CN111116559A - Pyridine urea compound and preparation method and pharmaceutical application thereof - Google Patents

Pyridine urea compound and preparation method and pharmaceutical application thereof Download PDF

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CN111116559A
CN111116559A CN201811296151.0A CN201811296151A CN111116559A CN 111116559 A CN111116559 A CN 111116559A CN 201811296151 A CN201811296151 A CN 201811296151A CN 111116559 A CN111116559 A CN 111116559A
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pyridylurea
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孙逊
俞立挺
陈代杰
董晓景
唐美麟
孟志
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Fudan University
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    • C07—ORGANIC CHEMISTRY
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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
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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Abstract

The invention belongs to the field of biological medicines, and relates to a pyridylurea compound, a preparation method and medicinal application thereof, in particular to application in preparation of a gram-positive bacteria resistant medicament. The structural formula of the pyridylurea compound and the salt thereof is shown as a formula (I). The experimental result shows that the compound has single or combined gram-positive bacteria resistant activity and can be specifically used for resisting methicillin-resistant staphylococcus, linezolid-resistant staphylococcus, vancomycin-resistant enterococcus, staphylococcus and streptococcus pneumoniae.

Description

Pyridine urea compound and preparation method and pharmaceutical application thereof
Technical Field
The invention belongs to the field of biological medicines, and relates to a pyridylurea compound, a preparation method and pharmaceutical application thereof, in particular to application in preparation of medicaments for resisting gram-positive bacteria.
Background
Since the discovery of penicillin by fleming in the last 30 centuries, the widespread use of antibiotics has been reported to save the health of millions of people and also to lead to drug resistance of a large number of bacteria, MRSA (methicillin-resistant staphylococcus aureus) represented by positive resistant bacteria has risen to the first place of clinically isolating positive pathogenic bacteria, and vancomycin, the "last line of defense" for treating MRSA, has also been taken.
Researches show that the mechanism of MRSA drug resistance is various, including target change (PBP2a), reduction of bacterial membrane permeability, influence of efflux pumps, generation of broad-spectrum hydrolase and the like, and the drug resistance mechanism causes the previously widely used β -lactams, glycopeptides, tetracyclines, quinolones and the like to be in failure, so that the research of antibacterial drugs based on new targets has great practical significance.
It is now known that helicases and topoisomerase IV are enzymes specific to bacteria and indispensable in DNA replication, transcription and recombination processes, in which helicases are composed of homodimers (GyrA)2(GyrB)2The topoisomerase IV consists of homodimers (ParC)2(ParE)2The composition has a structure which is highly conserved among different strains, and lays a foundation for finding broad-spectrum antibacterial drugs; in amino acid sequence and protein space structure, GyrA is similar to ParC, and GyrB is similar to ParE, which provides favorable conditions for finding double-target small-molecule inhibitors; currently, dual inhibitors acting on GyrB and ParE are mainly in preclinical research stage, and because the probability of simultaneous mutation of two targets is low, the active small molecules are not easy to have drug resistance.
Based on the current research situation of the prior art, the inventor of the application intends to provide a gyrB/ParE dual inhibitor and medicinal application thereof.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a gyrB/ParE dual inhibitor, in particular to a pyridylurea compound and a pharmaceutically acceptable salt thereof.
A second object of the present invention is to provide a process for the preparation of the pyridylurea compound as described above.
The third object of the present invention is to provide the use of the above-mentioned pyridylurea compound or a pharmaceutically acceptable salt thereof.
The purpose of the invention is implemented by the following technical scheme:
the invention provides a pyridylurea compound which is characterized by being a compound shown as a formula I
Figure BDA0001851227320000021
Wherein the content of the first and second substances,
R1is selected from
Figure BDA0001851227320000022
R2Is selected from
Figure BDA0001851227320000023
R3Is selected from C1-6An alkyl group;
R4is selected from
Figure BDA0001851227320000024
R5、R6、R7、R8Independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-6Alkoxy, hydroxy, C1-6Alkyl, acyloxy, amido, trifluoromethyl,
Figure BDA0001851227320000025
Or R5、R6、R7Any 2 of which form a 6-membered oxygen atom containing heterocyclic ring;
R9selected from H, C1-6An alkyl group;
R10selected from trifluoromethyl, difluoromethyl, trifluoromethylthio, C1-6An alkyl group;
n is 0, 1,2, 3.
In an embodiment of the invention, R5、R6、R7、R8Independently selected from hydrogen, chlorine, cyano, methoxy, hydroxy, methyl, acetoxy, methoxy,
Figure BDA0001851227320000031
or R5、R6、R7Any 2 of which form a dioxane;
in an embodiment of the invention, R5、R6、R7At least two are not hydrogen;
in an embodiment of the invention, R3Is ethyl;
in an embodiment of the invention, R9Is methyl;
in an embodiment of the invention, R4Is selected from
Figure BDA0001851227320000032
In an embodiment of the invention, R2Is selected from
Figure BDA0001851227320000033
In an embodiment of the invention, R1Is composed of
Figure BDA0001851227320000034
In an embodiment of the invention, R1Is composed of
Figure BDA0001851227320000035
In an embodiment of the present invention, the pyridinureas and pharmaceutically acceptable salts thereof are selected from:
Figure BDA0001851227320000041
Figure BDA0001851227320000051
the pharmaceutically acceptable salts of the pyridylurea compounds comprise organic alkali salts, inorganic alkali salts, organic acid salts or inorganic acid salts thereof; wherein the inorganic base includes, but is not limited to, sodium hydroxide, potassium carbonate, sodium carbonate; the organic bases include, but are not limited to, methylamine, ethylamine, triethylamine; such organic acids include, but are not limited to, fumaric acid, maleic acid, tartaric acid, malic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, formic acid; the inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid.
The invention provides a preparation method of the pyridylurea compound, which comprises the following steps:
the reaction scheme of the preparation method of the compounds 1a-1i and 1w-1z is as follows:
Scheme 1
Figure BDA0001851227320000052
the method comprises the following steps:
1) general procedure for the synthesis of intermediate 2: dissolving the compound 1 in N, N-dimethylformamide, adding N-iodosuccinimide (NIS), stirring at 70 deg.C until the reaction is complete, and separating by chromatographic column to obtain intermediate 2;
2) general procedure for the synthesis of intermediate 3: dissolving the intermediate 2 in an organic solvent such as pyridine, 1, 2-dichloroethane and the like, then adding ethyl isocyanate, stirring at 70-110 ℃ until the reaction is complete, removing the solvent by spinning, and washing residues with tert-butyl methyl ether to obtain an intermediate 3;
3) general procedure for the synthesis of target compound 4: dissolving compound 3 and different arylboronic acids (esters) in an organic solvent such as 1, 4-dioxane, adding Pd (dppf) Cl under the protection of inert gas2Potassium carbonate aqueous solution, stirring at 80-100 ℃ until the reaction is complete, and thenSeparating by a chromatographic column to obtain a target compound 4;
4) general procedure for the synthesis of target compound 5: dissolving the intermediate 4 in an organic solvent such as dichloromethane, adding a dichloromethane solution of boron tribromide at 0 ℃, stirring at room temperature until the reaction is complete, adding methanol to quench the reaction, and performing LC-MS (liquid chromatography-mass spectrometry) preparation, separation and purification to obtain a target compound 5;
5) general procedure for the synthesis of target compound 6: dissolving the intermediate 5 in an organic solvent such as pyridine, adding acetic anhydride, stirring at room temperature until the reaction is complete, removing the solvent by spinning, and separating the residue by a chromatographic column to obtain a target compound 6;
6) general procedure for the synthesis of target compound 7: dissolving compound 3 and different arylboronic acids (esters) in an organic solvent such as 1, 4-dioxane, adding Pd (dppf) Cl under the protection of inert gas2And potassium carbonate aqueous solution, stirring at the temperature of 80-100 ℃ until the reaction is complete, and separating by a chromatographic column to obtain a target compound 7.
Compounds 1j-1v, the reaction scheme of the preparation method is as follows:
Scheme 2
Figure BDA0001851227320000061
the method comprises the following steps:
1) general procedure for the synthesis of intermediate 8: dissolving 3 and 5-chloro-3-pyridineboronic acid in an organic solvent such as 1, 4-dioxane; adding Pd (dppf) Cl under the protection of inert gas2Stirring a potassium carbonate aqueous solution at the temperature of 80-100 ℃ until the reaction is complete, removing the solvent by spinning, washing the residue with water, and washing the residue with tert-butyl methyl ether to obtain an intermediate 8;
2) general procedure for the synthesis of target compound 9: dissolving 8 and various arylboronic acids (esters) in organic solvents such as n-butanol and water; under the protection of inert gas, adding palladium acetate, 2-dicyclohexyl phosphorus-2 ', 4 ', 6 ' -triisopropyl biphenyl (Xphos) and cesium hydroxide aqueous solution, stirring at room temperature until the reaction is complete, and separating by a chromatographic column to obtain the target compound 9.
Furthermore, the invention provides the application of the pyridylurea compound in preparing medicaments for resisting gram-positive bacteria; the gram-positive bacteria are staphylococcus, methicillin-resistant staphylococcus, linezolid-resistant staphylococcus, enterococcus, vancomycin-resistant enterococcus and streptococcus pneumoniae; the compound is subjected to in vitro antibacterial activity test, and the experimental result shows that part of the compound has better activity for resisting MRSA, vancomycin-resistant enterococcus and linezolid-resistant staphylococcus; the results show that the compound and the salt thereof can be used for resisting gram-positive bacteria.
The invention also provides a pharmaceutical composition, which is characterized by comprising a therapeutically effective amount of the pyridylurea compound and pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients, and the pharmaceutical composition can be used for resisting gram-positive bacteria.
The invention provides a pyridylurea compound, a preparation method and medicinal application thereof, in particular to application in preparing medicaments for resisting gram-positive bacteria. Experimental results show that the pyridylurea compound and the salt thereof have single or combined gram-positive bacteria resistant activity, and can be used for preparing medicines for resisting methicillin-resistant staphylococcus, linezolid-resistant staphylococcus, vancomycin-resistant enterococcus, staphylococcus and streptococcus pneumoniae.
Detailed Description
The present invention will be further illustrated with reference to the following specific embodiments, but these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
Example 1: 5-iodo-4- (3- (trifluoromethyl) -1H-pyrazol-1-yl) pyridin-2-amine
Figure BDA0001851227320000071
2-amino-4- (3-trifluoromethyl-1H-pyrazol-1-yl) pyridine (11.6g, 50.9mmol) was weighed out and placed in a 250mL three-necked flask, N-dimethylformamide (120mL) was added, N-iodosuccinimide (NIS) (12.5g, 55.3mmol) was added, and stirring was carried out at 60 ℃ overnight. After cooling, water was added, ethyl acetate was extracted three times, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was washed with tert-butyl methyl ether to give 11.5g of a gray solid in 64% yield.
Example 2
1-ethyl-3-(5-iodo-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)urea
Figure BDA0001851227320000081
The above intermediate 10(11.5g,32.5mmol) was placed in a 250mL eggplant-shaped flask, dissolved in pyridine (100mL), and ethyl isocyanate (12mL) was added thereto, followed by stirring at 90 ℃ overnight. The reaction was cooled and concentrated, and the residue was washed with t-butyl methyl ether to give 8.6g of a white solid in 62% yield.
Example 3:
1-(5'-(2,3-dimethoxyphenyl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyri din]-6-yl)-3-ethylurea
Figure BDA0001851227320000082
intermediate 11(2g,4.7mmol) and 5- (2, 3-dimethoxyphenyl) pyridine-3-boronic acid ester (1.92g, 5.64mmol) were dissolved in 1, 4-dioxane (47ml) and Pd (PPh) was added under inert gas3)2Cl2(383mg, 0.47mmol), potassium carbonate (1.3g, 9.4mmol) and water (4.7ml) were then stirred at 100 ℃ until the starting material reaction was complete. After cooling, the solvent was removed by rotation, water was added to the residue, extraction was carried out three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated by chromatography to give 1a 1.7g of a white solid with a yield of 70%.1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.63(d,J＝2.0Hz,1H),8.52(s,1H),8.33(d,J＝2.1Hz,1H),8.03(s,1H),7.93(s,1H),7.48–7.40(m,2H),7.16–7.07(m,2H),6.95(d,J＝2.4Hz,1H),6.80(dd,J＝6.7,2.5Hz,1H),3.84(s,3H),3.51(s,3H),3.25–3.13(m,2H),1.10(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.38,154.18,152.76,149.71,148.53,147.17,145.97,145.33,142.78(q,J＝37.0Hz),135.81,134.31,133.02,131.06,130.00,124.33,121.77,121.49,121.02(q,J＝267.0Hz),113.25,107.21,106.04,60.15,55.79,33.92,15.18.19F NMR(376MHz,DMSO-d6)δ-60.77(s,3F).HRMS(ESI)calcd for C25H24F3N6O3 +[(M+H)+]513.1857,found 513.1864。
Example 4:
1-(5'-(2,3-dihydroxyphenyl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyrid in]-6-yl)-3-ethylurea
Figure BDA0001851227320000091
the intermediate 1a (1g, 1.95mmol) was weighed, placed in a 50mL eggplant-shaped bottle, dichloromethane (20mL) was added, stirred for 5 minutes in an ice-water bath, a solution of boron tribromide in dichloromethane (20mL, 1M) was added, stirred overnight at room temperature, methanol was added dropwise to quench the reaction, the solvent was removed by spinning, and the residue was purified by LC-MS separation to give 520mg of a white solid, yield 55%.1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),9.57(s,1H),8.73(d,J＝1.4Hz,1H),8.60(s,1H),8.52(s,1H),8.22(d,J＝1.6Hz,1H),8.00(s,1H),7.92(s,1H),7.49(s,1H),7.45(s,1H),6.95(d,J＝1.9Hz,1H),6.82(d,J＝7.5Hz,1H),6.69(t,J＝7.8Hz,1H),6.60(d,J＝7.4Hz,1H),3.25–3.12(m,2H),1.10(t,J＝7.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.33,154.20,149.71,148.77,146.25,145.65,145.27,142.81(q,J＝37.0Hz),142.81,135.65,134.34,133.94,129.81,124.33,121.57,121.06(q,J＝267.0Hz),120.31,119.37,115.26,107.26,106.12,33.94,15.20.19F NMR(376MHz,DMSO-d6)δ-60.68(s,3F).HRMS(ESI)calcd for C23H20F3N6O3 +[(M+H)+]485.1543,found 485.1548。
Example 5:
3-(6'-(3-ethylureido)-4'-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-5-y l)-1,2-phenylene diacetate
Figure BDA0001851227320000101
intermediate 1b (484mg,1mmol) was dissolved in pyridine (10ml), acetic anhydride (1ml, 10mmol) was added and then stirred at room temperature until the starting material reaction was complete. The solvent was removed by rotation and the residue was chromatographed to give 1c 280mg of a white solid in 49% yield.1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.51(s,2H),8.24(s,1H),8.07(s,1H),7.94(s,1H),7.54(s,1H),7.42(t,J＝7.7Hz,2H),7.37(d,J＝7.2Hz,1H),7.28(d,J＝7.4Hz,1H),6.96(d,J＝1.8Hz,1H),3.24–3.15(m,2H),2.29(s,3H),2.13(s,3H),1.10(t,J＝7.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ168.15,167.90,154.50,154.20,149.80,148.06,147.57,145.29,142.83(q,J＝37.0Hz),142.82,139.54,135.68,134.24,132.19,131.69,130.53,127.61,126.86,123.95,121.18,120.99(q,J＝268.0Hz),107.05,106.12,33.95,20.35,19.85,15.20.19F NMR(376MHz,DMSO-d6)δ-60.82(s,3F).HRMS(ESI)calcd forC27H24F3N6O5 +[(M+H)+]569.1755,found 569.1760。
Example 6:
1-(5'-(3,4-dimethoxyphenyl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyri din]-6-yl)-3-ethylurea
Figure BDA0001851227320000111
the same procedures used in example 3 were repeated to give 1d 1.3g of a white solid in a yield of 80%.1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.83(d,J＝1.8Hz,1H),8.57(s,1H),8.20(d,J＝1.7Hz,1H),8.03(d,J＝1.6Hz,1H),7.94(s,1H),7.69(s,1H),7.45(s,1H),7.22–7.13(m,2H),7.07–7.01(m,1H),6.97(d,J＝2.5Hz,1H),3.81(d,J＝11.7Hz,6H),3.24–3.13(m,2H),1.10(t,J＝6.9Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.36,154.17,149.86,149.21,149.17,146.73,146.42,145.24,142.78(q,J＝37.7Hz),135.06,134.35,133.23,130.28,129.04,121.40,120.02(q,J＝267.0Hz),119.13,112.18,110.44,107.11,106.00,55.56(d,J＝2.4Hz),33.91,15.17.19F NMR(376MHz,DMSO-d6)δ-60.68(s,3F).HRMS(ESI)calcd for C25H24F3N6O3 +[(M+H)+]513.1857,found 513.1861。
Example 7:
1-(5'-(3,4-dihydroxyphenyl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyrid in]-6-yl)-3-ethylurea
Figure BDA0001851227320000112
the same procedures used in example 4 were repeated to give 1e 650mg of a white solid in a yield of 57%.1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),9.30(s,1H),9.05(s,1H),8.68(d,J＝2.0Hz,1H),8.55(s,1H),8.17(d,J＝1.9Hz,1H),8.01(s,1H),7.92(s,1H),7.52(t,J＝1.9Hz,1H),7.44(s,1H),7.01(d,J＝1.9Hz,1H),6.95(d,J＝2.4Hz,1H),6.85(dd,J＝8.2,1.9Hz,1H),6.81(d,J＝8.2Hz,1H),3.26–3.14(m,2H),1.10(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.33,154.20,149.77,146.32,145.99,145.82,145.30,142.79(q,J＝37.0Hz),135.41,134.39,132.84,130.23,127.68,121.62,121.05(q,J＝276.0Hz),117.98,116.05,114.07,107.22,106.06,33.93,15.20.19F NMR(376MHz,DMSO-d6)δ-60.69(s,3F).HRMS(ESI)calcd for C23H20F3N6O3 +[(M+H)+]485.1543,found 485.1547。
Example 8:
4-(6'-(3-ethylureido)-4'-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-5-y l)-1,2-phenylene diacetate
Figure BDA0001851227320000121
the same procedures used in example 5 were repeated to give 1f 230mg of a white solid in a yield of 80%.1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),8.86(t,J＝6.7Hz,1H),8.59(s,1H),8.24(d,J＝1.6Hz,1H),8.03(d,J＝1.3Hz,1H),7.94(s,1H),7.94(s,1H),7.75(d,J＝1.9Hz,1H),7.62(dd,J＝8.4,2.0Hz,1H),7.56(d,J＝2.0Hz,1H),7.44(s,1H),7.39(d,J＝8.4Hz,1H),6.95(d,J＝2.4Hz,1H),3.25–3.12(m,2H),2.35–2.28(m,6H),1.10(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ168.15,168.11,154.47,154.20,149.94,147.80,146.56,145.29,142.84(q,J＝37.0Hz),142.52,142.22,135.16,134.46,133.87,133.58,130.46,124.98,124.29,122.06,121.26,121.04(q,J＝267.0Hz),107.17,106.11,33.95,20.33,20.22,15.20.19FNMR(376MHz,DMSO-d6)δ-60.75(s,3F).HRMS(ESI)calcd for C27H24F3N6O5 +[(M+H)+]569.1755,found569.1760。
Example 9:
1-(5-(5,6-dimethoxyquinolin-3-yl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridi n-2-yl)-3-ethylurea
Figure BDA0001851227320000131
the same procedures used in example 3 were repeated to give 1g 1.4g of a white solid in a yield of 58%.1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),8.50(s,1H),8.13(d,J＝2.0Hz,1H),8.05(d,J＝1.8Hz,1H),7.96(s,1H),7.88(s,1H),7.44(s,1H),7.35(s,1H),7.28(s,1H),6.88(d,J＝2.3Hz,1H),3.93(s,3H),3.89(s,3H),3.26–3.15(m,2H),1.10(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.21,154.13,152.50,150.02,149.81,147.01,145.15,143.66,142.73(q,J＝38.0Hz),134.22,133.34,125.78,122.88,121.89,121.04(q,J＝267.0Hz),107.37,106.97,106.04,105.65,55.69,55.67,33.92,15.20.19F NMR(376MHz,DMSO-d6)δ-60.68(s,3F).HRMS(ESI)calcd for C23H22F3N6O3 +[(M+H)+]487.1700,found 487.1705。
Example 10:
1-(5-(5,6-dihydroxyquinolin-3-yl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)-3-ethylurea
Figure BDA0001851227320000132
the same procedure used in example 4 was repeated to give 1h 620mg of a yellow solid in 67% yield.1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.95(s,1H),9.53(s,1H),8.50(s,1H),8.05(d,J＝2.1Hz,1H),7.92(s,1H),7.88–7.79(m,2H),7.46(s,1H),7.20(s,1H),7.05(s,1H),6.87(d,J＝2.3Hz,1H),3.25–3.14(m,2H),1.10(t,J＝7.2Hz,3H).13CNMR(100MHz,DMSO-d6)δ154.26,153.98,150.65,149.99,147.75,146.06,145.15,143.33,142.71(q,J＝38.0Hz),134.27,132.71,124.64,122.72,122.18,121.11(q,J＝267.0Hz),110.27,108.69,107.10,106.00,33.95,15.23.19F NMR(376MHz,DMSO-d6)δ-60.62(s,3F).HRMS(ESI)calcd for C21H18F3N6O3 +[(M+H)+]459.1387,found 459.1389。
Example 11:
3-(6-(3-ethylureido)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)quinoline-5,6-diyl diacetate
Figure BDA0001851227320000141
the same procedures used in example 5 were repeated to give 1i 340mg of a white solid in a yield of 73%.1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),8.55(s,1H),8.36(d,J＝2.1Hz,1H),8.31(d,J＝1.7Hz,1H),7.99(s,2H),7.88(d,J＝8.2Hz,2H),7.44(s,1H),6.89(d,J＝2.4Hz,1H),3.26–3.15(m,2H),2.42–2.31(m,6H),1.11(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ168.36,168.22,154.51,154.17,150.41,150.32,145.14,144.55,144.05,142.93(q,J＝37.0Hz),141.63,134.74,134.35,128.28,125.59,122.04,120.98(q,J＝267.0Hz),120.96,120.92,106.77,106.27,33.94,20.36,20.30,15.19.19F NMR(376MHz,DMSO-d6)δ-60.75(s,3F).HRMS(ESI)calcd forC25H22F3N6O5 +[(M+H)+]543.1598,found 543.1598。
Example 12:
1-(5'-(2,3-dimethoxyphenyl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-6-yl)-3-ethylurea
Figure BDA0001851227320000151
intermediate 11(17g,40mmol) and 5-chloropyridine-3-boronic acid (9.42g, 60mmol) were dissolved in 1, 4-dioxane (300ml) and Pd (PPh) was added under inert gas blanket3)2Cl2(3.26g, 4mmol), sodium carbonate (8.48g, 80mmol) and water (80ml) were then stirred at 80 ℃ until the starting material reaction was complete. After cooling, the solvent was removed by rotation, water was added to the residue, extraction was carried out three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated by chromatography to give 15.8g of a white solid with a yield of 96%.1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),8.56(d,J＝1.8Hz,1H),8.48(s,1H),8.18(s,1H),8.10(d,J＝1.0Hz,1H),7.94(s,1H),7.64(d,J＝1.8Hz,1H),7.40(s,1H),6.96(d,J＝2.2Hz,1H),3.25–3.13(m,2H),1.09(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.68,154.13,149.90,147.02,146.92,145.16,142.88(q,J＝37.8Hz),135.47,134.28,132.05,130.73,120.94(q,J＝267.0Hz),120.01,106.85,106.13,33.93,15.15.19FNMR(376MHz,DMSO-d6)δ-60.91(s,3F).HRMS(ESI)calcd for C17H15ClF3N6O+[(M+H)+]411.0942,found 411.0952。
Example 13:
1-ethyl-3-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-5'-(3,4,5-trimethoxyphenyl)-[3,3'-bipyridin]-6-yl)urea
Figure BDA0001851227320000152
dissolving intermediate 12(410mg,1mmol) and 3,4, 5-trimethoxyphenylboronic acid (318mg, 1.5mmol) in n-butanol (5ml), adding palladium acetate (22mg, 0.1mmol), Xphos (51mg, 0.125mmol), cesium hydroxide aqueous solution (0.3ml, 50%) andwater (1ml) was then stirred at room temperature until the starting material reaction was complete. Water was added to the reaction system, extraction was carried out three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated by chromatography to give 1j 450mg of a white solid with a yield of 83%.1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.88(d,J＝2.0Hz,1H),8.57(s,1H),8.22(d,J＝1.9Hz,1H),8.04(d,J＝1.3Hz,1H),7.95(s,1H),7.76(s,1H),7.45(s,1H),6.99(d,J＝2.3Hz,1H),6.89(s,2H),3.84(s,6H),3.67(d,J＝10.8Hz,3H),3.26–3.13(m,2H),1.10(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.41,154.20,153.37,149.97,147.24,146.80,145.23,142.83(q,J＝37.7Hz),137.81,135.27,134.33,133.72,132.16,130.32,121.24,121.03(q,J＝267.0Hz),107.04,106.02,104.41,60.03,56.00,33.94,15.19.19FNMR(376MHz,DMSO-d6)δ-60.67(s,3F).HRMS(ESI)calcd forC26H26F3N6O4 +[(M+H)+]543.1962,found 543.1984。
Example 14:
1-ethyl-3-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-5'-(2,3,4-trimethoxyphenyl)-[3,3'-bipyridin]-6-yl)urea
Figure BDA0001851227320000161
the same procedures used in example 13 were repeated to give 1k 460mg of a white solid in 85% yield.1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.60(d,J＝2.0Hz,1H),8.51(s,1H),8.27(d,J＝2.1Hz,1H),8.02(d,J＝1.5Hz,1H),7.92(s,1H),7.49–7.40(m,2H),6.99–6.93(m,2H),6.88(d,J＝8.8Hz,1H),3.83(s,3H),3.77(s,3H),3.57(s,3H),3.25–3.14(m,2H),1.10(t,J＝7.2Hz,3H).13CNMR(100MHz,DMSO-d6)δ154.37,154.21,153.75,150.79,149.74,148.41,146.75,145.33,142.79(q,J＝37.7Hz),142.04,135.65,134.32,133.01,130.01,124.53,123.58,121.56,121.05(q,J＝267.0Hz),108.32,107.20,106.06,60.74,60.41,55.91,33.94,15.20.19FNMR(376MHz,DMSO-d6)δ-60.75(s,3F).HRMS(ESI)calcd for C26H26F3N6O4 +[(M+H)+]543.1962,found 543.1984。
Example 15:
1-(5'-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-6-yl)-3-ethylurea
Figure BDA0001851227320000171
the same procedures used in example 13 were repeated to give 1l 440mg of a white solid in a yield of 86%.1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.76(d,J＝2.1Hz,1H),8.56(s,1H),8.20(d,J＝2.0Hz,1H),8.03(d,J＝1.4Hz,1H),7.93(s,1H),7.60(t,J＝2.0Hz,1H),7.44(s,1H),7.15(d,J＝2.1Hz,1H),7.08(dd,J＝8.4,2.1Hz,1H),6.94(dd,J＝8.5,5.4Hz,2H),4.28(s,4H),3.24–3.15(m,2H),1.10(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.38,154.20,149.85,146.86,146.31,145.28,143.85,143.82,142.82(q,J＝37.7Hz),134.64,134.40,133.20,130.29,129.67,121.46,121.04(q,J＝267.0Hz),119.70,117.59,115.38,107.20,106.06,64.17,64.07,33.94,15.20.19FNMR(376MHz,DMSO-d6)δ-60.69(s,3F).HRMS(ESI)calcd forC25H22F3N6O3 +[(M+H)+]511.1700,found 511.1716。
Example 16:
1-(5'-(3-chloro-4,5-dimethoxyphenyl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-6-yl)-3-ethylurea
Figure BDA0001851227320000181
the same procedures used in example 13 were repeated to give 1m 200mg of a white solid in a yield of 37%.1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.88(d,J＝2.0Hz,1H),8.58(s,1H),8.23(d,J＝1.8Hz,1H),8.02(s,1H),7.95(s,1H),7.79(s,1H),7.44(s,1H),7.32(d,J＝1.8Hz,1H),7.28(d,J＝1.7Hz,1H),6.97(d,J＝2.3Hz,1H),3.92(s,3H),3.79(s,3H),3.27–3.14(m,2H),1.10(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.42,154.17,153.90,149.99,147.67,146.71,145.22,144.78,142.82(q,J＝37.0Hz),134.38,133.87,133.77,133.33,130.37,127.56,121.16,121.01(q,J＝267.0Hz),119.70,110.59,107.05,106.02,60.25,56.29,33.92,15.18.19F NMR(376MHz,DMSO-d6)δ-60.69(s,3F).HRMS(ESI)calcd for C25H23F3N6O3 +[(M+H)+]547.1467,found 547.1482。
Example 17:
1-(5'-(3,4-bis(2-methoxyethoxy)phenyl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-6-yl)-3-ethylurea
Figure BDA0001851227320000182
the same procedures used in example 13 were repeated to give 1n 500mg of a white solid in a yield of 83%.1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.82(s,1H),8.56(s,1H),8.19(s,1H),8.02(s,1H),7.94(s,1H),7.71(s,1H),7.46(s,1H),7.22(s,1H),7.17(d,J＝8.0Hz,1H),7.05(d,J＝8.2Hz,1H),6.95(s,1H),4.16(d,J＝16.4Hz,4H),3.68(d,J＝2.5Hz,4H),3.34(s,6H),3.25–3.13(m,2H),1.10(t,J＝7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.38,154.20,149.89,148.76,148.69,146.79,146.42,145.25,142.80(q,J＝37.7Hz),134.95,134.35,133.30,130.31,129.46,121.41,121.04(q,J＝267.0Hz),119.56,114.33,112.53,107.10,106.00,70.42,70.40,68.09,58.20,33.93,15.18.19F NMR(376MHz,DMSO-d6)δ-60.71(s,3F).HRMS(ESI)calcd forC29H32F3N6O5 +[(M+H)+]601.2381,found 601.2408。
Example 18:
1-(5'-(3-cyano-4,5-dimethoxyphenyl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-6-yl)-3-ethylurea
Figure BDA0001851227320000191
the same procedures used in example 13 were repeated to give 1o 433mg of a white solid in 80% yield.1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.92(d,J＝2.0Hz,1H),8.59(s,1H),8.18(d,J＝1.8Hz,1H),8.02(d,J＝1.3Hz,1H),7.94(d,J＝11.7Hz,2H),7.68–7.61(m,2H),7.44(s,1H),6.96(d,J＝2.3Hz,1H),3.98–3.94(m,6H),3.24–3.15(m,2H),1.10(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.46,154.17,152.58,150.78,150.07,147.90,146.72,145.19,142.82(q,J＝37.7Hz),134.37,134.01,133.49,133.17,130.45,122.37,121.07,121.00(q,J＝267.0Hz),116.62,115.84,107.00,106.45,106.04,61.38,56.42,33.93,15.18.19F NMR(376MHz,DMSO-d6)δ-60.72(s,3F).HRMS(ESI)calcd for C26H23F3N7O3 +[(M+H)+]538.1809,found538.1812。
Example 19:
1-ethyl-3-(5'-(3-hydroxy-4-methoxyphenyl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-6-yl)urea
Figure BDA0001851227320000201
the same procedures used in example 13 were repeated to give 1p 483mg of a white solid in a yield of 97%.1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),9.14(s,1H),8.72(d,J＝2.1Hz,1H),8.55(s,1H),8.19(d,J＝2.0Hz,1H),8.03(d,J＝1.5Hz,1H),7.93(s,1H),7.56(t,J＝2.0Hz,1H),7.45(s,1H),7.05(s,1H),7.00(s,2H),6.95(d,J＝2.4Hz,1H),3.81(s,3H),3.25–3.14(m,2H),1.10(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.36,154.19,149.80,148.10,146.95,146.66,146.18,145.28,142.79(q,J＝37.7Hz),135.12,134.37,133.09,130.29,129.25,121.53,121.03(q,J＝267.0Hz),117.80,113.93,112.54,107.17,106.04,55.68,33.93,15.19.19FNMR(376MHz,DMSO-d6)δ-60.69(s,3F).HRMS(ESI)calcd for C24H22F3N6O3 +[(M+H)+]499.1700,found 499.1715。
Example 20:
1-(5'-(2-chloro-4,5-dimethoxyphenyl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-6-yl)-3-ethylurea
Figure BDA0001851227320000202
the same procedures used in example 13 were repeated to give 1q 193mg of a white solid in a yield of 35%.1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.61(d,J＝2.0Hz,1H),8.51(s,1H),8.38(d,J＝2.0Hz,1H),8.02(s,1H),7.93(s,1H),7.51–7.36(m,2H),7.13(s,1H),6.96(d,J＝2.4Hz,1H),6.87(s,1H),3.81(s,3H),3.77(s,3H),3.25–3.14(m,2H),1.10(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.41,154.16,149.79,149.40,148.83,147.97,147.40,145.29,142.83(q,J＝37.7Hz),136.43,134.28,133.99,129.92,127.56,122.45,121.15,121.01(q,J＝267.0Hz),114.06,113.14,107.10,106.08,56.00,55.80,33.91,15.18.19F NMR(376MHz,DMSO-d6)δ-60.70(s,3F).HRMS(ESI)calcd for C25H23ClF3N6O3 +[(M+H)+]547.1467,found547.1488。
Example 21:
1-ethyl-3-(5'-(4-hydroxy-3-methoxyphenyl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-6-yl)urea
Figure BDA0001851227320000211
the same procedures used in example 13 were repeated to give 1r 290mg of a white solid in a yield of 58%.1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),9.30(s,1H),8.80(d,J＝1.4Hz,1H),8.56(s,1H),8.19(d,J＝1.2Hz,1H),8.02(s,1H),7.94(s,1H),7.64(s,1H),7.46(s,1H),7.15(s,1H),7.04(d,J＝8.1Hz,1H),6.97(d,J＝1.9Hz,1H),6.85(d,J＝8.2Hz,1H),3.84(s,3H),3.26–3.15(m,2H),1.10(t,J＝7.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.36,154.21,149.86,148.13,147.16,146.43,146.29,145.28,142.80(q,J＝37.7Hz),135.35,134.39,133.01,130.23,127.60,121.51,121.06(q,J＝267.0Hz),119.45,115.95,110.85,107.18,106.04,55.70,33.94,15.21.19F NMR(376MHz,DMSO-d6)δ-60.68(s,3F).HRMS(ESI)calcd forC24H21F3N6O3Na+[(M+Na)+]521.1519,found 521.1531。
Example 22:
1-(5″,6″-dimethoxy-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3':5',3″-terpyridin]-6-yl)-3-ethylurea
Figure BDA0001851227320000221
the same procedures used in example 13 were repeated to give 1s 1.1g of a white solid in a yield of 71%.1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.88(d,J＝2.1Hz,1H),8.57(s,1H),8.20(d,J＝2.0Hz,1H),8.04(d,J＝1.5Hz,1H),7.99(d,J＝1.9Hz,1H),7.95(s,1H),7.81(t,J＝2.0Hz,1H),7.52(d,J＝1.8Hz,1H),7.45(s,1H),6.98(d,J＝2.4Hz,1H),3.90(s,3H),3.86(s,3H),3.25–3.13(m,2H),1.10(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.46,154.21,153.93,149.97,147.34,146.43,145.24,143.92,142.84(q,J＝37.7Hz),134.47,134.37,133.55,132.51,130.48,126.30,121.23,121.04(q,J＝267.0Hz),116.54,107.06,106.05,55.60,53.18,33.95,15.19.19F NMR(376MHz,DMSO-d6)δ-60.72(s,3F).HRMS(ESI)calcd for C24H23F3N7O3 +[(M+H)+]514.1809,found 514.1826。
Example 23:
1-ethyl-3-(5″-hydroxy-6″-oxo-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1″,6″-dihydro-[3,3':5',3″-terpyridin]-6-yl)urea
Figure BDA0001851227320000222
the same procedure as in example 13 was adoptedThe method described (1) gave 1t 170mg of a white solid in a yield of 72%.1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),9.57(s,1H),9.30(s,1H),8.72(s,1H),8.55(s,1H),8.05(s,1H),8.00(s,1H),7.92(s,1H),7.71–7.66(m,1H),7.45(s,1H),7.34(s,1H),7.08(d,J＝1.9Hz,1H),6.93(d,J＝2.0Hz,1H),3.25–3.12(m,2H),1.10(t,J＝7.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ157.85,154.41,154.25,150.02,147.49,146.57,145.47,145.24,142.84(q,J＝37.8Hz),134.41,132.55,132.13,130.37,122.25,121.39,121.06(q,J＝267.0Hz),115.05,114.24,107.07,106.06,33.98,15.23.19F NMR(376MHz,DMSO-d6)δ-60.68(s,3F).HRMS(ESI)calcdfor C22H19F3N7O3 +[(M+H)+]486.1496,found 486.1485。
Example 24:
1-ethyl-3-(5″-methoxy-6″-oxo-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1″,6″-dihydro-[3,3':5',3″-terpyridin]-6-yl)urea
Figure BDA0001851227320000231
the same procedures used in example 13 were repeated to give 1u 40mg of a white solid in a yield of 16%.1H NMR(400MHz,DMSO-d6)δ11.96(s,1H),9.57(s,1H),8.79(d,J＝2.1Hz,1H),8.55(s,1H),8.05(d,J＝1.9Hz,1H),8.00(s,1H),7.94(s,1H),7.80(d,J＝1.9Hz,1H),7.50–7.33(m,2H),7.10(d,J＝2.0Hz,1H),6.94(d,J＝2.4Hz,1H),3.78(s,3H),3.25–3.10(m,2H),1.10(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ156.83,154.39,154.21,150.03,149.70,146.56,145.57,145.19,142.80(q,J＝37.7Hz),134.34,132.54,132.11,130.34,123.61,121.30,121.04(q,J＝267.0Hz),113.87,112.84,106.99,106.00,55.52,33.95,15.19.19F NMR(376MHz,DMSO-d6)δ-60.68(s,3F).HRMS(ESI)calcd for C23H21F3N7O3 +[(M+H)+]500.1652,found500.1667。
Example 25:
1-(5″,6″-dimethoxy-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3':5',3″-terpyridin]-6-yl)-3-ethylurea
Figure BDA0001851227320000241
the same procedures used in example 13 were repeated to give 1v 110mg of a white solid in a yield of 20%.1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.55(d,J＝2.0Hz,1H),8.51(s,1H),8.39(d,J＝2.0Hz,1H),8.05(d,J＝1.4Hz,1H),7.91(s,1H),7.46–7.37(m,2H),7.13(d,J＝8.7Hz,1H),7.05(d,J＝8.6Hz,1H),6.95(d,J＝2.4Hz,1H),3.87(s,3H),3.76(s,3H),3.24–3.13(m,2H),1.10(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.42,154.19,153.43,149.74,148.67,147.47,145.36,145.03,142.85(q,J＝37.8Hz),136.43,134.32,133.85,129.89,128.91,125.99,121.31,121.03(q,J＝268.0Hz),111.64,107.22,106.12,60.04,56.14,33.93,15.19.19FNMR(376MHz,DMSO-d6)δ-60.72(s,3F).HRMS(ESI)calcd for C25H23ClF3N6O3 +[(M+H)+]547.1467,found 547.1452。
Example 26:
N-(benzyloxy)-N-(2-((6'-(3-ethylureido)-4'-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-5-yl)oxy)ethyl)acetamide
Figure BDA0001851227320000242
the same procedures used in example 3 were repeated to give 674mg of a white solid in a yield of 58%.1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.45(s,1H),8.21(d,J＝2.6Hz,1H),7.91(s,2H),7.80(d,J＝1.3Hz,1H),7.48–7.34(m,6H),7.14(s,1H),6.86(d,J＝2.4Hz,1H),4.91(s,2H),4.13(t,J＝5.4Hz,2H),3.96(t,J＝5.2Hz,2H),3.24–3.13(m,2H),2.01(s,3H),1.09(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ171.87,154.37,154.18,154.05,149.81,145.18,142.75(q,J＝37.7Hz),141.04,137.15,134.80,134.25,131.00,129.41,128.62,128.40,121.10,121.02(q,J＝267.0Hz),120.75,107.00,105.97,75.71,64.33,44.61,33.93,20.22,15.19.19F NMR(376MHz,DMSO-d6)δ-60.71(s,3F).HRMS(ESI)calcd for C28H29F3N7O4 +[(M+H)+]584.2228,found 584.2215。
Example 27:
N-(2-((6'-(3-ethylureido)-4'-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-5-yl)oxy)ethyl)-N-hydroxyacetamide
Figure BDA0001851227320000251
the above intermediate 13(500mg, 0.86mmol) was placed in a 100mL eggplant type flask, and methanol (60mL) and palladium hydroxide (250mg, 20 wt%) were added in this order, followed by stirring at room temperature for 6h under a hydrogen atmosphere. The catalyst was filtered off, the filtrate was concentrated and the residue was purified by LC-MS to give 1w 110mg of a white solid in 26% yield.1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),9.56(s,1H),8.46(s,1H),8.22(s,1H),7.92(d,J＝6.3Hz,2H),7.79(s,1H),7.43(s,1H),7.16(s,1H),6.91(s,1H),4.13(s,2H),3.83(s,2H),3.25–3.13(m,2H),1.99(s,3H),1.09(t,J＝7.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ171.06,154.39,154.21,149.84,145.21,142.79(q,J＝37.7Hz),140.98,137.23,134.28,131.00,121.15,121.06(q,J＝267.0Hz),120.83,107.06,106.05,64.21,46.33,33.95,20.27,15.20.19F NMR(376MHz,DMSO-d6)δ-60.69(s,3F).HRMS(ESI)calcd for C21H23F3N7O4 +[(M+H)+]494.1758,found 494.1749。
Example 28:
(E)-methyl 3-(6'-(3-ethylureido)-4'-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-5-yl)acrylate
Figure BDA0001851227320000261
in the same manner as in example 3 above, 3.25g of a gray solid was obtained and directly charged into a one-pot reaction.
Example 29:
N-(2-((6'-(3-ethylureido)-4'-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-5-yl)oxy)ethyl)-N-hydroxyacetamide
Figure BDA0001851227320000262
the above intermediate 14(3.25g, 7mmol) was placed in a 250mL eggplant type bottle, tetrahydrofuran (70mL), water (14mL) and lithium hydroxide (680mg, 28.3mmol) were added in this order, followed by stirring at room temperature until the starting material disappeared. Adding diluted hydrochloric acid (23ml, 1.2N) for neutralization, extracting with ethyl acetate for three times, combining, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain crude product 2.6 g.
Example 30:
(E)-N-(tert-butoxy)-3-(6'-(3-ethylureido)-4'-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-5-yl)acrylamide
Figure BDA0001851227320000263
the above intermediate 15(1.6g, 3.6mmol) and O-t-butylhydroxylamine (540mg, 4.32mmol) were placed in a 50mL eggplant-shaped flask, and N, N-dimethylformamide (20mL), triethylamine (0.7mL, 8.3mmol) and HATU (2g, 7.2mmol) were added in this order, followed by stirring at room temperature until the starting materials disappeared. Water and ethyl acetate were added for extraction three times, combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column chromatography to give 1.4g of a white solid with a yield of 75%.
Example 31:
(E)-3-(6'-(3-ethylureido)-4'-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-5-yl)-N-hydroxyacrylamide
Figure BDA0001851227320000271
intermediate 16(550mg, 1.06mmol) above was placed in a 50mL eggplant-shaped flask and dichloromethane (5mL) and tris (hydroxymethyl) phosphonium were added sequentiallyFluoroacetic acid (10ml) was then stirred at room temperature until the starting material disappeared. The solvent was removed by rotation and the residue was purified on a reverse phase column to give 1X 130mg of a white solid in 27% yield.1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),9.58(s,1H),9.14(s,1H),8.70(s,1H),8.50(s,1H),8.16(d,J＝1.5Hz,1H),8.05(s,1H),7.94(s,1H),7.70(s,1H),7.50–7.35(m,2H),6.94(d,J＝2.1Hz,1H),6.51(d,J＝15.9Hz,1H),3.26–3.13(m,2H),1.10(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ162.16,154.53,154.23,149.87,149.08,147.92,145.24,142.86(q,J＝37.8Hz),134.59,134.34,133.70,130.66,130.36,121.63,121.10,121.02(q,J＝267.0Hz),107.00,106.14,33.99,15.22.19F NMR(376MHz,DMSO-d6)δ-60.76(s,3F).HRMS(ESI)calcd for C20H19F3N7O3 +[(M+H)+]462.1496,found462.1487。
Example 32:
N-(tert-butoxy)-3-(6'-(3-ethylureido)-4'-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-5-yl)propanamide
Figure BDA0001851227320000281
the above intermediate 16(680mg, 1.3mmol) was placed in a 50mL eggplant type bottle, and methanol (20mL) and palladium on carbon (200mg, 10 wt%) were added in this order, followed by stirring under a hydrogen atmosphere at 50 ℃ until the starting material disappeared. The catalyst is filtered off, the filtrate is concentrated, and the residue is directly put into a pot for reaction.
Example 33:
3-(6'-(3-ethylureido)-4'-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[3,3'-bipyridin]-5-yl)-N-hydroxypropanamide
Figure BDA0001851227320000282
the above intermediate 17 was placed in a 50mL eggplant type bottle, and methylene chloride (5mL) and trifluoroacetic acid (10mL) were sequentially added thereto, followed by stirring at 50 ℃ until the starting material disappeared. Removing solvent by rotation, and purifying the residue with reverse phase column to obtain white solid 1y150mg, yield 25%.1H NMR(400MHz,DMSO-d6)δ10.39(d,J＝1.3Hz,1H),9.56(s,1H),8.77(d,J＝1.5Hz,1H),8.44(s,1H),8.37(d,J＝1.9Hz,1H),8.06(d,J＝2.0Hz,1H),7.96–7.86(m,2H),7.42(s,1H),7.31(d,J＝1.9Hz,1H),6.91(d,J＝2.4Hz,1H),3.25–3.12(m,2H),2.77(t,J＝7.5Hz,2H),2.21(t,J＝7.6Hz,2H),1.09(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ167.88,154.37,154.25,149.72,148.64,146.47,145.24,142.81(q,J＝37.7Hz),136.16,135.63,134.26,129.97,121.53,121.09(q,J＝267.0Hz),107.13,106.05,33.98,33.26,27.82,15.23.19F NMR(376MHz,DMSO-d6)δ-60.69(s,3F).HRMS(ESI)calcd for C20H21F3N7O3 +[(M+H)+]464.1652,found 464.1649。
Example 34:
1-(4-chloro-5'-(3,4-dimethoxyphenyl)-[3,3'-bipyridin]-6-yl)-3-ethylurea
Figure BDA0001851227320000291
the same procedures used in example 3 were repeated to give 2.6g of a white solid in a yield of 63%.1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.93(d,J＝1.8Hz,1H),8.60(d,J＝1.5Hz,1H),8.37(s,1H),8.17(s,1H),7.84(s,1H),7.50(s,1H),7.41–7.29(m,2H),7.08(d,J＝8.3Hz,1H),3.86(s,3H),3.80(s,3H),3.25–3.13(m,2H),1.09(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ154.17,153.92,149.31,149.21,148.92,147.81,146.68,142.47,135.13,134.41,130.99,129.14,125.47,119.32,112.29,111.23,110.70,55.66,55.57,33.92,15.20.HRMS(ESI)calcd forC21H22ClN4O3 +[(M+H)+]413.1375,found 413.1386。
Example 35: (Z) -tert-butyl (1- (2- (4- (5'- (3,4-dimethoxyphenyl) -6- (3-ethyllueido) - [3,3' -dipyridine ] -4-yl) thiophen-2-yl) -1-fluorovinylenyl) cyclopropenyl) carbamate
Figure BDA0001851227320000292
Intermediate 18(413mg,1mmol) and thiophene boronate derivative (655mg, 1.5mmol) were dissolved in 1, 4-dioxane (10ml) and Pd was added under inert gas2(dba)3(92mg, 0.1mmol), Xphos (96mg, 0.2mmol), sodium carbonate (212mg, 2mmol) and water (2ml) were then stirred at 100 ℃ until the starting material reaction was complete. After cooling, the solvent was removed by rotation, water was added to the residue, extraction was carried out three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated by chromatography to give 600mg of a white solid with a yield of 87%.
Example 36:
(Z)-1-(4-(5-(2-(1-aminocyclopentyl)-2-fluorovinyl)thiophen-3-yl)-5'-(3,4-dimethoxyphenyl)-[3,3'-bipyridin]-6-yl)-3-ethylurea
Figure BDA0001851227320000301
intermediate 19(600mg,0.87mmol) was dissolved in dichloromethane (6ml), trifluoroacetic acid (2ml) was added, and the mixture was stirred at room temperature until the starting material reaction was complete. Sodium bicarbonate (0.1M) was added to the reaction system to neutralize, followed by extraction three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was subjected to chromatography to give 1z332mg as a white solid with a yield of 65%.1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.77(d,J＝1.8Hz,1H),8.34(s,2H),7.92(s,1H),7.75(s,1H),7.59(s,1H),7.32(s,1H),7.17(dd,J＝8.2,1.5Hz,1H),7.08–6.97(m,2H),6.85(s,1H),6.34(d,J＝40.5Hz,1H),3.79(d,J＝7.1Hz,6H),3.21(dt,J＝13.5,6.9Hz,3H),1.80(s,4H),1.61(s,2H),1.47(s,2H),1.10(t,J＝7.1Hz,3H).13CNMR(100MHz,DMSO-d6)δ165.82(d,J＝270.8Hz),154.50,153.46,149.22,149.05,147.96,147.51,145.89,144.36,138.28,136.36(d,J＝2.3Hz),134.84,134.20,132.87,129.41,126.97,125.21(d,J＝10.1Hz),125.07,119.16,112.19,111.36,110.34,97.74(d,J＝11.6Hz),61.89(d,J＝24.9Hz),55.55,37.90,33.88,23.77,15.33.19F NMR(376MHz,DMSO-d6)δ-107.16(s,1F).HRMS(ESI)calcdfor C32H34FN5O3SNa+[(M+Na)+]610.2259,found610.2278。
Example 37: experiment of antibacterial Activity
Compound antibacterial activity test, the strain is MRSA (ATCC 43300).
The experimental procedure was as follows:
1. preparing the antibacterial agent and the culture medium by a broth dilution method with the same constant quantity;
2, preparing an MIC plate for aseptic operation, adding antibacterial drug solutions with different concentrations after dilution by multiple times into a sterilized 96-hole polystyrene plate, adding 10 mu l of liquid medicine into the 1 st to 9 th holes, not adding the medicine into the 10 th hole as a growth control, and storing the product at the temperature of below-20 ℃ for later use after freeze drying;
3. preparation of inoculum bacterial suspension prepared by growth method or direct suspension method, the concentration of which is equal to 0.5 McLeod's ratio standard, is diluted by MH broth 1: 1000, 100 μ l is added into each hole, sealed and placed in a common air incubator at 35 ℃, and the result is judged after incubation for 24 h. At this time, the drug concentrations of the 1 st to 9 th wells are 32, 16, 8, 4, 2, 1, 0.5, 0.25 and 0.125. mu.g/ml respectively;
4. the result judges that the lowest drug concentration for completely inhibiting the growth of bacteria in the small hole is MIC;
the results of the experiments are shown in table 1,
table 1: minimum inhibitory concentration (unit: μ g/ml) of Compound against MRSA (ATCC43300)
Figure BDA0001851227320000311
Figure BDA0001851227320000321
。
The experimental results show that part of the compounds (1d, 1g, 1j, 1l, 1m, 1o and 1p) of the invention have excellent anti-MRSA activity and are the preferred compounds of the invention.
Example 38: preferred compounds of the invention are tested against other gram-positive bacteria
The experimental procedure was the same as in example 37 above;
table 2: minimum inhibitory concentration (MIC, unit: mu g/ml)
Figure BDA0001851227320000322
[a] The strain is provided by Shanghai pharmaceutical industry research institute;
the results of in vitro antibacterial activity show that the preferred compounds of the invention (1d, 1g, 1j, 1l, 1m, 1o and 1p) have significant activity against staphylococcus linezolid (staphylococcus linezolid-32), enterococcus faecalis (ATCC51299 and ATCC29212) and enterococcus faecium (ATCC35667), and thus the compounds of the invention and their salts are useful against gram-positive bacteria.
The foregoing embodiments illustrate and describe the basic principles, main features and advantages of the present invention, but the present invention is not limited to the embodiments, and various changes and modifications may be made without departing from the spirit and scope of the invention, which fall within the scope of the claimed invention.

Claims (15)

1. A pyridylurea compound and a medicinal salt thereof, wherein the structure of the pyridylurea compound is shown as a formula (I):
Figure FDA0001851227310000011
wherein the content of the first and second substances,
R1is selected from
Figure FDA0001851227310000012
R2Is selected from
Figure FDA0001851227310000013
R3Is selected from C1-6An alkyl group;
R4is selected from
Figure FDA0001851227310000014
R5、R6、R7、R8Independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-6Alkoxy, hydroxy, C1-6Alkyl, acyloxy, amido, trifluoromethyl,
Figure FDA0001851227310000015
Or R5、R6、R7Any 2 of which form a 6-membered oxygen atom containing heterocyclic ring;
R9selected from H, C1-6An alkyl group;
R10selected from trifluoromethyl, difluoromethyl, trifluoromethylthio, C1-6An alkyl group;
n is 0, 1,2, 3.
2. The pyridylurea compound and pharmaceutically acceptable salts thereof as claimed in claim 1, wherein R is5、R6、R7、R8Independently selected from hydrogen, chlorine, cyano, methoxy, hydroxy, methyl, acetoxy, methoxy,
Figure FDA0001851227310000016
or R5、R6、R7Any 2 of which form a dioxane.
3. The pyridylurea compound and pharmaceutically acceptable salts thereof as claimed in claim 1, wherein R is5、R6、R7At least two are not hydrogen.
4. The pyridylurea compound and pharmaceutically acceptable salts thereof as claimed in claim 1, wherein R is3Is ethyl.
5. The pyridylurea compound as claimed in claim 1 and a drug containing the sameA salt, characterized in that R9Is methyl.
6. The pyridylurea compound and pharmaceutically acceptable salts thereof as claimed in claim 1, wherein R is4Is composed of
Figure FDA0001851227310000021
7. The pyridylurea compound and pharmaceutically acceptable salts thereof as claimed in claim 1, wherein R is2Is selected from
Figure FDA0001851227310000022
8. The pyridylurea compound and pharmaceutically acceptable salts thereof as claimed in claim 1, wherein R is1Is composed of
Figure FDA0001851227310000023
9. The pyridylurea compound and pharmaceutically acceptable salts thereof as claimed in claim 1, wherein R is1Is composed of
Figure FDA0001851227310000024
10. The pyridylurea compound and pharmaceutically acceptable salts thereof as claimed in claim 1, wherein the pyridylurea compound and pharmaceutically acceptable salts thereof are selected from the group consisting of:
Figure FDA0001851227310000025
Figure FDA0001851227310000031
11. the pyridylurea compound and pharmaceutically acceptable salts thereof as claimed in claim 1, wherein the salts include organic base salts, inorganic base salts, organic acid salts or inorganic acid salts thereof; the inorganic base is selected from sodium hydroxide, potassium carbonate and sodium carbonate; the organic base is selected from methylamine, ethylamine and triethylamine; the organic acid is selected from fumaric acid, maleic acid, tartaric acid, malic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, formic acid; the inorganic acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid and phosphoric acid.
12. A process for preparing a pyridylurea compound as claimed in any one of claims 1 to 11, wherein the reaction scheme of the process for preparing the compounds 1a-1i, 1w-1z is as follows:
Scheme 1
Figure FDA0001851227310000041
the method comprises the following steps:
1) synthesis of intermediate 2: dissolving the compound 1 in N, N-dimethylformamide, adding N-iodosuccinimide (NIS), stirring at 70 deg.C until the reaction is complete, and separating by chromatographic column to obtain intermediate 2;
2) synthesis of intermediate 3: dissolving the intermediate 2 in an organic solvent such as pyridine, 1, 2-dichloroethane and the like, then adding ethyl isocyanate, stirring at 70-110 ℃ until the reaction is complete, removing the solvent by spinning, and washing residues with tert-butyl methyl ether to obtain an intermediate 3;
3) synthesis of target compound 4: dissolving a compound 3 and different aryl boric acids (esters) in an organic solvent such as 1, 4-dioxane, adding Pd (dppf) Cl2 and a potassium carbonate aqueous solution under the protection of inert gas, stirring at the temperature of 80-100 ℃ until the reaction is complete, and separating by a chromatographic column to obtain a target compound 4;
4) synthesis of target compound 5: dissolving the intermediate 4 in an organic solvent such as dichloromethane, adding a dichloromethane solution of boron tribromide at 0 ℃, stirring at room temperature until the reaction is complete, adding methanol to quench the reaction, and performing LC-MS (liquid chromatography-mass spectrometry) preparation, separation and purification to obtain a target compound 5;
5) synthesis of target compound 6: dissolving the intermediate 5 in an organic solvent such as pyridine, adding acetic anhydride, stirring at room temperature until the reaction is complete, removing the solvent by spinning, and separating the residue by a chromatographic column to obtain a target compound 6;
6) synthesis of target compound 7: dissolving a compound 3 and different aryl boric acids (esters) in an organic solvent such as 1, 4-dioxane, adding Pd (dppf) Cl2 and a potassium carbonate aqueous solution under the protection of inert gas, stirring at the temperature of 80-100 ℃ until the reaction is complete, and separating by a chromatographic column to obtain a target compound 7;
the reaction scheme of the preparation method of the compounds 1j-1v is as follows:
Scheme 2
Figure FDA0001851227310000042
the method comprises the following steps:
1) synthesis of intermediate 8: dissolving 3 and 5-chloro-3-pyridineboronic acid in an organic solvent such as 1, 4-dioxane; under the protection of inert gas, adding Pd (dppf) Cl2 and a potassium carbonate aqueous solution, stirring at 80-100 ℃ until the reaction is complete, removing the solvent by spinning, washing the residue with water and tert-butyl methyl ether to obtain an intermediate 8;
2) synthesis of target compound 9: dissolving 8 and various arylboronic acids (esters) in organic solvents such as n-butanol and water; under the protection of inert gas, adding palladium acetate, 2-dicyclohexyl phosphorus-2 ', 4 ', 6 ' -triisopropyl biphenyl (Xphos) and cesium hydroxide aqueous solution, stirring at room temperature until the reaction is complete, and separating by a chromatographic column to obtain the target compound 9.
13. A pharmaceutical composition comprising a therapeutically effective amount of a pyridylurea compound as claimed in any one of claims 1 to 11 and pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.
14. Use of a pyridylurea compound as claimed in any one of claims 1 to 11 and pharmaceutically acceptable salts thereof or a pharmaceutical composition as claimed in claim 13 for the manufacture of a medicament against gram-positive bacteria.
15. The use according to claim 14, wherein the gram-positive bacteria are methicillin-resistant staphylococcus, linezolid-resistant staphylococcus, vancomycin-resistant enterococcus, staphylococcus and streptococcus pneumoniae.
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CN102015699A (en) * 2008-02-26 2011-04-13 阿斯利康(瑞典)有限公司 Heterocyclic urea derivatives and methods of use thereof-211
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Application publication date: 20200508