CN111187215B - Fluorine-containing pyrazole amide derivative, preparation method and application thereof - Google Patents

Fluorine-containing pyrazole amide derivative, preparation method and application thereof Download PDF

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CN111187215B
CN111187215B CN202010071859.7A CN202010071859A CN111187215B CN 111187215 B CN111187215 B CN 111187215B CN 202010071859 A CN202010071859 A CN 202010071859A CN 111187215 B CN111187215 B CN 111187215B
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pyridyl
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徐功
王伟
徐丹
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Abstract

The invention discloses a fluorine-containing pyrazole amide derivative, a preparation method and application thereof, wherein the structural formula of the fluorine-containing pyrazole amide derivative is as follows:
Figure DDA0002377501420000011
wherein R is 1 Is trifluoromethyl, difluoromethyl; r 2 Hydrogen, chlorine, fluorine, bromine, iodine; r 3 Is polysubstituted benzene or polysubstituted pyridine. The fluorine-containing pyrazole amide derivative has remarkable antifungal activity, and can provide a basis for developing a novel bactericide taking the fluorine-containing pyrazole amide derivative as an active ingredient.

Description

Fluorine-containing pyrazole amide derivative, preparation method and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a fluorine-containing pyrazole amide derivative, a preparation method of the fluorine-containing pyrazole amide derivative and application of the fluorine-containing pyrazole amide derivative.
Background
The SDHIs bactericide has a target site of action of a protein complex II, namely succinate dehydrogenase or succinate-ubiquinone reductase, on a respiratory electron transfer chain of mitochondria of pathogenic bacteria; the enzyme complex is a functional part of tricarboxylic acid cycle, is connected with a mitochondrial electron transfer chain, catalyzes a coupling reaction from the oxidation of succinic acid to fumaric acid and the reduction of ubiquinone (coenzyme Q) to ubiquinol, and consists of 4 subunits such as flavoprotein (Fp, sdhA), iron-sulfur protein (Ip, sdhB) and two other membrane-embedded proteins (SdhC and SdhD), wherein the SdhA and SdhB form a peripheral membrane domain of succinate dehydrogenase, and the domain is relatively conservative and has the activity of the succinate dehydrogenase. The SDHIs bactericide influences the respiratory chain electron transfer system of pathogenic bacteria by acting on a protein complex II, so that energy metabolism is hindered, the growth of the pathogenic bacteria is inhibited, and the pathogenic bacteria die, thereby achieving the purpose of preventing diseases.
The SDHIs bactericides contain acylamino in the aspect of chemical structure, the newly developed bactericides are derived by substituting the existing base groups, nearly 20 varieties of the developed bactericides, such as products mainly taking flazaquin, flutolanil, fluopyram, thifluzamide and the like as active ingredients, the bactericides are used for fungal diseases on a plurality of crops, and the bactericides become important bactericide varieties in production. However, in recent years, the problem of fungicide resistance has been increasingly highlighted due to the long-term use of conventional fungicides, and therefore, the discovery of a new target or mechanism of action to develop an existing fungicide is very important to solve the existing problem.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art.
Therefore, the invention provides a fluorine-containing pyrazole amide derivative which has anti-fungal activity.
The invention also provides a preparation method of the fluorine-containing pyrazole amide derivative, and the preparation method has the advantages of simple equipment, easiness in implementation and the like.
The invention also provides application of the fluorine-containing pyrazole amide derivative, and the prepared pyrazole amide derivative can be applied to different fungal diseases.
The structural formula of the fluorine-containing pyrazole amide derivative according to the embodiment of the first aspect of the invention is as follows:
Figure BDA0002377501410000021
wherein R is 1 Is trifluoromethyl, difluoromethyl; r 2 Hydrogen, chlorine, fluorine, bromine, iodine; r is 3 Is polysubstituted benzene or polysubstituted pyridine.
The fluorine-containing pyrazole amide derivatives have potential antifungal activity, and the identification result shows that the fluorine-containing pyrazole amide derivatives have particularly remarkable disease inhibition effect when applied to different fungal diseases.
According to one embodiment of the invention, R 3 Is 3-pyridyl, 4-pyridyl, 2-chloro-3-pyridyl, 6-chloro-3-pyridyl, 2-fluoro-3-pyridyl, 6-fluoro-3-pyridyl, 2-methyl-3-pyridyl, 6-methyl-3-pyridyl, 2-trifluoromethyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl.
The preparation method of the fluorine-containing pyrazole amide derivative according to the embodiment of the second aspect of the invention comprises the following steps: reacting the intermediate II with acyl chloride containing aromatic ring active groups to obtain a fluorine-containing pyrazole amide derivative III, wherein the reaction formula is as follows:
Figure BDA0002377501410000022
wherein R is 1 Is trifluoromethyl, difluoromethyl; r is 2 Hydrogen, chlorine, fluorine, bromine, iodine; r 3 Is polysubstituted benzene or polysubstituted pyridine.
According to one embodiment of the invention, R 3 Is 3-pyridyl, 4-pyridyl, 2-chloro-3-pyridyl, 6-chloro-3-pyridyl, 2-fluoro-3-pyridyl, 6-fluoro-3-pyridyl, 2-methyl-3-pyridyl, 6-methyl-3-pyridyl, 2-trifluoromethyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl.
According to one embodiment of the invention, the intermediate II is mixed and reacted with an acid containing an aromatic ring active group and phosphorus oxychloride or thionyl chloride.
According to one embodiment of the invention, the solvent in the reaction is pyridine.
According to one embodiment of the invention, the acid containing an aromatic ring reactive group is a nicotinic acid or benzoic acid substituent.
According to one embodiment of the invention, the preparation method of the intermediate II comprises the following steps:
s1, reacting ethyl trifluoroacetate or ethyl difluoroacetate and acetonitrile serving as raw materials under strong alkali to obtain an intermediate I, wherein the reaction formula is as follows:
Figure BDA0002377501410000031
s2, reacting the intermediate I with methylhydrazine sulfate to obtain an intermediate IIa, wherein the reaction formula is as follows:
Figure BDA0002377501410000032
s3, carrying out selective halogenation reaction on the intermediate IIa obtained in the step S2 to obtain R 2 The intermediates IIb to IIe being fluorine, chlorine, bromine or iodine.
According to one embodiment of the invention, in step S3, said intermediate IIa is reacted with a selective fluorine reagent in a solvent to give R 2 Said intermediate IIb being fluorine; reacting the intermediate IIa with a selective chlorine reagent in a solvent to obtain R 2 Said intermediate IIc being chloro; reacting the intermediate IIa with a selective bromine reagent in a solvent to obtain R 2 Said intermediate IId being bromine; reacting the intermediate IIa with a selective iodine reagent in a solvent to obtain R 2 Said intermediate IIe being iodine; the respective reaction formulae of step S3 are as follows:
Figure BDA0002377501410000041
according to an embodiment of the present invention, the solvent in step S31 is acetonitrile, the solvents in steps S32, S33, and S34 are dichloromethane, the selective chlorine reagent in step S32 is N-chlorosuccinimide, the selective bromine reagent in step S33 is N-bromosuccinimide, and the selective iodine reagent in step S34 is N-iodosuccinimide.
According to one embodiment of the invention, the ratio of the amount of acetonitrile to ethyl trifluoroacetate or ethyl difluoroacetate material in step S1 is 1:1.
according to one embodiment of the invention, the reflux is carried out at a temperature of 70 ℃ to 80 ℃ for 3h to 4h in step S1.
According to one embodiment of the invention, the strong base in step S1 is sodium hydrogen and the solvent is tetrahydrofuran.
According to one embodiment of the invention, the ratio of the amount of intermediate I to methylhydrazine sulfate species in step S2 is 1:1.
According to one embodiment of the invention, the step S2 is performed for 3 to 4 hours under reflux in the ethanol solution at 70 to 80 ℃.
According to the application of the fluorine-containing pyrazole amide derivative in the third aspect of the invention, the fluorine-containing pyrazole amide derivative is applied to antifungal bactericides.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like reference numerals refer to the same or similar elements or elements having the same or similar functions throughout. The following examples are illustrative only and are not to be construed as limiting the invention.
The fluorine-containing pyrazole amide derivatives, the preparation method and the application thereof according to the embodiment of the present invention are specifically described below.
The fluorine-containing pyrazole amide derivative provided by the embodiment of the invention has the following structural formula:
Figure BDA0002377501410000051
wherein R is 1 Is trifluoromethyl, difluoromethyl; r 2 Hydrogen, chlorine, fluorine, bromine, iodine; r 3 Is polysubstituted benzene or polysubstituted pyridine.
The fluorine-containing pyrazole amide derivative provided by the embodiment of the invention has antibacterial activity and can be used for a novel antibacterial agent.
According to one embodiment of the invention, R 3 Is 3-pyridyl, 4-pyridyl, 2-chloro-3-pyridyl, 6-chloro-3-pyridyl, 2-fluoro-3-pyridyl, 6-fluoro-3-pyridyl, 2-methyl-3-pyridyl, 6-methyl-3-pyridyl, 2-trifluoromethyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl.
The preparation method of the fluorine-containing pyrazole amide derivative comprises the following steps:
reacting the intermediate II with acyl chloride containing aromatic ring active groups to obtain a fluorine-containing pyrazole amide derivative III, wherein the reaction formula is as follows:
Figure BDA0002377501410000052
wherein R is 1 Is trifluoromethyl, difluoromethyl; r 2 Hydrogen, chlorine, fluorine, bromine, iodine; r 3 Is polysubstituted benzene or polysubstituted pyridine.
In some embodiments of the invention, R 3 Is 3-pyridyl, 4-pyridyl, 2-chloro-3-pyridyl, 6-chloro-3-pyridonePyridyl group, 2-fluoro-3-pyridyl group, 6-fluoro-3-pyridyl group, 2-methyl-3-pyridyl group, 6-methyl-3-pyridyl group, 2-trifluoromethyl-3-pyridyl group, 6-trifluoromethyl-3-pyridyl group, phenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group.
According to one embodiment of the present invention, the intermediate ii is mixed with an acid containing an aromatic ring active group and phosphorus oxychloride or thionyl chloride, and the reaction formula can be shown as follows:
Figure BDA0002377501410000061
in some embodiments of the invention, the solvent in the reaction is pyridine.
According to one embodiment of the present invention, the acid containing an aromatic ring reactive group is selected from nicotinic acid or benzoic acid substitution.
In some embodiments of the invention, the process for preparing intermediate ii comprises the steps of:
s1, reacting ethyl trifluoroacetate or ethyl difluoroacetate and acetonitrile serving as raw materials under strong alkali to obtain an intermediate I, wherein the reaction formula is as follows:
Figure BDA0002377501410000062
s2, reacting the intermediate I with methylhydrazine sulfate to obtain an intermediate IIa, wherein the reaction formula is as follows:
Figure BDA0002377501410000063
s3, carrying out selective halogenation reaction on the intermediate IIa obtained in the step S2 to obtain R 2 The intermediates IIb to IIe being fluorine, chlorine, bromine or iodine.。
Alternatively, in step S3, when R 2 When fluorine is used, the intermediate IIa reacts with a selective fluorine reagent in the presence of a solvent to obtain R 2 Said intermediate IIb being fluorine; when R is 2 When chlorine is used, the intermediate IIa is reacted with a selective chlorine reagent in a solvent to obtain R 2 Said intermediate IIc being chloro; when R is 2 When the intermediate IIa is bromine, the intermediate IIa is reacted with a selective bromine reagent in a solvent to obtain R 2 Said intermediate IId being bromine; when R is 2 In the case of iodine, the intermediate IIa is reacted with a selective iodine reagent in the presence of a solvent to obtain R 2 Said intermediate IIe being iodine.
Wherein, each reaction formula of the step S3 is as follows:
Figure BDA0002377501410000071
optionally, the solvent in step S31 is acetonitrile, the solvents in steps S32, S33, and S34 are respectively dichloromethane, the selective chlorine reagent in step S32 is N-chlorosuccinimide, the selective bromine reagent in step S33 is N-bromosuccinimide, and the selective iodine reagent in step S34 is N-iodosuccinimide.
Further, the ratio of the amount of acetonitrile to ethyl trifluoroacetate or ethyl difluoroacetate material in step S1 is 1:1.
according to one embodiment of the invention, the reflux is carried out at a temperature of 70 ℃ to 80 ℃ for 3h to 4h in step S1.
In some embodiments of the present invention, the strong base in step S1 is sodium hydrogen, the solvent is tetrahydrofuran, and the reaction formula can be represented by the following formula:
Figure BDA0002377501410000081
according to one embodiment of the invention, the ratio of the amount of intermediate I to methylhydrazine sulfate species in step S2 is 1:1.
In some embodiments of the present invention, the ethanol solution is refluxed at 70-80 ℃ for 3-4 h in step S2, and the reaction formula can be shown as follows:
Figure BDA0002377501410000082
according to one embodiment of the invention, when R 2 In the case of hydrogen, the preparation process of the fluorine-containing pyrazole amide derivative (compound III) can adopt the following route:
Figure BDA0002377501410000083
according to the application of the fluorine-containing pyrazole amide derivative disclosed by the embodiment of the invention, the fluorine-containing pyrazole amide derivative is applied to an antifungal bactericide.
The following will explain in detail the fluorine-containing pyrazole amide derivatives, the preparation method and the application thereof according to the embodiments of the present invention with reference to specific examples.
Example 1
The preparation method of the fluorine-containing pyrazole amide derivative III comprises the following steps:
when R is 2 When H, the preparation method comprises:
(1) Dissolving 10mmol of ethyl trifluoroacetate in tetrahydrofuran, adding 10mmol of acetonitrile, adding 10mmol of sodium hydride, reacting at 80 ℃ for 3 hours, cooling, adding a proper amount of concentrated hydrochloric acid, extracting with ethyl acetate, and concentrating to obtain a light yellow solid (I);
(2) Dissolving 5mmol of methylhydrazine sulfate in 100mL of ethanol, adding 5mmol of the obtained intermediate I, refluxing at 80 ℃ for 3 hours and tracing reaction by TLC; filtering, drying to obtain light yellow crystal, namely intermediate IIa, wherein the chemical formula of intermediate IIa is shown as the following formula:
Figure BDA0002377501410000091
(3) Dissolving 1mmol of intermediate IIa in pyridine, adding 1.1mmol of benzoic acid, dropwise adding phosphorus oxychloride at 0 ℃, refluxing at 80 ℃ for 3 hours, respectively extracting with dilute hydrochloric acid solution, saturated sodium carbonate solution and dichloromethane, drying with anhydrous sodium sulfate, concentrating, and separating with silica gel column (eluting reagent: petroleum ether: ethyl acetate is 5:1) to obtain off-white solid, namely fluorine-containing pyrazole amide derivative III.
When R is 2 When fluorine, chlorine, bromine and iodine are used, the preparation methods of the corresponding intermediates IIb, IIc, IId and IIe are respectively shown as the following formulas:
Figure BDA0002377501410000101
wherein, intermediate IIa
1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-amine
White solid, yield, 70%; melting point is 96.3-97 ℃; 1 H NMR(500MHz,Chloroform-d)δ5.76(s,1H, Ar-H),3.67(s,3H,N-CH 3 ),3.58(s,2H,NH 2 ). 13 C NMR(126MHz,CDCl 3 )δ145.50,140.86, 140.56,140.26,124.53,122.39,120.26,118.13,89.48,34.76.ESI-MS calculated for C 5 H 7 F 3 N 3 [M+H] + ,166.1；found,166.1。
intermediate IIa
3- (difluoromethyl) -1-methyl-1H-pyrazol-5-amine
Yellow oil; the yield is 31.6 percent; melting point 29.9-32.6 deg.C; 1 H NMR(500MHz,DMSO-d 6 )δ6.66(t,J＝ 55.1Hz,1H CHF 2 ),5.47(s,1H,Ar-H),5.39(s,2H,NH 2 ),3.54(s,3H,N-CH 3 ). 13 C NMR(126 MHz,DMSO-d 6 )δ148.58,144.41,144.19,143.97,114.42,112.59,110.75,85.35,34.86.ESI-MS calculated for C 5 H 8 F 2 N 3 [M+H] + ,148.1；found,148.1。
intermediate IIb
4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-amine
Light brown solid, yield, 77%; the melting point is 92.4-94.1 ℃; 1 H NMR(500MHz,DMSO-d 6 )δ5.61(s,2H, NH 2 ),3.58(s,3H,N-CH 3 ). 13 C NMR(126MHz,DMSO-d 6 )δ134.85,134.67,130.83,128.93, 125.24,125.19,124.94,124.90,124.64,124.60,124.34,124.30,124.05,124.02,121.92,121.89, 119.79,119.76,117.66,117.64,35.88.ESI-MS calculated for C 5 H 6 F 4 N 3 [M+H]+,184.1；found, 184.1.
intermediate IIb
3- (difluoromethyl) -4-fluoro-1-methyl-1H-pyrazol-5-amine
A yellow solid; the yield is 33%; the melting point is 65.4-67 ℃; 1 H NMR(600MHz,DMSO-d6)δ6.79(t,J＝53.7 Hz,1H,CHF 2 ),5.41(s,2H,-NH 2 ),3.53(s,3H,N-CH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ 134.66,131.70,130.32–129.83,111.82,35.97.ESI-MS calculated for C 5 H 7 F 3 N 3 [M+H]+,166.1； found,166.1.
intermediate IIc
4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-amine
Yellow solid, yield, 77%; melting point is 46.5-48.7 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ5.88(s,2H), 3.60(s,3H,N-CH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ145.77,135.27,135.03,134.80,134.56, 124.08,122.30,120.52,118.74,86.85,36.35.ESI-MS calculated for C 5 H 6 ClF 3 N 3 [M+H] + ,200.0； found,200.0.
intermediate IIc
4-chloro-3- (difluoromethyl) -1-methyl-1H-pyrazol-5-amine
A yellow solid; the yield is 40.6 percent; melting point of 75.6-77.9 deg.C; 1 H NMR(500MHz,DMSO-d 6 )δ6.75(t,J＝ 53.4Hz,1H,CHF 2 ),5.70(s,2H,-NH 2 ),3.58(s,3H,N-CH 3 ). 13 C NMR(151MHz,DMSO--d 6 )δ 145.23,139.49,111.98,86.75,36.03.ESI-MS calculated for C 5 H 7 ClF 2 N 3 [M+H]+,182.0； found,182.1.
intermediate IId
4-bromo-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-amine
Yellow solid, yield, 77%; melting point is 200.1-201.4 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ5.82(s,2H, -NH 2 ),3.61(s,3H,N-CH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ147.22,136.84–136.08(m), 121.50,70.94,36.39.ESI-MS calculated for C 5 H 6 BrF 3 N 3 [M+H]+,244.0；found,244.0.
intermediate IIe
4-iodo-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-amine
Yellow solid, yield, 77%; melting point is 200.2-201.9 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ5.67(d,J＝ 98.1Hz,2H),3.66(s,3H,N-CH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ150.23,139.52(q,J＝35.2, 34.5Hz),121.72(q,J＝269.3Hz),37.04,36.35.ESI-MS calculated for C 5 H 6 F 3 IN 3 [M+H]+, 292.0；found,292.0.
compound 1
N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
White solid, yield 93%; melting point, 160.1-161.7 ℃; 1 H NMR(600MHz,Chloroform-d)δ7.90(s, 1H,CONH-H),7.89(s,1H,Ph-H),7.68–7.61(m,2H,Ph-H),7.54(t,J＝7.5Hz,2H,Ph-H),6.59(s,1H,Ar-H), 3.87(s,3H,NCH 3 ). 13 C NMR(151MHz,Chloroform-d)δ165.82,141.04,136.37,133.00,132.51,129.09, 127.39,120.11,99.45,77.24,77.03,76.82,36.51.ESI-MS calculated for C 12 H 11 F 3 N 3 O[M+H] + ,270.1；found, 270.1.
compound 2
2-methyl-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
Yellow solid, yield 86%; melting point, 133.1-135.3 ℃; 1 H NMR(600MHz,Chloroform-d)δ7.53(s,1H,Ph-H), 7.43(d,J＝7.6Hz,1H,Ph-H),7.39(s,1H,Ph-H),7.34–7.29(m,2H,Ph-H),6.63(s,1H,Ar-H),3.87(s,3H, NCH 3 ),2.53(s,3H). 13 C NMR(151MHz,Chloroform-d)δ166.28,141.50,141.25,140.99,140.74,139.15, 136.54,133.74,132.51,128.91,128.14,124.36,123.71,121.93,120.15,118.37,99.44,77.27,77.06,76.84, 36.43,21.30.ESI-MS calculatedforC 13 H 13 F 3 N 3 O[M+H] + ,284.1；found,284.1.
compound 3
3-methyl-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
Yellow solid, yield 91%; melting point, 118.5-119.4 ℃; 1 H NMR(600MHz,Chloroform-d)δ7.70(s,1H,Ph-H), 7.68(s,1H,CONH-H),7.66(d,J＝6.9Hz,1H,Ph-H),7.42(d,J＝12.7Hz,2H,Ph-H),6.56(s,1H,Ar-H),3.85 (s,3H,NCH 3 ),2.45(s,3H,Ph-CH 3 ). 13 C NMR(151MHz,Chloroform-d)δ166.28,141.50,141.25,140.99, 140.74,139.15,136.54,133.74,132.51,128.91,128.14,124.36,123.71,121.93,120.15,118.37,99.44,77.27, 77.06,76.84,36.43,21.30.ESI-MS calculated for C 13 H 13 F 3 N 3 O[M+H] + 284.1,；found,284.1.
compound 4
4-methyl-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
White solid, yield 91%; melting point, 152.1-152.3 ℃; 1 H NMR(600MHz,Chloroform-d)δ7.79(s,2H,Ph-H), 7.65(s,1H,CONH-H),7.33(s,2H,Ph-H),6.57(s,1H,Ar-H),3.85(s,3H,NCH 3 ),2.45(s,3H,Ph-CH 3 ). 13 C NMR(126MHz,Chloroform-d)δ145.57,143.54,141.30,140.99,138.56,135.54,133.58,129.85,128.59, 126.62,122.27,120.14,97.64,36.32,21.43.ESI-MS calculated for C 13 H 13 F 3 N 3 O[M+H] + ,284.1；found,284.1.
compound 5
2-chloro-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
White solid, 91% yield; melting point, 142.6-144.1 ℃; 1 H NMR(500MHz,Chloroform-d)δ8.44(s,1H),7.68(s,1H, Ph-H),7.43(s,2H,Ph-H),7.35(t,J＝5.5Hz,1H,Ph-H),6.55(s,1H,Ar-H),3.79(s,3H,NCH 3 ). 13 C NMR(126 MHz,Chloroform-d)δ164.71,141.50,141.20,140.89,140.58,132.68,130.58,127.50,124.12,121.98,119.85, 117.71,98.99,36.51.ESI-MS calculated for C 12 H 10 ClF 3 N 3 O[M+H] + ,304.0；found,304.0.
compound 6
3-chloro-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
White solid, yield 87%; melting point, 139.2-141.5 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.72(s,1H,CONH-H), 8.05(t,J＝1.8Hz,1H,Ph-H),7.95(dt,J＝7.7,1.3Hz,1H,Ph-H),7.73(ddd,J＝8.0,2.1,1.1Hz,1H,Ph-H), 7.61(t,J＝7.9Hz,1H,Ph-H),6.75(s,1H,Ar-H),3.84(s,3H,NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ164.91, 149.95,140.03,139.53,139.03,138.53,138.25,135.40,133.81,132.63,131.03,128.24,127.26,127.10,123.54, 119.99,99.40,99.37,99.34,37.09.ESI-MS calculated for C 12 H 10 ClF 3 N 3 O[M+H] + ,304.0；found,304.0.
compound 7
4-chloro-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
White solid, yield 89%; melting point, 150.1-153.0 ℃; 1 H NMR(600MHz,Chloroform-d)δ7.83(d,J＝8.0Hz,2H, Ph-H),7.69(s,1H,CONH-H),7.51(s,2H,Ph-H),6.56(s,1H,Ar-H),3.85(s,3H,NCH 3 ). 13 C NMR(151MHz, DMSO-d 6 )δ165.24,139.64,139.39,139.15,138.90,137.75,132.14,130.42,129.14,124.45,122.67,120.90, 119.12,99.42,37.06.ESI-MS calculated for C 12 H 10 ClF 3 N 3 O[M+H] + ,304.0；found,304.0.
compound 8
2-fluoro-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
White solid, yield 94%; melting point, 110.2-111.5 ℃; 1 H NMR(600MHz,Chloroform-d)δ8.35(s,1H),8.20(s, 1H,Ph-H),7.62(s,1H,Ph-H),7.38(s,1H,Ph-H),6.71(s,1H,Ar-H),3.88(s,3H,NCH 3 ). 13 C NMR(151MHz, DMSO-d 6 )δ163.24,160.56,158.90,150.08,139.71,139.46,139.21,138.96,138.11,134.02,133.96,130.80, 125.15,124.44,123.38,123.29,122.66,120.88,119.11,116.89,116.75,98.50,37.01.ESI-MS calculated for C 13 H 10 F 6 N 3 O[M+H] + ,288.1；found,288.1.
compound 9
3-fluoro-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
White solid, yield 91%; melting point, 171.2-173.4 ℃; 1 H NMR(500MHz,Chloroform-d)δ8.12(s,1H,Ph-H), 7.70(d,J＝7.7Hz,1H,Ph-H),7.65(d,J＝8.9Hz,1H,Ph-H),7.58–7.51(m,1H,Ph-H),7.37(d,J＝8.3Hz, 1H,Ph-H),6.59(s,1H,Ar-H),3.88(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ164.98,163.20,161.58, 150.00,139.70,139.45,139.20,138.95,138.27,135.70,135.66,131.26,131.20,122.66,120.88,119.81,119.67, 115.25,99.39,37.06.ESI-MS calculated for C 12 H 10 F 4 N 3 O[M+H] + ,288.1；found,288.1.
compound 10
4-fluoro-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
White solid, yield 88%; melting point, 164.1-165.8 ℃; 1 H NMR(600MHz,Chloroform-d)δ7.91(s,2H),7.69(s, 1H),7.21(s,2H),6.55(s,1H,Ar-H),3.85(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ165.83,165.19, 164.18,150.06,139.63,139.38,139.13,138.88,138.47,136.57,131.28,129.87,124.35,122.68,120.91,119.13, 115.98,99.42,37.04.ESI-MS calculated for C 12 H 10 F 4 N 3 O[M+H] + ,288.1；found,288.1.
compound 11
2-methoxy-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
White solid, yield 89%; melting point, 159.5-162.4 ℃; 1 H NMR(600MHz,Chloroform-d)δ7.74(s,1H),7.42(d, J＝20.7Hz,3H,Ph-H),7.15(d,J＝7.5Hz,1H,Ph-H),6.56(s,1H,Ar-H),3.88(s,3H),3.85(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ164.33,157.58,139.59,139.34,139.09,138.84,138.49,133.76,130.90,122.74, 122.59,121.15,120.96,120.80,112.72,111.52,98.03,56.56,36.77.ESI-MS calculated for C 13 H 13 F 3 N 3 O 2 [M+H]+,300.1；found,300.1.
compound 12
3-methoxy-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
Yellow solid, yield 92%; melting point, 135.3-137.7 ℃; 1 H NMR(600MHz,Chloroform-d)δ7.81(s,1H),7.70 (s,3H,Ph-H),7.41(s,1H,Ph-H),6.63(s,1H,Ar-H),3.88(s,3H). 13 C NMR(151MHz,DMSO-d 6 )δ166.02, 159.74,139.64,139.39,139.14,138.89,138.53,134.74,130.22,124.47,122.70,120.92,120.65,119.14,118.63, 113.65,99.47,55.84,37.05.ESI-MS calculated for C 13 H 13 F 3 N 3 O 2 [M+H] + ,300.1；found,300.0.
compound 13
4-methoxy-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
White solid, yield 91%; melting point, 149.8-151.7 ℃; 1 H NMR(500MHz,Chloroform-d)δ7.83(d,J＝8.8Hz, 2H,Ph-H),7.75(s,1H,Ph-H),6.98(d,J＝8.8Hz,2H,Ph-H),6.52(s,1H,Ar-H),3.89(s,3H),3.82(s,3H, NCH 3 ). 13 C NMR(151MHz,Chloroform-d)δ165.17,163.41,141.20,140.94,136.56,129.41,124.54,120.11, 114.29,99.35,55.62,36.56.ESI-MS calculated for C 13 H 13 F 3 N 3 O 2 [M+H] + ,300.1；found,300.1.
compound 14
N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -2- (trifluoromethyl) benzamide
Yellow solid, yield 87%; melting point, 145.8-147.0 ℃; 1 H NMR(600MHz,Chloroform-d)δ7.81(s,1H),7.70(s, 3H,Ph-H),7.41(s,1H,Ph-H),6.63(s,1H,Ar-H),3.88(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ166.17, 139.82,139.58,139.33,139.08,138.00,135.02,133.09,131.14,127.43,126.96,126.93,126.83,126.71,126.50, 126.30,125.02,123.21,121.39,98.10,37.02.ESI-MS calculated for C 13 H 10 F 6 N 3 O[M+H]+,338.1；found,338.1.
compound 15
N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -3- (trifluoromethyl) benzamide
Yellow solid, yield 93%; melting point, 151.7-152.9 ℃; 1 H NMR(600MHz,Chloroform-d)δ8.15(s,1H， CONH-H),8.09(d,J＝6.9Hz,1H,Ph-H),7.89(d,J＝7.0Hz,1H,Ph-H),7.79(s,1H,Ph-H),7.69(s,1H,Ph-H), 6.57(s,1H,Ar-H),3.87(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ164.96,139.69,139.45,139.20, 138.95,138.20,134.36,132.61,130.37,130.14,129.92,129.71,129.50,129.36,129.34,127.04,125.23,125.07, 124.43,123.43,122.65,121.62,120.88,99.51,37.12.ESI-MS calculated for C 13 H 10 F 6 N 3 O[M+H] + ,338.1；found,338.1.
compound 16
N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -4- (trifluoromethyl) benzamide
Yellow solid, yield 92%; melting point, 183.3-186.1 ℃; 1 H NMR(500MHz,Chloroform-d)δ8.20(dd,J＝9.0, 5.3Hz,2H,Ph-H),7.21–7.16(m,2H,Ph-H),7.00(s,1H,Ar-H),4.02(s,3H,NCH 3 ). 13 C NMR(126MHz, Chloroform-d)δ145.57,143.54,141.30,140.99,138.56,135.54,133.58,129.85,128.59,126.62,122.27,120.14, 97.64,36.32,21.43.ESI-MS calculatedfor C 13 H 10 F 6 N 3 O[M+H] + ,338.1；found,338.1.
compound 17
N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) benzamide
White solid, yield 90%; melting point, 137.3-138.2 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.49(s,1H,CONH-H), 7.99(d,J＝7.2Hz,2H,Ph-H),7.69–7.51(m,3H,Ph-H),6.92(s,1H,CHF 2 -H),6.53(s,1H,Ar-H),3.77(s,3H, NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ166.22,144.69,144.31,143.93,138.14,133.56,132.77,129.02, 128.42,115.10,112.04,108.97,98.48,36.64.ESI-MS calculated for C 12 H 12 F 2 N 3 O[M+H] + ,252.1；found,252.1.
compound 18
N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzamide
Yellow solid, yield 79%; melting point, 102.9-103.2 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.56(s,1H,CONH-H), 7.61(d,J＝7.3Hz,1H,Ph-H),7.40(dd,J＝25.6,7.0Hz,4H,Ph-H),6.95(s,1H,CHF 2 -H),6.61(s,1H,Ar-H), 3.82(s,3H,NCH 3 ),2.46(s,3H,CH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ168.22,144.72,144.34,143.97,138.10, 136.29,135.88,131.17,128.12,126.14,115.11,112.04,108.97,97.46,36.71,19.94.ESI-MS calculated for C 13 H 14 F 2 N 3 O[M+H] + ,266.1；found,266.1.
compound 19
N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) -3-methylbenzamide
White solid, yield 81%; melting point, 87.5-87.9 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.45(s,1H,CONH-H), 7.81(d,J＝8.3Hz,2H,Ph-H),7.45(d,J＝4.6Hz,2H,Ph-H),6.93(t,J＝54.7Hz,1H,CHF 2 -H),6.52(s,1H, Ar-H),3.77(s,3H,NCH 3 ),2.41(s,3H,CH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ166.34,144.70,144.32,143.94, 138.41,138.21,133.58,133.32,128.91,125.58,115.12,112.06,108.99,98.43,36.63,21.37..ESI-MS calculated for C 13 H 14 F 2 N 3 O[M+H] + ,266.1；found,266.1.
compound 20
N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) -4-methylbenzamide
Yellow solid, yield 78%; melting point, 113.2-114.5 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.40(s,1H,CONH-H), 7.91(d,J＝8.1Hz,2H,Ph-H),7.36(d,J＝8.1Hz,2H,Ph-H),6.92(t,J＝54.7Hz,1H,CHF 2 -H),6.52(s,1H, Ar-H),3.76(s,3H,NCH 3 ),2.40(s,3H,CH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ166.06,144.68,144.30,143.92, 142.92,138.24,130.73,129.53,128.47,115.12,112.06,108.99,98.46,36.61,21.53.ESI-MS calculated for C 13 H 14 F 2 N 3 O[M+H] + ,266.1；found,266.1.
compound 21
2-chloro-N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) benzamide
Yellow solid, yield 83%; melting point, 117.2-117.8 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.80(s,1H,CONH-H), 7.66(dd,J＝7.3,1.7Hz,1H,Ph-H),7.61–7.44(m,3H,Ph-H),6.91(t,J＝54.6Hz,1H,CHF 2 -H),6.58(s,1H, Ar-H),3.79(s,3H,NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ165.39,144.82,144.44,144.06,137.56,135.98, 132.11,130.54,130.23,129.70,127.75,115.02,111.95,108.88,97.30,36.77.ESI-MS calculated for C 12 H 11 ClF 2 N 3 O[M+H] + ,286.1；found,286.1.
compound 22
3-chloro-N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) benzamide
White solid, yield 89%; melting point, 131.6-132.5 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.62(s,1H,CONH-H), 8.05(s,1H,Ph-H),7.95(d,J＝7.8Hz,1H,Ph-H),7.72(d,J＝9.0Hz,1H,Ph-H),7.60(t,J＝7.9Hz,1H,Ph-H), 6.93(t,J＝54.7Hz,1H,CHF 2 -H),6.55(s,1H,Ar-H),3.79(s,3H,NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ 164.85,144.72,144.34,143.96,137.81,135.56,133.81,132.53,131.00,128.21,127.21,115.06,111.99,108.92, 98.45,36.69.ESI-MS calculated for C 12 H 11 ClF 2 N 3 O[M+H] + ,286.1；found,286.1.
compound 23
4-chloro-N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) benzamide
White solid, yield 85%; melting point, 141.6-143.2 ℃; 1 H NMR(500MHz,Chloroform-d)δ8.00(s,1H),7.80(d,J ＝6.8Hz,2H,Ph-H),7.65(d,J＝7.6Hz,1H,Ph-H),7.43(dd,J＝36.7,7.5Hz,3H,Ph-H),6.74–6.48(m,1H, CHF 2 -H),6.39(d,J＝42.8Hz,1H,Ar-H),3.76(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ165.19, 144.53,144.34,144.15,137.92,137.65,132.30,130.38,129.11,113.54,112.01,110.47,98.48,36.67.ESI-MS calculated for C 12 H 11 ClF 2 N 3 O[M+H] + ,286.1；found,286.1.
compound 24
N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) -2-fluorobenzamide
White solid, yield 86%; melting point, 89.2-89.4 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.63(s,1H,CONH-H), 7.77(t,J＝8.0Hz,1H,Ph-H),7.64(q,J＝7.3Hz,1H,Ph-H),7.38(q,J＝8.3,7.2Hz,2H,Ph-H),6.93(t,J＝ 54.6Hz,1H,CHF 2 -H),6.59(s,1H,Ar-H),3.79(s,3H,NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ163.17,161.36, 158.04,144.78,144.02,137.66,133.78,130.75,125.14,125.10,123.43,116.91,116.62,115.03,111.96,108.90, 97.57,36.59.ESI-MS calculated for C 12 H 11 F 3 N 3 O[M+H] + ,270.1；found,270.0.
compound 25
N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) -3-fluorobenzamide
White solid, yield 87%; melting point, 117.5-118.3 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.60(s,1H,CONH-H), 7.83(dd,J＝26.3,8.7Hz,2H,Ph-H),7.62(td,J＝8.0,5.9Hz,1H,Ph-H),7.50(td,J＝8.4,2.2Hz,1H,Ph-H), 6.93(t,J＝54.7Hz,1H,CHF 2 -H),6.55(s,1H,Ar-H),3.78(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ 164.93,163.20,161.58,144.55,144.36,144.17,137.82,135.82,131.26,124.66,119.73,119.60,115.37,115.21, 113.53,112.00,110.46,98.50,36.67.ESI-MS calculated for C 12 H 11 F 3 N 3 O[M+H] + ,270.1；found,270.0.
compound 26
N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) -4-fluorobenzamide
White solid, yield 77%; melting point, 130.9-131.4 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.53(s,1H,CONH-H), 8.09(dd,J＝8.5,5.6Hz,2H,Ph-H),7.40(t,J＝8.8Hz,2H,Ph-H),6.93(t,J＝54.7Hz,1H,CHF 2 -H),6.54(s, 1H,Ar-H),3.78(s,3H,NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ166.60,165.14,163.29,144.71,144.33, 143.95,138.03,131.29,131.17,130.05,130.01,116.13,115.84,115.08,112.01,108.94,98.46,36.62.ESI-MS calculated for C 12 H 11 F 3 N 3 O[M+H] + ,270.1；found,270.0.
compound 27
N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) -2-methoxybenzamide
Yellow solid, yield 82%; melting point, 162.7-163.4 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ10.30(s,1H,CONH-H), 7.79(dd,J＝7.6,1.7Hz,1H,Ph-H),7.57(t,J＝8.7Hz,1H,Ph-H),7.23(d,J＝8.3Hz,1H,Ph-H),7.10(t,J＝ 7.5Hz,1H,Ph-H),6.93(t,J＝54.7Hz,1H,CHF 2 -H),6.59(s,1H,Ar-H),3.95(s,3H,OCH 3 ),3.79(s,3H, NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ164.22,157.55,144.51,144.32,144.13,138.09,133.62,130.91, 122.76,121.13,113.60,112.66,112.07,110.53,97.01,56.52,36.36.ESI-MS calculated for C 13 H 14 F 2 N 3 O 2 [M+H] + ,282.1；found,282.0.
compound 28
N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) -3-methoxybenzamide
Yellow solid, yield 88%; melting point, 144.5-145.3 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.52(s,1H,CONH-H), 7.60(d,J＝7.7Hz,1H,Ph-H),7.56(s,1H,Ph-H),7.49(t,J＝7.9Hz,1H,Ph-H),7.22(dd,J＝8.2,2.1Hz,1H, Ph-H),6.95(t,J＝54.7Hz,1H,CHF 2 -H),6.56(s,1H,Ar-H),3.86(s,3H,OCH 3 ),3.79(s,3H,NCH 3 ). 13 C NMR (151MHz,DMSO-d 6 )δ165.99,159.74,144.53,144.34,144.15,138.10,134.91,130.18,120.62,118.54,113.60, 112.04,110.51,98.53,55.81,36.64.ESI-MS calculated for C 13 H 14 F 2 N 3 O 2 [M+H] + ,282.1；found,282.1.
compound 29
N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) -4-methoxybenzamide
White solid, yield 90%; the melting point is 166.2-167.4 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.32(s,1H,CONH-H), 7.99(d,J＝8.9Hz,2H,Ph-H),7.09(d,J＝8.8Hz,2H,Ph-H),6.92(s,1H,CHF 2 -H),6.50(s,1H,Ar-H),3.85(s, 3H,OCH 3 ),3.75(s,3H,NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ165.57,162.89,144.63,144.25,143.87, 138.34,130.42,125.58,115.12,114.23,112.05,108.98,98.43,55.94,36.59.ESI-MS calculated for C 13 H 14 F 2 N 3 O 2 [M+H] + ,282.1；found,282.1.
compound 30
N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) -2- (trifluoromethyl) benzamide
White solid, yield 82%; melting point, 137.1-138.8 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.90(s,1H,CONH-H), 7.86(dd,J＝18.1,5.7Hz,4H,Ph-H),6.94(t,J＝54.6Hz,1H,CHF 2 -H),6.59(s,1H,Ar-H),3.80(s,3H, NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ166.14,144.85,144.47,144.09,137.55,135.25,131.03,129.28,115.01, 111.94,108.87,97.31,36.60.ESI-MS calculated for C 13 H 11 F 5 N 3 O[M+H] + ,320.1；found,320.1.
compound 31
N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) -3- (trifluoromethyl) benzamide
Yellow solid, yield 86%; melting point, 103.5-104.2 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.77(s,1H,CONH-H), 8.40–8.26(m,2H,Ph-H),8.03(d,J＝7.8Hz,1H,Ph-H),7.83(t,J＝7.8Hz,1H,Ph-H),6.95(t,J＝54.7Hz, 1H,CHF 2 -H),6.57(s,1H,Ar-H),3.80(s,3H,NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ164.88,144.76,144.38, 144.00,137.74,134.50,132.54,130.32,130.02,129.59,129.20,126.13,125.01,122.52,115.05,111.98,108.91, 98.55,36.70.ESI-MS calculated for C 13 H 11 F 5 N 3 O[M+H] + ,320.1；found,320.1.
compound 32
N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) -4- (trifluoromethyl) benzamide
Yellow solid, yield 91%; melting point, 101.1-101.9 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.75(s,1H,CONH-H), 8.19(d,J＝8.1Hz,2H,Ph-H),7.95(d,J＝8.2Hz,2H,Ph-H),6.94(t,J＝54.7Hz,1H,CHF 2 -H),6.57(s,1H, Ar-H),3.80(s,3H,NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ165.13,144.76,144.38,144.00,137.74,137.38, 133.09,132.66,132.24,131.81,129.36,125.96,122.47,115.04,111.97,108.90,98.44,36.68.ESI-MS calculated for C 13 H 11 F 5 N 3 O[M+H] + ,320.1；found,320.1.
compound 33
N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
White solid, yield 96%; melting point, 159.3-160.0 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.82(s,1H,CONH-H), 9.17(d,J＝1.7Hz,1H,aromatic H in pyridyl ring),8.82(dd,J＝4.8,1.6Hz,1H,aromatic H in pyridyl ring), 8.38–8.30(m,1H,aromatic H in pyridyl ring),7.61(dd,J＝8.3,5.2Hz,1H,aromatic H in pyridyl ring),6.78 (s,1H,Ar-H),3.86(s,3H,NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ164.89,153.27,149.46,140.09,139.59, 139.09,138.60,138.18,136.28,129.27,127.10,124.06,123.55,119.99,116.44,99.25,37.10.ESI-MS calculated for C 11 H 10 F 3 N 4 O[M+H] + ,271.1；found,271.1.
compound 34
N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) isonicotinamide
White solid, yield 92%; melting point, 126.1-126.9 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.90(s,1H,CONH-H), 8.84(dd,J＝4.6,1.4Hz,2H,aromatic H in pyridyl ring),7.90(dd,J＝4.6,1.4Hz,2H,aromatic H in pyridyl ring),6.78(s,1H,Ar-H),3.85(s,3H,NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ164.92,150.90,140.49,140.12, 139.62,139.12,138.63,137.96,127.07,123.52,122.19,119.96,116.41,99.44,37.11.ESI-MS calculated for C 11 H 10 F 3 N 4 O[M+H] + ,271.1；found,271.1.
compound 35
2-chloro-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
Yellow solid, yield 91%; melting point, 109.1-109.9 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ11.12(s,1H,CONH-H), 8.59(dd,J＝4.8,1.9Hz,1H,aromatic H in pyridyl ring),8.18(dd,J＝7.6,1.9Hz,1H,aromatic H in pyridyl ring),7.61(dd,J＝7.6,4.8Hz,1H,aromatic H in pyridyl ring),6.83(s,1H,Ar-H),3.88(s,3H,NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ164.10,151.54,147.02,140.25,139.75,139.25,138.75,137.78,132.21,127.06, 123.59,123.51,119.95,116.40,97.92,37.19.ESI-MS calculated for C 11 H 9 ClF 3 N 4 O[M+H] + ,305.0；found, 305.0.
compound 36
6-chloro-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
Yellow solid, yield 93%; melting point, 169.3-171.3 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.88(s,1H,CONH-H), 8.99(d,J＝2.2Hz,1H,aromatic H in pyridyl ring),8.38(dd,J＝8.3,2.5Hz,1H,aromatic H in pyridyl ring), 7.76(d,J＝8.3Hz,1H,aromatic H in pyridyl ring),6.77(s,1H,Ar-H),3.85(s,3H,NCH 3 ). 13 C NMR(75MHz, DMSO-d 6 )δ163.84,153.97,150.12,140.10,139.82,139.60,139.11,138.61,137.98,128.71,127.07,124.76, 123.52,119.97,116.42,99.24,37.14.ESI-MS calculated for C 11 H 9 ClF 3 N 4 O[M+H] + ,305.0；found,305.1.
compound 37
2-fluoro-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
White solid, yield 89%; melting point, 126.1-126.8 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.92(s,1H,CONH-H), 8.47(d,J＝4.5Hz,1H,aromatic H in pyridyl ring),8.35(ddd,J＝9.4,7.6,1.8Hz,1H,aromatic H in pyridyl ring),7.56(ddd,J＝7.1,4.9,1.9Hz,1H,aromatic H in pyridyl ring),6.81(s,1H,Ar-H),3.86(s,3H,NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ162.14,158.11,150.85,142.39,140.17,139.67,139.17,138.67,137.85,127.06, 123.51,122.80,119.96,118.30,117.91,98.35,40.27,37.05.ESI-MS calculated for C 11 H 9 F 4 N 4 O[M+H] + ,289.1； found,289.1.
compound 38
6-fluoro-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
White solid, yield 91%; melting point, 179.2-180.1 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.85(s,1H,CONH-H), 8.88(d,J＝2.4Hz,1H,aromatic H in pyridyl ring),8.54(td,J＝8.4,2.5Hz,1H,aromatic H in pyridyl ring), 7.41(dd,J＝8.6,2.5Hz,1H,aromatic H in pyridyl ring),6.77(s,1H,Ar-H),3.87(s,3H,NCH 3 ). 13 C NMR(75 MHz,DMSO-d 6 )δ166.74,163.67,148.87,148.65,142.76,142.63,140.10,139.60,139.10,138.60,138.04, 128.05,124.98,123.51,119.96,110.38,109.88,99.20,37.09.ESI-MS calculated for C 11 H 9 F 4 N 4 O[M+H] + , 289.1；found,289.1.
compound 39
2-methoxy-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
Yellow solid, yield 87%; melting point, 141.6-141.3 deg.C; 1 H NMR(300MHz,DMSO-d 6 )δ10.46(s,1H,CONH-H), 8.41(dd,J＝4.9,1.8Hz,1H,aromatic H in pyridyl ring),8.20(dd,J＝7.4,1.8Hz,1H,aromatic H in pyridyl ring),7.19(dd,J＝7.4,4.9Hz,1H,aromatic H in pyridyl ring),6.79(s,1H,Ar-H),4.04(s,3H),3.85(s,3H, NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ163.23,160.67,150.52,140.63,140.05,139.55,139.05,138.55, 138.18,127.12,123.57,120.02,117.88,117.15,116.46,98.16,54.41,36.79.ESI-MS calculated for C 12 H 12 F 3 N 4 O 2 [M+H] + ,301.1；found,301.1.
compound 40
6-methoxy-N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
White solid, yield 92%; melting point, 141.8-142.5 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ10.46(s,1H,CONH-H), 8.41(dd,J＝4.9,1.9Hz,1H,aromatic H in pyridyl ring),8.20(dd,J＝7.4,1.9Hz,1H,aromatic H in pyridyl ring),7.19(dd,J＝7.4,4.9Hz,1H,aromatic H in pyridyl ring),6.79(s,1H,Ar-H),4.05(s,3H,NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ163.22,160.67,150.52,140.64,140.05,139.56,139.06,138.56,138.18,127.12, 123.57,120.02,117.87,117.14,116.46,98.18,98.15,54.40,36.78.ESI-MS calculated for C 12 H 12 F 3 N 4 O 2 [M+H] + ,301.1；found,301.0.
compound 41
N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -2- (trifluoromethyl) nicotinamide
White solid, yield 88%; melting point, 175.2-176.3 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ11.20(s,1H,CONH-H), 8.92(d,J＝4.6Hz,1H,aromatic H in pyridyl ring),8.35(d,J＝8.5Hz,1H,aromatic H in pyridyl ring),7.92 (dd,J＝7.8,4.8Hz,1H,aromatic H in pyridyl ring),6.82(s,1H,Ar-H),3.86(s,3H,NCH 3 ). 13 C NMR(75MHz, DMSO-d 6 )δ164.42,151.05,143.80,143.36,142.91,142.46,140.27,139.77,139.27,138.77,138.16,137.72, 131.42,131.40,127.62,127.23,127.03,123.59,123.48,119.94,116.37,116.29,97.87,97.84,97.81,97.78, 37.04.ESI-MS calculated for C 12 H 9 F 6 N 4 O[M+H] + ,339.1；found,339.1.
compound 42
N- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -6- (trifluoromethyl) nicotinamide
White solid, yield 84%; melting point, 188.4-189.1 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ11.07(s,1H,CONH-H), 9.32(s,1H,aromatic H in pyridyl ring),8.67–8.60(m,1H,aromatic H inpyridyl ring),8.14(d,J＝8.2Hz,1H, aromatic H in pyridyl ring),6.81(s,1H,Ar-H),3.91(s,3H,NCH 3 ). 13 C NMR(75MHz,DMSO-d 6 )δ163.70, 150.02,149.51,149.35,149.05,148.60,140.22,139.72,139.22,138.69,138.32,137.86,132.42,127.17,127.02, 123.53,123.47,121.08,121.04,121.01,120.97,119.92,119.90,116.36,116.26,99.10,99.07,99.04,99.01, 37.09.ESI-MS calculated for C 12 H 9 F 6 N 4 O[M+H] + ,339.1；found,339.1.
compound 43
N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) -2-fluoronicotinamide
Yellow solid, yield 67%; melting point, 117.3-119.0 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.87(s,1H,CONH-H), 8.47(s,1H,aromatic H in pyridyl ring),8.36(s,1H,aromatic H in pyridyl ring),7.55(s,1H,aromatic H in pyridyl ring),6.95(t,J＝54.7Hz,1H),6.64(s,1H,Ar-H),3.82(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 ) δ162.03,160.51,158.93,150.57,144.67,144.48,144.29,142.32,137.43,122.71,118.38,113.48,111.95, 110.41,97.46,36.65.ESI-MS calculated for C 11 H 9 F 3 N 4 O[M+H] + ,271.1；found,271.1.
compound 44
N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) -2- (trifluoromethyl) nicotinamide
Yellow solid, yield 62%; melting point, 113.6-114.2 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ11.12(s,1H,CONH-H), 8.92(s,1H,aromatic H in pyridyl ring),8.33(s,1H,aromatic H in pyridyl ring),7.90(s,1H,aromatic H in pyridyl ring),6.95(t,J＝54.7Hz,1H),6.63(s,1H,Ar-H),3.81(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 ) δ164.41,150.98,144.73,144.54,144.35,143.44,143.22,142.99,142.77,138.63,138.16,137.29,131.59, 127.63,124.53,122.71,120.89,119.06,113.44,111.90,110.37,97.07,36.65.ESI-MS calculated for C 12 H 9 F 5 N 4 O[M+H] + ,321.1；found,321.1.
compound 45
N- (3- (difluoromethyl) -1-methyl-1H-pyrazol-5-yl) -6- (trifluoromethyl) nicotinamide
Yellow solid, yield 64%; melting point, 132.1-133.8 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.95(s,1H,CONH-H), 9.29(s,1H,aromatic H in pyridyl ring),8.61(s,1H,aromatic H in pyridyl ring),8.14(s,1H,aromatic H in pyridyl ring),6.95(t,J＝54.7Hz,1H),6.60(s,1H,Ar-H),3.82(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 ) δ163.66,150.02,149.47,149.24,149.02,148.79,144.64,144.45,144.26,138.75,137.40,132.63,124.50, 122.68,121.18,120.86,119.04,113.47,111.94,110.40,98.25,36.77.ESI-MS calculated for C 12 H 9 F 5 N 4 O [M+H] + ,321.1；found,321.1.
compound 46
N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
Yellow solid, yield 91%; melting point, 150.3-151.1 ℃; 1 H NMR(500MHz,Chloroform-d)δ8.13(s,1H,CONH-H), 7.86(s,2H,Ph-H),7.62(s,1H,Ph-H),7.48(s,2H,Ph-H),3.77(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 ) δ166.48,136.36,135.97,135.73,135.48,135.23,133.20,132.59,129.37,129.15,128.48,123.65,121.87, 120.09,118.30,104.01,37.83.ESI-MS calculatedfor C 12 H 10 ClF 3 N 3 O[M+H] + ,304.0；found,304.1.
compound 47
2-methyl-N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
Yellow solid, yield 93%; melting point, 189.2-191.0 ℃; 1 H NMR(500MHz,Chloroform-d)δ8.08(d,J＝35.1Hz, 1H,CONH-H),7.75(s,2H,Ph-H),7.27(s,2H,Ph-H),3.77(s,3H,NCH 3 ),2.44(s,3H，CH 3 ).ESI-MS calculated for C 13 H 12 ClF 3 N 3 O[M+H] + ,318.1；found,318.0.
compound 48
3-methyl-N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
Yellow solid, yield 87%; melting point, 127.4-128.2 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ10.64(s,1H,CONH-H), 7.85(s,2H,Ph-H),7.49(s,2H,Ph-H),3.81(s,3H,NCH 3 ),2.42(s,3H,CH 3 ).ESI-MS calculated for C 13 H 12 ClF 3 N 3 O[M+H] + ,318.1；found,318.0.
compound 49
4-methyl-N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
White solid, yield 88%; melting point, 172.6-174.4 ℃; 13 C NMR(151MHz,DMSO-d 6 )δ166.32,143.47,136.46, 135.93,135.68,135.44,135.19,129.66,128.52,123.65,121.87,120.09,118.31,103.98,37.81,21.51.ESI-MS calculated for C 13 H 12 ClF 3 N 3 O[M+H] + ,318.0；found,318.1.
compound 50
2-chloro-N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
Yellow solid, yield 89%; melting point, 149.0-154.2 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ10.94(s,1H,CONH-H), 7.71(dd,J＝7.4,1.8Hz,1H,Ph-H),7.65–7.56(m,2H,Ph-H),7.52(td,J＝7.4,1.5Hz,1H,Ph-H),3.87(s,3H, NCH 3 ).ESI-MS calculatedfor C 12 H 8 Cl 2 F 3 N 3 O[M+H] + ,338.0；found,337.9.
compound 51
3-chloro-N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
White solid, yield 86%; melting point, 178.4-179.6 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.85(s,1H,CONH-H), 8.07(s,1H,Ph-H),7.98(d,J＝7.8Hz,1H,Ph-H),7.75(d,J＝8.0Hz,1H,Ph-H),7.63(d,J＝7.9Hz,1H, Ph-H),3.82(s,3H,NCH 3 ).ESI-MS calculated for C 12 H 8 Cl 2 F 3 N 3 O[M+H] + ,318.0；found,337.9.
compound 52
4-chloro-N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
Yellow solid, yield 81%; melting point, 167.1-168.2 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.68(s,1H,CONH-H), 7.66(d,J＝7.4Hz,1H,Ph-H),7.48(t,J＝7.3Hz,1H,Ph-H),7.38(dd,J＝7.1,4.1Hz,2H,Ph-H),3.87(s,3H, NCH 3 ).ESI-MS calculatedfor C 12 H 8 Cl 2 F 3 N 3 O[M+H] + ,318.0；found,318.0.
compound 53
N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -2-fluorobenzamide
Yellow solid, yield 83%; melting point, 127.3-128.5 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.69(s,1H,CONH-H), 7.84(t,J＝8.1Hz,1H,Ph-H),7.71–7.65(m,1H,Ph-H),7.46–7.37(m,2H,Ph-H),3.85(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ163.90,160.72,159.05,136.23,136.03,135.53,135.29,134.37,130.85,125.22, 123.61,121.83,120.05,117.00,116.85,103.99,37.82.ESI-MS calculated for C 12 H 9 ClF 4 N 3 O[M+H] + ,322.0； found,322.1.
compound 54
3-fluoro-N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
White solid, yield 90%; melting point, 161.9-163.4 ℃; 1 H NMR(500MHz,Chloroform-d)δ7.82(s,1H,CONH-H), 7.74–7.59(m,2H,Ph-H),7.58–7.48(m,1H,Ph-H),7.35(s,1H,Ph-H),3.84(s,3H,NCH 3 ). 13 C NMR(151 MHz,DMSO-d 6 )δ165.20,163.26,161.64,136.01,135.97,135.73,135.48,135.23,134.86,134.81,131.44, 124.72,121.83,120.26,120.12,118.26,115.41,115.25,103.99,37.88.ESI-MS calculated for C 12 H 9 ClF 4 N 3 O [M+H] + ,322.0；found,322.0.
compound 55
4-fluoro-N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
Yellow solid, yield 91%; melting point, 154.8-155.6 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.73(s,1H,CONH-H), 8.12(dd,J＝8.3,5.6Hz,2H,Ph-H),7.42(t,J＝8.8Hz,2H,Ph-H),3.82(s,3H,NCH 3 ). 13 C NMR(151MHz, DMSO-d 6 )δ166.05,164.39,136.23,135.99,135.74,135.49,135.25,131.38,129.08,123.62,121.84,120.06, 118.28,116.12,103.98,37.82.ESI-MS calculatedfor C 12 H 9 ClF 4 N 3 O[M+H] + ,322.0；found,322.1.
compound 56
2-methoxy-N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
Yellow solid, yield 88%; melting point, 159.6-160.8 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.22(s,1H,CONH-H), 7.83(dd,J＝7.6,1.5Hz,1H,Ph-H),7.61(t,J＝7.9Hz,1H,Ph-H),7.26(d,J＝8.4Hz,1H,Ph-H),7.12(t,J＝ 7.5Hz,1H,Ph-H),3.97(s,3H),3.80(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ168.64,165.30,157.88, 156.56,149.79,136.53,136.13,135.55,135.31,135.06,134.61,134.19,131.12,122.60,121.60,121.14,120.78, 120.14,112.79,104.05,56.52,37.78.ESI-MS calculated for C 13 H 12 ClF 3 N 3 O 2 [M+H] + ,334.1；found,334.1.
compound 57
4-methoxy-N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
Yellow colourSolids, yield 79%; melting point, 178.8-179.6 ℃; 1 H NMR(500MHz,Chloroform-d)δ7.88(s,2H),7.67(s, 1H),7.00(s,2H,Ph-H),3.87(d,J＝32.4Hz,6H). 13 C NMR(151MHz,DMSO-d 6 )δ165.83,163.25,136.59, 135.89,135.65,135.40,135.15,130.55,124.64,123.66,121.88,120.10,118.32,114.40,103.94,55.98, 37.79.ESI-MS calculated for C 13 H 12 ClF 3 N 3 O 2 [M+H] + ,334.1；found,334.0.
compound 58
N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -2- (trifluoromethyl) benzamide
White solid, yield 82%; melting point, 174.4-175.9 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ11.07(s,1H,CONH-H), 7.92(d,J＝7.9Hz,1H,Ph-H),7.88(t,J＝5.5Hz,2H,Ph-H),7.81–7.77(m,1H,Ph-H),3.87(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ167.16,136.09,135.84,135.60,135.35,135.29,134.42,133.19,131.44, 129.34,127.10,127.07,127.04,127.01,126.77,126.75,126.56,126.35,124.93,123.58,123.12,121.80,121.31, 120.02,118.24,103.87,37.82.ESI-MS calculatedfor C 13 H 9 ClF 6 N 3 O[M+H] + ,372.0；found,372.0.
compound 59
N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -3- (trifluoromethyl) benzamide
White solid, yield 81%; melting point, 163.2-164.4 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.99(s,1H,CONH-H), 8.38(s,1H,Ph-H),8.33(d,J＝7.8Hz,1H,Ph-H),8.04(d,J＝7.8Hz,1H,Ph-H),7.84(t,J＝7.8Hz,1H,Ph-H), 3.84(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ165.15,150.01,136.04,135.91,135.79,135.54,135.30, 133.53,132.61,130.51,130.31,130.10,129.69,129.67,129.50,126.98,125.17,125.09,123.59,123.37,121.81, 121.56,121.53,120.03,118.25,103.91,37.91.ESI-MS calculated for C 13 H 9 ClF 6 N 3 O[M+H] + ,372.0；found, 372.0.
compound 60
N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -4- (trifluoromethyl) benzamide
Yellow solid, yield 86%; melting point, 215.5-216.0 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.97(s,1H,CONH-H), 8.23(d,J＝8.1Hz,2H,Ph-H),7.97(d,J＝8.2Hz,2H,Ph-H),3.84(s,3H,NCH 3 ). 13 C NMR(151MHz, DMSO-d 6 )δ165.40,150.03,136.35,136.05,135.80,135.56,135.31,133.23,133.02,132.80,132.59,129.43, 126.91,126.16,126.14,125.11,123.59,123.30,121.81,121.49,120.03,118.25,103.99,37.87.ESI-MS calculated for C 13 H 9 ClF 6 N 3 O[M+H] + ,372.0；found,372.0.
compound 61
N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
White solid, yield 80%; melting point, 161.3-162.5 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.94(s,1H,CONH-H), 9.20(s,1H,aromatic H in pyridyl ring),8.89–8.80(m,1H,aromatic H inpyridyl ring),8.37(d,J＝7.9Hz,1H, aromatic H in pyridyl ring),7.62(dd,J＝7.8,4.9Hz,1H,aromatic H in pyridyl ring),3.84(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ165.20,153.63,149.47,136.02,135.86,135.77,135.53,135.28,128.45,124.19, 123.60,121.82,120.03,118.25,103.98,37.91.ESI-MS calculated for C 11 H 9 ClF 3 N 4 O[M+H] + ,305.0；found, 304.9.
compound 62
N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) isonicotinamide
Yellow solid, yield 74%; melting point, 170.1-171.3 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ11.05(s,1H,CONH-H), 8.86(s,2H,aromatic H in pyridyl ring),7.93(s,2H,aromatic H in pyridyl ring),3.85(s,3H,NCH 3 ). 13 C NMR (151MHz,DMSO-d 6 )δ165.18,151.04,139.63,136.11,135.86,135.65,135.62,135.37,123.57,122.10,121.78, 120.00,118.22,104.05,37.89.ESI-MS calculated for C 11 H 9 ClF 3 N 4 O[M+H] + ,305.0；found,305.0.
compound 63
2-chloro-N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
Yellow solid, yield 76%; melting point, 141.9-142.8 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ11.15(s,1H,CONH-H), 8.61(dd,J＝4.8,1.9Hz,1H,aromatic H in pyridyl ring),8.21(dd,J＝7.5,1.9Hz,1H,aromatic H in pyridyl ring),7.63(dd,J＝7.5,4.8Hz,1H,aromatic H in pyridyl ring),3.88(s,3H,NCH 3 ). 13 C NMR(151MHz, DMSO-d 6 )δ165.12,151.84,146.84,139.06,136.10,135.85,135.61,135.36,135.07,131.66,123.68,123.56, 121.78,120.00,118.21,103.75,38.10.ESI-MS calculated for C 11 H 8 Cl 2 F 3 N 4 O[M+H] + ,339.0；found,338.8.
compound 64
6-chloro-N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
Yellow solid, yield 81%; melting point, 178.7-180.2 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ11.01(s,1H,CONH-H), 9.01(s,1H,aromatic H in pyridyl ring),8.39(s,1H,aromatic H in pyridyl ring),7.77(s,1H,aromatic H in pyridyl ring),3.83(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ164.17,154.35,150.14,139.80,136.02, 135.78,135.64,135.53,135.28,127.91,124.94,123.58,121.80,120.02,118.23,103.94,37.96.ESI-MS calculated for C 11 H 8 Cl 2 F 3 N 4 O[M+H] + ,339.0；found,338.8.
compound 65
2-fluoro-N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
White solid, yield 82%; melting point, 136.6-137.5 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.87(s,1H,CONH-H), 8.48(d,J＝4.6Hz,1H,aromatic H in pyridyl ring),8.42–8.35(m,1H,aromatic H in pyridyl ring),7.57(t,J＝ 6.1Hz,1H,aromatic H in pyridyl ring),3.84(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ162.80,160.57, 158.98,151.27,151.17,142.53,136.05,135.80,135.56,135.43,135.31,123.57,122.90,122.87,121.79,120.01, 118.23,117.31,117.12,103.94,37.89.ESI-MS calculated for C 11 H 8 ClF 4 N 4 O[M+H] + ,323.0；found,322.9.
compound 66
6-fluoro-N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
Yellow solid, yield 83%; melting point, 188.2-189.1 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.97(s,1H,CONH-H), 8.90(s,1H,aromatic H in pyridyl ring),8.56(s,1H,aromatic H in pyridyl ring),7.41(d,J＝7.1Hz,1H, aromatic H in pyridyl ring),3.84(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ166.15,164.55,164.00, 148.92,142.66,136.05,135.80,135.72,135.56,135.31,127.27,125.23,123.57,121.79,120.01,118.23,110.22, 103.95,37.91.ESI-MS calculated for C 11 H 8 ClF 4 N 4 O[M+H] + ,323.0；found,322.9.
compound 67
2-methoxy-N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
White solid, yield 74%; melting point, 149.6-150.2 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.33(s,1H,CONH-H), 8.43(d,J＝1.8Hz,1H,aromatic H in pyridyl ring),8.25(dd,J＝7.4,1.8Hz,1H,aromatic H in pyridyl ring), 7.21(dd,J＝7.4,4.9Hz,1H,aromatic H inpyridyl ring),4.06(s,3H),3.82(s,3H,NCH 3 ). 13 C NMR(151MHz, DMSO-d 6 )δ167.41,164.12,160.89,159.31,152.07,151.09,141.06,140.74,136.15,135.75,135.62,135.37, 135.12,123.66,121.88,120.10,118.31,117.98,117.81,116.06,104.16,54.50,37.80.ESI-MS calculated for C 12 H 11 ClF 3 N 4 O 2 [M+H] + ,335.1；found,335.0.
compound 68
6-methoxy-N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
Yellow solid, yield 75%; melting point, 146.7-148.0 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.32(s,1H,CONH-H), 8.44(dd,J＝4.9,1.9Hz,1H,aromatic H in pyridyl ring),8.25(dd,J＝7.5,1.9Hz,1H,aromatic H in pyridyl ring),7.21(dd,J＝7.4,4.9Hz,1H,aromatic H in pyridyl ring),4.05(s,3H),3.82(s,3H,NCH 3 ). 13 C NMR(151 MHz,DMSO-d 6 )δ167.41,164.12,160.89,159.31,152.06,151.08,141.04,140.73,135.76,135.62,135.38, 135.13,123.66,121.88,120.10,118.32,117.98,117.81,117.14,116.08,104.16,54.50,37.80.ESI-MS calculated for C 12 H 11 ClF 3 N 4 O 2 [M+H] + ,335.1；found,335.0.
compound 69
N- (4-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -6- (trifluoromethyl) nicotinamide (WW-Cl-42)
Yellow solid, 73% yield; melting point, 210.3-211.6 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ11.18(s,1H,CONH-H), 9.32(s,1H,aromatic H inpyridyl ring),8.64(d,J＝9.6Hz,1H,aromatic H in pyridyl ring),8.17(d,J＝8.2Hz, 1H,aromatic H in pyridyl ring),3.85(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ164.06,150.06,149.88, 149.65,149.42,149.19,138.86,136.08,135.83,135.58,135.49,135.34,131.62,124.44,123.57,122.62,121.79, 121.32,120.81,120.00,118.99,118.22,103.94,38.00.ESI-MS calculated for C 12 H 8 ClF 6 N 4 O[M+H] + ,373.0； found,373.0.
compound 70
N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -3-methylbenzamide
White solid, yield 71%; melting point, 105.1-106.3 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.63(s,1H,CONH-H), 7.88–7.81(m,2H,Ph-H),7.48(q,J＝8.4,7.5Hz,2H,Ph-H),3.79(s,3H,NCH 3 ),2.42(s,3H). 13 C NMR(151 MHz,DMSO-d 6 )δ166.55,139.88,138.59,138.21,133.75,132.56,129.04,128.93,125.62,125.38,125.34, 125.21,125.06,123.47,121.69,119.92,118.12,99.59,37.81,21.31.ESI-MS calculated for C 13 H 12 F 4 N 3 O [M+H] + ,302.1；found,302.1.
compound 71
N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -4-methylbenzamide
Yellow solid, yield 74%; melting point, 109.2-109.6 ℃; 1 H NMR(600MHz,Chloroform-d)δ8.42(s,1H,CONH-H), 7.70(d,J＝8.1Hz,2H,Ph-H),7.23(d,J＝8.0Hz,2H,Ph-H),3.67(s,3H,NCH 3 ),2.42(s,3H). 13 C NMR(151 MHz,Methanol-d 4 )δ163.70,136.26,134.57,125.59,124.63,123.60,119.27,119.12,118.78,117.00,115.22, 113.45,33.19,17.50.ESI-MS calculated for C 13 H 12 F 4 N 3 O[M+H] + ,302.1；found,302.1.
compound 72
2-chloro-N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
Yellow solid, yield 76%; melting point, 136.2-137.8 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.94(s,1H,CONH-H), 7.74(dd,J＝7.5,1.4Hz,1H,Ph-H),7.64(d,J＝8.0Hz,1H,Ph-H),7.59(td,J＝7.8,1.6Hz,1H,Ph-H),7.55– 7.49(m,1H,Ph-H),3.85(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ166.26,139.62,138.03,137.94, 135.80,135.18,132.45,132.18,130.60,130.47,130.38,130.25,129.65,126.06,126.02,125.81,125.77,125.55, 125.51,125.29,125.25,124.35,124.20,122.65,121.61,119.83,118.06,98.12,38.02.ESI-MS calculated for C 12 H 9 ClF 4 N 3 O[M+H] + ,322.0；found,322.1.
compound 73
3-chloro-N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
White solid, yield 79%; melting point, 152.6-153.4 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.80(s,1H,CONH-H), 8.07(s,1H,Ph-H),7.98(d,J＝7.7Hz,1H,Ph-H),7.74(d,J＝7.3Hz,1H,Ph-H),7.62(t,J＝7.9Hz,1H,Ph-H), 3.80(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ165.10,139.82,138.14,134.56,133.97,132.96,131.12, 128.27,127.26,125.95,125.91,125.70,125.66,125.44,125.40,125.19,125.15,124.81,124.67,123.40,121.62, 119.85,118.07,37.88.ESI-MS calculated for C 12 H 9 ClF 4 N 3 O[M+H] + ,322.0；found,322.1.
compound 74
4-chloro-N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
Yellow solid, yield 71%; melting point, 149.3-150.4 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.75(s,1H,CONH-H), 8.03(s,2H,Ph-H),7.65(s,2H,Ph-H),3.79(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ165.43,150.01, 139.84,138.14,136.55,131.30,130.41,129.26,125.94,125.90,125.68,125.64,125.43,125.39,125.17,125.13, 124.93,124.79,123.40,121.63,119.88,118.08,37.85.ESI-MS calculated for C 12 H 9 ClF 4 N 3 O[M+H] + ,322.0； found,322.1.
compound 75
2-fluoro-N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
Yellow solid, yield 68%; melting point, 97.6-98.2 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.65(s,1H,CONH-H),7.83 (t,J＝8.2Hz,1H,Ph-H),7.72–7.63(m,1H,Ph-H),7.46–7.35(m,2H,Ph-H),3.81(s,3H,NCH 3 ). 13 C NMR (151MHz,DMSO-d 6 )δ163.84,160.72,159.06,139.78,138.10,134.46,130.92,125.98,125.93,125.72,125.68, 125.47,125.43,125.26,125.23,125.12,125.10,124.60,124.45,123.40,122.38,122.29,121.62,119.85,118.09, 116.85,37.80.ESI-MS calculated for C 12 H 9 F 5 N 3 O[M+H] + ,306.1；found,306.2.
compound 76
4-fluoro-N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzamide
Yellow solid, yield 72%; melting point of 160.3-161.2 deg.C； 1 H NMR(600MHz,DMSO-d 6 )δ10.70(s,1H,CONH-H), 8.11(dd,J＝8.5,5.5Hz,2H,Ph-H),7.43(t,J＝8.7Hz,2H,Ph-H),3.80(s,3H,NCH 3 ). 13 C NMR(151MHz, DMSO-d 6 )δ166.03,165.35,164.37,150.02,139.86,138.18,131.33,125.90,125.86,125.65,125.61,125.39, 125.35,125.13,125.09,125.04,124.89,123.41,121.64,119.89,118.09,116.13,37.83.ESI-MS calculated for C 12 H 9 F 5 N 3 O[M+H] + ,306.1；found,306.1.
Compound 77
N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -2-methoxybenzamide
White solid, yield 74%; melting point, 107.2-108.9 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.22(s,1H,CONH-H), 7.85(d,J＝9.3Hz,1H,Ph-H),7.61(t,J＝7.9Hz,1H,Ph-H),7.25(d,J＝8.3Hz,1H,Ph-H),7.12(t,J＝7.8Hz, 1H,Ph-H),3.97(s,3H),3.79(s,3H,NCH 3 ).ESI-MS calculated for C 13 H 12 F 4 N 3 O 2 [M+H] + ,318.1；found,318.1.
compound 78
N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -4-methoxybenzamide
White solid, yield 79%; melting point, 121.3-122.7 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.78(s,1H,CONH-H), 7.89(d,J＝7.7Hz,1H,Ph-H),7.84(d,J＝9.6Hz,1H,Ph-H),7.68–7.62(m,1H,Ph-H),7.54(dd,J＝8.5,2.2 Hz,1H,Ph-H),3.81(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ165.16,163.26,161.64,139.85,138.27, 138.18,134.85,134.80,131.39,131.34,125.97,125.94,125.72,125.68,125.46,125.42,125.21,125.17,124.83, 124.68,123.42,123.40,122.65,121.64,121.62,120.88,120.17,120.03,119.87,119.85,119.79,119.65,118.09, 118.07,115.42,115.26,99.38,37.84.ESI-MS calculated for C 13 H 12 F 4 N 3 O 2 [M+H] + ,318.1；found,318.0.
compound 79
N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -3- (trifluoromethyl) benzamide
Yellow solid, yield 81%; melting point, 136.2-137.8 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.95(s,1H,CONH-H), 8.37(s,1H,Ph-H),8.33(d,J＝7.8Hz,1H,Ph-H),8.06(d,J＝7.8Hz,1H,Ph-H),7.85(t,J＝7.8Hz,1H,Ph-H), 3.82(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ165.10,139.79,138.11,133.52,132.63,130.51,130.26, 130.05,129.84,129.67,129.62,126.99,125.96,125.91,125.70,125.66,125.44,125.40,125.28,125.24,125.18, 125.14,125.12,125.09,125.07,124.75,124.61,123.37,121.64,121.57,119.86,119.84,118.09,118.07, 37.93.ESI-MS calculated for C 13 H 9 F 7 N 3 O[M+H] + ,356.1；found,356.1.
compound 80
N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -4- (trifluoromethyl) benzamide
Yellow solid, 73% yield; melting point, 197.9-198.6 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.92(s,1H,CONH-H), 8.22(d,J＝8.1Hz,2H),7.96(d,J＝8.2Hz,2H),3.81(s,3H). 13 C NMR(151MHz,DMSO-d 6 )δ165.35, 149.90,139.83,138.15,133.20,132.98,132.77,132.56,129.43,126.91,126.10,125.98,125.95,125.74,125.70, 125.48,125.44,125.11,124.75,124.60,123.41,123.38,123.30,121.50,119.86,119.83,118.08,118.06,99.35, 37.88.ESI-MS calculated for C 13 H 9 F 7 N 3 O[M+H] + ,356.1；found,356.1.
compound 81
N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
White solid, yield 77%; melting point, 124.1-125.5 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.90(s,1H,CONH-H), 9.19(s,1H,aromatic H in pyridyl ring),8.83(s,1H,aromatic H in pyridyl ring),8.36(s,1H,aromatic H in pyridyl ring),7.61(s,1H,aromatic H in pyridyl ring),3.82(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ 165.15,153.57,149.47,139.83,138.15,136.30,128.46,125.98,125.94,125.72,125.68,125.47,125.43,125.21, 125.17,124.69,124.54,124.16,123.39,121.64,119.86,118.09,37.90.ESI-MS calculated for C 11 H 9 F 4 N 4 O [M+H] + ,289.1；found,289.1.
compound 82
N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) isonicotinamide
Yellow solid, yield 78%; melting point, 132.2-133.4 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.99(s,1H,CONH-H),8.85(s, 2H),7.91(s,2H),3.81(s,3H,NCH 3 ).ESI-MS calculatedfor C 11 H 9 F 4 N 4 O[M+H] + ,289.1；found,289.0.
compound 83
2-chloro-N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
Yellow solid, yield 71%; melting point, 142.8-143.9 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ11.12(s,1H,CONH-H),8.62(s, 1H,aromatic H inpyridyl ring),8.25(s,1H,aromatic H in pyridyl ring),7.63(s,1H,aromatic H inpyridyl ring), 3.86(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ165.03,157.35,152.22,151.82,149.82,147.43,146.89, 140.43,139.56,139.10,137.88,136.76,131.60,126.10,126.05,125.84,125.80,125.59,125.55,125.33,125.29, 123.66,123.37,123.34,121.59,121.57,119.81,119.79,118.04,118.02,97.91,38.07.ESI-MS calculated for C 11 H 8 ClF 4 N 4 O[M+H] + ,323.0；found,323.1.
compound 84
6-chloro-N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide as a white solid in 75% yield; melting point, 148.1-150.0 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.98(s,1H,CONH-H),9.01 (s,1H,aromatic H in pyridyl ring),8.41(s,1H,aromatic H in pyridyl ring),7.78(s,1H,aromatic H in pyridyl ring),3.80(s,3H,NCH 3 ).ESI-MS calculated for C 11 H 8 ClF 4 N 4 O[M+H] + ,323.0；found,323.1.
compound 85
2-fluoro-N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide as a white solid in 80% yield; melting point, 108.2-109.1 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.84(s,1H,CONH-H),8.50(d, J＝4.7Hz,1H,aromatic H in pyridyl ring),8.45–8.39(m,1H,aromatic H in pyridyl ring),7.59(s,1H, aromatic H in pyridyl ring),3.83(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ164.13,154.29,150.16, 139.82,126.04,126.03,125.71,125.67,125.45,125.41,125.20,125.19,124.90,124.50,124.35,123.40,123.37, 121.62,121.60,119.85,119.83,118.08,118.05,37.96.ESI-MS calculated for C 11 H 8 F 5 N 4 O[M+H] + ,307.1；found, 307.0.
compound 86
6-fluoro-N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) nicotinamide
Yellow solid, yield 71%; melting point, 141.2-142.7 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.31(s,1H,CONH-H),8.44 (dd,J＝4.9,1.9Hz,1H,aromatic H in pyridyl ring),8.27(dd,J＝7.5,1.9Hz,1H,aromatic H in pyridyl ring), 7.21(dd,J＝7.5,4.9Hz,1H,aromatic H in pyridyl ring),4.07(s,3H),3.81(s,3H,NCH 3 ).ESI-MS calculated for C 11 H 8 F 5 N 4 O[M+H] + ,307.1；found,307.0.
compound 87
N- (4-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -2- (trifluoromethyl) nicotinamide
Yellow solid, yield 76%; melting point, 157.0-158.2 ℃; 1 HNMR(600MHz,DMSO-d 6 )δ11.20(s,1H,CONH-H),8.95(s, 1H,aromatic H inpyridyl ring),8.41(s,1H,aromatic H inpyridyl ring),7.93(s,1H,aromatic H inpyridyl ring), 3.86(s,3H,NCH 3 ).ESI-MS calculatedfor C 12 H 8 F 7 N 4 O[M+H] + ,357.1；found,357.0.
compound 88
N- (4-fluoro-1-methyl-3- (trifluoromethyl)) -1H-pyrazol-5-yl) -6- (trifluoromethyl) nicotinamide as a white solid in 73% yield; melting point, 197.6-198.2 deg.C; 1 HNMR(600MHz,DMSO-d 6 )δ11.16(s,1H,CONH-H),9.35(s, 1H,aromatic H inpyridyl ring),8.66(s,1H,aromatic H inpyridyl ring),8.17(s,1H,aromatic H inpyridyl ring), 3.86(s,3H,NCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ164.01,151.08,150.07,149.85,149.62,149.39,149.17, 147.58,141.43,139.76,138.82,138.08,136.94,131.61,131.61,124.43,124.34,124.19,123.37,123.34,122.61, 121.59,121.57,121.21,120.79,119.82,119.79,118.97,118.04,118.02,37.95.ESI-MS calculated for C 12 H 8 F 7 N 4 O[M+H] + ,357.1；found,357.0.
the study of the antifungal activity of pyrazole amide derivatives according to the examples of the present invention is described in detail below.
(1) Test object
Pyrazole amide derivatives 1 to 88, i.e., compounds 1 to 88, prepared in the above examples, respectively.
(2) Experimental methods
The in vitro inhibitory activity of compounds 1 to 42 was determined on 2 test phytopathogenic fungi, provided by the plant protection institute of the university of agriculture and forestry, northwest, by the hyphal linear growth rate method.
Taking a 50mg/L pyrimethanil solution as a positive control, taking a 5% DMSO aqueous solution as a blank control, completely dissolving a precisely weighed compound to be detected in a 5% DMSO (v/v) aqueous solution, and rapidly and uniformly mixing 10mL of liquid to be detected or a control solution with a 90 mL sterile PDA culture medium at 50 ℃ to obtain a medicine-containing solution with the mass concentration of 50 mg/L; the mixture was poured into sterilized petri dishes at a volume of 10mL per dish while it was hot, and cooled for use. Inoculating the test plant pathogenic fungi (the diameter of the fungus cake is 5 mm) into the culture dish, and arranging 3 test groups in parallel; after culturing in a constant temperature incubator at 25 ℃ for 72 hours, the colony diameter (mm) was measured by the cross method, and the hypha growth Inhibition Ratio (IR) was calculated according to the formula (1): IR (%) = [ (d) c -d 0 )- (ds-d 0 )]/(d c -d 0 )×100 (1); wherein the formula comprises: d 0 The diameter of the fungus cake is (5 mm), d c The average diameter (mm) of colonies in the blank control group and the average diameter (mm) of colonies in the sample group are ds.
The experimental results are shown in table 1.
TABLE 1 in vitro bacteriostatic activity (inhibition,%) of different pyrazole amide derivatives
Figure BDA0002377501410000351
Figure BDA0002377501410000361
In summary, the pyrazole amide compounds according to the embodiments of the present invention all have antifungal activity, and especially exhibit particularly significant antibacterial activity against pathogenic bacteria, which provides a direction for further research on the antifungal activity of different compounds, and lays a foundation for preparation of a bactericide using the pyrazole amide derivatives as main antifungal active ingredients.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an illustrative embodiment," "an example," "a specific example," or "some examples" or the like mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
While embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.

Claims (13)

1. The fluorine-containing pyrazole amide derivative is characterized by having a structural formula as follows:
Figure FDA0003956033540000011
wherein R is 1 Is trifluoromethyl, difluoromethyl; r 2 Hydrogen, chlorine, fluorine, bromine, iodine;
R 3 is 3-pyridyl, 4-pyridyl, 2-chloro-3-pyridyl, 6-chloro-3-pyridyl, 2-fluoro-3-pyridyl, 6-fluoro-3-pyridyl, 2-methyl-3-pyridyl, 6-methyl-3-pyridyl, 2-trifluoromethyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl.
2. The preparation method of the fluorine-containing pyrazole amide derivative is characterized by comprising the following steps:
and (3) reacting the intermediate II with acyl chloride containing aromatic ring active groups to obtain a fluorine-containing pyrazole amide derivative III, wherein the reaction formula is as follows:
Figure FDA0003956033540000012
wherein R is 1 Is trifluoromethyl, difluoromethyl; r 2 Hydrogen, chlorine, fluorine, bromine, iodine;
R 3 is 3-pyridyl, 4-pyridyl, 2-chloro-3-pyridyl, 6-chloro-3-pyridyl, 2-fluoro-3-pyridyl, 6-fluoro-3-pyridyl, 2-methyl-3-pyridyl, 6-methyl-3-pyridyl, 2-trifluoromethyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluoro-3-pyridylPhenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl.
3. The process for producing a fluorine-containing pyrazole amide derivative according to claim 2, wherein the intermediate II is subjected to a mixing reaction with an acid containing an aromatic ring active group and phosphorus oxychloride or thionyl chloride.
4. The process for producing a fluorine-containing pyrazole amide derivative according to any one of claims 2 to 3, wherein the solvent used in the reaction is pyridine.
5. The process for producing a fluorine-containing pyrazolecarboxamide derivative according to claim 3, wherein the acid having an aromatic ring active group is a nicotinic acid or benzoic acid substituent.
6. The process for preparing fluorine-containing pyrazole amide derivatives according to claim 2, wherein the process for preparing the intermediate II comprises the steps of:
s1, reacting ethyl trifluoroacetate or ethyl difluoroacetate and acetonitrile serving as raw materials under strong alkali to obtain an intermediate I, wherein the reaction formula is as follows:
Figure FDA0003956033540000021
s2, reacting the intermediate I with methylhydrazine sulfate to obtain an intermediate IIa, wherein the reaction formula is as follows:
Figure FDA0003956033540000022
s3, carrying out selective halogenation reaction on the intermediate IIa obtained in the step S2 to obtain R 2 Is fluorineThe intermediates IIb to IIe of chlorine, bromine or iodine;
in the step S3, the process is carried out,
reacting the intermediate IIa with a selective fluorine reagent in a solvent to obtain R 2 Intermediate IIb which is fluorine;
reacting the intermediate IIa with a selective chlorine reagent in a solvent to obtain R 2 Intermediate IIc which is chloro;
reacting the intermediate IIa with a selective bromine reagent in a solvent to obtain R 2 Intermediate IId which is bromine;
reacting the intermediate IIa with a selective iodine reagent in a solvent to obtain R 2 Intermediate IIe which is iodine; the respective reaction formulae of step S3 are as follows:
Figure FDA0003956033540000031
7. the method for preparing fluorine-containing pyrazole amide derivatives according to claim 6, wherein the solvent in step S31 is acetonitrile, the solvents in steps S32, S33 and S34 are dichloromethane, respectively, the selective chlorine reagent in step S32 is N-chlorosuccinimide, the selective bromine reagent in step S33 is N-bromosuccinimide, and the selective iodine reagent in step S34 is N-iodosuccinimide.
8. The process for producing fluorine-containing pyrazole amide derivatives according to claim 6, wherein the ratio of the amount of acetonitrile to ethyl trifluoroacetate or ethyl difluoroacetate in step S1 is 1:1.
9. the method for preparing fluorine-containing pyrazole amide derivatives according to claim 6, wherein the refluxing is carried out at 70-80 ℃ for 3-4 h in step S1.
10. The method for preparing fluorine-containing pyrazole amide derivatives according to claim 6, wherein the strong base in step S1 is sodium hydrogen, and the solvent is tetrahydrofuran.
11. The method for preparing fluorine-containing pyrazole amide derivatives according to claim 6, wherein the ratio of the amount of the intermediate I to the amount of the methylhydrazine sulfate substance in step S2 is 1:1.
12. the method for preparing fluorine-containing pyrazole amide derivatives according to claim 6, wherein the reflux in step S2 is performed at 70-80 ℃ for 3-4 h in ethanol solution.
13. The use of the fluorine-containing pyrazole amide derivative according to claim 1 for preparing an antifungal agent.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010132404A1 (en) * 2009-05-12 2010-11-18 Romark Laboratories L.C. Haloalkyl heteroaryl benzamide compounds
CN102993097A (en) * 2012-11-09 2013-03-27 贵州大学 Pyrazole amide compound and application thereof
CN109956904A (en) * 2017-12-22 2019-07-02 华中师范大学 Pyrazol acid amide compounds and its application and fungicide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010132404A1 (en) * 2009-05-12 2010-11-18 Romark Laboratories L.C. Haloalkyl heteroaryl benzamide compounds
CN102993097A (en) * 2012-11-09 2013-03-27 贵州大学 Pyrazole amide compound and application thereof
CN109956904A (en) * 2017-12-22 2019-07-02 华中师范大学 Pyrazol acid amide compounds and its application and fungicide

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Novel N-(1H-Pyrazol-5-yl)nicotinamide Derivatives: Design, Synthesis and Antifungal Activity;Wei Wang et al.;《RESEARCH ARTICLE》;20220311;第19卷;第1-8页 *
STN检索报告;Columbus, Ohio, US Registry[Online];《STN Registry》;20200110;第1-12页 *
Synthesis and Biological Activity of Novel Pyrazol-5-yl-benzamide Derivatives as Potential Succinate Dehydrogenase Inhibitors;Wei Wang et al.;《J.Agric.Food Chem.》;20210514;第69卷;第5746-5754页 *
新型苯甲酰胺基吡唑类衍生物的设计、合成与抗真菌活性的研究;王建花;《中国优秀博硕士学位论文全文数据库(硕士)工程科技Ⅰ辑》;20220315(第03期);B016-1919 *

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