, prostate cancer, thyroid cancer, skin cancer, colorectal cancer, pancreatic cancer, ovarian cancer, breast cancer, myelodysplastic syndrome, esophageal cancer, gastrointestinal cancer or mesothelioma, etc.

Detailed ways

The melting point was measured with a b-shaped melting point tube, the medium was methyl silicone oil, and the thermometer was not corrected; ^the IR spectrum was measured with a Nicolet Impact 410 infrared spectrometer, and KBr was pressed into tablets; Resonance instrument and BRUKER AM-500 nuclear magnetic resonance instrument are completed (TMS internal standard); MS is determined with Nicolet2000 Fourier transform mass spectrometer and MAT-212 mass spectrometer.

Example 1

2-Hydroxy-3-nitro-6-methylpyridine (I-a)

Slowly add 300 mL of concentrated sulfuric acid into a reaction flask containing 152 g (1.4 mol) of 2-hydroxy-6-picoline, and after the addition is complete, add 92 mL (1.47 mol) of fuming nitric acid dropwise at room temperature. Control the dropping rate so that the internal temperature is lower than 60°C. After dropping, stir at room temperature for 1 hr. The reaction solution was poured into ice water, a solid was precipitated and filtered. The filtrate was adjusted to pH 5-6 with sodium carbonate, solid precipitated, and filtered with suction. The solid was washed with absolute ethanol, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, and the solvent was recovered under reduced pressure. After drying, 120 g (56%) of a yellow solid was obtained. (unseparated, directly submitted to the next reaction)

Example 2

2-Chloro-3-nitro-6-methylpyridine (I-b)

Add 120 g (0.8 mol) of the above mixture, 400 mL of phosphorus oxychloride and 200 mL of toluene into the reaction flask, stir mechanically, and heat up to reflux. TLC tracking, the raw material disappeared after 6hrs. Excess phosphorus oxychloride and toluene were recovered under reduced pressure, the residual paste was poured into ice water, and the pH value was adjusted to 8-9 with aqueous sodium hydroxide solution. Extract with ethyl acetate 200mL×5, combine the organic phases, and recover the solvent under reduced pressure. The crude product was subjected to column chromatography (developing solvent: ethyl acetate:petroleum ether=1:40) to obtain 45 g of 2-chloro-3-nitro-6-picoline as a pale yellow solid (yield: 33%), mp: 58～60℃.

¹ HNMR (300MHz, CDCl ₃ ): 2.51 (3H, s, -CH ₃ ), 7.80-7.81 (1H, m, ArH), 8.92-8.96 (1H, m, ArH),)

Example 3

2-Chloro-3-amino-6-methylpyridine (I-c)

Add 2 g (0.012 mol) of 2-chloro-3-nitro-6-picoline, 4 g of iron powder, 0.2 g of ammonium chloride, 15 mL of water and 1 mL of ethanol into the reaction flask, stir mechanically, and heat up to reflux. After 1 hr, TLC showed disappearance of starting material. Filter while hot, wash the filter cake with 5 mL×3 ethyl acetate, and extract the aqueous phase with 5 mL×5 ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was recovered under reduced pressure to obtain 1.4 g (0.01 mol) of a dark red solid (yield: 83%), mp: 82-83°C.

¹ HNMR (300MHz, CDCl ₃ ): 2.52 (3H, s, -CH ₃ ), 5.62～5.63 (2H, s, -NH ₂ ), 7.80～7.81 (1H, m, ArH), 8.92～8.96 (1H, m, ArH),)

Example 4

2-Phenyl-6-methylthiazo[5,4-b]pyridine (I-d)

1.4 g (0.01 mol) of 2-chloro-3-amino-6-picoline and 10 mL of anhydrous xylene were added to the reaction flask, and 260 mg (10.8 mmol) of sodium hydride was added after drying with N ₂ for 5 mins. The internal temperature was raised to 100°C, and 1.63 g (0.01 mol) of ethyl thiobenzoate was added. Heat up to reflux for 12hrs. Cool down, add a small amount of ethanol dropwise to decompose excess sodium hydride. The crude product was subjected to column chromatography (developer: ethyl acetate:petroleum ether=1:40) to obtain 1.8 g (7.9 mmol) of a light yellow solid (yield: 79%), mp: 102-104°C.

¹ HNMR (300MHz, CDCl ₃ ): 2.54 (3H, s, -CH ₃ ), 7.24-7.26 (2H, m, ArH), 7.52-7.56 (2H, m, ArH), 7.74-7.80 (1H, m, ArH), 8.03～8.08(1H, m, ArH), 8.11～8.13(1H, m, ArH)

MS(m/z): 227(M+H), 249(M+Na)

Example 5

2-Phenyl-6-methylthiazo[5,4-b]pyridinium oxide (I-e)

1.8 g (7.9 mmol) of 2-phenyl-5-methylthiazolopyridine and 4 mL of glacial acetic acid were added to a round bottom flask, the temperature was raised to 105°C, and 4 mL (35 mmol) of hydrogen peroxide was added dropwise. After dripping, keep warm for 4hrs. TLC detection, raw material has reacted completely. Cool down, precipitate out solid, and filter. After drying, 1.56 g (6.4 mmol) of the sample was obtained (yield: 81%), mp: 154-155°C.

¹ HNMR (300MHz, DMSO): 2.55 (3H, s, -CH ₃ ), 7.25-7.26 (2H, m, ArH), 7.60-7.62 (2H, m, ArH), 7.74-7.81 (1H, m, ArH ), 8.05～8.08(1H, m, ArH), 8.15～8.17(1H, m, ArH)

MS (m/z): 243 (M+H)

Example 6

2-Phenyl-6-acetoxymethylthiazo[5,4-b]pyridine (I-f)

1.56 g (6.4 mmol) of 2-phenyl-5-methylthiazolopyridine nitroxide and 4 mL of glacial acetic acid were added to a round-bottomed flask, and the temperature was raised to 105° C., and 2 mL (21 mmol) of acetic anhydride was added dropwise. After dropping, the temperature was raised to 130° C. for 2 hrs. TLC detection, raw material disappears. Cool down, precipitate out solid, and filter. After drying, 1.23 g (4.3 mmol) of solid was obtained (yield: 70%), mp: 132-134°C.

¹ HNMR (300MHz, CDCl ₃ ): 3.39 (3H, s, -COCH ₃ ), 5.10 (2H, s, -OCH ₂ -), 7.48～7.49 (1H, m, ArH), 7.53～7.56 (2H, m , ArH), 8.05~8.09 (3H, m, ArH), 8.13~8.14 (1H, m, ArH)

MS (m/z): 273 (M+H)

Example 7

2-Phenyl-6-hydroxymethylthiazo[5,4-b]pyridine (I-g)

1.23 g (4.3 mmol) of compound I-7, 5 mL of methanol and 0.26 g of potassium hydroxide were added to a round bottom flask, and the temperature was raised to 50° C. for 2 hrs. TLC detected that the raw material disappeared. Cool down, recover the solvent under reduced pressure, add 5 mL of water, extract with ethyl acetate 5 mL×4, combine the organic phases, dry over anhydrous magnesium sulfate, filter, recover the solvent under reduced pressure, and obtain 0.98 g (4 mmol) of solid (yield: 93%) , mp: 165-166°C.

¹ HNMR (300MHz, CDCl ₃ ): 5.12 (2H, s, -OCH ₂ -), 5.39 (1H, br, -CH ₂ OH), 7.46-7.48 (1H, m, ArH), 7.53-7.55 (2H, m, ArH), 8.05 ~ 8.09 (3H, m, ArH), 8.13 ~ 8.14 (1H, m, ArH)

MS (m/z): 243 (M+H)

Example 8

2-Phenyl-6-formylthiazo[5,4-b]pyridine (I-h)

0.98 grams (4 mmol) of compound (I-8), 5 mL of anhydrous acetone and 0.72 grams (8 mmol) of active manganese dioxide were added to a round bottom flask, stirred at room temperature for 72 hrs, and TLC detected that the raw materials were not completely reacted. The crude product was subjected to column chromatography (developing solvent: ethyl acetate:petroleum ether=1:40) to obtain a sample of 0.11 g (0.45 mmol) (yield: 11%), mp: 176-178°C.

¹ HNMR (300MHz, CDCl ₃ ): 7.55～7.58(3H, m, ArH), 8.12～8.17(3H, m, ArH), 8,423～8.426(1H, m, ArH), 10.16(1H, s, -CHO ).

MS (m/z): 242 (M+H)

Example 9

Synthesis of 2-phenyl-6-(4'-methylbenziminomethyl)thiazo[5,4-b]pyridine (I-1)

Add 150 mg (0.62 mmol) of the compound 2-phenyl-6-formylthiazo[5,4-b] pyridine, 10 mL of anhydrous methanol and 70 mg (0.65 mmol) of p-toluidine into a round-bottomed flask, heat up to reflux, React for 8hrs and cool down. Filter, wash the filter cake with methanol 2mL×2, and recrystallize the filter cake with ethyl acetate-tetrahydrofuran to obtain a sample of 130 mg (0.4 mmol) (yield: 63%), mp: 187-188°C.

IR (KBr, v, cm ^-1 ): 3022, 1620, 1568, 1500, 1465, 1436, 1203, 836, 757

¹ HNMR (300MHz, CDCl ₃ ) 2.32 (3H, s, -CH ₃ ), 7.22-7.26 (2H, m, ArH), 7.29 (2H, m, ArH), 7.53-7.55 (3H, m, ArH), 8.12～8.14(2H, m, ArH), 8.15～8.36(2H, m, ArH), 8.72(1H, s, -HC=N-)

MS: 330.10650 (C ₂₀ H ₁₆ N ₃ S ⁺¹ )

Example 10

Synthesis of 2-phenyl-6-(2'-methylbenziminomethyl)thiazo[5,4-b]pyridine (I-2)

The preparation method was similar to (I-1), and 120 mg of PyS-2 was obtained as a solid (yield: 58%), mp: 187-189°C. IR (KBr, v, cm ^-1 ): 3047, 2921, 1625, 1465, 1440, 1224, 840, 754

¹ HNMR (300MHz, DMSO) 2.50 (3H, s, -CH ₃ ), 7.20-7.29 (4H, m, ArH), 7.63-7.66 (3H, m, ArH), 8.16-8.19 (2H, m, ArH) , 8.59 (1H, s, ArH), 8.60 (1H, s, ArH), 8.63 (1H, s, -HC=N-)

MS: 330.10651 (C ₂₀ H ₁₆ N ₃ S ⁺¹ )

Example 11

2-Phenyl-6-(3'-methylbenziminomethyl)thiazo[5,4-b]pyridine (I-3) was prepared in a similar way to (I-1), and 90 mg of sample was obtained (Yield: 44%), mp: 138-139°C.

IR (KBr, v, cm ^-1 ): 3033, 2904, 1627, 1598, 1573, 1465, 844, 757

¹ HNMR (300MHz, DMSO) 2.37 (3H, s, -CH ₃ ), 7.13-7.22 (3H, m, ArH), 7.32-7.38 (1H, m, ArH), 7.61-7.67 (3H, m, ArH) , 8.16~8.19 (2H, m, ArH), 8.34~8.37 (1H, d, ArH), 8.55~8.58 (1H, d, ArH), 8.73 (1H, s, -HC=N-)

MS: 330.10594 (C ₂₀ H ₁₆ N ₃ S ⁺¹ )

Example 12

Synthesis of 2-phenyl-6-(4'-chlorophenyliminomethyl)thiazo[5,4-b]pyridine(I-4)

The preparation method was similar to (I-1), and 80 mg of the sample was obtained (yield: 37%), mp: 218-219°C. IR (KB r, v, cm ^-1 ): 3031, 2902, 1622, 1550, 1467, 1191, 840, 759

¹ HNMR (300MHz, DMSO) 7.38～7.43(2H, m, ArH), 7.59～7.67(3H, m, ArH), 8.15～8.18(2H, m, ArH), 8.34～8.17(1H, d, ArH) , 8.56～8.59 (1H, d, ArH), 8.82 (1H, s, -HC=N-)

MS: 350.05187 (C ₁₉ H ₁₃ ClN ₃ S ⁺¹ )

Example 13

Synthesis of 2-phenyl-6-(2',3',4'-trifluorophenyliminomethyl)thiazo[5,4-b]pyridine (I-5)

The preparation method was similar to (I-1), and 90 mg of the sample was obtained (yield: 39%), mp: 213-214°C.

IR (KBr, v, cm ^-1 ): 3041, 2920, 1703, 1562, 1502, 1467, 1224, 823, 759

¹ HNMR (300MHz, DMSO) 7.38～7.43(2H, m, ArH), 7.59～7.67(3H, m, ArH), 8.15～8.18(2H, m, ArH), 8.34～8.17(1H, d, ArH) , 8.56～8.59 (1H, d, ArH), 8.82 (1H, s, -HC=N-)

MS: 369.0548 (C ₁₉ H ₁₀ N ₃ SF ₃ )

Example 14

Synthesis of 2-phenyl-6-(2',5'-dimethylbenziminomethyl)thiazo[5,4-b]pyridine (I-6)

The preparation method was similar to (I-1), and 85 mg of the sample was obtained (yield: 40%), mp: 156-157°C.

IR (KBr, v, cm ^-1 ): 3043, 2912, 1622, 1564, 1500, 1461, 1431, 1200, 833, 757

¹ HNMR (300MHz, DMSO) 2.32 (6H, s, -CH ₃ ), 7.01-7.03 (2H, m, ArH), 7.16-7.19 (1H, m, ArH), 8.16-8.19 (2H, m, ArH) , 8.37～8.40 (1H, d, ArH), 8.56 (1H, m, ArH), 8.65 (1H, s, -HC=N-)

MS: 344.12159 (C ₂₁ H ₁₈ N ₃ S ⁺¹ )

Example 15

Synthesis of 2-phenyl-6-(3'-chlorophenyliminomethyl)thiazo[5,4-b]pyridine(I-7)

The preparation method was similar to (I-1), and 105 mg of the sample was obtained (yield: 48%), mp: 194-195°C.

IR (KBr, v, cm ^-1 ): 3035, 1625, 1581, 1558, 1463, 1197, 833, 761

¹ HNMR (300MHz, DMSO) 7.35～7.39(2H, m, ArH), 7.47～7.49(2H, m, ArH), 7.63～7.66(3H, m, ArH), 8.16～8.19(2H, m, ArH) , 8.34～8.37(1H, m, ArH), 8.57～8.60(1H, m, ArH), 8.76(1H, s, -HC=N-)

MS: 350.05188 (C ₁₉ H ₁₃ ClN ₃ S ⁺¹ )

Example 16

Synthesis of 2-phenyl-6-phenyliminomethylthiazo[5,4-b]pyridine(I-8)

The preparation method was similar to (I-1), and 105 mg of the sample was obtained (yield: 53%), mp: 163-164°C.

IR (KBr, v, cm ^-1 ): 3033, 2931, 1625, 1585, 1550, 1463, 1201, 854, 757

¹ HNMR (300MHz, DMSO) 7.32～7.35(1H, m, ArH), 7.38～7.41(2H, m, ArH), 7.45～7.50(2H, m, ArH), 7.62～7.66(3H, m, ArH) , 8.16~8.19 (2H, m, ArH), 8.35~8.38 (1H, d, ArH), 8.55~8.58 (1H, m, ArH), 8.74 (1H, s, -HC=N-)

MS: 316.0909 (C ₁₉ H ₁₄ N ₃ S ⁺¹ )

Example 17

Synthesis of 2-phenyl-6-[2-(2'-benzo[1,3]cyclopentadioxane)ethyliminomethyl]thiazo[5,4-b]pyridine (I-9)

The preparation method was similar to (I-1), and 105 mg of the sample was obtained (yield: 53%), mp: 152-153°C.

IR (KBr, v, cm ^-1 ): 3056, 2929, 2885, 1641, 1552, 1492, 1473, 1434, 1236, 1188, 829, 813, 761

¹ HNMR (300MHz, DMSO) 2.88～2.93 (2H, t, -CH ₂ -Ph), 3.88～3.92 (2H, t, -CH ₂ -N), 5.95 (2H, s, -O-CH ₂ -O -), 6.70～6.71(1H, m, ArH), 6.73～6.41(1H, m, ArH), 6.87～6.88(1H, m, ArH), 7.61～7.64(3H, m, ArH), 8.13～8.16 (3H, m, ArH), 8.47～8.50 (1H, d, ArH), 8.39 (1H, s, -HC=N-)

MS: 388.11142 (C ₂₂ H ₁₈ N ₃ O ₂ S ⁺¹ )

Example 18

Synthesis of 2-phenyl-6-(4'-methoxyphenyliminomethyl)thiazo[5,4-b]pyridine(I-10)

The preparation method was similar to (I-1), and 110 mg of the sample was obtained (yield: 51%), mp: 171-172°C.

IR (KBr, v, cm ^-1 ): 3037, 1625, 1554, 1504, 1458, 1436, 1240, 842, 765

¹ HNMR (300MHz, CDCl ₃ ) 3.86 (3H, s, -OCH ₃ ), 6.94～6.97 (2H, m, ArH), 7.35～7.38 (2H, m, ArH), 7.51～7.53 (3H, m, ArH ), 8.10～8.12 (2H, m, ArH), 8.33 (2H, m, ArH), 8.71 (1H, s, -HC=N-)

MS: 346.10086 (C ₂₀ H ₁₆ N ₃ OS ⁺¹ )

Example 19

Synthesis of 2-phenyl-6-[2-(5'-ethoxybenzothiazole))iminomethyl]thiazo[5,4-b]pyridine (I-11)

The preparation method was similar to (I-1), and 125 mg of the sample was obtained (yield: 48%), mp: 235-236°C.

IR (KBr, v, cm ^-1 ): 3055, 2975, 1593, 1550, 1469, 1433, 1222, 827, 761

¹ HNMR (300MHz, DMSO) 1.35～1.40 (3H, t, -O-CH ₂ -CH ₃ ), 4.10～4.16 (2H, q, -O-CH ₂ -CH ₃ ), 7.12～7.15 (1H, m , ArH), 7.64～7.68(4H, m, ArH), 7.88～7.91(1H, m, ArH), 8.19～8.21(2H, m, ArH), 8.43～8.46(1H, m, ArH), 8.61～ 8.64 (1H, m, ArH), 9.15 (1H, s, -HC=N-)

MS: 418.0921 (C ₂₂ H ₁₈ N ₄ OS ₂ ⁺¹ )

Example 20

Synthesis of 2-phenyl-6-(4'-fluorophenyliminomethyl)thiazo[5,4-b]pyridine(I-12)

The preparation method was similar to (I-1), and 85 mg of the sample was obtained (yield: 41%), mp: 158-159°C.

IR (KBr, v, cm ^-1 ): 3031, 2902, 1623, 1589, 1554, 1494, 1465, 1222, 842, 761

¹ HNMR (300MHz, DMSO) 7.26～7.32(2H, m, ArH), 7.45～7.50(2H, m, ArH), 7.58～7.65(3H, m, ArH), 8.14～8.17(2H, m, ArH) , 8.32～8.35(1H, d, ArH), 8.53～8.56(1H, d, ArH), 8.74(1H, s, -HC=N-)

MS: 334.08087 (C ₁₉ H ₁₃ N ₃ FS ⁺¹ )

Example 21

Synthesis of 2-phenyl-6-(3',4'-difluorophenyliminomethyl)thiazo[5,4-b]pyridine (I-13)

The preparation method was similar to (I-1), and 90 mg of the sample was obtained (yield: 41%), mp: 188-189°C.

IR (KBr, v, cm ^-1 ): 3041, 2891, 1598, 1550, 1508, 1463, 1284, 1226, 871, 765

¹ HNMR (300MHz, DMSO) 7.28～7.32(1H, m, ArH), 7.48～7.68(5H, m, ArH), 8.15～8.18(2H, m, ArH), 8.32～8.35(1H, d, ArH) , 8.56～8.58 (1H, d, ArH), 8.77 (1H, s, -HC=N-)

MS: 352.07201 (C ₁₉ H ₁₂ N ₃ F ₂ S ⁺¹ )

Example 22

Synthesis of 2-phenyl-6-(2',4'-dichlorobenzimidomethyl)thiazo[5,4-b]pyridine (I-14)

The preparation method was similar to (I-1), and 120 mg of the sample was obtained (yield: 50%), mp: 199-200°C.

IR (KBr, v, cm ^-1 ): 3047, 2896, 1623, 1564, 1554, 1465, 1436, 1209, 840, 765

¹ HNMR (300MHz, DMSO) 7.46～7.48(1H, m, ArH), 7.50～7.52(1H, m, ArH), 7.63～7.66(3H, m, ArH), 7.73～7.74(1H, d, ArH) , 8.16～8.19(2H, m, ArH), 8.36～8.39(1H, m, ArH), 8.58～8.61(1H, m, ArH), 8.71(1H, s, -HC=N-)

MS: 384.01235 (C ₁₉ H ₁₂ Cl ₂ N ₃ S ⁺¹ )

Example 23

N-(2-Chloro-6-methylpyridine-3-)aminobenzamide (II-a)

Add 1.4 grams (1 mmol) of 2-chloro-3-amino-6-methylpyridine, 10 mL of anhydrous chloroform and 1.5 mL of triethylamine into the three-necked flask, and drop the internal temperature to -5°C, and start to add 1.5 grams of benzyl A solution of acid chloride (1 mmol) dissolved in 3 mL of anhydrous chloroform. Control the dropping rate so that the internal temperature is not higher than 0°C. After dripping, stir overnight. Filter, wash the filtrate with water 5mL×2, wash with saturated aqueous sodium carbonate solution 5mL×3, and then wash with water 5mL×2. Separate the liquid, dry the organic phase with anhydrous magnesium sulfate, filter, and recover the solvent under reduced pressure. After drying, 1.05 g of white solid was obtained (yield: 39%), mp: 110-112°C.

¹ HNMR (300MHz, CDCl ₃ ): 2.53 (3H, s, -CH3), 7.53-7.55 (3H, m, ArH), 7.58-7.60 (1H, m, ArH), 7.71-7.73 (1H, m, ArH ), 7.96～8.01 (2H, m, ArH), 10.2 (1H, s, -NHCO)

MS (m/z): 247 (M+H)

Example 24

2-Phenyl-6-methyloxazol[5,4-b]pyridine (II-b)

Under nitrogen protection, 3.2 g of phosphorus pentoxide (0.022 mol) and 6 mL of silicon ether were added into the three-necked flask, and the temperature was raised to reflux until the solid of phosphorus pentoxide disappeared. 1.05 g (0.004 mol) of compound (III-5) and 2 mL of o-dichlorobenzene were added, and the inner temperature rose to 180°C. Refluxed for 4hrs, TLC showed disappearance of starting material. Cool down, pour the reaction solution into 15 grams of crushed ice, adjust the pH to 7-8 with 1N sodium hydroxide, extract with 5 mL×3 chloroform, and get the crude product by column chromatography (developing solvent: ethyl acetate:petroleum ether=1:40) to obtain 0.8 g of white solid (yield: 93%), mp: 84-86°C.

¹ HNMR: 2.7 (3H, s, -CH ₃ ); 7.31-7.33 (1H, m, ArH); 7.50-7.62 (3H, m, ArH); 7.91-7.92 (1H, m, ArH); 8.33-8.35 (2H, m, ArH)

MS (m/z): 211 (M+H)

Example 25

2-Phenyl-6-(1,1-dibromomethyl)oxazol[5,4-b]pyridine (II-c)

Add 0.5 g (2.4 mmol) of compound (II-b), 5 mL of carbon tetrachloride, 0.45 g of N.B.S (2.5 mmol) and a small amount of benzoyl peroxide into a round bottom flask, and raise the temperature to reflux. Add 0.45g of N.B.S after 8hrs. Continue to reflux for 8hrs, TLC shows that the starting material disappears. The crude product was subjected to column chromatography (developer: ethyl acetate:petroleum ether=1:40) to obtain 0.65 g (yield: 74%) of a white solid, mp: 119-120°C.

¹ HNMR (300MHz, CDCl ₃ ): 6.76 (1H, s, -CHBr ₂ ), 7.25-7.61 (3H, m, ArH), 7.80-7.82 (1H, m, ArH), 8.08-8.11 (1H, m, ArH), 8.27～8.30 (2H, m, ArH).

MS (m/z): 211 (M+H)

Example 26

2-Phenyl-6-(1',1'dimethoxymethyl)oxazol[5,4-b]pyridine (II-d)

Add 0.5 g (1.4 mmol) of compound (II-c), 4 mL of methanol and 0.3 g (5 mmol) of potassium hydroxide into a round bottom flask, and raise the temperature to 50°C. After 2hrs TLC showed disappearance of starting material. The crude product was subjected to column chromatography (developer: ethyl acetate:petroleum ether=1:40) to obtain 0.21 g (yield: 57%) of a white solid, mp: 149-150°C.

¹ HNMR (300MHz, CDCl ₃ ): 3.25 (6H, s, -OCH ₃ ), 5.46 (1H, s, -CH(OCH ₃ ) ₂ ), 7.49-7.51 (1H, m, ArH), 7.62-7.64 ( 2H, m, ArH), 7.75~7.76 (1H, m, ArH), 8.06~8.07 (1H, m, ArH), 8.17~8.19 (2H, m, ArH).

MS (m/z): 271 (M+H)

Example 27

2-Phenyl-6-formyloxazol[5,4-b]pyridine (II-e)

Under nitrogen protection, 0.5 g (1.8 mmol) of compound (II-d), 5 ml of ethyl acetate, 5 mL of water and 2 drops of glacial acetic acid were added into a three-necked flask, and the temperature was raised to 50°C. After 2hrs, TLC showed that the starting material had disappeared. The liquids were separated, and the aqueous phase was extracted with ethyl acetate 2 mL×2, the organic phases were combined, and the solvent was recovered under reduced pressure. The crude product was subjected to column chromatography (developing solvent: ethyl acetate:petroleum ether=1:40) to obtain 0.21 g (yield: 54%) of a white solid, mp: 134-136°C.

¹ HNMR (300MHz, CDCl ₃ ): 7.58～7.65(3H, m, ArH), 8.09～8.12(1H, m, ArH), 8.20～8.21(1H, m, ArH), 8.32～8.35(2H, m, ArH), 10.11 (1H, s, -CHO)

MS (m/z): 225 (M+H)

Example 28

Synthesis of 2-phenyl-6-(4'-methylbenziminomethyl)oxazol[5,4-b]pyridine(II-1)

Add 150mg of compound 2-phenyl-6-formyloxazol[5,4-b]pyridine (0.67mmol), 10mL of anhydrous methanol and 75mg of p-toluidine (0.70mmol) into a round bottom flask, warm to reflux , reflux for 8hrs, and cool down. After filtering, the filter cake was washed with methanol 2mLX2, and the filter cake was recrystallized from ethyl acetate-tetrahydrofuran to obtain a sample of 110 mg (yield: 52%), mp: 169-170°C.

IR (KBr, v, cm ^-1 ): 3014, 2906, 1610, 1537, 1490, 1456, 1244, 835, 771

¹ HNMR (300MHz, DMSO) 2.35(3H, s, -CH ₃ ), 7.25～7.33(4H, m, ArH), 7.67～7.71(3H, m, ArH), 8.25～8.30(3H, m, ArH) , 8.37～8.40 (1H, m, ArH), 8.68 (1H, s, -HC=N-)

MS: 314.12879 (C ₂₀ H ₁₆ N ₃ O ⁺¹ )

Example 29

Synthesis of 2-phenyl-6-(2'-methylbenziminomethyl)oxazol[5,4-b]pyridine(II-2)

The preparation method was similar to (II-1), and 90 mg of the sample was obtained (yield: 43%), mp: 124-125°C.

IR (KBr, v, cm ^-1 ): 3066, 2904, 1604, 1542, 1483, 1452, 1245, 848, 756

¹ HNMR (300MHz, DMSO) 2.36 (3H, s, -CH ₃ ), 7.16-7.31 (3H, m, ArH), 7.64-7.72 (3H, m, ArH), 8.26-8.27 (2H, m, ArH) , 8.29～8.31(1H, m, ArH), 8.39～8.42(1H, m, ArH), 8.56(1H, s, -HC=N-)

MS: 314.12934 (C ₂₀ H ₁₆ N ₃ O ⁺¹ )

Example 30

Synthesis of 2-phenyl-6-(3'-methylbenziminomethyl)oxazol[5,4-b]pyridine(II-3)

The preparation method was similar to (II-1), and 70 mg of the sample was obtained (yield: 33%), mp: 134-135°C.

IR (KBr, v, cm ^-1 ): 2910, 1600, 1585, 1537, 1481, 1238, 837, 777

¹ HNMR (300MHz, DMSO) 2.37 (3H, s, -CH ₃ ), 7.12-7.16 (3H, m, ArH), 7.32-7.37 (1H, m, ArH), 7.64-7.72 (3H, m, ArH) , 8.25～8.30(3H, m, ArH), 8.37～8.40(1H, d, ArH), 8.66(1H, s, -HC=N-)

MS: 314.12879 (C ₂₀ H ₁₆ N ₃ O ⁺¹ )

Example 31

Synthesis of 2-phenyl-6-(4'-chlorophenyliminomethyl)oxazol[5,4-b]pyridine(II-4)

The preparation method was similar to (II-1), and 100 mg of the sample was obtained (yield: 45%), mp: 214-215°C.

IR (KBr, v, cm ^-1 ): 3060, 1635, 1608, 1541, 1483, 1448, 1244, 838, 786

¹ HNMR (300MHz, DMSO) 7.41～7.44(2H, m, ArH), 7.50～7.53(2H, m, ArH), 7.65～7.72(3H, m, ArH), 8.26～8.30(3H, m, ArH) , 8.39～8.41 (1H, d, ArH), 8.69 (1H, s, -HC=N-)

MS: 334.07472 (C ₁₉ H ₁₃ ClN ₃ O ⁺¹ )

Example 32

Synthesis of 2-phenyl-6-phenyliminomethyloxazol[5,4-b]pyridine(II-5)

The preparation method was similar to (II-1), and 105 mg of the sample was obtained (yield: 52%), mp: 182-183°C.

IR (KBr, v, cm ^-1 ): 3056, 2889, 1606, 1581, 1539, 1483, 1242, 842, 765

¹ HNMR (300MHz, DMSO) 7.32～7.40(3H, m, ArH), 7.45～7.50(2H, m, ArH), 7.67～7.71(3H, m, ArH), 8.26～8.31(3H, m, ArH) , 8.38～8.41 (1H, m, ArH), 8.68 (1H, s, -HC=N-) MS: 300.11314 (C ₁₉ H ₁₄ N ₃ O ⁺¹ )

Example 33

2-phenyl-6-[2-(2'-benzo[1,3]cyclopentadioxane)ethyliminomethyl]oxazol[5,4-b]pyridine (II-6) synthesis

The preparation method was similar to (II-1), and 145 mg of the sample was obtained (yield: 56%), mp: 124-125°C.

IR (KBr, v, cm ^-1 ): 3006, 2933, 1647, 1614, 1539, 1490, 1242, 1041, 810, 775

¹ HNMR (300MHz, CDCl ₃ ) 2.96～3.01 (2H, t, -CH ₂ -Ph), 3.89～3.94 (2H, t, -CH ₂ -N-), 5.91 (2H, s, -O-CH ₂ -O-), 6.69～6.75(3H, m, ArH), 7.55～7.60(3H, m, ArH), 8.08～8.09(2H, m, ArH), 8.27～8.31(2H, m, ArH), 8.32 (1H, s, -HC=N-)

MS: 372.13427 (C ₂₂ H ₁₈ N ₃ O ₃ ⁺¹ )

Example 34

Synthesis of 2-phenyl-6-(2',5'-dimethylbenziminomethyl)oxazol[5,4-b]pyridine(II-7)

The preparation method was similar to (II-1), and 85 mg of the sample was obtained (yield: 39%), mp: 173-174°C.

IR (KBr, v, cm ^-1 ): 3064, 2916, 1602, 1535, 1475, 1405, 1238, 833, 775

¹ HNMR (300MHz, DMSO) 2.31 (3H, s, -CH ₃ ), 2.32 (3H, s, -CH ₃ ), 6.99～7.02 (2H, m, ArH), 7.16～7.18 (1H, m, ArH) , 7.70~7.72 (3H, m, ArH), 8.26~8.34 (3H, m, ArH), 8.39~8.42 (1H, m, ArH), 8.56 (1H, s, -HC=N-)

MS; 328.14518 (C ₂₁ H ₁₈ N ₃ O ⁺¹ )

Example 35

Synthesis of 2-phenyl-6-(2'-phenylethyliminomethyl)oxazol[5,4-b]pyridine(II-8)

The preparation method was similar to (II-1), and 95 mg of the sample was obtained (yield: 45%), mp: 134-135°C.

IR (KBr, v, cm ^-1 ): 3024, 1639, 1606, 1539, 1481, 1242, 1029, 842, 748

¹ HNMR (300MHz, DMSO) 4.91 (2H, s, -CH ₂ -Ph), 7.28 ~ 7.31 (1H, m, ArH), 7.36 ~ 7.37 (4H, m, ArH), 7.52 ~ 7.60 (3H, m, ArH), 8.06～8.09(1H, m, ArH), 8.18～8.21(1H, d, ArH), 8.28～8.31(2H, m, ArH), 8.52(1H, s, -HC=N-)

MS: 314.12879 (C ₂₀ H ₁₆ N ₃ O ⁺¹ )

Example 36

Synthesis of 2-phenyl-6-(4'-bromophenyliminomethyl)oxazol[5,4-b]pyridine(II-9)

The preparation method was similar to (II-1), and 115 mg of the sample was obtained (yield: 46%), mp: 225-226°C.

IR (KBr, v, cm ^-1 ): 3056, 1606, 1539, 1481, 1452, 1244, 1068, 837, 786

¹ HNMR (300MHz, DMSO) 7.34～7.37(2H, m, ArH), 7.63～7.72(5H, m, ArH), 8.26～8.30(3H, m, ArH), 8.39～8.41(1H, d, ArH) , 8.69 (1H, s, -HC=N-)

MS: 318.10427 (C ₁₉ H ₁₃ N ₃ FO ⁺¹ )

Example 37

Synthesis of 2-phenyl-6-(4'-fluorophenyliminomethyl)oxazol[5,4-b]pyridine(II-10)

The preparation method was similar to that of (II-1), and 85 mg of the sample was obtained (yield: 40%), mp: 199-201°C.

IR (KBr, v, cm ^-1 ): 3046, 1604, 1539, 1489, 1452, 1244, 840, 773

¹ HNMR (300MHz, DMSO): 7.26～7.32(2H, m, ArH), 7.45～7.50(2H, m, ArH), 7.69～7.70(3H, m, ArH), 8.26～8.29(3H, m, ArH ), 8.30～8.41 (1H, m, ArH), 8.69 (1H, s, -HC=N-)

MS: 318.10372 (C ₁₉ H ₁₃ N ₃ FO ⁺¹ )

Example 38

Synthesis of 2-phenyl-6-(2',4'-dichlorobenzimidomethyl)oxazol[5,4-b]pyridine(II-11)

The preparation method was similar to (II-1), and 135 mg of the sample was obtained (yield: 55%), mp: 207-208°C.

IR (KBr, v, cm ^-1 ): 3051, 2974, 1622, 1537, 1477, 1244, 1049, 808, 763

¹ HNMR (300MHz, DMSO): 7.42～7.45(1H, m, ArH), 7.49～7.52(1H, m, ArH), 7.56～7.73(4H, m, ArH), 8.27～8.33(3H, m, ArH ), 8.41～8.44 (1H, m, ArH), 8.65 (1H, s, -HC=N-)

MS: 368.03575 (C ₁₉ H ₁₂ N ₃ Cl ₂ O ⁺¹ )

Example 39

Synthesis of 2-phenyl-6-(2'-methyl 5'-chlorophenyliminomethyl)oxazol[5,4-b]pyridine(II-12)

The preparation method was similar to (II-1), and 90 mg of the sample was obtained (yield: 39%), mp: 177-178°C.

IR (KBr, v, cm ^-1 ): 3066, 2918, 1635, 1596, 1533, 1477, 1240, 829, 775

¹ HNMR (300MHz, DMSO) 2.32(3H, s, -CH ₃ ), 7.22～7.33(3H, m, ArH), 7.65～7.73(3H, m, ArH), 8.27～8.30(3H, m, ArH) , 8.40～8.43 (1H, d, ArH), 8.59 (1H, s, -HC=N-)

MS: 348.08982 (C ₂₀ H ₁₅ ClN ₃ O ⁺¹ )

Example 40

Synthesis of 2-phenyl-6-(3'-acetylphenyliminomethyl)oxazol[5,4-b]pyridine(II-13)

The preparation method was similar to (II-1), and 80 mg of the sample was obtained (yield: 35%), mp: 158-159°C.

IR (KBr, v, cm ^-1 ): 3064, 2889, 1679, 1606, 1541, 1454, 1240, 1174, 844, 783

¹ HNMR (300MHz, DMSO) 2.49 (3H, s, -COCH ₃ ), 7.60-7.74 (5H, m, ArH), 7.88-7.90 (2H, m, ArH), 8.27-8.29 (2H, m, ArH) , 8.32～8.33(1H, m, ArH), 8.41～8.43(1H, d, ArH), 8.76(1H, s, -HC=N-)

MS: 342.12370 (C ₂₁ H ₁₆ N ₃ O ₂ ⁺¹ )

Example 41

Synthesis of 2-phenyl-6-(3'-chlorophenyliminomethyl)oxazol[5,4-b]pyridine(II-14)

The preparation method was similar to (II-1), and 85 mg of the sample was obtained (yield: 38%), mp: 159-160°C.

IR (KBr, v, cm ^-1 ): 3062, 1618, 1571, 1544, 1479, 1400, 1242, 850, 775

¹ HNMR (300MHz, DMSO) 7.34～7.38(2H, m, ArH), 7.38～7.49(2H, m, ArH), 7.66～7.74(3H, m, ArH), 8.27～8.29(3H, m, ArH) , 8.40～8.41 (1H, d, ArH), 8.69 (1H, s, -HC=N-)

MS: 336.09429 (C ₁₉ H ₁₂ N ₃ F ₂ O ⁺¹ )

Example 42

Synthesis of 2-phenyl-6-(3',4'-difluorophenyliminomethyl)oxazol[5,4-b]pyridine(II-15)

The preparation method was similar to (II-1), and 90 mg of the sample was obtained (yield: 40%), mp: 174-175°C.

IR (KBr, v, cm ^-1 ): 1610, 1542, 1508, 1483, 1244, 869, 783

¹ HNMR (300MHz, DMSO) 7.72～7.30(1H, m, ArH), 7.50～7.61(2H, m, ArH), 7.66～7.73(3H, m, ArH), 8.27～8.29(3H, m, ArH) , 8.40～8.41 (1H, d, ArH), 8.72 (1H, s, -HC=N-)

MS: 336.09483 (C ₁₉ H ₁₂ N ₃ F ₂ O ⁺¹ )

Example 43

Synthesis of 2-phenyl-6-(2',4'-difluorophenyliminomethyl)oxazol[5,4-b]pyridine(II-16)

The preparation method was similar to (II-1), and 95 mg of the sample was obtained (yield: 42%), mp: 187-189°C.

IR (KBr, v, cm ^-1 ): 3080, 1618, 1544, 1494, 1402, 1272, 850, 781

¹ HNMR (300MHz, DMSO) 7.17～7.19(1H, m, ArH), 7.37～7.41(1H, m, ArH), 7.54～7.59(1H, m, ArH), 7.65～7.73(3H, m, ArH) , 8.26～8.30(3H, m, ArH), 8.39～8.41(1H, d, ArH), 8.74(1H, s, -HC=N-)

MS: 336.09486 (C ₁₉ H ₁₂ N ₃ F ₂ O ⁺¹ )

Example 44

The synthesis and preparation method of 2-phenyl-6-(4'-methoxyphenyliminomethyl)oxazol[5,4-b]pyridine (II-17) is similar to (II-1), and the sample 85 mg (yield: 38%), mp: 163-164°C.

IR (KBr, v, cm ^-1 ): 3051, 1595, 1492, 1587, 1535, 1492, 1240, 840, 771

¹ HNMR (300MHz, DMSO) 3.82(3H, s, -OCH ₃ ), 6.98～7.01(2H, m, ArH), 7.38～7.41(2H, m, ArH), 7.63～7.68(3H, m, ArH) , 8.25～8.27 (2H, m, ArH), 8.28 (2H, m, ArH), 8.67 (1H, s, -HC=N-)

MS: 330.12426 (C ₂₀ H ₁₆ N ₃ O ₂ ⁺¹ )

Example 45

Synthesis of 2-phenyl-6-(3'-chloro4'-fluorophenyliminomethyl)oxazol[5,4-b]pyridine(II-18)

The preparation method was similar to (II-1), and 105 mg of the sample was obtained (yield: 45%), mp: 175-176°C.

IR (KBr, v, cm ^-1 ): 3058, 1606, 1581, 1539, 1492, 1249, 844, 775

¹ HNMR (300MHz, DMSO) 7.42～7.44(1H, m, ArH), 7.45～7.52(1H, m, ArH), 7.64～7.72(4H, m, ArH), 8.24～8.27(3H, m, ArH) , 8.37～8.40 (1H, d, ArH), 8.70 (1H, s, -HC=N-)

MS: 352.06527 (C ₁₉ H ₁₂ N ₃ FClO ⁺¹ )

Example 46

Synthesis of 2-phenyl-6-(2',3'-dichlorobenzimidomethyl)oxazol[5,4-b]pyridine(II-19)

The preparation method was similar to (II-1), and 120 mg of the sample was obtained (yield: 49%), mp: 236-239°C.

IR (KBr, v, cm ^-1 ): 1703, 1616, 1583, 1531, 1245, 854, 773

¹ HNMR (300MHz, DMSO) 7.44～7.54(2H, m, ArH), 7.65～7.74(3H, m, ArH), 8.19～8.22(1H, m, ArH), 8.28～8.33(3H, m, ArH) , 8.49～8.52 (1H, d, ArH), 10.55 (1H, s, -HC=N-) MS: 368.03573 (C ₁₉ H ₁₂ Cl ₂ N ₃ O ⁺¹ )

Claims (9)

1. the compound of general formula (I) or its pharmacy acceptable salt:

R wherein ¹, R ²Represent hydrogen, hydroxyl, nitro, amino, methyl, trifluoromethyl, fluorine, chlorine, bromine, iodine or itrile group independently of one another;

X represents N, O or S;

M represent key ,-(CH ₂) _m-O-(CH ₂) _n-,-(CH ₂) _m-(CH ₂) _n-,-(CH ₂) _m-C (O)-(CH ₂) _n-,-(CH ₂) _m-NR ³-(CH ₂) _n-,-(CH ₂) _m-NR ³C (O)-(CH ₂) _n-,-(CH ₂) _m-S-(CH ₂) _n-,-(CH ₂) _m-CF ₂-(CH ₂) _n-or-(CH ₂) _m-S (O)-(CH ₂) _n-, m=0～4, n=0～4; R ³Expression hydrogen, methyl, ethyl or propyl group;

Q wherein ¹, Q ²Represent phenyl independently of one another, contain 1～3 substituent phenyl, contain 1～2 substituent naphthyl, contain five yuan or hexa-atomic substituted heterocycle of two compositions among N, O, the S, described replacement is meant by hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, amino, cyano group, methoxy or ethoxy and replaces.

2. the compound of claim 1 or its pharmacy acceptable salt, wherein X represents O or S.

3. the compound of claim 1 or its pharmacy acceptable salt, wherein M represent singly-bound or-CH ₂-.

4. the compound of claim 1 or its pharmacy acceptable salt, wherein Q ¹, Q ²Represent phenyl independently of one another.

5. the compound of claim 1 or its pharmacy acceptable salt, wherein R ¹, R ²Expression hydrogen.

6. the compound of claim 1 or its pharmacy acceptable salt, wherein pharmacy acceptable salt comprises the acid salt that general formula (I) compound and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, citric acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetate, toxilic acid or Phenylsulfonic acid.

7. pharmaceutical composition wherein contains general formula (I) compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.

8. the compound of the general formula of claim 1 (I) or its pharmacy acceptable salt are used for preventing or the purposes of the medicine of treatment and telomerase inhibitor diseases associated in preparation.

9. the purposes of claim 8 is melanoma, liver cancer, kidney, acute, leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome, the esophageal carcinoma, gastrointestinal cancer or mesothelioma with the telomerase inhibitor diseases associated wherein.