Bipyridine compounds, pharmaceutically acceptable salts thereof, and preparation methods and applications thereof

Abstract

The present invention discloses a class of bipyridine compounds or pharmaceutically acceptable salts thereof, as well as a preparation method and application in medicine. The present invention also discloses 46 specific compounds of this type and chemical synthesis methods thereof, with a simple synthesis route, easy operation and implementation, and the required reagents are easy to purchase. The proliferation inhibition activity of 46 compounds on 9 kinds of tumor cells was tested at the same time, and the results showed that the proliferation inhibition activity of the compounds was greatly improved compared to the 30 μM (IC50) of the proliferation inhibition activity of such natural products, and the activity can reach tens to hundreds of nanomoles after structural modification. In addition, the proliferation activity of multiple compounds on a variety of cancer cells is better than the effect of doxorubicin, which is comparable to the results of 5-fluorouracil, and can be used as a therapeutic drug for a variety of cancer-related diseases, and can also be used as a protein inhibitor for the treatment of related diseases or conditions.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a class of bipyridine compounds, pharmaceutically acceptable salts thereof, and preparation methods and applications thereof. Background Art

[0002] Cancer is the leading cause of health and quality of life for human beings, and it is also a global problem. Clinical treatment methods mainly include local treatments such as surgical resection, radiotherapy and chemotherapy. Currently, chemotherapy drugs include paclitaxel, platinum-containing drugs, 5-fluorouracil, etc. However, broad-spectrum anti-tumor drugs also have some adverse reactions, such as bone marrow toxicity, gastrointestinal reactions, liver toxicity, etc., which are difficult to control.

[0003] Bipyridine derivatives are a class of alkaloids with a unique dipyridine skeleton. The first bipyridine compound, Careulomycin A, was discovered and isolated from Streptomyces caeruleus (Funk, A.; Divekar, PVCaerulomycin, a new antibiotic from Streptomyces caeruleus Baldacci. I. Production, isolation, assay, and biological properties [J]. Can. J. Microbiol. 1959, 5, 317-321.), and subsequently, several derivatives Careulomycin BN and analogs were discovered. This type of compound usually has a unique 2,2′-bipyridine skeleton, and initial studies found that they have strong antibacterial and immunosuppressive activities. Among them, the inventors isolated four natural products with bipyridine structures as shown in the following formulas 1-4. Studies have found that bipyridine compounds have inhibitory effects on the proliferation of tumor cells HL-60, K562, KB and A549, among which compound a has an inhibitory activity of 1.6 μM (IC 50 ) and 8.4 μM (IC 50 ), compound b had inhibitory activity on the proliferation of tumor cells HL-60, K562, KB and A549, with the inhibitory activity greater than 50 μM (IC 50 )、1.8μM(IC 50 ), greater than 50μM (IC 50 ) and 3.1 μM (IC 50 ), the proliferation inhibition activities of compound c and compound d on four tumor cells, HL-60, K562, KB and A549, were greater than 50 μM (IC 50) (dx.doi.org / 10.1021 / np200258h, J.Nat.Prod.2011,74,1751-1756). In addition, the inventors tested the proliferation inhibition activity of compound ad on tumor cells HCT-116 and MDA-MB-231, and the activity was greater than 30 μM (IC 50 ).

[0004]

[0005] In the early stage, we isolated several bipyridine natural products from the secondary metabolites of Streptomyces sp.BC6, an actinomycete from the deep sea of ​​the western Pacific Ocean. After testing, we found that the compounds had a certain inhibitory effect on the proliferation of various cancer cells, but the activity needs to be improved. This time, we obtained a series of bipyridine derivatives through chemical synthesis for the treatment of cancer-related diseases or symptoms. Summary of the invention

[0006] The present invention provides a class of bipyridine compounds or pharmaceutically acceptable salts thereof, which have the effect of inhibiting cell proliferation on a variety of cancer cells. The present invention also provides pharmaceutical compositions and drugs, which include the compounds or salts of the present invention alone or in combination with additional anticancer therapeutic agents or mitigating agents.

[0007] A bipyridine compound or a pharmaceutically acceptable salt thereof, wherein the bipyridine compound has a structure as shown in the following formula I:

[0008]

[0009] In Formula I:

[0010] X 1 , X 2 , X 3 are independently C atoms or N atoms and X 1 , X 2 , X 3 There is only one N atom in Y 1 , Y 2 are different and are independently C atoms or N atoms, L is an amide bond, an ester bond or a N atom;

[0011] R a , R b are independently hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl or heterocyclic;

[0012] R 1It is an alkyl group, an alkoxy group, a cycloalkyl group or a heterocyclic group, wherein the alkyl group, the alkoxy group and the heterocyclic group may be optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl and heterocyclic group.

[0013] Further, a bipyridine compound or a pharmaceutically acceptable salt thereof, wherein the bipyridine compound has a structure as shown in any one of the following formulae II to XIV:

[0014]

[0015]

[0016] In formula II to XIV, X 1 , X 2 , X 3 are independently C atoms or N atoms and X 1 , X 2 , X 3 There is only one N atom in R 2 is H, hydroxyl or alkoxy, R 3 is H or alkyl;

[0017] In formula II, V, VIII, X, XII, R 4 , R 5 are independently H, alkyl, amide, ester, cyano, hydroxyalkyl, nitro, aromatic, amino, alkoxy, cycloalkyl or heterocyclic, or, R 4 , R 5 Connect into a ring;

[0018] In Formula III, R 4 , R 5 are independently H, alkyl, amide, ester, cyano, hydroxyalkyl, nitro, aromatic, amino, alkoxy, cycloalkyl or heterocyclic;

[0019] In formula IV and IX, R 5 is H, alkyl, amide, ester, cyano, hydroxyalkyl, nitro, aromatic, amino, alkoxy, cycloalkyl or heterocyclic;

[0020] In Formula VI, VII and XI, R 4 -R 8 are independently H, alkyl, amide, ester, cyano, hydroxyalkyl, nitro, aromatic, amino, alkoxy, cycloalkyl or heterocyclic;

[0021] In Formula XIII, R 4 -R 6are independently H, alkyl, amide, ester, cyano, hydroxyalkyl, nitro, aromatic, amino, alkoxy, cycloalkyl or heterocyclic;

[0022] In Formula XIV, R 4 -R 10 Each is independently H, alkyl, amide, ester, cyano, hydroxyalkyl, nitro, aromatic, amino, alkoxy, cycloalkyl or heterocyclic.

[0023] Furthermore, the bipyridine compound is any of the following compounds:

[0024]

[0025] The present invention also provides a method for preparing the bipyridine compound, wherein the bipyridine compound has a structure as shown in any one of formulas II to VII, and the preparation method comprises using the corresponding raw materials to form an amide bond by condensation reaction under alkaline conditions. Thus, a bipyridine compound having a structure as shown in any one of formulae II to VII is obtained.

[0026] The present invention also provides a method for preparing the bipyridine compound, wherein the bipyridine compound has a structure as shown in any one of formulas VIII to XIV. The preparation method comprises using corresponding raw materials to carry out a coupling reaction between the halogen atom on the bipyridine ring and a primary amine or a tertiary amine under alkaline conditions and in the presence of a catalyst by microwave or heating, thereby obtaining a bipyridine compound with a structure as shown in any one of formulas VIII to XIV.

[0027] The reagents providing alkaline conditions in the above synthesis scheme include organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably N,N-diisopropylethylamine and / or triethylamine.

[0028] The condensing agent described in the above synthesis scheme includes but is not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole -1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate; preferably 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl).

[0029] In the above synthesis scheme, the reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof.

[0030] The present invention also provides a pharmaceutical composition, which contains the bipyridine compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents and / or excipients.

[0031] The present invention relates to a compound of the present invention or a pharmaceutically acceptable salt thereof for use as a medicament, especially for use in the treatment of cancer.

[0032] The present invention relates to compounds of the present invention or pharmaceutically acceptable salts thereof for use in treating abnormal cell growth, particularly cancer, in a subject.

[0033] The present invention provides the use of a compound of any of the formulae described herein or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating abnormal cell growth in a subject.

[0034] In common embodiments of the foregoing compounds, methods and uses, the abnormal cell growth is cancer.

[0035] The present invention also provides the use of the bipyridine compound or its pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of a medicament for treating and / or preventing a disease. The disease is preferably cancer. The cancer is preferably breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, urothelial cancer, urethral cancer, prostate cancer, testicular cancer, colorectal cancer, sarcoma, bone cancer, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyomas, fibromas, lipomas, teratomas, pharyngeal cancer, nasopharyngeal cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, small intestine cancer, gastric cancer, esophageal cancer, pancreatic cancer, liver cancer, bile duct cancer, neurofibroma, glioma, neuroblastoma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer and gastrointestinal stromal tumor. DETAILED DESCRIPTION

[0036] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0037] Scheme 1, general reaction formula of intermediate:

[0038]

[0039] first step

[0040] Meta-chloroperbenzoic acid (8.1 g, 32.86 mmol) was dissolved in dichloromethane (6.5 mL) and stirred thoroughly to dissolve. Under ice-water bath conditions, the meta-chloroperbenzoic acid solution was slowly added to a dichloromethane (25 mL) solution of bipyridine a (5.0 g, 32.1 mmol) and reacted at room temperature for 2 h. After the reaction was completed: the reaction mixture was diluted with dichloromethane to a final volume of 150 mL, and washed with saturated sodium thiosulfate (2×20 mL) and 20% aqueous sodium hydroxide solution (2×20 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was passed through a column, hexane / petroleum ether (6:1, 250 mL) to obtain 2-pyridin-2-ylpyridine-1-oxide b, 4.7 g, with a yield of 94%.

[0041] Step 2

[0042] Under ice bath conditions, concentrated sulfuric acid (0.04 vol, 8 mL) was added to a 1 L flask. 2,2'-bipyridine N-oxide b (1.883 g, 11 mmol) was slowly added to the concentrated sulfuric acid under vigorous stirring (addition time, 15 min, exothermic reaction). The temperature of the reaction system was kept below 80 °C (the solution was dark brown). After stirring for 10 min, concentrated nitric acid (0.02 vol, 4 mL) was slowly added through the addition funnel (addition time, within 12 min). A color change from brown to orange was observed. The resulting reaction system was heated to 105 °C for 4.5 h. During this period, a large amount of NO 2 Gases were released (a sodium hydroxide aqueous solution trap was installed to neutralize these gases). After the reaction was completed: the reaction mixture was cooled to room temperature and poured into a conical flask. Then, it was neutralized with 36% sodium hydroxide aqueous solution to pH 4.0, and precipitation of the desired product was observed, which was filtered immediately after neutralization. The product was washed with water and dried in vacuo to obtain the desired product as a yellow solid, 1.56 g, with a yield of 83%.

[0043] Step 3

[0044] Under ice-water bath conditions, sodium methoxide (0.03 equiv, 1.250 g, 2.31 mmol) was slowly added to an appropriate amount of anhydrous methanol (note: slightly exothermic reaction), compound c (1.676 g, 7.7 mmol) was slowly added to the reaction system, and the reaction system was heated to 68 ° C and refluxed for 1 h. After the reaction was completed: the reaction system was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a yellow solid d, 1.35 g, with a yield of 81%.

[0045] Step 4

[0046] Compound d (1.35 g, 6.7 mmol) was dissolved in an appropriate amount of acetonitrile, stirred at room temperature, triethylamine (1.2 mL, 0.80 mol) and diethyl cyanophosphate (3 mL, 0.2 mmol) were added, and the reaction mixture was heated to 82 ° C for 30 min. After the reaction was completed: the reaction solution was poured into a 2L conical flask and a precipitate was formed after cooling. Filter, wash with acetonitrile, and dry under reduced pressure to obtain the product, white solid e, 0.986 g, with a yield of 73%.

[0047] Step 5

[0048] Dissolve compound e (1.175 g, 5.5 mmol) in 10 ml of ethanol, stir, and slowly add sodium hydroxide solution (14.8 mM, 15 mL) to the reaction solution. There is a certain exothermic phenomenon. The reaction mixture is heated to 82 ° C and reacted for 1.5 hours. After the reaction is completed: cool the reaction solution to 10 ° C, pour it into a 2L conical flask, filter it directly, wash the obtained solid with ethanol and water, and dry it in a vacuum drying oven to obtain a sodium salt as a white solid. Then add hydrochloric acid in a 1:1 molar ratio to obtain compound f as a white solid, with a mass of 1.06 g and a yield of 90.2%.

[0049] Step 6

[0050] The reaction substrate f (130.0 mg, 0.93 mmol) was dissolved in 10 ml of N,N-dimethylformamide, triethylamine (336.0 mg, 3.3 mmol) was added to the reaction system, and substrate R was added at a molar ratio of 1:1.2. 1 And 1-hydroxybenzotriazole (135.0 mg, 0.998 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (191.0 mg, 0.998 mmol). Stir the reaction at room temperature for 18 hours. After the reaction is completed: remove N, N-dimethylformamide by vacuum rotary evaporation (50 ° C), add 10 ml of water, and extract with ethyl acetate (3X10 mL). Dry with anhydrous sodium sulfate, vacuum rotary evaporation, column, and purify to obtain each example compound with a yield of 29%-56%.

[0051] 4-Methoxy-N-(thiazol-2-yl)-[2,2'-bipyridine]-6-carboxamide

[0052]

[0053] Yellow solid, yield: 48%. 1 H NMR (600MHz, METHANOL-D4) δ8.82–8.77(m,1H),8.75(d,J=8.1Hz,1H),8.28(td,J=7.8,1.7Hz,1H),8.15(d,J=2.4Hz,1 H),7.88(d,J=2.4Hz,1H),7.73(ddd,J=7.6,5.1,1.2Hz,1H),7.55(d,J=3.5Hz,1H),7.24(d,J=3.6Hz,1H),4.06(s,4H). 13C NMR (151MHz, METHANOL-D4) δ170.34,151.17,148.10,142.39,142.35,138.70,127.04,124.20,115.43,111.86,111.18,56.91.HRESIMS m / z313.0756[M+H] + (calcd for C 15 H 12 N 4 O 2 S 313.0759).

[0054] 4-Methoxy-N-(5-methylthiazol-2-yl)-[2,2'-bipyridine]-6-carboxamide

[0055]

[0056] Pale yellow solid, yield: 56%. 1 H NMR (600MHz, DMSO-d6) δ12.36(s,1H),9.04(dd,J=8.0,1.1Hz,1H),8.76(dt,J=4.7,1.4Hz,1H),8.17(d,J=2.5Hz,1H), 8.14–8.09(m,1H),7.74(d,J=2.4Hz,1H),7.65–7.57(m,1H),7.29(d,J=1.3Hz,1H),4.02(s,3H),2.41(d,J=1.3Hz,3H). 13 C NMR(151MHz,DMSO-D6)δ168.26,162.68,158.78,156.35,153.58,150.44,148.89,1 39.04,135.76,128.00,125.81,123.16,110.20,109.92,56.64,11.68.HRESIMSm / z 327.0915[M+H] + (calcd for C 16 H 14 N 4 O 2 S 327.0916).

[0057] 2-(4-methoxy-[2,2'-bipyridine]-6-carboxamido)thiazole-4-carboxamide

[0058]

[0059] White solid, yield: 36%. 1H NMR (600MHz, DMSO-d6) δ12.64(s,1H),9.07(dt,J=7.9,1.2Hz,1H),8.80–8.76(m,1H),8.20(dd,J=2.5,1.1Hz,1H),8. 17–8.06(m,1H),7.96(s,1H),7.78(dd,J=2.5,1.2Hz,1H),7.64(s,1H),7.63–7.58(m,1H),7.46(s,1H),4.04(s,2H). 13 C NMR(151MHz,DMSO-D6)δ167.73,163.04,162.46,157.42,153.64,153.17,149.51, 148.61,145.30,138.06,125.24,122.53,118.66,109.85,109.50,56.13.HRESIMS m / z356.0816[M+H] + (calcd for C 16 H 14 N 5 O 3 S 356.0817).

[0060] 2-(4-methoxy-[2,2'-bipyridine]-6-carboxamido)thiazole-4-carboxylic acid ethyl ester

[0061]

[0062] White solid, yield: 43%. 1 H NMR (600MHz, DMSO-d6) δ13.06(s,1H),9.17(dt,J=8.0,1.1Hz,1H),8.78(d,J=4.5Hz,1H),8.21(s,1H),8.21(d,J=2.5Hz,1H), 8.13(t,J=7.6Hz,1H),7.78(d,J=2.5Hz,1H),7.61(t,J=6.2Hz,1H),4.33(q,J=7.1Hz,2H),4.04(s,3H),1.33(t,J=7.1Hz,3H). 13C NMR (151MHz, DMSO-D6) δ168.20,164.02,161.57,158.67,150.16,141.92,133.83,128.27 ,125.79,124.26,123.35,112.78,112.17,110.54,110.04,61.23,56.65,14.78.HRESIMS m / z 385.0968[M+H] + (calcd for C 18 H 17 N 4 O 4 S385.0971).

[0063] N-(5-cyanothiazol-2-yl)-4-methoxy-[2,2'-bipyridine]-6-carboxamide

[0064]

[0065] Yellow solid, yield: 32%. 1 H NMR(600MHz, DMSO-d6)δ13.49(s,1H),9.11(dt,J=7.9,1.2Hz,1H),8.74–8.67(m,1H),8.51(s,1H),8.17(d,J= 2.5Hz,1H),8.01(td,J=7.7,1.8Hz,1H),7.74(d,J=2.5Hz,1H),7.51(ddd,J=7.4,4.7,1.2Hz,1H),4.00(s,3H). 13 CNMR(151MHz,DMSO-D6)δ167.59,164.02,162.22,150.25,148.98,128.81,128.62 ,128.01,126.38,125.10,122.58,113.31,110.27,109.52,98.50,56.10.HRESIMS m / z338.0708[M+H] + (calcd for C 15 H 12 N 4 O 2 S 338.0712).

[0066] N-(4-methoxy-2-yl)-4-methoxy-[2,2'-bipyridine]-6-carboxamide

[0067]

[0068] Pale yellow solid, yield: 29%.1 H NMR(600MHz,DMSO-d6)δ13.15(s,1H),9.16(dt,J=8.0,1.1Hz,1H),8.75(dd,J=4.9,1.8Hz,1H),8.52(s,1H),8.2 1(d,J=2.5Hz,1H),8.08(td,J=7.8,1.8Hz,1H),7.77(d,J=2.5Hz,1H),7.58(dd,J=7.6,4.8Hz,1H),4.03(s,3H). 13 C NMR(151MHz,NONE)δ167.61,163.56,159.31,153.31,149.17,148.66,137.8 5,128.00,125.15,122.64,120.58,114.86,110.07,109.42,56.08.HRESIMS m / z 338.0706[M+H] + (calcd for C 15 H 12 N 4 O 2 S 338.0712).

[0069] Scheme 2, reaction formula of intermediate:

[0070]

[0071] first step

[0072] Metachloroperbenzoic acid (mCPBA 8.1g, 32.86mmol) was dissolved in dichloromethane (6.5mL) and stirred thoroughly to dissolve. Under ice-water bath conditions, the solution of metachloroperbenzoic acid was slowly added to a solution of dichloromethane (25mL) dissolved with bipyridine 1 (5.0g, 32.1mmol) and reacted at room temperature for 2h. After the reaction was completed: the reaction mixture was diluted with dichloromethane to a final volume of 150mL, and washed with saturated sodium thiosulfate solution (2×20mL) and 20% sodium hydroxide solution (2×20mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was passed through a column, hexane / petroleum ether (6:1, 250mL) to obtain compound 2.

[0073] Step 2

[0074] Compound 2 (1.35 g, 6.7 mmol) was dissolved in an appropriate amount of acetonitrile, stirred at room temperature, triethylamine (1.2 mL, 0.80 mol) and diethyl cyanophosphate (3 mL, 0.2 mmol) were added, the reaction mixture was heated to 82 °C, slowly dissolved, and reacted for 30 min. After the reaction was completed: the reaction solution was poured into a 2L conical flask, and a precipitate was formed after cooling. Filter, wash with acetonitrile, and dry under reduced pressure to obtain the product as a white solid 3.

[0075] Step 3

[0076] Compound 3 (1.175 g, 5.5 mmol) was dissolved in 10 ml of ethanol and stirred. Sodium hydroxide solution (14.8 mM, 15 mL) was slowly added to the reaction solution. There was a certain exothermic phenomenon. The reaction mixture was heated to 82°C and reacted for 1.5 hours. After the reaction was completed: the reaction solution was cooled to 10°C, poured into a 2L conical flask, filtered directly, and the solid was washed with ethanol and water, and dried in a vacuum drying oven to obtain a sodium salt as a white solid. Then hydrochloric acid was added in a 1:1 molar ratio to obtain compound 4.

[0077] Step 4

[0078] The reaction substrate 4 (130.0 mg, 0.93 mmol) was dissolved in 10 ml of N,N-dimethylformamide, triethylamine (336.0 mg, 3.3 mmol) was added to the reaction system, and substrate R was added to the reaction system at a molar ratio of 1:1.2. 1 And 1-hydroxybenzotriazole (135.0 mg, 0.998 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (191.0 mg, 0.998 mmol). Reaction at room temperature for 18 hours. After the reaction is completed: remove N, N-dimethylformamide by vacuum rotary evaporation (50 ° C), add 10 ml of water, and extract with ethyl acetate. The organic phase is washed with water, dried over anhydrous sodium sulfate, spin-dried, passed through a column, and purified to obtain each example compound with a yield of 17%-83%.

[0079] N-(Thiazol-2-yl)-[2,2'-bipyridine]-6-carboxamide

[0080]

[0081] Yellow solid, yield: 53%. 1 H NMR (600 MHz, DMSO-d 6)δ12.65(s,1H),9.04(dt,J=8.1,1.1Hz,1H),8.81(d,J=5.0Hz,1H),8.67(ddd,J=6.6,2.3,0.9Hz,1H) ,8.28–8.22(m,2H),8.21(s,1H),7.66(d,J=8.8Hz,1H),7.61(d,J=3.5Hz,1H),7.36(d,J=3.5Hz,1H). 13 C NMR (151 MHz, DMSO-D 6 )δ162.49,158.33,158.08,157.75,148.00,147.63,139.60,137.95,125.50,124.51,123.90,122.83,116.32,114.56.HRESIMS m / z 283.0650[M+H] + (calcdfor C 14 H 10 N 4 OS 283.0654).

[0082] N-((Thiazol-5-yl)-[2,2'-bipyridine]-6-carboxamide

[0083]

[0084] Yellow solid, yield: 45%. 1 H NMR (600 MHz, DMSO-d 6 )δ11.98(s,1H),8.98(dt,J=7.9,1.2Hz,1H),8.78(ddd,J=4.9,1.8,0.8Hz,1H),8.74(s,1H),8.68(dd,J=6.7,2.3 Hz,1H),8.29–8.21(m,2H),8.13(td,J=7.7,1.7Hz,1H),8.11(d,J=0.9Hz,1H),7.59(ddd,J=7.5,4.8,1.2Hz,1H). 13 C NMR (151 MHz, DMSO-D 6 )δ162.11,154.90,154.17,149.51,148.85,147.45,139.93,138.54,135.68,130.85,125.59,124.45,123.90,122.63.HRESIMS m / z283.0653[M+H] + (calcd for C 14 H10 N 4 OS 283.0654).

[0085] N-(5-methylthiazol-2-yl)-[2,2'-bipyridine]-6-carboxamide

[0086]

[0087] Pale yellow solid, yield: 52%. 1 H NMR (600 MHz, DMSO-d 6 )δ12.42(s,1H),9.03(dt,J=8.0,1.1Hz,1H),8.80–8.73(m,1H),8.70–8.60(m,1H),8.29–8.19(m,2H), 8.12(t,J=7.7Hz,1H),7.60(t,J=6.4Hz,1H),7.29(s,0H),7.26(q,J=1.2Hz,1H),2.38(d,J=1.3Hz,3H). 13 C NMR (151 MHz, DMSO-D 6 )δ162.88,158.84,158.60,156.44,148.81,148.63,140.02,135.73,127.95,125.80,124.83,124.19,123.14,115.22,11.68.HRESIMS m / z 297.0804[M+H] + (calcd for C 15 H 12 N 4 OS 297.0810).

[0088] N-(4-(Trifluoromethyl)thiazol-2-yl)-[2,2'-bipyridine]-6-carboxamide

[0089]

[0090] White solid, yield: 18%. 1 H NMR (600 MHz, DMSO-d 6 )δ13.18(s,1H),9.15(dt,J=7.9,1.2Hz,1H),8.76–8.72(m,1H),8.67(dd,J= 7.4,1.6Hz,1H),8.26–8.19(m,2H),8.10–8.05(m,2H),7.56(t,J=6.1Hz,1H). 13 C NMR (151 MHz, DMSO-D 6)δ164.34,160.65,158.78,158.54,149.15,148.11,139.95,138.63,138.38,125.66,125.03,124.42,123.21,118.02,118.01.HRESIMS m / z 351.0524[M+H] + (calcd for C 15 H 9 F 3 N 4 OS 351.0527).

[0091] N-(4-Methylthiazol-2-yl)-[2,2'-bipyridine]-6-carboxamide

[0092]

[0093] White solid, yield: 49%. 1 H NMR (600 MHz, DMSO-d 6 )δ12.56(s,1H),9.07(dt,J=8.0,1.1Hz,1H),8.76(d,J=5.1Hz,1H),8.68–8.62(m,1H),8.25–8.18 (m,2H),8.11(t,J=7.8Hz,1H),7.59(t,J=6.3Hz,1H),6.89(p,J=1.1Hz,1H),2.32(d,J=1.1Hz,3H). 13 C NMR (151 MHz, DMSO-D 6 )δ163.12,158.81,158.57,157.62,148.87,148.60,147.67,140.01,139.37,125.76,124.82,124.15,123.17,109.37,17.41.HRESIMS m / z 297.0808[M+H] + (calcd for C 15 H 12 N 4 OS 297.0810).

[0094] N-(4-(Hydroxymethyl)thiazol-2-yl)-[2,2'-bipyridine]-6-carboxamide

[0095]

[0096] White solid, yield: 59%. 1 H NMR (600 MHz, DMSO-d6 )δ12.59(s,1H),9.07(dt,J=8.0,1.1Hz,1H),8.77–8.74(m,1H),8.65(dd,J=6.1,2.9Hz,1H),8.23– 8.19(m,2H),8.14–8.04(m,1H),7.58(t,J=6.1Hz,1H),7.05(t,J=1.2Hz,1H),4.52(d,J=1.2Hz,2H). 13 C NMR (151 MHz, DMSO-D 6 )δ162.71,158.26,157.45,152.82,148.45,148.03,139.45,125.16,124.26,123.59,122.57,116.78,114.89,108.92,59.91.HRESIMS m / z313.0756[M+H] + (calcd for C 15 H 13 N 4 O 2 S 313.0759).

[0097] N-(4-Carboxyethylthiazol-2-yl)[2,2'-bipyridine]-6-carboxamide

[0098]

[0099] White solid, yield: 47%. 1 H NMR (600 MHz, DMSO-d 6 )δ13.11(s,1H),9.16(dt,J=8.0,1.1Hz,1H),8.80(d,J=4.8Hz,1H),8.70(dd,J=7.2,1.8Hz,1H),8.30– 8.22(m,2H),8.20(s,1H),8.18–8.15(m,1H),7.63(s,1H),4.32(q,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H). 13 CNMR(151MHz,CHLOROFORM-D)δ163.55,161.44,160.96,158.19,158.11,157.94,147.74,1 41.30,139.38,128.91,125.17,124.41,123.84,123.60,122.69,60.61,14.16.HRESIMSm / z 355.0869[M+H] +(calcd for C 17 H 14 N 4 O 3 S 355.0865).

[0100] 2-([2,2'-Bipyridine]-6-carboxamido)thiazole-5-carboxylic acid ethyl ester

[0101]

[0102] White solid, yield: 37%. 1 H NMR (600 MHz, DMSO-d 6 )δ13.13(s,1H),9.08(dt,J=8.0,1.1Hz,1H),8.73(dt,J=4.8,1.5Hz,1H),8.67(dd,J=7.2,1.8Hz,1H),8.27(s,1H), 8.25–8.19(m,2H),8.10–8.04(m,1H),7.56–7.50(m,1H),4.27(dq,J=12.4,7.1Hz,2H),1.28(dt,J=9.0,7.1Hz,3H). 13 C NMR (151 MHz, DMSO-D 6 )δ164.21,162.73,161.96,149.20,148.07,145.76,139.99,133.58,129.2 2,128.90,125.67,125.09,124.49,123.09,122.67,61.54,14.73.HRESIMS m / z 355.0861[M+H] + (calcd for C 17 H 14 N 4 O 3 S355.0865).

[0103] 2-([2,2'-Bipyridine]-6-carboxamido)thiazole-4-carboxamide

[0104]

[0105] Yellow solid, yield: 33%. 1 H NMR (600 MHz, DMSO-d 6)δ12.68(s,1H),9.08(dt,J=8.0,1.1Hz,1H),8.77(dt,J=4.8,1.5Hz,1H),8.68(dd,J=7.1,1.9Hz,1H), 8.28–8.23(m,2H),8.15–8.06(m,1H),7.94(s,1H),7.66–7.61(m,1H),7.60–7.56(m,1H),7.45(s,1H). 13 C NMR(151MHz,CHLOROFORM-D)δ168.57,167.76,162.80,158.86,154.15,154.10,1 52.99,150.59,144.75,144.67,130.38,129.73,128.91,127.68,123.89.HRESIMS m / z 326.0709[M+H] + (calcd for C 15 H 11 N 5 O 2 S 326.0712).

[0106] 2-([2,2'-Bipyridine]-6-carboxamide)-N,N-dimethylthiazole-4-carboxamide

[0107]

[0108] Yellow solid, yield: 19%. 1 H NMR (600 MHz, DMSO-d 6 )δ12.85(s,1H),12.54(s,1H),9.08(dt,J=7.9,1.2Hz,1H),8.73–8.69(m,1H),8.66(dd,J=7.4,1.6Hz,1H),8.43(d,J=0.8H z,1H),8.26–8.18(m,2H),8.04(td,J=7.7,1.8Hz,1H),7.52(ddd,J=7.6,4.8,1.1Hz,1H),2.97(s,3H),2.92(s,3H).HRESIMS m / z 354.1020[M+H] + (calcd for C 17 H 15 N 5 O 2 S354.1025).

[0109] N-(4-cyanothiazol-2-yl)-[2,2'-bipyridine]-6-carboxamide

[0110]

[0111] Yellow solid, yield: 27%. 1 H NMR (600 MHz, DMSO-d 6 )δ13.21(s,1H),9.17(dt,J=8.0,1.1Hz,1H),8.79(dd,J=5.0,1.6Hz,1H),8.72(dd,J=7.0,2.1 Hz,1H),8.52(d,J=0.8Hz,1H),8.32–8.24(m,2H),8.14(t,J=7.9Hz,1H),7.62(t,J=6.2Hz,1H). 13 CNMR (151MHz, DMSO-D 6 )δ164.25,159.95,158.62,153.70,149.02,147.95,140.05,139.01,128.55,125.77,125.17,124.52,123.22,121.14,115.43.HRESIMS m / z 307.0604[M+H] + (calcdfor C 15 H 9 N 5 OS 307.0606).

[0112] N-(5-cyanothiazol-2-yl)-[2,2'-bipyridine]-6-carboxamide

[0113]

[0114] Yellow solid, yield: 23%. 1 H NMR (600 MHz, DMSO-d 6 )δ13.54(s,1H),9.12(dt,J=8.0,1.1Hz,1H),8.75–8.69(m,1H),8.67(dd,J=7.5,1.5Hz,1H),8.51 (s,1H),8.26–8.19(m,2H),8.02(td,J=7.6,1.8Hz,1H),7.51(ddd,J=7.5,4.7,1.2Hz,1H).HRESIMS m / z308.0603[M+H] + (calcd for C 15 H 9 N 5 OS 308.0606).

[0115] N-(5-nitrothiazol-2-yl)-[2,2'-bipyridine]-6-carboxamide

[0116]

[0117] Yellow solid, yield: 64%. 1 H NMR (600MHz, DMSO-d6) δ13.65(s,1H),9.10(dt,J=8.0,1.1Hz,1H),8.78–8.73(m,2H),8.69(dd,J=7. 4,1.5Hz,1H),8.29–8.20(m,2H),8.10(td,J=7.7,1.8Hz,1H),7.58(ddd,J=7.5,4.8,1.2Hz,1H).13C NMR(151MHz,DMSO-D6)δ164.37,161.87,158.31,158.06,152.98,148.41,146.98,142.55,139.50,138.42,125.21,124.86,124.33,122.65.HRESIMS m / z 328.0500[M+H]+(calcd for C14H9N5O3S 328.0504).

[0118] N-(2'-amino-[4,4'-bithiazole]-2-yl)-[2,2'-bipyridine]-6-carboxamide

[0119]

[0120] Yellow solid, yield: 68%. 1 H NMR (600 MHz, DMSO-d 6 )δ12.79(s,1H),9.17(dt,J=8.0,1.1Hz,1H),8.72(ddd,J=4.7,1.8,0.9Hz,1H),8.66(dd,J=7.3,1.7Hz,1H),8.26–8.17(m,2H),8.05(td, J=7.7,1.8Hz,1H),7.52(ddd,J=7.5,4.7,1.3Hz,1H),7.32(s,1H),7.10(s,2H),6.93(s,1H),3.32(s,3H),3.16(d,J=5.2Hz,3H).HRESIMS m / z381.0607[M+H] + (calcdfor C 17 H 13 N 6 OS 2 381.0592).

[0121] N-(4-phenylthiazol-2-yl)-[2,2'-bipyridine]-6-carboxamide

[0122]

[0123] White solid, yield: 72%. 1 H NMR (600 MHz, DMSO-d 6 )δ12.76(s,1H),9.09(dd,J=8.0,1.2Hz,1H),8.80(d,J=4.9Hz,1H),8.67(dd,J=7.4,1.5Hz,1H),8.30–8.21(m,1H),8.12–8.05(m,1H ),7.99–7.96(m,1H),7.95–7.90(m,1H),7.75(s,1H),7.68–7.58(m,1H),7.55–7.49(m,1H),7.46–7.38(m,2H),7.35–7.27(m,1H).13C NMR(151MHz,DMSO-D6)δ165.24,162.93,158.51,157.76,149.43,147.99,139.55,134.21, 132.61,131.96,128.72,128.57,128.16,127.84,125.88,125.35,123.37,108.82.HRESIMS m / z359.0962[M+H] + (calcd for C 20 H 14 N 4 OS 359.0967).

[0124] N-(5-amino-1,3,4-thiadiazol-2-yl)-[2,2'-bipyridine]-6-carboxamide

[0125]

[0126] White solid, yield: 53%. 1 H NMR (600 MHz, DMSO-d 6)δ12.38(s,1H),9.09(dt,J=7.9,1.1Hz,1H),8.71(ddd,J=4.8,1.9,0.9Hz,1H),8.65(dd,J=6.6,2.4H z,1H),8.31–8.11(m,2H),8.02(td,J=7.7,1.8Hz,1H),7.51(ddd,J=7.4,4.7,1.2Hz,1H),6.97(s,2H). 13 C NMR (151 MHz, DMSO-D 6 )δ165.02,162.08,154.94,153.99,149.09,148.69,147.82,139.15,137.30,124.77,123.96,123.30,122.19.HRESIMS m / z 299.0718[M+H] + (calcd for C 13 H 10 N 6 OS 299.0715).

[0127] N-(Isoxazol-3-yl)-[2,2'-bipyridine]-6-carboxamide

[0128]

[0129] White solid, yield: 48%. 1 H NMR (600 MHz, DMSO-d 6 )δ11.60(s,1H),9.07–8.95(m,1H),8.89(d,J=1.8Hz,1H),8.78(d,J=4.8Hz,1H),8.66(dd,J=6.2, 2.8Hz,1H),8.27–8.18(m,2H),8.15(t,J=7.8Hz,1H),7.62(t,J=6.3Hz,1H),7.11(d,J=1.7Hz,1H). 13 CNMR (151MHz, DMSO-D 6 )δ162.87,160.46,157.41,148.59,148.05,139.54,139.24,125.37,124.35,123.59,122.66,116.44,114.51,99.84.HRESIMS m / z 267.0877[M+H] + (calcd for C 14 H 10 N 6 O 2267.0882).

[0130] N-(1,3,4-thiadiazol-2-yl)-[2,2'-bipyridine]-6-carboxamide

[0131]

[0132] Yellow solid, yield: 46%. 1 H NMR (600 MHz, DMSO-d 6 )δ13.13(s,1H),9.29(s,1H),9.13(dt,J=8.0,1.1Hz,1H),8.76–8.74(m,1H),8.6 8(dd,J=7.2,1.8Hz,1H),8.26–8.19(m,2H),8.12–8.07(m,1H),7.60–7.54(m,1H). 13 C NMR (151 MHz, DMSO-D 6 )δ163.72,159.41,153.84,150.06,149.13,148.14,139.99,128.79,127.41,125.70,125.10,124.53,123.17.HRESIMS m / z 284.0602[M+H] + (calcd for C 13 H 9 N 5 O 284.0606).

[0133] N-(Benzothiazol-2-yl)-[2,2'-bipyridine]-6-carboxamide

[0134]

[0135] White solid, yield: 52%. 1 H NMR (600 MHz, DMSO-d 6 )δ9.13(dt,J=8.0,1.1Hz,1H),8.88–8.84(m,1H),8.73(dd,J=7.6,1.3Hz ,1H),8.35–8.22(m,2H),8.17–8.12(m,1H),8.05(ddt,J=35.5,7.9,1.0Hz ,1H),7.87–7.74(m,1H),7.74–7.63(m,1H),7.60–7.54(m,1H),7.48(ddd d,J=24.9,8.3,7.1,1.3Hz,1H),7.36(dddd,J=26.1,8.2,7.1,1.2Hz,1H).13 CNMR (151MHz, DMSO-D 6 )δ163.99,158.93,158.68,158.42,149.16,148.33,140.27,133.44,132.30,129. 20,128.87,126.89,126.74,124.55,124.25,122.45,122.30,121.25.HRESIMSm / z 333.0809[M+H] + (calcd for C 18 H 12 N 4 OS 333.0810).

[0136] N-(1H-Indol-7-yl)-[2,2'-bipyridine]-6-carboxamide

[0137]

[0138] Yellow solid, yield: 37%. 1 H NMR (600 MHz, DMSO-d 6 )δ10.86(s,1H),8.98(d,J=8.0Hz,1H),8.78(dd,J=4.3,2.0Hz,1H),8.66(ddd,J=6.0,3.1,1.1Hz,1H) ,8.30–8.20(m,2H),8.13(s,2H),7.65(d,J=8.0Hz,1H),7.63–7.56(m,2H),7.14(t,J=7.7Hz,1H).13C NMR(151MHz,DMSO-D6)δ163.17,158.96,158.71,150.14,148.85,148.78,142.98,142.93,13 9.91,127.89,127.50,126.72,125.79,124.19,123.69,122.87,120.94,118.54.HRESIMSm / z 316.1194[M+H] + (calcd for C 18 H 13 N 5 O 316.1198).

[0139] N-(1H-Indol-3-yl)-[2,2'-bipyridine]-6-carboxamide

[0140]

[0141] Yellow solid, yield: 27%. 1 H NMR (600 MHz, DMSO-d 6 )δ12.91(s,1H),11.09(s,1H),9.01(dq,J=8.0,1.3Hz,1H),8.75(d,J=4 .8Hz,1H),8.65(dd,J=6.9,2.1Hz,1H),8.27–8.17(m,2H),8.06(t,J=7.8 Hz,1H),7.76(dd,J=8.2,4.8Hz,1H),7.56(t,J=6.2Hz,1H),7.49(d,J=8.4Hz,1H),7.35(ddd,J=8.3,6.8,1.1Hz,1H),7.08(dd,J=8.1,6.9Hz,1H). 13 C NMR (151 MHz, DMSO-D 6 )δ162.25,159.30,156.05,149.75,149.72,149.11,139.89,139.83,127.01 ,125.61,124.19,123.51,122.77,122.25,120.39,117.59,110.84.HRESIMS m / z316.1197[M+H] + (calcd for C 18 H 13 N 5 O 316.1198).

[0142] N-(4-cyanothiazol-2-yl)-[2,4'-bipyridine]-6-carboxamide

[0143]

[0144] White solid, yield: 37%. 1 H NMR (600 MHz, DMSO-d 6 )δ12.83(s,1H),8.87(dd,J=5.0,0.8Hz,1H),8.81(dd,J=2.0,0.8Hz,1H),8.77(ddd,J=4.7,1.9,0.9Hz,1H),8.45(s,1H) ,8.36(dd,J=5.1,1.8Hz,1H),8.24(dt,J=8.0,1.1Hz,1H),7.99(td,J=7.7,1.8Hz,1H),7.52(ddd,J=7.6,4.7,1.1Hz,1H). 13 C NMR (151 MHz, DMSO-D 6)δ164.41,159.62,152.85,150.72,150.55,149.19,148.05,138.44,128.57,125.53,125.06,122.11,121.22,120.70,115.50.HRESIMS m / z 308.0605[M+H] + (calcd for C 15 H 10 N 5 OS 308.0606).

[0145] Scheme 3, reaction formula of intermediate:

[0146]

[0147] First, using a Schlenk high temperature and high pressure tube, compound A (23.58 mg, 1 mmol) was dissolved in 5 mL of toluene, and substrate amine (1.05-1.4 equiv), anhydrous potassium carbonate 106 mg (1.4 equiv), tris (dibenzylideneacetone) dipalladium 3.6 mg (4% mmol), Xantphos 5.2 mg (12% mmol) were added to the reaction solution, nitrogen protection, 110 ° C, and reacted for 20 hours. After the reaction was completed, the room temperature was cooled, diluted with tetrahydrofuran, and concentrated under reduced pressure. The obtained crude product was passed through a column, and then separated and purified by a silica gel column and a liquid phase preparation column to obtain each example compound with a yield of 17%-75%.

[0148] N-([2,2'-Bipyridyl]-6-yl)thiazol-2-amine

[0149]

[0150] Yellow solid, yield: 45%. 1 H NMR (600 MHz, DMSO-d 6 )δ11.41(s,1H),8.66(ddd,J=4.7,1.9,1.0Hz,1H),8.59(dt,J=8.0,1.2Hz,1H),8.00(tt,J=7.7,1.6Hz,1H),7.93(dt,J=7.5,1.1Hz, 1H),7.81(td,J=7.7,1.3Hz,1H),7.43(ddd,J=7.5,4.7,1.2Hz,1H),7.41(d,J=3.6Hz,1H),7.09(d,J=0.9Hz,1H),7.10–7.03(m,1H). 13 C NMR (151 MHz, DMSO-D 6)δ159.92,155.65,153.74,152.02,149.84,139.32,138.27,137.92,124.67,121.46,113.36,112.06,111.39.HRESIMS m / z 255.0706[M+H] + (calcd for C 13 H 10 N 4 S255.0704).

[0151] N-([2,2'-Bipyridyl]-6-yl)-N-methylthiazol-2-amine

[0152]

[0153] White solid, yield: 33%. 1 H NMR (600 MHz, DMSO-d 6 )δ8.69(ddd,J=4.7,1.9,0.9Hz,1H),8.59(dt,J=7.9,1.1Hz,1H),8.04(dd,J=7.6,0.8Hz,1H),8.00(td,J=7.7,1.9Hz ,1H),7.97(dd,J=8.4,7.5Hz,1H),7.48–7.42(m,2H),7.34(dd,J=8.4,0.8Hz,1H),7.11(d,J=3.6Hz,1H),3.81(s,3H). 13 C NMR (151 MHz, METHANOL-D 4 )δ162.47,156.23,154.67,154.37,150.77,140.85,138.77,138.31,125.66,122.78,115.33,113.80,111.89,37.27.HRESIMS m / z 269.0858[M+H] + (calcd for C 14 H 12 N 4 S 269.0861).

[0154] Ethyl 2-([2,2'-bipyridyl]-6-ylamino)thiazole-5-carboxylate

[0155]

[0156] White solid, yield: 33%. 1 H NMR (600 MHz, DMSO-d 6)δ12.04(s,1H),8.73–8.67(m,1H),8.52(d,J=7.9Hz,1H),8.09(s,1H),8.05–7.97(m,2H),7.91(t,J=7.9Hz,1 H),7.47(ddd,J=7.5,4.8,1.2Hz,1H),7.18(d,J=8.1Hz,1H),4.25(d,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H).13C NMR(151MHz,DMSO-D6)δ161.74,156.09,154.76,153.31,149.49,145.74,139.34 ,137.25,133.48,128.81,124.39,120.80,118.81,114.23,60.48,14.19.HRESIMS m / z327.0913[M+H] + (calcd for C 16 H 14 N 4 O 2 S 327.0916).

[0157] 2-([2,2'-Bipyridyl]-6-ylamino)thiazole-4-carboxamide

[0158]

[0159] Yellow solid, yield: 29%. 1 H NMR (600 MHz, DMSO-d 6 )δ11.57(s,1H),8.70(ddd,J=4.8,1.9,0.9Hz,1H),8.57(dt,J=8.0,1.1Hz,1H),8.03(td,J=7.7,1.8Hz,1H),7.99(dd,J=7.5,0.9Hz,1H),7. 91–7.83(m,1H),7.68(d,J=0.8Hz,1H),7.57–7.53(m,1H),7.47(ddd,J=7.5,4.7,1.2Hz,1H),7.24–7.21(m,1H),7.17(dd,J=8.2,0.9Hz,1H). 13 CNMR (151MHz, DMSO-D 6)δ162.77,158.83,154.87,153.19,151.30,149.30,144.88,138.96,137.38,124.15,120.87,115.16,113.27,111.66.HRESIMS m / z 298.0755[M+H] + (calcd for C 14 H 11 N 5 OS 298.0763).

[0160] N-(pyrimidin-2-yl)-[2,2'-bipyridyl]-6-amine

[0161]

[0162] Yellow solid, yield: 25%. 1 H NMR (600 MHz, DMSO-d 6 )δ9.88(s,1H),8.66(ddd,J=4.8,1.8,0.9Hz,1H),8.58(d,J=4.8Hz,2H),8.41(dt,J=7.9,1.2Hz,1H),8.34–8.27(m,1H),7.99(dd ,J=7.6,0.9Hz,1H),7.95(td,J=7.7,1.8Hz,1H),7.90(t,J=7.9Hz,1H),7.43(ddd,J=7.5,4.7,1.3Hz,1H),6.98(t,J=4.8Hz,1H). 13 C NMR (151 MHz, DMSO-D 6 )δ159.75,158.73,155.66,154.12,153.00,149.70,139.36,137.67,124.61,121.14,114.52,114.24,113.62.HRESIMS m / z 250.1091[M+H] + (calcd for C 14 H 11 N 5 250.1093).

[0163] N-([2,3'-Bipyridyl]-6-yl)thiazol-2-amine

[0164]

[0165] Yellow solid, yield: 42%. 1 H NMR (600 MHz, DMSO-d 6)δ11.47(s,1H),9.44(dd,J=2.3,0.9Hz,1H),8.67(dd,J=4.8,1.6Hz,1H),8.58(ddd,J=8.0,2.4,1.7Hz,1H),7.84(dd,J=8.3,7.5Hz,1H), 7.62(dd,J=7.5,0.7Hz,1H),7.58(ddd,J=7.9,4.7,0.9Hz,1H),7.45(d,J=3.6Hz,1H),7.12(d,J=3.6Hz,1H),7.10(dd,J=8.2,0.7Hz,1H). 13 C NMR (151 MHz, DMSO-D 6 )δ159.88,152.37,152.23,150.41,148.54,139.47,138.22,134.53,134.42,124.33,113.20,111.55,111.07.HRESIMS m / z 255.0707[M+H] + (calcd for C 13 H 10 N 4 S 255.0704).

[0166] N-([2,2'-Bipyridyl]-6-yl)-1H-indazol-3-amine

[0167]

[0168] Yellow solid, yield: 31%. 1 H NMR (600 MHz, DMSO-d 6 )δ8.80–8.75(m,1H),8.73(ddd,J=4.8,1.9,0.9Hz,1H),8.43(dt,J=7.9, 1.1Hz,1H),8.10–8.04(m,2H),8.02–7.96(m,1H),7.93–7.87(m,2H),7.77 (dd,J=8.3,1.0Hz,1H),7.58(ddd,J=8.3,7.0,1.2Hz,1H),7.49(dddd,J=7.2,5.9,4.7,1.2Hz,2H),7.23(ddd,J=7.9,6.9,0.9Hz,1H),6.24(s,2H). 13CNMR(151MHz,DMSO-D6)δ156.58,155.13,153.60,151.59,149.44,140.84,139.15,137 .61,128.50,124.52,120.95,120.71,120.46,119.76,118.50,114.39,111.78.HRESIMS m / z288.1244[M+H] + (calcd for C 17 H 13 N 5 288.1249).

[0169] N-([2,2'-Bipyridyl]-6-yl)-6-fluoro-1H-indazol-3-amine

[0170]

[0171] Yellow solid, yield: 22%. 1 H NMR (600 MHz, DMSO-d 6 )δ8.74(ddd,J=4.7,1.9,0.8Hz,1H),8.44(dd,J=10.6,2.3Hz,1H),8.34(dt,J=7.9,1.2Hz,1H),8.12–8.06(m,2H),8.03–7.99(m,1H), 7.93(dd,J=8.7,5.5Hz,1H), 7.76(dd,J=8.2,1.0Hz,1H), 7.50(ddd,J=7.5,4.7,1.2Hz,1H), 7.12(td,J=8.9,2.3Hz,1H), 6.31(s,2H). 13 C NMR (151MHz, DMSO-D6) δ162.71,155.11,153.90,153.18,151.50,149.55,139.78,139. 05,137.68,124.35,122.61,120.32,115.50,115.12,111.81,109.73,100.34.HRESIMS m / z 306.1149[M+H] + (calcdfor C 17 H 12 FN 5 306.1155).

[0172] N-([2,2'-bipyridyl]-6-yl)-1,3,4-thiadiazol-2-amine

[0173]

[0174] Yellow solid, yield: 41%. 1 H NMR (600 MHz, DMSO-d 6 )δ11.86(s,1H),9.07(s,0H),8.70(ddd,J=4.7,1.8,0.8Hz,1H),8.52(dt,J=7.9,1.1Hz,1H),8.0 6–8.00(m,2H),7.93–7.88(m,1H),7.48(ddd,J=7.5,4.7,1.2Hz,1H),7.17(dd,J=8.1,0.9Hz,1H). 13 C NMR (151 MHz, DMSO-D 6 )δ159.64,154.77,153.32,150.61,149.36,146.36,139.35,137.40,124.23,120.84,113.71,111.88.HRESIMS m / z 256.0655[M+H] + (calcd for C 12 H 9 N 5 S256.0657).

[0175] N-([2,2'-Bipyridyl]-6-yl)isoxazol-3-amine

[0176]

[0177] White solid, yield: 43%. 1 H NMR (600 MHz, DMSO-d 6 )δ10.02(s,1H),8.69(d,J=1.7Hz,1H),8.64(ddd,J=4.7,1.9,0.9Hz,1H),8.26(dt,J=8.0,1.1Hz,1H),7.93(td,J=7.7,1.8H z,1H),7.86(dd,J=7.5,0.9Hz,1H),7.82–7.76(m,1H),7.44–7.37(m,1H),7.34(dd,J=8.2,1.0Hz,1H),6.83(d,J=1.8Hz,1H). 13 C NMR (151 MHz, DMSO-D 6)δ159.17,158.88,155.23,153.61,153.28,149.21,139.10,137.20,123.97,120.25,112.65,111.17,98.73.HRESIMS m / z 239.0932[M+H] + (calcd for C 13 H 10 N 4 O 239.0933).

[0178] N-([2,2'-Bipyridyl]-5-yl)thiazol-2-amine

[0179]

[0180] Yellow solid, yield: 38%. 1 H NMR (600MHz, Methanol-d 4 )δ10.64(s,1H),8.81(dd,J=2.4,0.8Hz,1H),8.62(ddd,J=4.8,1.9,0.9Hz,1H),8.35(qd,J=8.7,1.7Hz,2H),8.29(dt,J=8. 0,1.1Hz,1H),7.88(td,J=7.7,1.8Hz,1H),7.36(ddd,J=7.4,4.7,1.3Hz,1H),7.33(d,J=3.7Hz,1H),7.02(d,J=3.6Hz,1H). 13 C NMR (151 MHz, DMSO-D 6 )δ163.63,161.64,155.80,149.64,148.25,139.52,138.54,137.68,124.16,123.74,121.31,120.12,110.38.HRESIMS m / z 255.0702[M+H] + (calcd for C 13 H 10 N 4 S 255.0704).

[0181] 2-([2,2'-Bipyridyl]-6-ylamino)-N-(4-(trifluoromethoxy)phenyl)thiazole-5-carboxamide

[0182]

[0183] Yellow solid, yield: 27%. 1H NMR (600MHz, DMSO-d6) δ11.93(s,1H),10.31(s,1H),8.72(ddd,J=4.7,1.8,0.8Hz,1H),8.58(dt,J=7.9,1.1Hz,1H),8.34(s,1H ),8.10–8.03(m,2H),7.96–7.90(m,1H),7.87–7.81(m,2H),7.52–7.46(m,1H),7.39–7.34(m,2H),7.19(dd,J=8.1,0.9Hz,1H). 13 C NMR (151MHz, DMSO-D6) δ165.10,163.16,160.60,158.18,155.37,151.26,150.01,139.79,138. 74,137.93,132.25,129.96,125.30,124.91,122.09,121.86,121.36,114.56,112.68.HRESIMS m / z 458.0897[M+H] + (calcd for C 21 H 14 F 3 N 5 O 2 S458.0899).

[0184] 2-([2,2'-Bipyridyl]-6-ylamino)-N-(3,5-difluorobenzyl)thiazole-5-carboxamide

[0185]

[0186] White solid, yield: 35%. 1 H NMR (600 MHz, DMSO-d 6 )δ11.80(s,1H),9.02(t,J=6.0Hz,1H),8.71(ddd,J=4.7,1.8,0.9Hz,1H),8.55(dt,J=8.0,1.2Hz,1H),8.13(s,1H),8.05–7.99(m,2H),7 .93–7.87(m,1H),7.48(ddd,J=7.5,4.7,1.2Hz,1H),7.40(d,J=3.6Hz,1H),7.20–7.16(m,1H),7.06–7.02(m,2H),4.47(d,J=5.9Hz,2H). 13 C NMR (151 MHz, DMSO-D 6)δ163.14,161.97,161.43,154.82,153.31,150.80,149.38,144.59,140.29,139.11,137.31, 129.00,128.81,128.52,126.18,124.25,120.77,113.76,110.18,110.01,41.74.HRESIMSm / z 424.1040[M+H] + (calcd for C 21 H 15 F 2 N 5 OS 424.1044).

[0187] 2-([2,2'-Bipyridyl]-6-ylamino)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)thiazole-5-carboxamide

[0188]

[0189] Yellow solid, yield: 17%. 1 H NMR (600 MHz, DMSO-d 6 )δ11.98(s,1H),10.56(s,1H),8.70(dt,J=4.8,1.5Hz,1H),8.54(dt,J=7. 9,1.1Hz,1H),8.36(s,1H),8.23(s,1H),8.06(td,J=7.7,1.8Hz,1H),8.04 –8.02(m,2H),7.91(t,J=7.8Hz,1H),7.69(s,1H),7.52(s,2H),7.47(ddd, J=7.5,4.7,1.2Hz,1H),7.18(dd,J=8.2,0.9Hz,1H),2.16(d,J=1.1Hz,3H). 13 CNMR(151MHz,DMSO-D6)δ161.00,159.06,156.29,153.95,153.57,150.02,141.66,139.88,139.52,139.43,138.53,138 .02,135.55,134.16,127.52,127.36,127.22,124.94,121.32,114.82,112.77,110.97,106.78,101.90,14.04.HRESIMS m / z 522.1323[M+H] + (calcd for C 25 H18 F 3 N 7 OS 522.1324).

[0190] N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-[2,2'-bipyridyl]-6-amine

[0191]

[0192] Yellow solid, yield: 56%. 1 H NMR (600 MHz, DMSO-d 6 )δ10.09(d,J=8.0Hz,1H),9.64–9.58(m,1H),8.70(dt,J=4.5,1.5Hz,1H),8.58(q,J =2.0Hz,1H),8.39(q,J=2.0Hz,1H),8.26(dt,J=8.0,1.1Hz,1H),8.07(q,J=1.3Hz,1H ),7.92(ddt,J=7.7,6.1,1.9Hz,2H),7.85(t,J=7.8Hz,1H),7.67(d,J=1.8Hz,1H),7 .47(ddd,J=7.5,4.8,1.2Hz,1H),7.01(dd,J=8.2,1.1Hz,1H),2.38(d,J=1.0Hz,3H). 13 C NMR (151 MHz, DMSO-D 6 )δ158.90,158.66,155.72,154.88,153.48,149.79,144.36,139.66,137.91,136.79,134.8 3,131.55,124.77,120.94,118.07,114.83,114.61,113.58,112.95,110.53,10.36.HRESIMS m / z396.1435[M+H] + (calcd for C 21 H 16 F 3 N 5 396.1436).

[0193] 2-([2,3'-Bipyridyl]-6-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

[0194]

[0195] White solid, yield: 37%. 1H NMR (600MHz, Methanol-d 4 )δ11.88(s,1H),9.94(s,1H),9.40(dd,J=2.4,0.9Hz,1H),8.65(dd,J=4.8,1.6Hz,1H),8.52(dt,J=8.1,2.0Hz,1H),8.31(s,1H),8.00–7.87(m,1 H),7.67(d,J=7.5Hz,1H),7.54(ddd,J=8.0,4.7,0.9Hz,1H),7.40(dd,J=7.9,1.7Hz,1H),7.33–7.22(m,2H),7.15(d,J=8.2Hz,1H),2.24(s,3H). 13 CNMR (151MHz, DMSO-D 6 )δ160.52,152.50,151.66,150.56,148.52,141.62,139.92,139.38,134.63,134.25,13 4.01,132.99,129.58,128.77,127.54,124.96,124.36,114.43,111.61,18.83.HRESIMS m / z 422.0839[M+H] + (calcd for C 21 H 15 C1N 5 OS 422.0842).

[0196] 2-([2,3'-Bipyridyl]-6-ylamino)-N-(4-(trifluoromethoxy)phenyl)thiazole-5-carboxamide

[0197]

[0198] Yellow solid, yield: 41%. 1 H NMR (600MHz, Methanol-d 4 )δ11.92(s,1H),10.29(s,1H),9.42(dd,J=2.3,0.8Hz,1H),8.68(dd,J=4.7,1.6Hz,1H),8.54(dt,J=8.0,1.9Hz,1H),8.33(s ,1H),7.94–7.88(m,1H),7.85–7.80(m,2H),7.68(d,J=7.5Hz,1H),7.59(ddd,J=8.0,4.7,0.9Hz,1H),7.15(d,J=8.2Hz,1H). 13C NMR (151 MHz, DMSO-D 6 )δ163.15,160.59,152.52,151.62,150.60,148.56,144.23,141.90,139.95,138.72,134.62 ,134.25,132.12,131.89,128.68,125.51,124.38,122.09,121.84,114.51,111.65.HRESIMS m / z 458.0893[M+H] + (calcd for C 21 H 14 F 3 N 5 O 2 S 458.0899).

[0199] 2-([2,2'-Bipyridyl]-5-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

[0200]

[0201] Yellow solid, yield: 39%. 1 H NMR (600MHz, Methanol-d 4 )δ11.16(s,1H),10.02(s,1H),9.13–8.78(m,1H),8.68(dt,J=4.8,1.5Hz,1H),8.40(d,J=21.0Hz,3H),8.21(s, 1H),8.05(t,J=7.7Hz,1H),7.50(t,J=6.3Hz,1H),7.40(dd,J=7.8,1.7Hz,1H),7.31–7.24(m,2H),2.23(s,3H). 13 C NMR (151 MHz, DMSO-D 6 )δ166.35,158.61,148.30,142.67,140.94,139.89,139.29,139.12,138.58,137.13,13 3.76,132.87,129.64,128.91,127.59,125.58,124.66,122.19,121.20,18.77.HRESIMS m / z 422.0838[M+H] + (calcd for C 21 H 15 C1N 5 OS422.0842).

[0202] Biological activity

[0203] Cells in the logarithmic growth phase were collected and counted at 5 × 10 3 The density of cells / well was seeded in a 96-well plate. After overnight culture, drugs were added. Adriamycin and 5-fluoro were used as positive drugs. Three sub-wells were set for each concentration and culture was continued for 72 hours. After 72 hours, the 96-well plate was taken out, and 100 μL of 10% trichloroacetic acid aqueous solution was added to each well after discarding the culture medium. It was fixed in a 4°C refrigerator for at least 2 hours. After fixation, the 96-well plate was taken out, the trichloroacetic acid solution was discarded, and it was rinsed at least 4 times with slowly flowing water and dried. Then 80 μL of 0.4% SRB solution prepared with 1% acetic acid was added to stain for 20 minutes. During this period, 1% acetic acid aqueous solution was prepared. After staining, it was rinsed 4 times with 1% acetic acid aqueous solution to remove unbound dyes and dried again. After the 96-well plate was completely dried, 100 μL of 10mM Tris solution was added to each well, and the dye bound to the protein was completely dissolved by shaking. The absorbance was detected at 515nm in an ELISA reader.

[0204] Inhibition rate = (OD value of control group - OD value of drug administration group) / OD value of control group × 100%, IC 50 The values ​​were calculated using Calcusyn software.

[0205] Table 1. IC values ​​of cytotoxicity of active compounds 50 (μM)

[0206]

[0207]

[0208] The specific embodiment of the present invention discloses 46 specific compounds and chemical synthesis methods thereof. The synthesis route is simple, easy to operate and implement, and the required reagents are easy to purchase. The proliferation inhibition activity of the 46 compounds on 9 types of tumor cells was tested at the same time. The results showed that compared with the 30 μM (IC50) of the proliferation inhibition activity of such natural products, the proliferation inhibition activity of the compounds was greatly improved, and the activity could reach tens to hundreds of nanomoles after structural modification. In addition, the proliferation activity of multiple compounds on a variety of cancer cells is better than that of doxorubicin, and is comparable to the results of 5-fluorouracil. They can be used as therapeutic drugs for a variety of cancer-related diseases, and can also be used as protein inhibitors for the treatment of related diseases or conditions.

[0209] In addition, it should be understood that after reading the above description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A bipyridine compound or a pharmaceutically acceptable salt thereof, characterized in that: The bipyridine compound is any of the following compounds:

2. The method for preparing a bipyridine compound according to claim 1, characterized in that: The bipyridine compound is compound 1 to 6, IV1 to IV16, IV18, IV19 or IV22, and the preparation method is to form an amide bond by condensing the corresponding raw materials through an amidation reaction under alkaline conditions. Thus, bipyridine compounds 1-6, IV1-IV16, IV18, IV19 or IV22 are obtained.

3. The method for preparing a bipyridine compound according to claim 1, characterized in that: The bipyridine compound is compound V1, V3, V4, V6, V12-V14 or V16-V18, and the preparation method is to use corresponding raw materials to carry out coupling reaction between the halogen atom on the bipyridine ring and the primary amine under alkaline conditions and in the presence of a catalyst by microwave or heating, thereby obtaining the bipyridine compound V1, V3, V4, V6, V12-V14 or V16-V18.

4. A pharmaceutical composition, characterized in that The pharmaceutical composition contains the bipyridine compound or a pharmaceutically acceptable salt thereof according to claim 1, and one or more pharmaceutically acceptable carriers, diluents and / or excipients.

5. Use of the bipyridine compound or a pharmaceutically acceptable salt thereof according to claim 1 or the pharmaceutical composition according to claim 4 in the preparation of a medicament for treating and / or preventing a disease, characterized in that: The disease is cancer, and the cancer is colon cancer, breast cancer, lung cancer, liver cancer, pancreatic cancer, kidney cancer, osteosarcoma, and gastric cancer.

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