CN116751195A - Bipyridine compound, pharmaceutically acceptable salt thereof, preparation method and application - Google Patents

Bipyridine compound, pharmaceutically acceptable salt thereof, preparation method and application Download PDF

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CN116751195A
CN116751195A CN202310742655.5A CN202310742655A CN116751195A CN 116751195 A CN116751195 A CN 116751195A CN 202310742655 A CN202310742655 A CN 202310742655A CN 116751195 A CN116751195 A CN 116751195A
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cancer
bipyridine
alkoxy
alkyl
nmr
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马忠俊
丁婉婧
汤震
张宁静
陈爽
王金慧
陈晓铭
刘美星
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Hangzhou Kexing Biochem Co ltd
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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Abstract

The application discloses bipyridine compounds or pharmaceutically acceptable salts thereof, a preparation method and application thereof in medicines. The application also discloses 46 specific compounds of the type and a chemical synthesis method thereof, the synthetic route is simple, the operation and the implementation are easy, and the required reagents are easy to purchase. Meanwhile, the proliferation inhibition activity of 46 compounds on 9 tumor cells is tested, and the result shows that compared with the proliferation inhibition activity of the natural products, the proliferation inhibition activity of the compounds is greatly improved by 30 mu M (IC 50), and the activity can reach tens to hundreds of sodium moles after structural modification. In addition, the proliferation activity of the compounds on various cancer cells is better than the action effect of doxorubicin, is equivalent to the result of 5-fluorouracil, can be used as a therapeutic drug for various cancer-related diseases, and can also be used as a protein inhibitor for treating related diseases or symptoms.

Description

Bipyridine compound, pharmaceutically acceptable salt thereof, preparation method and application
Technical Field
The application relates to the technical field of medicines, in particular to a bipyridine compound, pharmaceutically acceptable salts thereof, a preparation method and application.
Background
Cancer is the first leading cause of impact on human life health and quality of life, and is also a worldwide problem. Clinical treatments mainly include therapies such as surgical excision, radiation therapy, and chemotherapy. At present, chemotherapeutic drugs include taxol, platinum-containing drugs, 5-fluorouracil and the like. However, there are also adverse effects of broad-spectrum antitumor drugs, such as bone marrow toxicity, digestive tract reaction, hepatotoxicity, etc., which are difficult to control.
Bipyridine derivatives are a class of alkaloids with unique bipyridine backbones, and the first bipyridine compound, cerulomycin A (Funk, A.; divekar, P.V. caeulomycin, a new antibiotic from Streptomyces caeruleus Baldacci.I.production, isolation, assay, and biological properties [ J ], was found and isolated from Streptomyces bluish (Streptomyces caeruleus)]Several derivatives of Careulomycin B-N and the like were subsequently discovered. Compounds of this type generally have a unique 2,2' -bipyridine backbone, and initial studies have found that they have potent antibacterial and immunosuppressive activities. Wherein the inventor separates four natural products with bipyridine structures as shown in the following formulas 1-4, and researches show that bipyridine compounds have a therapeutic effect on tumor cells HL-60 and K562,The proliferation inhibition of both KB and A549 was 1.6. Mu.M (IC) for compound a 50 ) And 8.4. Mu.M (IC) 50 ) The compound b has inhibitory activity on proliferation of tumor cells HL-60, K562, KB and A549, respectively, greater than 50 μm (IC 50 )、1.8μM(IC 50 ) Greater than 50. Mu.M (IC) 50 ) And 3.1. Mu.M (IC) 50 ) The proliferation inhibition activity of the compound c and the compound d on four tumor cells of HL-60, K562, KB and A549 is more than 50 mu M (IC 50 ) (dx.doi.org/10.1021/np 200258h, J.Nat.Prod.2011,74, 1751-1756). In addition, the inventors have tested by themselves that compounds a-d have proliferation inhibitory activity on both tumor cells HCT-116 and MDA-MB-231 of greater than 30. Mu.M (IC 50 )。
In the early stage, a plurality of bipyridine natural products are separated from actinomycete Streptomyces sp.BC6 secondary metabolites from western Pacific deep sea, and the compounds are found to have a certain inhibition effect on proliferation of various cancer cells, but the activity is required to be improved. This time we have obtained a series of bipyridine derivatives by chemical synthesis for use in the treatment of cancer related diseases or conditions.
Disclosure of Invention
The application provides bipyridine compounds or pharmaceutically acceptable salts thereof, which have the effect of inhibiting cell proliferation on various cancer cells. The application also provides pharmaceutical compositions and medicaments comprising the compounds or salts of the application alone or in combination with additional anti-cancer therapeutic agents or remission agents.
Bipyridine compounds or pharmaceutically acceptable salts thereof, wherein the bipyridine compounds have a structure shown in the following formula I:
in formula I:
X 1 、X 2 、X 3 are each independently a C atom or an N atom and X 1 、X 2 、X 3 Wherein one and only one is an N atom, Y 1 、Y 2 Are different and are respectively and independently C atoms or N atoms, and L is an amide bond, an ester bond or N atoms;
R a 、R b each independently is a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, or heterocyclyl;
R 1 is alkyl, alkoxy, cycloalkyl or heterocyclyl, wherein alkyl, alkoxy, heterocyclyl may be optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, heterocyclyl.
Further, bipyridines or pharmaceutically acceptable salts thereof, said bipyridines having a structure according to any one of the following formulas II to XIV:
in the formulas II to XIV, X 1 、X 2 、X 3 Are each independently a C atom or an N atom and X 1 、X 2 、X 3 Wherein one and only one is an N atom, R 2 Is H, hydroxy or alkoxy, R 3 Is H or alkyl;
in formula II, V, VIII, X, XII, R 4 、R 5 Each independently is H, alkyl, amido, ester, cyano, hydroxyalkyl, nitro, aryl, amino, alkoxy, cycloalkyl, or heterocyclyl, or R 4 、R 5 Connected into a ring;
in formula III, R 4 、R 5 Are respectively and independently H, alkyl, amido, ester, cyano and hydroxylAminoalkyl, nitro, aryl, amino, alkoxy, cycloalkyl or heterocyclyl;
in formula IV, IX, R 5 Is H, alkyl, amido, ester, cyano, hydroxyalkyl, nitro, aryl, amino, alkoxy, cycloalkyl or heterocyclyl;
in formula VI, VII, XI, R 4 -R 8 Each independently is H, alkyl, amide, ester, cyano, hydroxyalkyl, nitro, aryl, amino, alkoxy, cycloalkyl, or heterocyclyl;
in formula XIII, R 4 -R 6 Each independently is H, alkyl, amide, ester, cyano, hydroxyalkyl, nitro, aryl, amino, alkoxy, cycloalkyl, or heterocyclyl;
in formula XIV, R 4 -R 10 Each independently is H, alkyl, amide, ester, cyano, hydroxyalkyl, nitro, aryl, amino, alkoxy, cycloalkyl, or heterocyclyl.
Further, the bipyridine compound is any one of the following compounds:
the application also provides a preparation method of the bipyridine compound, wherein the bipyridine compound has a structure shown in any one of formulas II-VII, and the preparation method is to form an amide bond by adopting corresponding raw materials through amidation reaction condensation under alkaline conditionsThereby obtaining bipyridine compounds with structures shown in any one of formulas II to VII.
The application also provides a preparation method of the bipyridine compound, wherein the bipyridine compound has a structure shown in any one of formulas VIII-XIV, and the preparation method adopts corresponding raw materials to carry out coupling reaction with primary amine or tertiary amine through halogen atoms on a bipyridine ring and microwave or heating under alkaline condition and in the presence of a catalyst, so as to obtain the bipyridine compound with the structure shown in any one of formulas VIII-XIV.
Reagents providing basic conditions in the above synthetic schemes include organic bases including, but not limited to, triethylamine, pyridine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium t-butoxide, potassium t-butoxide, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide; n, N-diisopropylethylamine and/or triethylamine are preferred.
Condensing agents described in the above synthetic schemes include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N '-dicyclohexylcarbodiimide, N, N' -diisopropylcarbodiimide, O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol, O-benzotriazol-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate, 1-ethyl- (3-dimethylaminopropyl) carbodiimidinate, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl) or benzotriazol-1-yloxy-pyrrolidinyl-hexafluorophosphate; preferably 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl).
In the above synthetic schemes, the reaction is preferably carried out in solvents including, but not limited to: pyridine, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane, and mixtures thereof.
The application also provides a pharmaceutical composition containing the bipyridine compound or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents and/or excipients.
The present application relates to a compound of the application or a pharmaceutically acceptable salt thereof for use as a medicament, in particular for the treatment of cancer.
The present application relates to a compound of the application, or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth, particularly cancer, in an individual.
The application provides the use of a compound of any one of the formulae described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating abnormal cell growth in a subject.
In a common embodiment of the foregoing compounds, methods and uses, the abnormal cell growth is cancer.
The application also provides application of the bipyridine compound or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparing medicines for treating and/or preventing diseases. The disease is preferably cancer. The cancer is preferably breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, renal cancer, bladder cancer, urothelial cancer, urinary tract cancer, prostate cancer, testicular cancer, colorectal cancer, sarcoma, bone cancer, multiple myeloma, leukemia, myxoma, rhabdomyoma, smooth myoma, fibroma, lipoma, teratoma, laryngeal cancer, nasopharyngeal cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, small intestine cancer, stomach cancer, esophageal cancer, pancreatic cancer, liver cancer, bile duct cancer, neurofibromas, glioma, neuroblastomas, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, and gastrointestinal stromal tumor.
Detailed Description
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application.
Scheme one, reaction formula of intermediate:
first step
M-chloroperoxybenzoic acid (8.1 g,32.86 mmol) was dissolved in methylene chloride (6.5 mL) and the solution was stirred well. The meta-chloroperoxybenzoic acid solution was slowly added to a solution of bipyridine a (5.0 g,32.1 mmol) in dichloromethane (25 mL) under ice-water bath conditions and reacted at room temperature for 2h. After the reaction is completed: the reaction mixture was diluted with dichloromethane to a final volume of 150mL 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 give 2-pyridin-2-ylpyridin-1-oxide b,4.7g, 94% yield.
Second step
In a 1L flask under ice-bath conditions, concentrated sulfuric acid (0.04 vol,8 mL) was added, 2' -bipyridine N-oxide b (1.883 g,11 mmol) was slowly added to the concentrated sulfuric acid with vigorous stirring (addition time, 15 minutes, exothermic reaction), the reaction system temperature was kept below 80 ℃ (the solution was dark brown), stirred for 10 minutes, then concentrated nitric acid (0.02 vol,4 mL) was slowly added through an addition funnel (addition time, 12 minutes), a color change from brown to orange was observed, the resulting reaction system was heated to 105℃for 4.5 hours, during which a large amount of NO was present 2 The gases are evolved (a trap of aqueous sodium hydroxide is installed to neutralize the gases). After the reaction is completed: the reaction mixture was cooled to room temperature and poured into a triangular flask. Then, neutralization with 36% aqueous sodium hydroxide solution to pH 4.0, precipitation of the desired product was observed, and filtration was performed immediately after neutralization. The product was washed with water and dried in vacuo to give the desired product as a yellow solid, 1.56g, 83% yield.
Third step
Sodium methoxide (0.03 equiv,1.250g,2.31 mmol) was slowly added to an appropriate amount of anhydrous methanol (note: slightly exothermic reaction) under ice-water bath conditions, and compound c (1.676 g,7.7 mmol) was slowly added to the reaction system, which was heated to 68℃and refluxed for 1h. After the reaction is completed: the reaction system was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. Extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give d as a yellow solid, 1.35g, 81% yield.
Fourth step
Compound d (1.35 g,6.7 mmol) was dissolved in an appropriate amount of acetonitrile, stirred well 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℃for 30min. After the reaction is completed: the reaction solution was poured into a 2L Erlenmeyer flask, and a precipitate formed after cooling. Filtration, washing with acetonitrile, drying under reduced pressure gave product, e, as a white solid, 0.986g, 73% yield.
Fifth step
Compound e (1.175 g,5.5 mmol) was dissolved in 10ml ethanol and stirred, sodium hydroxide solution (14.8 mM,15 mL) was slowly added to the reaction solution, and there was some exotherm, and the reaction mixture was heated to 82℃for 1.5h. After the reaction is completed: the reaction solution was cooled to 10 ℃, poured into a 2L conical flask, directly filtered, and the obtained solid was washed with ethanol and water and dried in a vacuum oven to obtain sodium salt as a white solid. Then according to 1: hydrochloric acid was added in an amount of 1 mol to give compound as a white solid f, 1.06g in mass, 90.2% in yield.
Sixth step
Reaction substrate f (130.0 mg,0.93 mmol) was dissolved in 10ml of N, N-dimethylformamide, and triethylamine (336.0 mg,3.3 mmol) was added to the reaction system in a molar ratio of 1:1.2 addition of substrate R 1 And 1-hydroxybenzotriazole (135.0 mg,0.998 mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (191.0 mg,0.998 mmol). The reaction was stirred at room temperature for 18h. After the reaction is completed: n, N-dimethylformamide was removed by rotary evaporation under reduced pressure (50 ℃ C.), 10mL of water was added thereto, and extraction was performed with ethyl acetate (3X 10 mL). Drying with anhydrous sodium sulfate, rotary steaming under reduced pressure, passing through a column, and purifying to obtain the compound of each example, wherein the yield is 29-56%.
4-methoxy-N- (thiazol-2-yl) - [2,2' -bipyridine ] -6-carboxamide
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,1H),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). 13 C 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).
4-methoxy-N- (5-methylthiazol-2-yl) - [2,2' -bipyridine ] -6-carboxamide
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)δ168.26,162.68,158.78,156.35,153.58,150.44,148.89,139.04,135.76,128.00,125.81,123.16,110.20,109.92,56.64,11.68.HRESIMS m/z 327.0915[M+H] + (calcd for C 16 H 14 N 4 O 2 S 327.0916).
2- (4-methoxy- [2,2' -bipyridine ] -6-carboxamide) thiazole-4-carboxamide
White solid, yield: 36%. 1 H 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/z 356.0816[M+H] + (calcd for C 16 H 14 N 5 O 3 S 356.0817).
2- (4-methoxy- [2,2' -bipyridine ] -6-carboxamide) thiazole-4-carboxylic acid ethyl ester
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). 13 C 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).
N- (5-benzothiazol-2-yl) -4-methoxy- [2,2' -bipyridine ] -6-carboxamide
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).
N- (4-methoxy-2-yl) -4-methoxy- [2,2' -bipyridine ] -6-carboxamide
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),8.21(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)δ167.61,163.56,159.31,153.31,149.17,148.66,137.85,128.00,125.15,122.64,120.58,114.86,110.07,109.42,56.08.HRESIMS m/z 338.0706[M+H] + (calcd for C 15 H 12 N 4 O 2 S 338.0712).
Scheme II, reaction general formula of intermediate:
first step
M-chloroperoxybenzoic acid (mCPBA 8.1g,32.86 mmol) was dissolved in methylene chloride (6.5 mL) and the solution was stirred well. A solution of m-chloroperoxybenzoic acid was slowly added to a solution of bipyridine 1 (5.0 g,32.1 mmol) in methylene chloride (25 mL) under ice-water bath conditions, and reacted at room temperature for 2h. After the reaction is completed: the reaction mixture was diluted with dichloromethane to a final volume of 150mL and washed with saturated sodium thiosulfate solution (2×20 mL) and 20% 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 give compound 2.
Second step
Compound 2 (1.35 g,6.7 mmol) was dissolved in an appropriate amount of acetonitrile, stirred well 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℃and dissolved slowly to react for 30min. After the reaction is completed: the reaction solution was poured into a 2L Erlenmeyer flask, and a precipitate formed after cooling. Filtering, washing with acetonitrile, and drying under reduced pressure to obtain white solid 3 of the product.
Third step
Compound 3 (1.175 g,5.5 mmol) was dissolved in 10ml ethanol and stirred, sodium hydroxide solution (14.8 mM,15 mL) was slowly added to the reaction solution, and there was some exotherm, and the reaction mixture was heated to 82℃for 1.5h. After the reaction is completed: the reaction solution was cooled to 10 ℃, poured into a 2L conical flask, directly filtered, and the obtained solid was washed with ethanol and water and dried in a vacuum oven to obtain sodium salt as a white solid. Then according to 1: hydrochloric acid was added in an amount of 1 mol to give compound 4.
Fourth step
Reaction substrate 4 (130.0 mg,0.93 mmol) was dissolved in 10ml of N, N-dimethylformamide, and triethylamine (336.0 mg,3.3 mmol) was added to the reaction system in a molar ratio of 1:1.2 addition of substrate R 1 And 1-hydroxybenzotriazole (135.0 mg,0.998 mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (191.0 mg,0.998 mmol). The reaction was carried out at room temperature for 18h. After the reaction is completed: n, N-dimethylformamide was removed by rotary evaporation under reduced pressure (50 ℃ C.), 10ml of water was added thereto, and extraction was performed with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate, spin-dried, passed through a column and purified to give the compounds of each example in 17% -83% yield.
N- (thiazol-2-yl) - [2,2' -bipyridine ] -6-carboxamide
Yellow solid, yield: 53%. 1 H NMR(600MHz,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(151MHz,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] + (calcd for C 14 H 10 N 4 OS 283.0654).
N- ((thiazol-5 yl) - [2,2' -bipyridine ] -6-carboxamide
Yellow solid, yield: 45%. 1 H NMR(600MHz,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＝6.7,2.3Hz,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(151MHz,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/z 283.0653[M+H] + (calcd for C 14 H 10 N 4 OS 283.0654).
N- (5-methylthiazol-2-yl) - [2,2' -bipyridine ] -6-carboxamide
Pale yellow solid, yield: 52%. 1 H NMR(600MHz,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(151MHz,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).
N- (4- (trifluoromethyl) thiazol-2-yl) - [2,2' -bipyridine ] -6-carboxamide
White solid, yield: 18%. 1 H NMR(600MHz,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(151MHz,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).
N- (4-methylthiazol-2-yl) - [2,2' -bipyridine ] -6-carboxamide
White solid, yield: 49%. 1 H NMR(600MHz,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(151MHz,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).
N- (4- (hydroxymethyl) thiazol-2-yl) - [2,2' -bipyridine ] -6-carboxamide
White solid, yield: 59%. 1 H NMR(600MHz,DMSO-d 6 )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(151MHz,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).
N- (4-Ethyl formate thiazol-2-yl) [2,2' -bipyridine ] -6-carboxamide
White solid, yield: 47%. 1 H NMR(600MHz,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 C NMR(151MHz,CHLOROFORM-D)δ163.55,161.44,160.96,158.19,158.11,157.94,147.74,141.30,139.38,128.91,125.17,124.41,123.84,123.60,122.69,60.61,14.16.HRESIMS m/z 355.0869[M+H] + (calcd for C 17 H 14 N 4 O 3 S 355.0865).
2- ([ 2,2' -bipyridine ] -6-carboxamido) thiazole-5-carboxylic acid ethyl ester
White solid, yield: 37%. 1 H NMR(600MHz,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(151MHz,DMSO-D 6 )δ164.21,162.73,161.96,149.20,148.07,145.76,139.99,133.58,129.22,128.90,125.67,125.09,124.49,123.09,122.67,61.54,14.73.HRESIMS m/z 355.0861[M+H] + (calcd for C 17 H 14 N 4 O 3 S355.0865).
2- ([ 2,2' -bipyridine ] -6-carboxamide) thiazole-4-carboxamide
Yellow solid, yield: 33%. 1 H NMR(600MHz,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)δ168.57,167.76,162.80,158.86,154.15,154.10,152.99,150.59,144.75,144.67,130.38,129.73,128.91,127.68,123.89.HRESIMS m/z 326.0709[M+H] + (calcd for C 15 H 11 N 5 O 2 S 326.0712).
2- ([ 2,2' -bipyridine ] -6-carboxamide) -N, N-dimethylthiazole-4-carboxamide
Yellow solid, yield: 19%. 1 H NMR(600MHz,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＝0.8Hz,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 S 354.1025).
N- (4-cyanothiazol-2-yl) - [2,2' -bipyridine ] -6-carboxamide
Yellow solid, yield: 27%. 1 H NMR(600MHz,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＝7.0,2.1Hz,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] + (calcd for C 15 H 9 N 5 OS 307.0606).
N- (5-cyanothiazol-2-yl) - [2,2' -bipyridine ] -6-carboxamide
Yellow solid, yield: 23%. 1 H NMR(600MHz,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/z 308.0603[M+H] + (calcd for C 15 H 9 N 5 OS 308.0606).
N- (5-nitrothiazol-2-yl) - [2,2' -bipyridine ] -6-carboxamide
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).
N- (2 ' -amino- [4,4' -bisthiazol ] -2-yl) - [2,2' -bipyridine ] -6-carboxamide
Yellow solid, yield: 68%. 1 H NMR(600MHz,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] + (calcd for C 17 H 13 N 6 OS 2 381.0592).
N- (4-phenylthiazol-2-yl) - [2,2' -bipyridine ] -6-carboxamide
White solid, yield: 72%. 1 H NMR(600MHz,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).
N- (5-amino-1, 3, 4-thiadiazol-2-yl) - [2,2' -bipyridine ] -6-carboxamide
White solid, yield: 53%. 1 H NMR(600MHz,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＝6.6,2.4Hz,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(151MHz,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).
N- (isoxazol-3-yl) - [2,2' -bipyridine ] -6-carboxamide
White solid, yield: 48%. 1 H NMR(600MHz,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 2 267.0882).
N- (1, 3, 4-thiadiazol-2-yl) - [2,2' -bipyridine ] -6-carboxamide
Yellow solid, yield: 46%. 1 H NMR(600MHz,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),8.68(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(151MHz,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).
N- (benzothiazol-2-yl) - [2,2' -bipyridine ] -6-carboxamide
White solid, yield: 52%. 1 H NMR(600MHz,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(dddd,J＝24.9,8.3,7.1,1.3Hz,1H),7.36(dddd,J＝26.1,8.2,7.1,1.2Hz,1H). 13 C NMR(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.HRESIMS m/z 333.0809[M+H] + (calcd for C 18 H 12 N 4 OS 333.0810).
N- (1H-indol-7-yl) - [2,2' -bipyridine ] -6-carboxamide
Yellow solid, yield: 37%. 1 H NMR(600MHz,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)δ163.17,158.96,158.71,150.14,148.85,148.78,142.98,142.93,139.91,127.89,127.50,126.72,125.79,124.19,123.69,122.87,120.94,118.54.HRESIMS m/z 316.1194[M+H] + (calcd for C 18 H 13 N 5 O 316.1198).
N- (1H-indol-3-yl) - [2,2' -bipyridine ] -6-carboxamide
Yellow solid, yield: 27%. 1 H NMR(600MHz,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＝7.8Hz,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(151MHz,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/z 316.1197[M+H] + (calcd for C 18 H 13 N 5 O 316.1198).
N- (4-cyanothiazol-2-yl) - [2,4' -bipyridine ] -6-carboxamide
White solid, yield: 37%. 1 H NMR(600MHz,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(151MHz,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).
Scheme three, reaction formula of intermediate:
first, using a schlenk high temperature and high pressure tube, compound a (23.58 mg,1 mmol) was dissolved in 5mL of toluene, and to the reaction solution, substrate amine (1.05-1.4 equiv), anhydrous potassium carbonate 106mg (1.4 equiv), tris (dibenzylideneacetone) dipalladium 3.6mg (4% mmol), xantphos 5.2mg (12% mmol), nitrogen protection, 110 ℃ C., was added, and reacted for 20 hours. After the reaction was completed, it was cooled at room temperature, diluted with tetrahydrofuran, and concentrated under reduced pressure. The crude product is passed through a column, and then is separated and purified through a silica gel column and a liquid phase preparation column, so that the compound of each example is obtained, and the yield is 17% -75%.
N- ([ 2,2' -bipyridyl ] -6-yl) thiazol-2-amine
Yellow solid, yield: 45%. 1 H NMR(600MHz,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(151MHz,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).
N- ([ 2,2' -bipyridyl ] -6-yl) -N-methylthiazol-2-amine
White solid, yield: 33%. 1 H NMR(600MHz,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(151MHz,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).
2- ([ 2,2' -bipyridyl ] -6-ylamino) thiazole-5-carboxylic acid ethyl ester
White solid, yield: 33%. 1 H NMR(600MHz,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,1H),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/z 327.0913[M+H] + (calcd for C 16 H 14 N 4 O 2 S 327.0916).
2- ([ 2,2' -bipyridyl ] -6-ylamino) thiazole-4-carboxamide
Yellow solid, yield: 29%. 1 H NMR(600MHz,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).
N- (pyrimidin-2-yl) - [2,2' -bipyridin ] -6-amine
Yellow solid, yield: 25%. 1 H NMR(600MHz,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(151MHz,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).
N- ([ 2,3' -bipyridyl ] -6-yl) thiazol-2-amine
Yellow solid, yield: 42%. 1 H NMR(600MHz,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(151MHz,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).
N- ([ 2,2' -bipyridyl ] -6-yl) -1H-indazol-3-amine
Yellow solid, yield: 31%. 1 H NMR(600MHz,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). 13 C NMR(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/z 288.1244[M+H] + (calcd for C 17 H 13 N 5 288.1249).
N- ([ 2,2' -bipyridyl ] -6-yl) -6-fluoro-1H-indazol-3-amine
Yellow solid, yield: 22%. 1 H NMR(600MHz,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] + (calcd for C 17 H 12 FN 5 306.1155).
N- ([ 2,2' -bipyridyl ] -6-yl) -1,3, 4-thiadiazol-2-amine
Yellow solid, yield: 41%. 1 H NMR(600MHz,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),8.06–8.00(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(151MHz,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).
N- ([ 2,2' -bipyridyl ] -6-yl) isoxazol-3-amine
White solid, yield: 43%. 1 H NMR(600MHz,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＝7.7,1.8Hz,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(151MHz,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).
N- ([ 2,2' -bipyridyl ] -5-yl) thiazol-2-amine
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(151MHz,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).
2- ([ 2,2' -bipyridyl ] -6-ylamino) -N- (4- (trifluoromethoxy) phenyl) thiazole-5-carboxamide
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Yellow solid, yield: 27%. 1 H 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 S 458.0899).
2- ([ 2,2' -bipyridyl ] -6-ylamino) -N- (3, 5-difluorobenzyl) thiazole-5-carboxamide
White solid, yield: 35%. 1 H NMR(600MHz,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(151MHz,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.HRESIMS m/z 424.1040[M+H] + (calcd for C 21 H 15 F 2 N 5 OS 424.1044).
2- ([ 2,2' -bipyridyl ] -6-ylamino) -N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) thiazole-5-carboxamide
Yellow solid, yield: 17%. 1 H NMR(600MHz,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 C NMR(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 H 18 F 3 N 7 OS 522.1324).
N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) - [2,2' -bipyridin ] -6-amine
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Yellow solidBody, yield: 56%. 1 H NMR(600MHz,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(151MHz,DMSO-D 6 )δ158.90,158.66,155.72,154.88,153.48,149.79,144.36,139.66,137.91,136.79,134.83,131.55,124.77,120.94,118.07,114.83,114.61,113.58,112.95,110.53,10.36.HRESIMS m/z 396.1435[M+H] + (calcd for C 21 H 16 F 3 N 5 396.1436).
2- ([ 2,3' -bipyridyl ] -6-ylamino) -N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
White solid, yield: 37%. 1 H 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,1H),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 C NMR(151MHz,DMSO-D 6 )δ160.52,152.50,151.66,150.56,148.52,141.62,139.92,139.38,134.63,134.25,134.01,132.99,129.58,128.77,127.54,124.96,124.36,114.43,111.61,18.83.HRESIMS m/z 422.0839[M+H] + (calcd for C 21 H 15 ClN 5 OS 422.0842).
2- ([ 2,3' -bipyridyl ] -6-ylamino) -N- (4- (trifluoromethoxy) phenyl) thiazole-5-carboxamide
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). 13 C NMR(151MHz,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).
2- ([ 2,2' -bipyridyl ] -5-ylamino) -N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
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(151MHz,DMSO-D 6 )δ166.35,158.61,148.30,142.67,140.94,139.89,139.29,139.12,138.58,137.13,133.76,132.87,129.64,128.91,127.59,125.58,124.66,122.19,121.20,18.77.HRESIMS m/z 422.0838[M+H] + (calcd for C 21 H 15 ClN 5 OS 422.0842).
Biological Activity
Cells in logarithmic growth phase were collected and grown at 5X 10 3 The density of cells/hole is planted in a 96-well plate, after overnight culture, the medicine is added, doxorubicin and 5-fluorine are taken as positive medicines, 3 auxiliary holes are arranged at each concentration, and the culture is continued for 72 hours. After 72h, the 96-well plates were removed, and after removal of the medium, 100. Mu.L of 10% aqueous trichloroacetic acid was added to each well and fixed in a refrigerator at 4℃for at least 2h. After fixing, the 96-well plate was removed, the trichloroacetic acid solution was discarded, washed with slowly flowing water for at least 4 times and dried, and then stained 2 with 80. Mu.L of 0.4% SRB solution prepared with 1% acetic acidAnd (3) preparing a 1% acetic acid aqueous solution during 0min, washing with the 1% acetic acid aqueous solution for 4 times after dyeing is finished to remove unbound dye, and drying again. After the 96-well plate was completely dried, 100. Mu.L of 10mM Tris solution was added to each well, and the dye bound to the protein was completely dissolved by shaking, and absorbance was measured at 515nm in a microplate reader.
Inhibition ratio = (control OD-dosing OD)/control OD x 100%, IC 50 The values were calculated using Calcusyn software.
TABLE 1 cytotoxic IC of active Compounds 50 (μM)
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The specific embodiment of the application discloses specific 46 compounds and a chemical synthesis method thereof, the synthesis route is simple, the operation and the implementation are easy, and the required reagents are easy to purchase. Meanwhile, the proliferation inhibition activity of 46 compounds on 9 tumor cells is tested, and the result shows that compared with the proliferation inhibition activity of the natural products, the proliferation inhibition activity of the compounds is greatly improved by 30 mu M (IC 50), and the activity can reach tens to hundreds of sodium moles after structural modification. In addition, the proliferation activity of the compounds on various cancer cells is better than the action effect of doxorubicin, is equivalent to the result of 5-fluorouracil, can be used as a therapeutic drug for various cancer-related diseases, and can also be used as a protein inhibitor for treating related diseases or symptoms.
Further, it is to be understood that various changes and modifications of the present application may be made by those skilled in the art after reading the above description of the application, and that such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (9)

1. Bipyridine compound or pharmaceutically acceptable salt thereof, wherein the bipyridine compound has a structure shown in the following formula I:
in formula I:
X 1 、X 2 、X 3 are each independently a C atom or an N atom and X 1 、X 2 、X 3 Wherein one and only one is an N atom, Y 1 、Y 2 Are different and are respectively and independently C atoms or N atoms, and L is an amide bond, an ester bond or N atoms;
R a 、R b each independently is a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, or heterocyclyl;
R 1 is alkyl, alkoxy, cycloalkyl or heterocyclyl, wherein alkyl, alkoxy, heterocyclyl may be optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, heterocyclyl.
2. Bipyridine compounds or pharmaceutically acceptable salts thereof, wherein the bipyridine compounds have a structure represented by any one of the following formulas II to XIV:
in the formulas II to XIV, X 1 、X 2 、X 3 Are each independently a C atom or an N atom and X 1 、X 2 、X 3 Wherein one and only one is an N atom, R 2 Is H, hydroxy or alkoxy, R 3 Is H orAn alkyl group;
in formula II, V, VIII, X, XII, R 4 、R 5 Each independently is H, alkyl, amido, ester, cyano, hydroxyalkyl, nitro, aryl, amino, alkoxy, cycloalkyl, or heterocyclyl, or R 4 、R 5 Connected into a ring;
in formula III, R 4 、R 5 Each independently is H, alkyl, amide, ester, cyano, hydroxyalkyl, nitro, aryl, amino, alkoxy, cycloalkyl, or heterocyclyl;
in formula IV, IX, R 5 Is H, alkyl, amido, ester, cyano, hydroxyalkyl, nitro, aryl, amino, alkoxy, cycloalkyl or heterocyclyl;
in formula VI, VII, XI, R 4 -R 8 Each independently is H, alkyl, amide, ester, cyano, hydroxyalkyl, nitro, aryl, amino, alkoxy, cycloalkyl, or heterocyclyl;
in formula XIII, R 4 -R 6 Each independently is H, alkyl, amide, ester, cyano, hydroxyalkyl, nitro, aryl, amino, alkoxy, cycloalkyl, or heterocyclyl;
in formula XIV, R 4 -R 10 Each independently is H, alkyl, amide, ester, cyano, hydroxyalkyl, nitro, aryl, amino, alkoxy, cycloalkyl, or heterocyclyl.
3. Bipyridines or pharmaceutically acceptable salts thereof according to claim 2, wherein the bipyridines are any of the following compounds:
4. the method for preparing bipyridine compounds according to claim 2, wherein the bipyridine compounds have a structure shown in any one of formulas II to VII, the method for preparing the bipyridine compounds comprises the steps ofTo form an amide bond by condensation of the corresponding raw materials by amidation reaction under alkaline conditionsThereby obtaining bipyridine compounds with structures shown in any one of formulas II to VII.
5. The preparation method of the bipyridine compound according to claim 2, wherein the bipyridine compound has a structure shown in any one of formulas VIII-XIV, and the preparation method is characterized in that the bipyridine compound shown in any one of formulas VIII-XIV is obtained by coupling reaction of corresponding raw materials through halogen atoms on a bipyridine ring or an oxazine ring and primary amine or tertiary amine under alkaline conditions and in the presence of a catalyst by microwave or heating.
6. A pharmaceutical composition comprising a bipyridine compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents and/or excipients.
7. Use of a bipyridine compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6 in the manufacture of a medicament for the treatment and/or prophylaxis of a disease.
8. The use according to claim 7, wherein the disease is cancer.
9. The use according to claim 8, wherein the cancer is breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, urothelial cancer, urinary tract cancer, prostate cancer, testicular cancer, colorectal cancer, sarcoma, bone cancer, multiple myeloma, leukemia, myxoma, rhabdomyoma, smooth myoma, fibroma, lipoma, teratoma, throat cancer, nasopharyngeal cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, small intestine cancer, stomach cancer, esophagus cancer, pancreatic cancer, liver cancer, bile duct cancer, neurofibromas, glioma, neuroblastomas, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer and gastrointestinal stromal tumor.
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CN109689632A (en) * 2016-07-11 2019-04-26 巴鲁克斯布伦博格研究所 Substituted-amino thiazole
CN115531387A (en) * 2016-10-26 2022-12-30 里格尔药品股份有限公司 Pyrazole amide compounds useful as IRAK inhibitors

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US20180273510A1 (en) * 2015-02-04 2018-09-27 Beyondbio Inc. Heterocyclic compound and pharmaceutical composition comprising same
CN105218523A (en) * 2015-09-18 2016-01-06 上海吉铠医药科技有限公司 Pyridine derivate PIM kinase inhibitor and preparation method thereof and the application in pharmacy
CN109689632A (en) * 2016-07-11 2019-04-26 巴鲁克斯布伦博格研究所 Substituted-amino thiazole
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